Bb3 WHO Classification of Tumors of Haemopoietic and Lymphoid Tissues 4th 2008 PG

World Health Orga nization Classifica tion of Tumours
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International Agency for Research on Cancer (IARC)
4th Edition
WHO Classification of Tumours of

Haematopoietic and Lymphoid Tissues
Edited by
Steven H. Swe rdlow

Elias Campo
Nancy Lee Harris
Elaine S. Jaffe
Stefano A. Pileri
Harald Stein
JOrgen Thiele
James W. Vardiman
Intern ational Agency for Resea rch on Cancer

Lyon , 2008
World Health Organization Classification of Tumours

Series Editors
Fred T. Bosman, M.D.

Elaine S. Jaffe. M.D.
Sunil R. Lakhani. M.D.
Hiroko Onqaki, Ph.D.
WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues

Editors
Sleven H. Swerdlow, M.D.

Elias Campo. M.D.
Nancy Lee Harris, M.D.
Elaine S. Jaffe , M D.
Stefano A. Pileri. M.D.
Harald Stein, M.D.
JOrg en Thiele, M.D.
James W. Vardi man, M.D.
Layout
Sebastien Antoni
Marlen Grassinger
Pascale Collard
Printed by
Publisher
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69250 Neuville s/SaOne, France
International Agency for
Research on Cance r (IARC)
69008 Lyon. France
This volume was produced with support from the
Associazione S.P.E.S. Onlus, Bologna

Friends of Jose Carreras International Leukemia Foundation
Leukemia Clinical Research Foundation
MEDIC Foundation
National Cancer Institute, USA
National Institutes of Health Office of Rare Diseases, USA
University of Chicago Cancer Research Center
The WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues

presented in this book reflects the views of a Working Group
that convened for an Editorial and Consensus Conference at the
International Agency for Research on Cancer (fARC), Lyon
October 25-27. 2007.
Members of the Working Grou p are indicated
in the List of Contributors on pages 369-374.
Published by the International Agenc y for Research 00 Cancer (IARC),

150 cou rs Albert Thomas, 69372 Lyon ceoex 08, France
C International Agency for Research on Cancer, 2008

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Format for bibliographic citations:

Swerdlow S.H., Campo E., Harris N,L., Jaffe E.S" Pileri S.A., Stein H" Thiele J , Vardiman J.w. (Eds.):
WHO Classification of Tumours of Haematopoietic and Lympho id Tissues,
IARC: Lyon 2008
IARC Ubrary Cataloguing in Publication Data

WHO Classific ation of Tumou rs of Haematopo ietic and Lymp hoid Tissues
Edited by Swerdlow S.H.. Campo E., Harris NL , Jaffe E.S. Piled SA, Stein H., Thiele J .. Vardiman JW.
1. Haematopoie hc System Neop lasms - genetics
2. Haematopoielic System Neop lasms - pathology

I. Swerdlow. Steven H.
ISBN 978-92-832-243 1-0
Contents
WHO Classifjcatioo
Summary table
Introduction to the classification of tumours of
haematopoietic and lymphoid tissues
Introduction and overview of the classification of
the myeloid neoplasms
2 Myeloproliferative neoplasms
10
14
17
31
Chronic myelogenous leukaemia. BCR-ABL 1 positive 32

Chronic neutrophilic leukaemia
PoIycythaemia vera
Primary myelofibrOsis
Essenliallhrombocythaemia
Chronic eosinophilic leukaemia. NOS

Mastocytosis
Cutaneous mastocytosis
Systemic mastocytosis
Masl cell leukaemia
Mast cell sarcoma

Extracutaneous mastocytoma
Myeloproliferative neoplasm, unc lassi fiable
38
40
44
48
51
54
57
58
61
61
61
64
3 Myeloid and lymphoid neoplasms with

eosinophilia and abnormalities of PDGFRA.
PDGFRB Of FGFRl
67
4 MyelodysplasticJmyeloproliferative neoplasms
75
Chronic mveiomonocync leukaemia
76
Atypical ctYonic myeloid leukaEmia. BCR-ABL 1 negative 80
Juvenile myelomonocytic leuk aemia
MyelodysplastiC/myeloproliferali ve neoplasm ,
urclasaifiable
5 Myelodysplastic syndromes
Myelodysplastic synd romes/n eo plasms , overview
Refractory cytope nia with unilineage dysplasia
Refractory anaemia with ring side rob lasts
Refractory cytopenia with multilineage dysplasia
Refractory anaemia with exc ess b lasts
Myelodysp lastic synd rome with isolated de l(5q)
Myelodysp lastic synd rome, uncrasslttabte
Childhood mye lodysp lastic synd rome
Refractory c ytopenia of c hild hood
82
85
87
88
94
96
98
100
102
103
104
104
6 Acute myeloid leukaemia (AML) and

related precursor neoplasms
AML with recurrent genet ic abn or malities
AML with t(8:21 )(q22:q22); RUNX1 -RUNX1T1
AML with inv( 16)( p 13.1q22) or
1(16:t6)(p 13.1;q22): CBFB-MYH 11
Acute orornveiocvnc leukaem ia with
t(15:17)(q22 :q 12): PML- RARA
AML with us.11)(p 22:q 23): MLLT3-MLL
AML with t(6:9)(p23 :q34); DEK-NU P2 14
AML with inv(3)( q2 1q26 .2) or t(3;3)( q2 1;q26.2);
RPNt EVI1
AML (megakaryoblastic) with t( 1;22)(p13;q 13):
RBM15-MKL 1
109
11 0
11 0
11 1
11 2
114
115
116
117
AML with mutated NPM 1

AMLwith mutated CEBPA
AML with myelo dysplas ia-related changes
Therapy -relate d myeloid neoplasms
Acu te myeloid leukaemia, NOS
AML with minimal diff erentiation
AML withOut matu ration
AML with maturabon
Acute myelomonocytic leukae mia
Acute monoblastic and monocytic leukaem ia
Acute erythroid leukaemia
Acu te megakaryoblastic leukaemia
Acute basophilic leukaemia
Acu te paomveosrs with myelofibros is
Myeloid sarcoma
Myeloid proli ferations related 10 Down synd rome
Transient abnOrmal myelopoiesis
Myeloid leukaemia associated with
Dc:rwn syndrome
Blastic plasmacytoid dendritic cell neoplasm
7 Acute leukaemiasof ambiguous lineage

Acute undlHerentiated leukaemia
Mixed phenotype acute leukaemia wilh
t(9;22)(q34;q 11.2): BCR-ABL 1
Mixed phenotype acute leukaemia with
t(v:11q 23): MLL rear ranged
Mixed phenotype acute leukaemia , B/myeloid, NOS
Mixed phenotype ac ute leukaemia , T/myeloid , NOS
Mixed phenoty pe acu te leukaemia, NOS rare
types
Other ambiguous lineage reukaerraes
Natura! killer (NK)-celilympho blastic
leukaemi a/lymphoma
120
122
124
127
130
130
131
131
132
133
134
136
137
138
140
142
142
143
145
149
151
15 1
152
152
153
154
t 55
155
8 Introduction and overview 01 the c lassification of

the lymphoid neoplasms
9 Precu rsor lymphoid neoplasms

B lymp hob lastic leukaemia/lymphoma, NOS
B lymphob lastic leukaemia/ lymphoma
with recu rrent gene tic abn orma lities
B lymphob lastic leukaem iallymphoma with
t(9 :22)(q 34;q 11.2): BCR-ABL 1
B lymp hoblastic leukaemia/ly mpho ma with
l(v:11q 23): ML L rearranged
B lympho blastic leukaemiall ymphom a with
t(12:2 1)(p1 3;q22 ): TEL-AMLl (ETV6--RUNX 1)
B lymphoblastic leukaemia/lymphoma with
hyperdi ploi dy
B lymphoblastic leukaemiallymphom a with
hypodiplOi dy (Hypodiploi d ALL)
B lymphoblastic leukaemiallymphoma with
t(5; 14)(q31;q32); IL3-IGH
B lymphoblastic leukaemiallymphoma with
t( 1;19) (q23:P13.3): E2A-PBX1( TCF3-PBXI)
T lymphoblastic leukaemiallymphoma
157
167
168
171
171
171
172
173
174
174
175
176
10 Mature B-ceUneoplasms
Chronic lymphocytic leukaemia Ismail
Iympt'locytic lymphoma :f
s-een prolyrTlhocytic leukaemia
Splenic B-cell marginal zone lymphoma
Hairy cell leukaemia
Splenic B-cell Iymphomalleukaemia, unclassiliable
Splenic diffuse red pulp small B-ceil lymphoma
Hairy cenleckaeme-....anent
lymphoplasmacytic lymphoma
Heavy chain diseases
Gamma heavy chain disease
Mu heavy chain disease
Alpha heavy chain disease
Plasma cell neoplasms
Monoc lonal gammop athy 01 undetermined
significance (MGUS)
Plasma ce ll myeloma
Solitary plasmacytoma of bone
Extraosseous plasmacytoma
Monoclonal immunoglobulin deposition diseases
Extranodat marginal zone lymphoma of mucosaassocia ted lymphoid tissue (MALT lymphoma)
Nodal marg inal zone lymphoma
Follicular lymphoma
Primary cutaneous follicle centre lymphoma
Mantle cell lymphoma
Diffuse large B-celllymphoma (DLBCl), NOS
T celilhi stiocyte-rich large B-ce ll lymphoma
Primary DlBCL of the CNS
Primary cutaneous DlBCl . leg type
EBV positive DLBCl of the elderly
DLBCL assoc iated with chronic inflammation
Lymphomatoid granulomatosis
Primary med iastinal (thymic) large B-celilymphoma
Intrav escurer large B-celi lymphoma
ALK positive large Been lymphoma
Plasmablastic lymphoma
large a-ceu lymphoma arising in HHV8-associated
multicent ric Castleman disease
Primary effusion lymphoma
Burkitllymp homa
B-cel1lymphoma, unclassiliab le, with features
intermediate between DLBCL and
Burkitllymphoma
B-ceillymphoma, unctessmebie. with features
intermediate between OLBCl and
clas sica l Hodgkin lymphoma
11 Mature T- and NK-cell neoplasms
r-cea prolymphocytic leukaemia
t- een large granular lymphocytic leukaemia
Chronic Iymphoproliferative disorder of NK cells
Aggressive NK cell leukaemia
Epstein-Barr virus (EBV) positive t-een
Iymphoprol ilerative diseases of ch ildhood
Systemic EBV+ t-een Iymphoproliferalive
disease of childhood
Hydroa vacclnrtorrne-uk e lymphoma
Adull T-ceil leukaemia/lymphoma
Extranodal NK/T-cell lymphoma. nasal type
179
180
183
185
188
191
191
192
194
196
196
197
198
200
200
202
Enteropathy -associated t-een lymphoma

Hepatosplenlc t -een lymphoma
Subcutaneous panniculitis-like t-een lymphoma
Mycosis fungoi des
Sezary syndrome
Primary cutaneous CD30 posi tive t-een
Iymphoprolilerative disorders
Primary cutaneous per ipheral t-een lymphoma s,
rare subtypes
Primary cutaneous garnna-della T-cen lymphoma
Primary cutaneous COB positive agg ressive
ep idermotrop ic cytotoxic T-celt lymphoma
Primary cutaneou s CD4 positive
small/medium T-cell lymphoma
Peripheral t-een lymphoma. NOS
Ang ioimmunoblastic t -een lymphoma
Anaplastic large cell lymphoma. AlK positive
Anapla stic large cell lymphoma . ALK negat ive
289
292
294
296
299
300
302
302
303
304
306
309
312
317
208
208
209
214
218
220
227
229
233
238
240
242
243
245
247
250
252
254
256
258
260
262
265
267
269
270
272
274
276
278
278
280
281
285
12 Hod gkin lymphoma

Introduction
Nodular lymphocyte predominant Hodgkin Iymptuna
Classical Hodgk in lymp homa. introduction
Nodular sclerosis classical Hodgkin lymphoma
Mixed ce llularity classical Hodgkin lymphoma
Lymphoc yte-rich classical Hodgkin lymphoma
lymphocyte-depleted classical Hodgkin lymphoma
32 1
322
323
326
330
331
332
334
13 1rnmunode ficiency-assoc iated

Iymphoproliferative disorde rs
335
Lymp hoproliferative diseases associated with
primary immune disorders
336
Lymphomas associa ted with HIV infection
340
Post-nansotanttsmpnooronterauve disorders (PTlD) 343
Plasmacytic hyperp lasia and infectiousrroooo ocieose-uke PTlD
345
Polymorphic PTlO
346
Monomorph ic PTlO
347
Classical Hodgkin lymphoma type PTLO
349
Other iatrogenic immunodeficiency-assoc iated
Iymphoproliferative disorders
350
14 Histiocytic and dendritic cell neoplasms
Introd uction
Histiocyt ic sarcoma
Tumours der ived from langerhans cells
Langerhans cell histiocytosis
Langerhans ce ll sarcoma
Interdigitating dendrit ic cell sarcoma
Follicular de ndritic ce ll sarcoma
Other rare dendritic cell tumours
Disseminated juvenile xanthogranuloma
Contributors
Clinical advi sory oorrrnittee
Source of Charts and photographs
References
Subject index
NOS, no! otherwise specifi ed
353
354
3S6
358
3S8
360
36 1
363
365
366
369
374
376
300
429
WHO Classification
4th Edition
-.,.e"
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WHO Classification of tumours of haematopoietic

and lymphoid tissues
MYELOPROLIFERATIVE NEOPLASMS
MYELODYSPLASTIC SYNDROMES
Chronic myelogenous leukaemia ,

BCR-ABL 1 positive
987513
996 3/3
Polycythaemia vera
995 0/3
Primary myelofibrosis
996 1/3
Essential thrombocythaemia
996213
Chronic eosinophilic leukaemia, NOS
9964 /3
Mastocytosis
Cutaneous mastocytosis
9 74011
9 74 1/3
Mast cell leukaemia
974 213
Mast cell sarcoma
974 0/3
974 0/1
Myeloproliferative neoplasm , unctassitlable
Refractory anaemia
9980/3
Refractory neutropenia
999 1/3
Refractory thrombocytopenia
9992/3
Refractory anaemia with ring sideroblasts
9962/3
Refractory cytopenia with

multitineage dysplasia
9965/3
Refractory anaemia with excess blasts
9983/3
MyelodysplasUc syndrome
associated with isolated del(Sq)
Myelodysplasticsyndrome, uncJassifiable
9966/3
9969/3
Childhood myelodyspla suc syndrome

Refractory cytopenia of childhood
996513
9975/3
MYELOID AND LYMPHOID NEOPLASMS

WITH EOSINOPHILIA AND ABNORMALITIES OF
PDGFRA, PDGFRB OR FGFRI
ACUTE MYELOID LEUKAEMIA (AML)

AND RELATED PRECURSOR NEOPLASMS
AML with recurr ent genetic abnormalities
AML with t(6 ;21)(q22;q2 2);

RUNXI-RUNX1Tl
9696/3
AML with inv(16)(pI 3.1q22 )

or t(16;16)(pI3.1;q2 2); CBFB-MYHl1
9671/3
Acute promyelccytlc leukaemia

with t(15 ;17)(q22 ;qI2); PML-RARA
9666/3
AML with t(9 ;11)(p22 ;q23); MLLT3-MLL
9697/3
AML with 1(6;9)(p2 3;q34 ); DEK-NUP214
986513
MYELODYSPLASTIC/MYELOPROLIFERAnVE
NEOPLASMS
AML with inv( 3)(q2 1q26.2)

ort(3; 3)(q21;q 26.2); RPNI -EV/1
9869/3
Chronic myetcmonocytic leukaemia
9945/3
Atypical chronic myeloid leukaemia.

BCR-ABL 1 negative
AML (megakaryoblastic)
with t(I ;22)(p I 3;q I 3); RBMI5-MKLI
9911/3
967613
AML with mutated NPM1
986 1/3
Juvenile myelomonocytic leukaemia
9946/3
AML wrlh mutated CEBPA
9661/3
Myeloid and lymphoid neoplasms

with PD GFRA rearrangement
Myeloid neoplasms
with PDGFRB rearrangement
with FGFR1 abnormalities
9965/3
9966/3
9967/3
Myelodysplasticlmyeloproliferative neoplasm.
unclassifiable
9975/3
associated WIth marked thrombocytosis
10
Refractory cytopenia with unilineage dysplasia
WHO ctassrtceton
AML with myelodysplasia-related changes 969513

Therapy-re lated myeloid neoplasm s
99 6213
99 2013
Acute myeloid leukaemla",NOS
9861/3
AML with minimal differentiation
987213
AML without maturation
9873/3
AML with maturation
9874 /3
Acute myelomonocytic leukaemia
9867 /3
Acute monob lastic and monocytic leukaemia 9891 /3

984013
Acute megakaryoblastic leukaemia
99 10/3
Acute basoph ilic leukaemia
987013
Acute panmyelosis with myelofibrosis
9931 13
Myeloid sarcoma
993013
Myeloid proliferations related to Down syndrome

Transient abnormal myelopoiesis
989811
Myeloid leukaemia
associated with Down syndrome
9898/3
Blastic plasmacytoid dendritic

cell neoplasm
9727/3
B lymphoblastic leukaemia/lymphoma
with recurrent genetic abnormalities
B lymphoblastic leukaemiaflymphoma
with 1(9;22)(q 34;q l 1.2); BCR-ABU
9812/3
B lymphoblastic leukaemiall ymphoma

with t(v;11q23); MLL rearranged
981Y3
B lymphoblastic leukaemiall ymphoma

with 1( 12;21)(p13;q22); TEL-AMU
(ETV6-RUNX1)
9814/3
B lymphoblastic leukaemiallymphoma
w ith hyperdiploidy
981513
with hypod iploidy (hypod iploid ALL)
981613
with t(5;14 Xq31 ;q32 ); IL3-IGH
9817/3
B lymphoblastic leukaemia/lymphoma with

t(1;19 )(q23 ;p13 .3); E2A-PBXl
(TCF3-PBX1)
9818/3
T lymphoblastic leukaemia/lymphoma
9837/3
MATURE B-CELL NEOPLASMS
ACUTE LEUKAEMIAS OF AMBIGUOUS LINEAGE

Acute undifferentiated leukaemia
980 1/3
Mixed phenotype ac ute leukaemia

with t(9;22)(q3 4;q 11.2); BCR-ABL1
980613
9807/3
Mixed phenotype ac ute leukaemia,

B/myeloid, NO S
9808/3
B-cell prolymphocytic leukaemia
983313
Splenic Bccell marginal zone lymphoma
968913
9940/3
Splenic diffuse red pulp small B-cell lymphoma
9591/3
Hairy eel/leukaemia-variant
959 1/3
9671/3
Lymphoplasmacytic lymphoma
9809/3
Natural killer (NK) cell lymphoblastic

!euKaemiallymphoma
waldenstrom macroglobulinemia
PRECURSOR LYMPHOID NEOPLASMS

B lymphoblastic leukaemiaflymphoma
B lymphoblastic leukaemiall ymphoma, NO S
982313
Splenic B-cell fymphomalleukaemia, unclassifiable 959 1/3
Mixed phenotype ac ute leuka em ia

with t{v;11q23); MLL rea rranged
Mixed phenotype ac ute leukaemia,

Tfmyeloid, NOS
Chronic lym phocytic leukaemia!

small lymphocytic lymphoma
98 11/3
9761/3
9762/3
9762/3
9762/3
Mu heavy cha in disease
9762/3
Plasma cell myeloma
9732/3
9731/3
9734/3
WHO classification
11
~l..
Systemic EBV positive T-celllymphoproliferative

disease of childhood
9724/3
Extranodal marginal zone lymphoma

of mucosa-associated lymphoid tissue
(MALT lymphoma)
9699/3
Hydroa vaccin iforme-like lymp homa
972513
Nodal marginal zone lymphom a
9699/3
Adult T-cell ieukaemia/lymphoma
9827/3
9699/3
Extranodal NKIT cell lym phoma, nasal type
9719 /3
9690/3
Enteropamy-associated T-cell lymphoma
9717/3
9690/3
Hepatosplenic T-cell lymp homa
971613
Primary cutaneous follicle centre lym phoma
959713
967313
Subcutaneous panniculitis-like
T-cell lymphoma
970813
Mycosis fungoides
970013
Sezary syndrome
970113
Paediatric nodal marginal zone lymphoma
Follicular lymphoma
Paediatric folliculaf lymphoma
Diffuse large B-eelllymphoma (OlBCl), NOS 968013

T-ceillhistiocyte rich large B-eelilymphorna
9688/3
Primary DLBCl of the CNS
968013
Primary cutaneous DlBCl. leg type
9680/3
EBV positive OLBCL of the elderly
9680/3
Ol BCl associated with chro nic inflammation 968013

l ymphomatoid granulomatosis
9766 /1
9679/3
Intravascular large B-cell lymphoma
971213
AlK positive large B-cell lym phoma
9737/3
973 5/3
l arge Bccell lymp homa arising in HHV8associated multicentric Castleman disease 9738/3
Primary effusio n lymphoma
9678/3
Burkitt lymph oma
968 7/3
B-ceillym phom a, uncl assifiable, with feature s

intermediate between diffuse large g-ceu
968 0/3
lymph oma and Burkitt lymph oma
B-ceil lymph oma , unclassifiable, with feat ures
intermediate betwee n diffuse large 8-cell
lymphoma and classica l Hodgkin lymphoma 9596/3
MATURE T-CELL AND NKCELL NEOPLASMS
j-cen prolymphocytic leukaemia
9834/3
'f-celllarqe granular lym phocytic leukaemi a
983 1/3
Chronic Iymphoproliferative disorder of

NK..cells
983113
Aggressive NK cell leukaemia
9948/3
WHO
ciassitcenon
lymphomatoid papulosis
9718/1
Primary cutaneous anaplastic large cell

lymphoma
9718/3
Primary cutaneous qamma-delta
r -ceuivmpncma
Primary med iastinal (thym ic) large

B-celllym phoma
12
Primary cutaneous CD30 positive F-eel!

Iymphoproliferative disorders
9726/3
Primary cutaneous COB positive aggressive

epidermotropic cytotoxic T-cefl lymphoma
9709/3
Primary cutaneous CD4 positive smalVmedium

T-cell lymphoma
9709/3
Peripheral Tccelllympboma, NOS
970213
Angioimmunoblastic 'l-cetl Iyrnphoma
970513
Anaplastic large cell lymp homa, ALK positive 97 14/3

Anaplastic large cell lymphoma, ALK negative
970213
HODGKIN LYMPHOMA
Nodular lymphocyte predomi nant
Hodgkin lymp homa
9659/3
Classical Hodgkin lymp homa
9650/3
Nodular sclerosis classical

Hodgkin lymphoma
9663/3
l ymphocyte-rich classica l
Hodgkin lymphoma
965113
Mixed cellularity classica l

Hodgkin lymphoma
965213
l ymphocyte-depleted classical
Hodgkin lymphoma
965313
HISTIOCYTIC AND DENDRITIC CELL NEOPLASMS
Histiocytic sarcoma
9755 /3
l angerhans cell histiocytosis
975 1/3
langerhans cell sarcoma
9756/3
Interdigitating dendritic cell sarcoma
9757/3
Follicular dendritic cell sarcoma
975813
Fibroblastic reticu lar cell tumour
9759/3
Indeterminate dendritic cell tumour
9757/3
POSTTRANS PLANT LYMPHOPROUFERATIVE

DISORDERS (PTLO)
Early lesi ons
P1asmacytic hyperplasia
9971/1
Infectious mononucleosis-like PTLD
9971 /1
Polymorphic PTLO
9971/3
Monomorphic PTlO (B- and TINK-cell types)'

Classical Hodgkin lym phoma type PTLO'"
NOS, not otherwise speci fied .

The italicized numbers are provi siona l cod es for the 4th
edition of lCD -D . While they are expected to be incorporated in the next ICD -O editi on , they currentty remain
subjectto changes.
The italicized histologi c type s are provisional enti ties , for
which the WHO Working Group fe ll the re was insufficient
evidence to recognize as distinct diseases at this time.
"These lesions are classi fied according to the leukaemia
or
lymphoma to which they correspond, and are assigned the

respective tCO-G code.
WHO classification
13
.. .
Introduction to the WHO classification

of tumours of-haernatopoletlc
and lymphoid tissues
NL Harris
E. Campo
E.S. Jaffe
SA Pileri
Why classify? Classification is the lan-
The WHO cl assification of tumours of the
classification , involvement of clinicians is

essential to ensure its usefulness and acceptance in daily practice 18971. At the lime
of publication of the WHO classi fication
(3rd edition), prop onents of other cla ssifications of haematologic neoplasms agreed
to use the new cl assification, thus ending
decad es of cont roversy over the classification of these tumo urs 147. 478 . t 89.
1B9A, 190, 673,7750 , 1344A. 18198 1,
haematopoietic an d lymphoid system is

based on the principles initially d efined in
the "Revised Europe an-Amer ican Classifica tion of Lymp hoid Neoplasms" (REAL).
from the Interna tiona l Lymphoma Stud y
Group (ILSG) 18981. In the WHO classification, these p rinciples have also been
appl ied to the class ification of myeloid
and his tiocy tic neoplasms, The gu id ing
prin cip le of the REAL and WHO cl assific ations is the attempt to define "real"
d iseases that c an be recognized by
pa tholo gi sts with availabl e techniques.
and that appear be distinct clinical entities . There are 3 important com ponents to
this p rocess First. recognizing tha t the
underlying c auses of these neo plasms
are often unknown and may vary, this approa ch to cl assifica tion uses all available
information - morpholog y, immunop henotype, genetic features, and cl inical features- to define diseases. The relative
impo rtance of eac h of these features
varies among diseases, d epend ing upon
the state of current knowledge, and there
is therefore no one "g old standard ," by
which all di seases are defined . Second.
rec ognizing that the com plexity 01 the
field makes it impossib le for a single
expert Of small g roup to be comptet ely
authoritative, and that broad agreement is
necessary if a classificati on is to be ac cep ted, this cta ssrncanon relies on bu ild ing a consensus among as many experts
as possible on the def inition and nomenclatu re of the diseases, We recognize that
com promise is essential in orde r to arrive
at a consensus, but bel ieve that the only
thing worse than an imperfect classification is multiple competing classifi cati ons .
Finally. wh ile patholog ists must take
pr imary respon sib ility for developing a
As indicated above , there is no one -gold

stand ard ," by which all diseases are
def ined in the WHO cl assific ation. Morpholog y is alway s important, and many
diseases have ch aracteristic or even diagnosti c morphologic featu res, Immunephe notype and genetic features are an
important part of the definition of tumours
of the naematopolettc and lymphoid
tissues , and the av ailability of this information makes arriving at conse nsus definitions easier now than it was when only
subjec tive morphologic criteria were
available . lrrmunophenotyping studies are
used in routine diagnosis in the vast
majority of haematolog ic mali gn ancies,
both to d etermine lineage in malig nant
processes and to dis tinguish be nig n lrom
ma lignant processes . Many disea ses
have a chara ct eristic immunophenotype.
such that one would hesitate to make the
diagnosis in the abse nce of the immunep henot yp e, while in others the immunoonenotvpe is only part of the diagnosis, In
some lymphoi d and in many myeloid ne0p lasms a speci fic genetic abnorma lity is
the key defining criterion, while etters lack
specific known genet ic ebnomantes.
Some g enetic abnormalities, while characteri stic of one dis ea se, are not specific
(such as MYC. CCND 1or BCl2 rearrangements or mutations in JAK2). and others
are prognostic factors in several diseases
(such as TP53 mutations or FLT3-ITO) ,
The inc lusion of jr munoohenotvoc leatures and genetic abnormalities to define
entities not only provides ob jective criteria
for disease recogni tion but has identified
antigens, genes or pathways that can be
targeted for therapy; the success of
rituxima b , an anti-CD20 molecule, in the
guage of medic ine: diseases must be

described , defin ed and named before the y
can be diagnosed , treated and stud ied .

A consensus on definition s and termin olog y is essent ial for both clinic al practice
and investigation . A cl assification should
contain diseases thai are clearly defin ed .
c linically d istinc tive . norKlVerlappi ng (mutually excllsive) and that together comprise
all known entities (collectively e xha ustive).
II should serve as a ba sis lor future investigation . and should be able to incorporate
new information as it becomes ava ilab le.
Classification has two aspects: clas s discovery - the proces s of identifying categories of diseases, and class pre diction
- the process of determining which cere-
gory an individual case belongs to. Pamerogi sts are critical to both processes .
The World Hea lth Org anizati on (WHO)
Classi fication of Tumours of the Haematopoietic and Lymp hOid Tissues (4th Edition ) was a coll aborative project of the
European Association for Haematopathology and the Society lor Hematopatholog y.
It is a revision and update of the 3rd Edition 11039 }. which was the first true
worldwide consensus c lassific ation of
baematoiocic malignancies. The update,
which began in 2006, had an a-me mbe r
steering committee composed of membe rs
of both societies, The Steering Comminee,
in a series of meetings and discussions,
agreed on a proposed list of diseases
and chapters and selec ted authors. with
input from both soc ieties. As with the
WHO 3fd ed ition 189 71. the advice of clin ical haematologists and oncologists was
obtained . in order to ensure that the classifica tion will be clinica lly useful. Two Clinic al Adv isory Committee s (CAG). one for
myeloid neoplasm s and other acut e
leukaemias and one for lym phoid neoplasms. were convened, The mee tings
were org anized aroun d a ser ies of
questions, inc luding disease definitions,
nomenclature, grading. and clinical relevance. The committ ees were able to
reach consensus on mos t of the questions po sed . and muc h of the inp ut of the
14
Introduction to the classification
committees was incorporated into the

class ification. Over 130 pa thologists and
haem ato logis ts from around the world
were involved in writing the chap ters. A
consensus meeting was held at the head quarters of the IARC in Lyon, France. to
make final d eci sions on the classi ficatio n
and the con tent of the book.
H. Stein
S.H. Swerdlow
J Thiele
J w. Vardiman
treatment of. B-cel! neoplasms, and 01

imatinib in the treatment of leukaemias associated with ABL 1 and oth re!lrrangements inv olving tryoene kinase genes are
testament to this approach. Finally. some
diseases require know ledge of clinical
features - age, nodal versus extranodal
presentanon. specific anatomic site . and
history 01 cytotoxic and other therapies
- to make the diagnosis. Most 01 the diseases described in the WHO classification
are considered to be distinct enti ties ;
howev er. some are not as clearly defined,
and these are listed as prov isional entities,
In addition . borderline categories ha....e
been created in this edition for cases that
do not c learly fit into one category, so that
well-de fined categories ca n be kept
homogeneous, and the borderline cases
can be stud ied further.
The WHO classification stratifiesneoplasms
primarily ac cording to lineag e: myeloid,
lymphoid, and histiocyticfdendritic c ell. A
normal c ounterpart is postulaled lor each
neoplasm. While the goal is to define the
lineag e of each neoplasm, lineage pla sticity may occur in precursor or imma ture
neoplasms, and has recently been identified in some mature haematotymphoid
neoplasms , In addition, genetic atooerreuues suc h as FGFR1, PDGFA and
PDGFB rearrangements may give rise to
neoplasms 01 either myel oid or lymphoid
lineage associated with eosinophilia ;
these disorders are now recognized as a
separate group. Precursor neoplasms
(acute myeloid reukaemes. lymphoblastic
Iymphomasfleukaemias, acute reukaerraas
01 amb iguo us lineag e, and blast ic p lasmacytoid de nd ritic ce ll neop lasm ) are
considered separately from mo re mature
neoplasms [myeloproliferative neoplasms
(MPN). myelodysplastic/myeloproliterative
neoplasms, myelodysplastic syndromes ,
mature (peripheral) B-cell and T/NK -cell
neoplasms, Hodgkin lymphoma. and hisIiocyteldeodritic-c ell neoplasms] . The mature myeloid neoplasms are stratified
according to the ir bi ologica l features
(myeIopl'oIiferative, with effective baereiopoiesis. ....ersus myelodysplastic , with ineffective neematcootesfs . as welt a s by
genetiC feature s). Within the mature lymphoid neop lasms , the diseases are listed
broadly ac cord ing to clinical presentation
(disseminated often leukaemi c, extran coat. indolent. aggressiv e). and to some
extent according to stage of differentiation
when this can be postulated: howe....er the
ord er of listing is in part arb itrary, and is

not an integral part of the cl assification.
The 4th ed ition of the WHO classification
inc orpo rates new information that has
emerged from basic and clinic al in....estrgat ions in the interva l since pu b lication of
the 3rd edition . It inc ludes new defining
criter ia for some disease s, as well as a
number of new entities. some def ined by
genetic criteria - particul arly among the
myeloid neoplasm s- and others by a
combination of morpholog y. immunoph eootype . and clinic al features. The frequent
application of immunophenotyping and
genetic stud ies to peripheral blood, bone
ma rrow, and lym ph node samp les has
also led to the de tection of small clonal
populations in asy mptomatic pe rsons .
These include small clones of cells with the
BCR-ABL 1 translocation seen in chronic
myelogenous leukaemia. small cl ones of
ce lls with BCL2-IGH rearrangement. and
small populat ions of c ells that have the
imm uoopheootype of chronic lymp hocytic
leukaemia (e l l ) or folli cu lar lymphoma
(mo noc lonal B lymphocytosis, follicular
lymphoma-in Situ , paediatric follicul ar hyperplas ia WIth monoclonal B c ells). In
man y case s. it is not clear whether these
represent earty involvement by a neoplasm,
a precursor iesoo. or an inconsequential
find ing. These situations have some
ana logies to the identification of small
monoclonal immunoglobulin components
in serum (monoclonal gammopathy of
unknown significance), The ch apters on
these neoplasms include recommendations for dea ling with these situations. The
rec omm end ations of international con sens us group s have bee n co nsidered.
with regard to criteria for the d iagnosis of
e ll, plasma cell myeloma, Waldenstr6m
macroglobulinemia, and new subtypes of
cutaneous lymphomas, as well as in the
development of new algorithms for the
diagnosis of MPN .
the WHO classification has produced a

new and exciting degree of cooperation
and conmunic ation among patholog ists
and oncologists from around the world .
which stould facilitate con tinued progress
in the understand ing and treatment of
haema totog ic manqnaocies . The mulliparameter approach to c lassification, with
an emphasis on defining real disease
entites. tha t has be en ad opted by the
WHO classification, has been shown in
inte rnational studi es 10 be reproducible:
the disea ses d efined are c linically disttnct iv e. and the uniform definitions and
terminology facilitate the interpretation of
clinical and translational stud ies 15 1, 791 .
In addition, accurate and precise classifi c ation of d isease entities has facilitated
the discovery of the genetic bas is of
my eloid and lymphoid neoplasms in the
ba sic science laboratory
A critic al feature of any class ification of

diseases is that it be periodically reviewed
and updated to incorpor ate new information. TheSocietyfor Haematopathology and
the European Association for Haematopathology now have a more than to-year
record of couebceaton and coo pe ration in
this effort. The societies are comm itted to
updating and revising the classification
as needed . with input lrom clinicians and
with the collaboration of the WHO . The
experience of developing and updating
Introdu ction to the cl assification
15
CHAPTER 1
Introduction and Overview
of the Classification
of the Myeloid Neoplasms
-,
"
..
Introduction and overview of the

classification of the myeloid neoplasms
J.w. Vardiman
A.D. Brunning
D.A . Arter
M.M.Le Beau
The WHO Classification of Tumours of the

Haematopoietic and Lymphoid Tissue s
(3rd edition) published in 200 1 reflected
a pa radigm shift in the approach to c lassification of myeloid neoplasms { 1039). For
the first time. genetic information was incor porated into diagnostic algorithms
provided lor the vario us en tities. The publicat ion was prefac ed with a comment
pred icti ng future revisions nec essitated
by rapidly eme rg ing gen el ic information.
The cu rrent revision is a commentary on
the significant ne w molecular insights mat
have bec ome avail abl e since the publication of the last ctass'ncauon .
The first entity described in this monograph . chronic myelogenous leukaemia
(CML) rema ins the prototype for the identification and c lassific atio n of myeloid
neoplasms This leukaemia is recognized
genetic features is used in an anerrctt c

define d isease entities , such as CML, that
are biolog ically homogeneous and clinically relevant - the same approach used
in the 3rd ed ition of the classification.
Altho ugh the previous scheme began to
open the door to including genetic abnormalities as c riteria to classi fy myeloid
neoplasms, this rev ision firmly acknow ledges that as in CML, recu rring ge netic
abno rmali ties provi de not onl y objec tive
c rite ria for recognition of speci fic entities
but also identification of abnormal gene
product s or pathways that are potent ial
targets for therapy. One example in this
revised sc heme is the addition of a new
subgroup of mye loid neoplasm s (Tabte
1.01) assoc iated with eos inoph ilia and
chromo somal ab normalities that involve
the oiateiet-oenved growth factor rece ptor
by its c linic al and morphologic features,

and its natural progression is charac terized by an inc rease in blasts of myeloid ,
lymphoid or m ixed myeloid/lymphoid
immunop henotype. It is always associated with the BCRABL 1 fusion gen e that
results in the production 01 an abnormal
protein tyros ine kinase (PTK) with enhance d enzyma tic ac tivity. This p rotein is
sut tcrentto ca use the leukaem ia and also
provides a targ et for prote in tyrosi ne
kinase inhibi tor (PTKI) the ra py tha t has
prolonge d the lives of thousands of pa tients with this often tatal illness {6 151.
This successful integ ratio n of cl inical ,
morphologi c and genetic information embodies the goal of the WHO classific ation
scheme.
In th is revis ion . a combination of c linica l,
morpholog ic . imm uno phe noty pic and
.-"""'"
Table 1.01 Themyeloid neoplasms' major sul:9'OUJlS and d\al;U::i tstic features at ~
0.....
MPN
MyeIoidIIymphoid
neoplasmswith
eosinophilia and abriof
malilies of PDGFRA.
8M ctllularity
'10 MIrf'OW bluts
Usually increased.
often normalin ET
tbmaJ or sIighlIy
increased: <10% in
dI'onic phase
Increased
Normal or $IigM~
increased: <20% irl
cnronc phase
Present
Nom1al or increased:
Preserlt
..........,
--
HatrnatopOitsit
G,,,''''''',
En-.
Relatively normal
Elfectrve
relabYe/y normal,
"""""""",
"""""'"
A. Porwit
A . retten
C.D. Bloomfield
J. Thiele
.... """"
VanabIe; 008 or
"""..-
IifIeage usually
irullallyincreased
Eosinophilia
Co<m>oo
Com~
j~t 5x10ir1.)
PDGFRB Of FGFRI
MOS
"''''as."
=-
~aror
M''''''PN
"""""'
"""'..."
"""" .......
""'.
~lasia
inoreor
-,,- --_""
incl'eased;<20'10
"""'"
Usually oneormae
......
rrft'!lal cIyspIaSIa
_>2ll%.
eQPl in some cases

'l'Illh specific cybJeneIlc
abnorrnaIilies or in
some cases of
erylhroIeukaemia
Inel!&Cti'Ie
Cytopenia(s)
U_
......
..--
\IariabIe. WBC
Co<m>oo
more myeloid lineage
......,
-......
"",",
May Of may J'IOl be
-...
""""""'"
dyspIaslai'loneor
Moy""Y ......
WllC_
........ ........
or e"ect1ve
.........
"""'-
Mf)N, myeloproliferative neoplasms: MDS, myelod)'spla:slic syndromes; MDSlMf)N, myeIodysplasbcJmyeloprolifefalive neoplasms: AMl, ICIJIe myeloid leukaemia; ET, esseflIlaj
Ihfombocylhaemia, JMML. ju&nile myelomonocytic leukaemia, wec. wniIe bloocI e&II$.
18
'
Introduction and overview of the c lassif ication of the mye loid neoplasms
alpha (PDG FflA) Of platelet de rived growth

factor recep tor beta (PDGFRB) genes
-a subgroup defined larg er9 by genetic
events that lead to consti tutive act ivat ion
of the receptor tyrosine kinase, PDGFA,
and that respond to PTKI therapy {13 1,
466. 8121 . Similar examples are found
througho ut the classification in each
major subgroup, and inclu de not only
neoplasms assoc iated with rmcroscoprcally rec og niza ble chromosomal abnormalities but also with gene mutations
without a cytogenetic correlate as weu.
On the other hand . the importance 01
careful clinical, morphological and immunophenotypic characterization of each
myeloid neoplasm and coeretanoo with

the genetic findings cannot be over-
emphasized. The discovery of activating

JAK2 mutations has revolutionized the
approach to the diagnosis of the myeloproliferative neoplasms (MPN) 1163, 1044 ,
1186,12681. Yet JAK2mutatiQns are not
specific for any single clinical or morphologic MPN phenotype, and are also
reported in some cases 01 myelodysplastic syndromes (MDS), myeiooysplasnc/
myeloproliferative neoplasms (MDSlMPN)
and ac ute mye loid leu kaemia (AMl).
Thus, an integ rate d, multidisciplinary
approach is necessary for the classification
of myeloid neoplasms.
With so muc h yet 10 learn, there may be
some 'missteps" as trad itional approaches
to categorization are fused with more
rrcecuarfy-orentec clessifcaton schemes ,
Nevertheless, thi s revi sion of th e WHO
classification is an attempt by the authors,
editors and the c linic ians who served as
members of the Clinica l Advisory Committee (CAC ) to p rovide an "evidencebased" c lass ifica tion that ca n be used in
daily p ractic e for therap euti c deci sions
and yet pr ovide a flexib le framework for
integration of new data ,
Prerequisites for classification

ofmyeloid neoplasms by
WHO criteria
The WHO c lassification of myeloid neoplasms relies on the morphologic, cytochemical and immunophenotypic features
of the neop lastic cells to esta bl ish thei r
lineage and deg ree 01 ma turation and to
decide whether cellular p rolife ration is
q101ogica lly normal or dysplastic or
esecuve or ineffec tive . The classification
is based on cr iteria applied 10 initial specimen s obtained prior to any definitive therapy, includ ing growth lactor therapy, for the
myeloid neoplasm. The blast percentage in
the per ip her al b lood , bone ma rrow an d
other involved tissues remains of p ractica l
impo rtance to categorize myeloid neoplas ms and to judge their progression .
Cytogenetic and molecular genetic studies are requ ired at the time of d iag nosis
not only for recoq r nton 01 specific genetically d efined entities, but for establiShing
a baseline against which futu re studies
can be judged to assess disease progression. Beca use of the multidisciplinary
approach req uired to diagnose and classify myeloid neoplasms it is recomnended
thaI the various diagnostic studies be
correlated with the clinical findings and
reported in a single, integ rated report. If
a definitive classification cannot be
reached the report should indicate the
reasons why and provide guidelines for
additional studies that may clarify the
diagnosis.
To obtain consistency, the following
guidelines are recommended for the evaluation of specimens when a myeloid neoplasm is suspected to be present. It is
assu me d tha t this evalua tion will be pe rformed with full knowled ge of the clinical
history and pertinent laboratory data.
Morphology
Periphera l blood: A perip heral b lood (PB)
smea r sho uld be exa mined and co rrelate d with result s of a co mple te b loo d
c ount. Freshly mad e smea rs shou ld be
sta ined with May-Gnmwald -Giernsa or
Wright-G iemsa and examined for wh ite
bloo d ce ll (WBC) , red b lood ce ll (AB C)
and plate let abnormal ities It is impo rtant
to ascerta in that the smears are we llstained, Evaluation of neutrophil g ranularity
is imp ortant when a myelo id d isor der is
suspected; de signat ion of neut rophils as
abnormal b ased o n hypog ranular cytoplasm alo ne shoul d not be conside red
unless the stain is well-controlled . Manual
2OO-cell leukocyte di fferentials of PB
smea rs are recommended in patients with
a myeloid neoplasm when the WBC count
permits.
Bone manowaspirate: Bone marrow (BM)
as pi rate smears should also be stained
with May-G rQnwald-G iemsa or WrightGie msa for optimal visua lization of cytoplas mic g ranules and nuclear chromatin.
Because the WHO Classification relies on
percentages of blasts and other specific
Introduction and overview of the
11111111 111I 1111 1111 111111
456
F'S!. 1.01 Bone marrow tIeI:Me biopsy, Bone marfOW
b'ephinebiopsies should be alleast 1.5 em in length and
ollt<w1ed at right angles10 the cortical bone.
cells to categorize some eoutes. it is recommended that 500 nucleated BM cells
be counted on cellular aspirate smears in
an area as close to the particle and as
undiluted with blood as possible. Countll"lQ
from multiple smears may reduce sampling error due to irregular distribution of
cells. The cells to be counted include
blasts and promonocytes (see definition
below) . pronveocvtes. myelocytes, metamyelocytes, band neutrophils, segmented
neutrophils, eosiropnns. basophils, fTlQIlOcytes , lymphocytes. plasma cells , erythrOid
precursors and mas t cells. Megakaryocvtes. including dysplastic forms. are not
inc lude d. If a concomitant non-mye loid
neoplasm is present, such as p lasma ceu
myeloma, it is reasonable to exclude
tho se neo plastic cells from the coun t
used to evaluate the myeloid neop lasm. If
an aspirate ca nnot be obta ined du e to
fibrosis Of ce llular packing, touch preparatio ns of the b iop sy may yield valuable
c yto log ic informa tion, but d ifferential
co unts from touc h preparations may not
be repr esentative . The d ifferential co unts
obta ined from marrow aspi rate s should
be compared to an estimate of the p ropo rtions of cells o bserved in avai lab le
biop sy sections,
Bone marrow trephine biopsy: The contribut ion of adequate 8M bio psy sections in
the diagnosis of myeloi d neoplasms cannot be overstated. The tre phine biopsy
provides information rega rdin g overall
cellularity and the to pog raphy, propo rtion
and maturation of baematopolenc cells ,
and allows evalu ation of 8M stroma. The
biopsy also provid es material for immunohistochemical studies th at may have
diagnostic and prognostic importance. A
biopsy is essential whenever there is
myelofibrosis, and the classification of sore
entities , partiCularly MPN, relies heavily on
trephine sections, The specimen must be
ctassncauoo at the myeloid neoplasms
19
adeq uate, Iake n at rig ht angle from the

cortica l bone and at least 1.5 cm in length
to enable the evaluation of at least 10 partially preserved inter-trabecular areas. It
should be well-fixed, thinly sectioned at
3-4 micra, and stained with haematoxylin
and eosin and/o r a stain such as Giemsa
that allows lor detailed morphologic evaluation . A silver impreg nation method for
reticulin fibres is recommended and
marrow fibrosis graded according to the
European consensus scoring system
122141, A periodic acid-Schitt (PAS) stain
may aid in detection 01 megakaryocytes.
Immunohistoc hemical (IHe) study of the
biopsy is often indispensable in the eva luation of myeloid neoplasms and is discussed belOw,
Blas ts: The percentage of myeloid blasts
is important for dl8gnosis and ctasstcaton
of myeloid neoplasms , In the PB the blast
percentage should be derived from a
200-cell leukocyte differential and in the
8M from a 500-cell count of cellular 8 M
aspirate smears as described above . The
blast percentage derived 'rom the 8 M
aspirate should correlate With an estimate
of the blast percentage in the trephine
biop sy. although large foca l clusters or
sheets 01 blasts in the biopsy should be
regarded as possible disease progression.
Immunohistochemical staining of the BM
biopsy for CD34+ blasts often aids in the
correlation of aspirate and trephine biopsy
findings, although in some myeloid neoplasms the blasts do not express CD34 ,
Flow cytometry determination of blast
percentage should not be used as a substitute for visual inspection. The spec imen
for flow c ytometry is otten haemoouute.
and may be affected by a number of preanalytic variabl es. and as noted for the
biopsy. not all blasts express CD34 .

Myeloblas ts. monoblasts and megakary<>
blasts are included in the blast count.
Myeloblasts vary from slightly larger than
mature lymphocytes to the size of monocvtes or larger. with moderate to abundant dark blue to blue-grey cytoplasm.
The nuclei are round to oval with finely
granul ar chromatin and usually several
nucleoli. but in some nuclear irregularities
may be prominent. The cytoplasm may
contain a few azurophil granules (Fig 1,03),
Monob lasts are large cells with abundant
c ytoplasm that can be light grey to deeply
blue and may show pseudopod formation
(Fig 1.04 A. S). Their nuc lei are usually
round with deli cate , lacy chromatin and
one or more large prominent nucleoli.
They are usually strongly positive for n0nspecific esterase(NSE) but have no or only
weak myeloperoxidase (MPO) activity,
Promonocytes are considered as ' rroooblast equivalents " when the requisite percentage 01 blasts is tallied for the
diagnosis of acute monoblastic . acute
monoc ytic and acute myerorronocync
leukaemia. Promonoc vtes have a delicately convoluted. folded or grooved
nucleus with finely dispersed chromatin,
a small , indistinct or absent nucleolus,
and finely granulated cytoplasm (Fig 1.04
C, 0), Most promonocytes express NSE
and are likely to have MPO activ ity. The
distinct ion between mono brasts and
prornonocvte s is often difficu lt. but
because the two cell types are summated
...
.,
20
Introduction and overview of the classification of the myeloid neoplasms
as rr onootasf s in making the diagnosis of

AML, the distinction between a monoblast
and promonocyte is not aly,.ogys critical.
On the other hand , distinguishin g promonocvtes from mo re matu re b ut abnormal leukaemic monocytes can also be
dilficult, but is critical, because the designation 01 a case as acu te monocytic or
acute myelomonocytic leukaemia versus
chronic myelomonocytic leukaemia olten
hinges on this distinclion . Abnormal
rrooocv tes have more clumped chromatin
than a p romonocyte, variably indented.
folded nucl ei and grey cytoplasm with
rrore abundant lilac -colored granules . Nucleoli are usually absent or indi stinct (Ftg
1.04 E.F). Abnormal monocytes are rot
consider ed as monoblast eouvaeots.
Megakaryoblasts are usually 01rreoen to
large size with a round , indented or
irregular nucleu s with finefy reticular
chromatin and one to three nucleoli. The
cytOplasm is basophiliC, usually agranular,
and may show cytoplasmic blebs (See
Chapter 6 on acute myeloid leukaemia,
NOS). Small dysplastic megakaryocytes
and micrornegal<.aryocyt es are not blasts.
Inacute promyelocytic leukaemia, the blast
equivalent is the abnormal promyelocyte .
Erythroid precursors (erythroblasts) are
rot included in the blast count except in
the rare instance of "pure" acute erythroid
leukaemia, in which case they are cons idered as blast equiva lents (See Chap ter 6
on acute myeloi d leukaemia, NOS).
Cytochemistry and other special steins:
Cytochemical stud ies are used to determine the lineage 01 blasts, althou gh in
some laboratories they have bee n supplanted by immun ologi c studies usin g
flow cytometry an d/or immunohistochem istry. They are usu ally perform ed on PB
and 8M aspirate smears but some can be
performed on sections 01 treph ine b iop sies or other tissues . Detec tion 01 MPO
indicates myeloid d ifferentia tion b ut its
absence does not exclude a myeloid lineage because early myelobl asts as well
asmonoblasts may lack MPO. The MPO
activity in rrweiobtasrs is usually granular
and etten concentrated in the Golgi region
whereas monobtasts. although usually
negative,may show line, scattered MPO+
granules, a pattern tha t becomes mo re
pronounced in prcmonocvtes . Erythroid
blasts, megakaryoblasts and Iymphoblasts
are MPO negat ive . Sudan Black B (SSBl
staining parallels M PO but is less speetc. Occ asional cases of lymphoblastic
leult.aemia exhibit SSB POSitiVIty, in which
-~
~
.

Fig. 1.04 Monoblasts, promonocytes and abnormal mcnccytea from a case of acute monocytic laukaemia.
A, B Monoblastsarelarge with abundant cylOlJlasm that ma y contain a few vacuoles Of fine granules and have roullCl
nuclei withlacy chroma~n and one Of more variably prominent nucleoli. C, D Prornor.ocytes have more irregular ancl
delicately folded n~ withfine chroma~n, small indistinct nucleoli and finely granulated cytoplasm. E, F Abnormal
monocytes appear immature, yet have more condensed nuclear chroma tin, con'o'Q/uled Of fdded nuclai, and more
cylopIasmiC granulaboo (Courtesy of Or. J. Goasguen).
case light grey granules are seen rather

than the deeply black granules that characterize mverobrasts. The non-specific
este rases . u nap hthyl butyrate (ANB) and
(,( naphthyl acetate (ANA). show diffuse
cytoplasmic activity in monoblasts and
monocytes. Lymphoblasts may have foca l
punctate activity with NSE but neutrophils
are usually negative. Megakaryoblasts
and erythroid b lasts may have some multitocal. punctate ANA positivity, b ut it is
partia lly resistant to natrium ffuorid e (NaF)
inhibition whereas monocyte NSE is totally
inhibi ted by NaF, The combination of NSE

and the specific esterase , naph thol-ASDchloroaceta te esterase (CAE), which stains
primarily cells 01 the neutroph il lineage
and mast cells, permits ident ification of
monccvtes and immature and mature
neutroph ils simultaneously. Some cells ,
particularty in myeIornonocytic leukaemias,
may exhib it NSE and CAE simultaneously.
While norma l eosinoph ils lack CAE, it may
be expressed by neop lastic eosooohne.
CAE can be performed on tissue sections
as well as PB ()( marrow asp irate smears.
Introduction and overview 01 the ctass.tcanoo 01 the myeloid neoplasms
21
In acute erythroid leukaemia. a PAS stain

may be helpful in that the cytoplasm of
the leukaemic oroervmrobreate may show
large globules of PAS positivity. Wellcontrolled iron stains should always be
per formed on the 8M aspirate to detect
iroo stores. normal side roblasts and ring
side robrasts. the latter of which are defined as erythroid precursors with 5 or
more granules of iron encircling one-third
or more of the nuc leus.
Immunop henotype
Immunophenotypic analysis using either
multiparameter flow cytometry or IHe is
an essential tool in the cha racterization of

myeloid neoplasms. Differootiation antigens
that appear at various stages of haematooo'euc develo pment and in corresponding myeloid neoplasms are illustrated in
Fig . 1.05. and a thorough descriplion of
lineage assignment criteria is provided in
the chapters on mixed phenotype acute
leukaemia, The techn iques employed and
the antigens anafyzed may vary according to the myeloid neoplasm suspected
and the information required 10 best characterize it as well as by the tissue available. Although often important in the
diagnosis ol any haematoiogicaJ neoplasm.
immunophenotyping in myeloid neoplasms

is most com monly required in AML and in
determining the phe notype of blasts at
the lime of transfo rmation of MOS.
MOS!MPN and MPN,
Mulliparameter flow cytometry is the
prefer red method of immuno phenotypic
analysis in AML due to the ability to analyze high numbers of cells in a relatively
short period of time with simultaneous
recording of information about severer
antigens for each individual cell. Usually.
rather extensive panels of monoclonal antibodies directed against leukocyte differentiation antigens are applied because
<--U II 7+
C U 1I7+
c m l 7-
lib-
llb-I+
C D.l6-
' fh+
C DJ6 -
CD l 6 -
CDIJ ~'-
Cll1J~.-
C D235. -
C U,J. C O lJ5.prvQ')"lbn>bla. 1
b ....p bllk:
tory l b rub l.,.
"'"
pc.ol ycbrvm.lk
toryl h ruh l 1
C U lM-
C I)l63+
C IU+
C OU +
+
C IUJ+
C O IS+
C IU J +
C D36-+
C I)6" +
HL-\ -DR +
C O ll b+
C D I 4+
C O}4...
C IU +
C D U'"
' r"",,::7:-:-~01 liLA-DR'"

C IU 3'"
II
C U34_
liLA -DR t-tl L -"-LO"--l,.

C U.\H++
C O l5-+-
COll ++
mon.. hl . ~1
p rumo"ucy'\'
,------''-,
r'----,
C O Il 7 +1C ll1 J+
C D 33 +
MPO+
C:0 6 5+
C D I5+/
C IH J d lm
C IU J +
MPO+
C ))65+
C D I5 +
C U ll b+'_
C D 3.. +-+
1I1.A.-UR
C D .\N+-+
m nmx: yl f'
em sC lU J '"
M''O+
C D6 5+
C U15+
C D I I II+
C1U 5tlim
e m s-
Un _
C D J .....
C IH M+
C D U JC1U5R A+
_n_
C D3.. +
ClHM _
C D IlJ-.
C1 U 5 HA TI'O -R+
22
C UJ4+I.
C DJ M., _
C D61+
C I).&I+
ce-e-
C DJ4
C DJ8+
C 06 1+
C 04I +
C04 l +I
mtrocucuco and overview of lhe classification of the myeloid neoplasms
C U.14C O.\ II++

C I)6 I++
C I).& 1-+-+
C U"' l+
C DJ ....
C OM+
IH...A-O R +
C O l lb++
C O l -t-t
J
the utility o f in,s:livid ual markers in identify-
ing commitme nt of leukaemic c ells into

the different haemat op oieti c tlneages is
limited Evaluation of exp ress ion patterns
of several antige ns, bo th membrane and
cytoplasmic, is necessary for lineage
assignment. to d etect mixed phenotype
acute leu kaemia, and 10 detect aberran t
phenotypes allowing lor follow-up of

minimal re sidua l d ise ase .
Irrmunopheootypic analysis has a ce ntral

role in disting uishing be tween minimally
dllferentiated acut e myeloid leu kaemia
and acute lymphoblastic leukaemia, and
in CML between myeloid blast pha se
and lymphoid blas t phase. Among AM L
WIth recurrent genetic abnormalities , sev eral have characteristic phenotypes. These
patterns. described in the respective

sections, can help to plan molecular
genetIC {lluorescence in situ hybrid ization
(FISHlI and molecular inv estigation s in
individual patie nts, lm munophe notyp ic
features or the other AMl categor ies are
extremely heterog eneo us. probably due
to high genetic d iver sity. Although it has
been sugges ted that express ion of c ertam antiqens, such as CD?, COO, C Ol lb,
C014. CD56 and CD34 cou ld be associated with an adver se prognosis in AMl,
their independe nt prognostic value is still
controversial. Aberrant or unusual omorophenotypes have been found in at
least 75% of ca ses of AMl. These c an be
described as c ross-lineage antigen expression, matura tional as ync hronous
expression of antigens , antigen overexpression, and the red uction or abse nce of
antigen expressio n, Sim ilar aberra ncies
have also been reported in MDS as we ll.
and their presence ca n be used to sup port
the diagnosis in ear ly o r morpholog ica lly
ambiguous cases of MDS (See Chapter 5).
lm11unophenotyping by IHC on 8 M b iopsy
sections can be applied if ma rrow cell
suspensions are nol available for flow cytcmetry analysis. Antibodies reactive with
paraffin-embedded BM biopsy tissue are
available for many lineage-associated
markers (e,g. MPO.lysozyme, CD3, PAX:s,
C033, etc.). As noted previously, CD34
staining of the biop sy can fac ilitate the
detection of blasts and their distribution ,
provided the blasts expres s CD341 1650/.
For cases rich in megalob lastoid erythroblasts. immunohistolog y for glycophorin
or haemoglobin may be helpful in dist inguishing those cells from myeicotasts
(eg. in cases of RAEB or acute erythro1eI.Memia), and COOl or CD42 oflen aid
cvto-
in the id entification of abnormal megaka rvoc ytes.

Genetic studi es
The WHO classi fication includes a numbe r of entities defined in part by scecmc
genetic abnormalities. including gene
rearrangemen ts due 10 chromosomal
nansrccarrons and to specific gene mutations. so de term ination of genet ic features
of the neoplastic cells must be performed
if possible. A complete cytogenetic ana lysis of 8M shou ld be perlormed at the time
of init ial eva luat ion to establish the cytogenetic profile, and at regu lar intervals
thereafter to detect evidence of genetic
evolution . Additional d iag nosti c genetic
studies should be guided by the diagnosis
suspected on clinica l, morpholog ic a nd
imTulophenotypi studies. In some cases,
reverse transc rip tase-pol ymerase c hain
reaction (AT-PCR) and/or FISH may detect gene rearrangements thai are present in low frequency and not observed in
the initial chromosomal ana lysis, in c ases
with var iants of typical cytogenetic
abnormalities, and in cases in which the
abnormality is cryptic , such as the
PDGFRA-FIP1L 1 fusion in myeloid neoplasms associated with eos inophilia, Depending on the abnormality, qu ant itative
PCR performe d at the time of diagnosis
may also p rovide a baseline against
whic h the response to therapy c an be
monitored . A num ber of gene mutations
d etect ed by gene sequencing, allelespe cific Pe A and othe r techniq ues have
em erge d as importa nt diagnostic and
prognostic ma rkers in all ca tegories of
mye loid neoplasm s, Mutat ion s of JAK2,
MPL , NRAS, NFl , PTPN 11, and KI T in
MPN and MDS/MPN, and NPM1, CEBPA,
FLT3, RUNX1 and KIT, among others. in
AMl are impo rta nt for d iagnosis and
p rognosis. and some. particularly JAK2,
FLT3, NPM 1 an d CE8PA figure importantly in this revised classification . Furthermore , the role of gene over- and
unde r-expression as well as loss of hete rozygosity and copy number variants
detected by array-based approaches are
on ly now being recognized as impo rtant
abnormalities that may well influence
d iagnostic and prognostic models in the
near future 11531AI . Nevertheless,
m icroarray prof iling studies. alt hough
import ant in the research setting , have not
yet been tested in cl inic al practice .
Revised WHO classification of

myeloid neoplasms
Table 1,0 1 lists the major subgroup s of
myelold neop lasms and their characteristic
features at diagnosis. The nomenclature
for the myeloprolife rative entities has been
c hanged from "c hronic mye lopro liferat ive
diseases" to myeIoproIiferative neoplasms"
and the subgroup formerly designated as
"myelod ys pl as ticfm y e lo p ro li fe rati v e
dis eases" has been ch ang ed to
"myelod ysplasticJmyelo proliferative ne0prasms" to und erscore the ir neoplast ic
nature . Beside s the addition of the new
subgroup. "Myeloi d and lymp hoid ne0plasms with eosinophil ia and abnormalities
of PDGFRA, PDGFR8 and FGFRt , new
entities have been added and/or diagnost ic criteria updated with in each subgroup.
Myeloproliferative neoplasms (MPN)
The MPN (Table 1.02) are c lonal haeretcporenc stem cell d isorders Characterized
by pr oliferation of one or more of the
myel oid lineages (l.e. granulocytic , ery thro id . megakaryocytic and mast cell).
They are primarily neoplasms of ad ults
that peak in frequency in the 5th to 7th
decade, but some subtypes. parti cu larly
CM l and essential thrombocythaemia
(ET), are reported in children as well. The
inc id enc e of all sub types combined is
6-10/ 100,000 population annually {1053,
1059. 1060 f,
Initially. MPN is cha racterized by hypercellularity of the BM with effective
naematoporetc maturation and increased
numbers of gra nulocytes, red blood ce lls
and/o r plate lets in the PB. Splenomegaly
and hep atomeg aly a re co mmon and
caused by sequestration of excess b lood
cells or proliferation of abnormal raematopoietic cells, Despite an insidious onset
each MPN has the potential to undergo a
Table 1.02 ~live neoplasms (MPN).
ChrtncITl)9logenous 1Bukaen'ia, BCR-ABI. posibYe

(CMl)
Clwtlnic. neutrophilic leubeml8 (CNL)

~'o'efil (PV}
"""'" _ _ (PM~
ESSoElI'IUl ~ (ET)
Oworic eosnophic Ieukaer'ru. NOS lea NOS)
"'-
MyelqiltMaabYeneoplasm,loI'ldasslJable (UPN,U)
introouctco and overview of the ctassrncanon of the myek>id neoplasms
23
ABU
CML
Myeloid neoplasms
with eosinoph ilia
PV
PDGFRA,PDGFRB,FGFR1
JAK2 V617F, JAK exon 12
PMF
JAK2V617F, MPL W15 1UK
ET
JAK2V617F, MPL W151 UK
Mastocytosis
KITD816V
Fig. ' .06 Myeloprololerative neoplasms (t.4PN)and oIhet myeloid neoplasms associated W11t1 mutaliOnlrearrangement of tyrosine kinase genes.
stepwise pr ogr ession that term inate s in

marrow failur e d ue to myelofib rosis , ineffective haemat opoi esis or Iransformalion
10 an acu te blast phase. Evid ence of ge netic evo lution usually heralds disease
progression as may increasing organamegaly, increasing or decreasing blood

counts , myelofi brosis and onset 01myelodysplasia. The finding of 10-19% b lasts
in the P8 Of 8M generally signi fies accelerated disease and 20% or more is
suHicient for a di ag nosis 01bla st pha se .
[
j
Rationale for tho diagnosis and

classification of MPN
In previous cl assification schemes the
detect ion of the Philadel phi a chromosome and/or BCR-ABL 1 fusion g ene was
used to coolirm the diagnosis of C Ml
wher eas the remaining MPN sub types
were diagnosed by their cli nical and
labo ratory features with relatively minor
contributions to the diagnosis from morph ologi c findings. A number of criteria
were required not only to distinguish
24
subtypes of MPN from each other but

from reacti ve granulocyt ic . erythroid andl
or megakaryocyt ic hyperplasia .
Revisions in the criteria for cla ssification
of MPN in the cu rrent scheme have been
influen ced by two fac tors - the recen t
discovery of gen etic abnorm alities involved in the pathogenesis of BCR-ABL 1
negative MPN and the wide r appreciation
that histologic features (megakaryocytic
morp hology and topograph y, marrow
stromal changes, id entific ation 01specific
cell lineages involved in the proliferation)
cor relate with clin ical features and c an be
used as criteria to identi fy MPN subtypes
{2 177. 22 16, 22221.
Mo st if not all MPN are assoc iated with
clona l abnormalities involving g enes that
encode c ytoplasmic or receptor PTKs.
The abnormalities described to da te
include transicc anons Of point mutations
of genes that result in abnormal, co nstitutively abnormal PTKs that activate signal
transdu cti on pathw ays leading to the
abnormal proliferation . In some c ases,
Introdu::tion and overview of the classi fication of the myeloid neoplasms
these genetic abnormalities. such as the
BCR-ABL1 fusion gene in CMl . are essocia ted with consistent clinical, laboratcry
and morp hologic find ing s that allow them
to be utilized as major criteria for classfication, whereas others provide proof that
the myeloid prolifera tion is neoplastic
rather than reactive.
Ac quired somat ic mutations of JAK2. at
chromosome 9p24. have been shown);)
playa p ivotal role in the pathogenesis d
many cases of BCR-ABL 1 negative MPH
11 04 4, 1163, 1186, 1287A , 12881. The
most comm on mutation , JAK2 V6 17F, results in a constitutively active cytoplasmic
JAK2 that activates signal transducer and
ac tivator of transcription (STAT), mitogen
activated p rotein kinase (MAPK) and
phospholidyllnositol a-kmase (P13K) sigo
naling pathways to prorote transforma1Ol
and proliferation of baemaroooenc pro.
g enitors (Fig. 1.07). The JAK2V617Fmutation is found In almost all patients wit~
polycythaemia vera (PV) and in n ear~
one-half of those with primary myelofil:Jrosis
(PfvlF) and wit~ esseotelmoroocvmaeraa

(ET), In the few PV patients wno lack the
JAK2 V6 17F, an acti vat ing JAK2exon 12
mutation may be fou nd , and in a small
proportion of cas es of PMF and ET, an activating mutation 0 1 MPL W5 15l or W5 15K
is seen. It is important 10 no te that JAK2
V617F is not specific for any MPN nor
does its absence exd ude MPN . Furthermore, it has been reported in some cases
of MDS/MPN, in rare cases of AMl, and
incombination w ith other well-defined genetic abnormalities such as the BCR-A8L 7
110641. Thus, diagnostic algorittvns for PIl,
ET and PMF have been altered to take the
mutationalstatus of JAK2 into account as
weN as 10outline the additional laboratory
and histo6ogic "ndi~JS required to reach
an accurate classification 01 c ases, regardless 01 whe ther the mu tation is or is
not present.
In addition to the changes in the cr iteria
lor N , ET and PMF, information reg ardi ng
abnormal PTK toncnon due to rearrangementsof the POGFRA, PDGFRBor FGFR1
genes in patients with myeloid neoplasms
associated with eosinop hilia led to reappraisaland new diag '1ostiC algorithms for
those syndromes as well (see below). The
appreciation 01 the role altered PTKs pla y
in the pathogenesis of C Ml, PV, ET and
PMF also argues lor the inclusion of similar chronic myelo id pronteranons related
10 PTK abnormalities under the MPN umbrella. Thus, systemic ma stocytosis, wh ich
has many features in common with other
MPN entities and is alm ost always associated with D816V mutation in the KIT
geneencoding the recep tor PTK, KIT, has
been added to this categ ory 121761 St ill,
tI"1e molecular pathogenesis of nearly half
of all cases of ET and PMF, of all cases of
chronic neutrophilic leukaemia and a
mm ber of myeloid neo plasms ass oc iated
with eosinophilia remai n unkn ow n . For
these reliance on cli nical, laboratory and
morphologic features is essenti al for
diagnosis and classification,
Stmnary 01major c hanges in the

classilication of MPN
I . The nomenclature , 'mveiopronte ranve
disease" has bee n changed to "myeloproliferative neoplasm "
2, Mastocytosishas been includ ed in the
MPN category
3 Some cases previously meeting th e
Cfllena for chronic eosinophilic leuka emia
(CEll may now be categorized as myeloid
(J ~ d neop lasms with eosinophilia
and ab normalities 01 PDGFRA. PDGFRB or

FGFR1 , If none of the se rearrangements
are d etec ted, and there is no BCR-ABL 7
fusio n gene , they should be ca tego rized
as GEL, not otherwise specified
4. The d iagnostic al go rithms for PV, ET
and PMF ha ve been substantially
c hanged to incl ude infor mation rega rd ing
JAK2 and similar ac tivat ing mutations as
well as pertinent histolog ic featu res 01 the
8M biopsy as d iag nostic Criteri a.
5. The threshold of the p latelet count for
the di ag nos is of ET has been lowered to
~4 5Ox 1 Q91l.
6. Crit er ia for CMl in accelerated phase
have been suggested w ith the caveat that
they have not been fully evaluated in the
era of PTKI therapy: studies 10 determine
their relevan ce are in progress and revisions may be necessary.

Myeloid and lymphoid neoplasms with
eosinophilia and abnormalitie s of
PDGFRA, PDGFRB or FGFR1

De termi ning the ca use of marked , persistent eosinophilia (~ 1 .5x1()9/l) in the
blood can be challengi ng and is sometimes cli nically urg ent beca use 01 the
potential damage to the heart, lungs , central nervous and other organ systems
caused by the eosinophilic infiltration and
release of cvtocnes. enzymes and other
proteins. The eoeoooous may be derived
from the neoplastic clone of a myeloid
neoplasm, such as GEL, GMl or AMl, or
lhey may be reactive due to abnormal
~
I
I
Akt
TO
""FoxO
'-.,
(0
I
E0
I
~0
I
@jJ
-- ----- -Activation of gene!o Important

in proliferation and survival
or
Fig. 1.07 MecRanism activatiOn aI JA1<2 kinase actMty by rn.rtaIiOns in the JAK2 Signalirg pathway. It. Cytokile
ligallds normaHy bind cytokine recepIors, .tlich results in JaI'llS ki\ase 2 (JAK2) pIlosphoryIatio, recruilmenI aIsq.at
\rcInsduc:er and actrvator allJansaipbon (Stal) signaling protelns and pIlospholyIation alld activatiOn of downstream
SigRaIing pathways ind\.I:lIng SIal ~ lactor&,lT\IlogefIlIdMlled proIeIn U1ase(MAPK) sigMWlg proteins , arIl
the phosphotidyinos 3-kinase (Pl3K)--Akt pathway B The JAK2 Vfi17F alld JAK2 ewn 121Tl11anl kilases bind
cytokine recepIors, are phosphorylated il the absence alligand and lead to ~ activation aI 0JwIn.
streamsignaing palhways. C Bycontrast, MPl. W515lA( rrUal'lllhiOi'~ recepb$ are able 10 phospI1Oi'y\ale
ri1-Iype JAK2lithe absence 01 hanbopoleIi., and red II tle aetwabon of signaling paltrways <townstream 01 IN<2.
Negative regulation 01 JAX2 sigNIng is nonnaIy medIaIed by suwessor of cytome s9laIilg (Socs) proWls, most
notably SOCSl alld SOCS3; recent dala i'ldic3Ie Ihalthe JAK2 V617F aIeIe night escape negatiYe IeectIacll by
SOCS3. Repro:U;:ed from {1287AI
Introduction and overview of the classification 01 the myeloid neoplasms
25
cytoki ne relea se from reactive or neoplastic r -ceus. In a numbe r of ca ses. no

underlying cause can be fOund and the
clonahty of the eos inophils ca nnot be
proven: these cases are app ropriately
termed "idiopathic hypereosinophilic ssndrome" (See Chapters 2 and 3).
Rationale for diagnosis and classification
of myeloid and lymphoid disorders with
eosinophilia and abnormalities of PDGFRA,
PDGFRB or FGFR,
Since the last edition of the WHO c lassification it has been recog nized that many
cases of eosinophilia, incl udin g a substantial number conside red as "idiopathic"
are clonal myeloid neoplasms caused by
abnormalities in genes that encode the
alpha or beta chains 01 the receptor PTKs,
platelet derived growth factor receptor
(PDGFR) or fibrobl ast gro wth fac tor reo
ce ptor 1 (FGFR1), Rearrangements 01
PDGFRB at chromo some band 5q33 that
lead to constitutive activation of the beta
moiety of PDGFA were first recogni zed in
cases variably reported as CEL or chronic
myelomonocy tic leukaemia (CMML) with
eosinophilia 11 31 , 8 12. 20851. More recen tly the gen e that encodes the alpha
moiety of the PDGFR, PDG FRA, at chromosome b and 4q12. was found to be
involved in cryptic translocat ions in CEl
and in nearty one-half of cases reported
as idiopathic hypereosinophilic syndrome
14661 In addition , rearrangements of the
FGFR 1 tyrosine kinase gene have also
bee n implic ated in myeio oronteratrons
with prom inent eosinophilia 13, 13541.
However, the c linica l and morphologi c
presen tations associat ed with FGFR 1
rearrangement are variable, and include
not only presentation as a myeloproliferative neop lasm with eosinophilia, bul also
as AML and they may even present as, or
evolve to. precursor T or B lymphoblastic
leukaemia/lymphoma with prominent eosinophits Cases associated with PDGFRA
rearrangements can likewise present as
AMl or precursor t -een neoplasms 114691.
Tlb.. 1.03 Myeloid and lymphoid neoplasms W11t1

eosmphi lia ard abnormal~m ol POOFRA, POOFRB, or
FGFR1 .
PDGFRA real1"angement
Myeloid nooplasms with PDGFRB
rearrangemeot
Myeloid aoo IylTVIOid neoplasms wiltl
FGFRf abnormallbes
Although it might seem most efficient to

categorize these cases as CEl within
MPN, this would ignOfe cases WIth
PDGFRB abnormalities that present as
CMML as well as cases of FGFR1 and
PDGFRA rearrange ments that may even
have a lymphoid conoooenr. To accommod ate Ihese transiccatons. a new subgroup defined largely by the genetic
abno rma lities of PDGFRA, PDGFRB or
FGFR1 has been added (Table 1.03).
Detect ion of one of these abnormalities
places the case in this category, regardless at the morpholog ic classification.
Cases of myeloid neoplasms with
eosinophilia that lack all of these abnormalities and that meet the criteria for
CEL. NOS, in the MPN catecov should
be placed in that group.
Myelodysplastic/myeloproliferative
neoplasms (MDSlMPN)
The MDS/M PN (Table 1.04) include clonal
myeloid neop lasms that at the time of initial presentation have some clinical, laborato ry or morphologic findi ng s that
support a diagnosis of MDS, and other
findings more consistent with MPN They
are usually cha racterized by bvpercenularity of the BM due to proliferation in one
or more of the myeloi d lineages . Frequently, the proliferation is effective in
some lineages with increased numbers of
circulating cells that may be morphologically and/or func tionally dysp lastic . Simultaneously, one or more 01 the other
lineages may exhi bit ineffective proliferation so that cytopenlate) may be present
as well. The blast percentage in the BM
and blood is always <20%, Although
hepatosplenom egaly is common, the clinical and labo ratory find ings vary and lie
along a continuum between those usually
associ ated with MDS or those usually
associated with MPN Patients with a welldefined MPN who develop dysplasia and
ineffective haematopoiesis as part of the
natu ral history of their disease or after
chemotherapy should not be placed in
this category. Rarely, some patients may
present in a transformed stage of an MPN
entity in which the chronic phase was not
reco gnized, and may have findin gs that
suggest that they belong to the MDS/MPN
gro up. In such cases, if c linical and laborato ry stud ies fail to reveal the nature of
the und erlying proce ss, the designation
of MDS/MPN, unc lassifiable may be ap
orcorare. Paneots wro have the BCRABL 1
fusion gene or rearrangements of PfX3FRA
nurooocuoo and overview 01 the classification of the myeloid neoplasms
TableU4
~neopIasms
(MDSlMPN).
cmnc myelomonocyllc leukaenU (CMMl)

Atypocal chrooiC myeloid leukae~ ,
BCR-ABLI negative (aCMl)
JIMIrIiIe myelomooocytic leukaemia (""' Ml)
MyekldysplastcIMyeloproliferative neoplasm,
undassdiable (MDSlMPN ,U)
Provisional entity: Refractory anaemia wittl Mrlg
sideroblasts and ltJramt>ocytasis (RARS-n
should not be categorized as MDS/MPN.
and in contras t to the criteria used in the
3rd edition of the WHO classification,
cases of CMML with PDGFRB rearrangements are also excluded
Rationale for diagnosis and classification
of MDSlMPN
This diagnostic ca tegory was introduced
in the 3rd edition amidst controversy as to
wl1ether some entities, particularly CMML,
would be better categorized as either
MDS or MPN depend ing on the extent of
mye loprol iferation as evidenced by the
WBC cou nt. Some cases of CMML have
low neutroph il co unts and only modestly
elevated monocyte co unts and resemble
MDS clinically and morphologically
whereas others have markedly elevated
WBC counts and org anomegaly more in
keep ing with MPN. yet criteria that clearly
distinguish biologiCally relevant subtypes
of CMML remain to be defined .
To date, a lew cases of CMML and atypical chronic myeloid leukaemia, BCR-ABL1
neg ative (aCML) have been reported to
demonstrate JAK2mutations that characterize BCR-ABL 1 negative MPN, but the
prol iferative aspec ts of most cases of
MPD/MPN are related to aberrancies in
the AAS/MAPK signaling p athways. In juvenile myelQmonocytic leukaemia (JMML)
nearly 80% of patients demonstrate
mutually exclusive mutations 01 PTNPN1',
NRAS or KRAS, or NFl 11329. 2096,
21621. all of wl1ich encode signaling proteins in AAS dependent pathways, and
approximately 30- 40% of cases of CMML
and aCML exhibit NRAS mutations {1686,
231 1, 24171. In view of the lack of any
spec ific genetic abno rmality 10 suggest
that these entities should be relocat ed 10
another myeloid subgroup, they remainin
this "mixed" category which acknowledges
the overlap that may occ ur between MDS
and MPN. Casesof CMML with eosinophilia
associated with PfX3FRB rearrangements
are excluded , but rare cases of CMML
with eosinophilia that do not ex hib it such

rearrangements sho uld be cJassified in
this categOry
The most controverstat issue in the su bgroup at MDSIMPN is the provisional entity.
refractory anaemia with ring siderob lasts
and thrombocytosis (RAR5-T). The ma jority (SO- 60%) 01 cases of RARS-T studied
lor JAK2V6 17F carry this mut ation 1234.
354.762 , 1835. 1839. 1969,2081,2139.
23581. This has prompted the notion that
RARS-T should be moved to the MPN
group of myeloid neoplasms. whereas
othershave argued thaI RARS-T is not an
entity at all but merely one of the better
recogniZed MPN entities, such as PMF or
ET. i'l which genetic evolution has led to a
dysplastic teanse. ring sideroblasls 11966.
2139. 23581. In a few cases reported.
hl:1Never. the cells of patients with RARS-T.
when studied by in vitro cul ture techniques, have growth characteristic more
in keeping with MOS than MPN 1234,
18351. An additional question is hOw to
clearly distinguish RAR5- T from RARS, in
which moderately elevated pla telet
counts are etten repo rted . This question
is morepressing in view of the revised c riteria for RARS-T that lowers the p latele t
threshold from ~x lrJl/L to ~450x 1rPlL,
in parallel with the revised threshold lor
Ef It is important to note that the d iagnostic criteria for RARS-T include not only
the Iinding of an elevated platelet coun t in
conjunction with anaem ia and ring elderoblasts in the 8 M, but al so mo rp hologicallyabnormal megakaryoc ytes similar to
those of ET or PMF. Only a few pat ient s
with RARS and plate let counts in the
450,500x W 9/L rang e have be en studi ed
for JAK2 mutat ions and in mo st with
platelet counts in the lower rang es no mutations have been found . Neverth ele ss,
more stud ies are need ed , and we rec ommend to test for JAK2 mutation s in patents who have RARS and pl atelet counts
above the normal range . The sum of current information reg arding RAR5-T argu es
for its continued placemen t in the
MDS/MPN category. but in view of the
debate regar ding its precise definition
and nature, it is best reg arded as a
'provisional entity" until more data are
available,
lastly. classification of myeloid neoplasms
that carry an isolated isochromosome t 7q
and that have less than 20% bl asts in the
P8 or BM may prove difficult. Some authOrs suggesl this cytogenetic defect
defines a unique disorder characterized
by mixed MOS and MPN features associated with pro minent pseuoo-Percer-Hoet
anomaly of me neutroot urs. low 8M blast
count, and a rap id ly p rog ressive clinical
course. Most c ases rep or ted have a
prominent monoc ytic component and
meet the c riteria lor CMML, b ut in some,
the PB monocyte coun t may not reach the
low er threshold fo r that dia gnosis 1708,
14371 In cases that do not fu" ill the c riteria
lor CMML or another well de fined myeloid
category. desig nation as MOSIMPN. unclassifiable. with isolated isochromosome
17q abnormality, is most ap propriate.
$urTmary of major changes in MDSIMPN

1. Some cases of CMML with eosinophilia
are relocated to the category, "Myeloid
neoplasms with PDGFRB rearrangement"
2 . The c ategory, "Atypical CML" has been
renamed as Atypical C ML . BCR-ABL 1
negative" to emphasize this disease is not
merely a va riant of BCR-ABL 1 positive
CM L.
3 . RAR$-T remains as a provisional enlity,
classified as MDS/MPN . uncrassiuabre .
until furthe r data clarifies its approp riate
designation. The crite ria for its recognition
have been modified. The platelet threshold has been lowered to ~ 45Ox 1rPll, and
meg akaryoc yte s w ith morp hology simil ar
to those seen in ETor PMF must be present
Myeladysplastic synd romes (MOS)
These disorders , usually characterized by
the simultaneous prolifer ation and apo ptests of baematopoienc cells that lead to a
normal or nvoerceuurar BM bi op sy and
PB c ytopenia(s), remain among the most
c halleng ing of the myeloid neop lasms for
p rope r d iagn osis and class ification , The
general fea tures of MOS, as well as
specific gu ide lines fo r diagnosis and
c lassific ation are outlined in Chapter 5.
An impo rtant add ition to the MOS ca tego ry (Table 1.05) is the provision al entity,
refractory c ytopenia of c hild hood (RCG),
This categ ory is reserved for c hildre n with
MOS who have <2% b lasts in their PB and
<5% in their 8M and pe rsistent cvtopenia(s) with d ysp lasia , In contrast to MDS
with ref rac tor y cvtc oentee in eo utts. the
majority of cases of ACC have hypoc ellular
8M bio psy specimens, and the d istinction
from acqui red apl astic anaemia and
inherited BM fai lure syn dromes is often
c hallengin g 117841,
An issue appro priate 10 menton at this
point is the cntene used for ctassmcatco
of myeloid neoplasms in which more lhan
50% of the BM ce lls are erythroid precutan d for which ac ute eryt hroid
leukaemia is co nsidered a po ssible dia gnosis. In such cas es. if blasts acc ount for
fewer than 20% of WBC in the PB and 01
all nucleated 8 M cells, and for less than
20% of the non-erythroid c ells in the BM
(lym phocytes, plasma c ells, etc. are also
excluded in this latter calculation), the
case is considered as MOS. In this scenario. there is lac k of consens us among
mem ber s of the WHO committee as to
whether the MOS should then be classified according to !he b last perceotace of
all nucleated 8 M cells or according 10the
blast percentage of all non-erythroid BM
cells. but the majority recommend s that
the MOS be classified using the blast percentage of all marrow nucleated cells.
Many cases of refractory anaemia with
ring sioerobrests as well as refrac tory
anaemia have marked eryth roid proliferation and using the b last percentage of the
non-erythroid cells lo r classification of
such cases might c ause these to be
placed in an unnecessarily high-risk category. On the other hand , if there is
severe multiline age dysplasia, very bizarre
erythroid morphology. and/o r minimal or
no maturation to segmented neut roobus.
and the btast percentage of total 8 M cells
is not sufficienl to place the c ase into a
hig h-g rade MOS c ategory, the case
shoul d be flag ged tor clin ical co rrelation
an d discussion, with ca refu l follow- up
(Tab le 1.06 ). More stud ies are needed
however to cla rify this controversial issue.
sors.
Acute myeloid leukaemia (AML)

AML is a d isease resul ting from the c lonal
expansion of my eloid blasts in the PB,
8M , or othe r tissue, It is a heterogeneou s
di sease c linically, mo rphologicall y and
ge neti cally and may involve only one or
Tabl. 1.05 Myelodysplastcsyndromes,
Reffacto!y ~nia wlltlll1 iWleage dysfllas48
(RCUD)
Reffa<:byanaemia (RA)
Refracloty neutropenia (RN)
Refradcry ltuQmbocytopenia (RT)
Re!fadclry allaemia with ri1gSiderObIasts (RARS)
Relractory cytlpenia with ITIJlblineage dysplasia
(RCMD)
Refractory all8e/l'M8 wiII1 excess bIasls (ME B)
MyelodyspIa$llc syncWmewilI1 iSOIatecI dfll(Sq)
Myelodysplllsbc syndrcIme. undas.sJliable (J.I>S.U)
C*hood ~ syrw:lrome
Pn:MsicnaI nty Refra:t:ry ~ ~ d*hlod
(ROC)
Introduction and overview of me classification 01 the myelOId neoplasms
27
... . -
Table 1.06 PMSib1e d~ when erythroid precursors ~50'10 of bone marrow nucleatedcells.
- -_."""""-
% Erythroid ~
Blocdhnarrow findirlgl.
0ltIer f1odlng&
DIagnosis
~ blasts in blood or
Case meets alteria lor

AMLwith my8lOdysplasia
AML With fl'lyelodyspIaSia

related changes
of all nucleatedmarrow
inmatln IJyIIwid
Few lit'{ myeIclt:Qsts
""""" ..., """'"

matlJflllJon
>5011
' 50'
blasts <m d II
"""""
<20% blasts in blood,

blasts <20% of all
"""'"' """""-
related changes
_01"
"""""'
Miwnall <Wly
fIm.>MiKi1I
~celsll
.."
"""""
... """""
Blasts <20% 01 all

in
~roid' cells
PIn 8I)tWIlid IeWemia
-,-.......
MDS: classifyMDS
acx:oroing 10 number of
blasts in blood and blasts
as pen:entIge d II
"""""" """""-
Erythroid precursors , lymphoid cells andplasmacens aresubtracledfrom a" nlJdeatedmarrowcells to calDJlate

the"noo-erythroid eels" in thebone marrow.
all myeloid lineages. Worldw ide the incidence is app roximately 2.5-3 cases per
100,000 popu lation per year, and is
reportedly highest in Australia. Western
Europe and the United States. The median age at diagnosis is 65 years, with a
slight male predominance in most c ountries. In Children less than 15 years of age,
AML com prises 15- 20% of all c ases of
acute leukaemia, with a peak incidence in
the first 3-4 years of lite 1559A, 2463AI.
The requisite blast perce ntage for a diag
rosrs of AML is 20% or more mveiobtasts
and/or monoblastslpromonocytes and/or
meg akaryo blasts in the P8 or BM. The di agnosis of myeloid sarcoma is synonymous with AML rega rdless of the numb er
of blasts in the PB or BM, unless the
patient has a prior history of MPN
or MDS/MPN, in wh ich c ase myeloid
sarcoma is evidence of acute transformation . The d iagnosis of AML can also
be mad e when the blast percentage in
the PB and/or BM is less than 20% if
there is an associated t(8;21XQ22;Q22),
inv(16)(p 13.1Q22), t(16:16XP13.1;Q22) or
t(15;17)(Q22:q 12) chromoso mal abnormality, and in some c ases of acute erythroid IeuI<aemia when eryttvoid precursors
ac count for more than SO% of the BM
ce lls and blasts account for more
than 20% of the non-erythroid marrow
ce lls (See Chapter on acute myeloid
leukaemia, NOS).
Although the diagnosis of AML using the
above guidelines is ope rationally useful to
indica te an unde rlying defec t in myeloid
28
IntroductIOn and
matur ation, the d iagnosis doe s not necessar ily translate into a mandate to treat
the pa tient for AML; c linical factors. including the pace of prog ression of the
dise ase, most atways be taken into consloerenon when deciding therapy.
Rationa le for the WHO diagnosis and
classification of AML
The 3rd edition 01 the WHO ctassrncatoo
ushered in the era of formal incorporati on
of gene tic abnormalities in the diagnostic
algor ithms for the diagnosis of AML. The
abnormalities included were mainly ch romosomal transiocenoee involVing transcription fac tors and associated with
charac teristic cl inical , morpholog ic and
immunophenotypic features Ihat formed
a clinico-pathologic-genelic entity. As
know ledge regarding leukaemogenes is
has increased, so has the acceptance
that the genetic abnormal ities leading to
leukaemia are not only heterogeneous,
but complex, and multiple aber rations
often coo perate in a multistep proce ss to
initiate the co mple te leukaemia phenotyp e. Expe rimental evide nce suggests
mat in many ca ses, although rearrangement of genes such as RUNX1, CBFB or
RARA that enc ode transcncuon factors
impair myeloid differentiation, a sec ond
genetic abnormality is necessa ry to promote proliferation or survival of the neoplastic clone (Fig . 1.08) 11135A I. Often.
the additional abnormalities are mutations
01genes such as FLT30 r KITthat encode
proteins that act ivate signal transduct ion
overvIew of the ctassuceuoo of the myeloid neoplasms
pathways to promote proliferation/survival

A similar multistep process is also evident
in AMl that evolves from MDS or that has
myelodyspl asia-related features, often
characterized by loss of genetic material
and haploinsufliciency of gene s. Within
the last few years, genetic mutations have
also been identilied in cytog enetically
normal AML 115321. Sane of the rrutations,
such as those of CEBPA and perhaps
NPM1 invdve transcriplion faclors. whereas
erne-e. including those of FlT.J and
NRASIKRAS. affect signal transduction.
Not only have these mutations led to an
unde rstand ing of leukaemoc enests in
c ytogenetic ally normal AML, bul they
have proved to be powe rful prog nostic
factors 115321. In summary, genetic abnormalit ies in AML eluci date the pathogenesis of the neoplasm, provide the
most reliable prognoslic information, and
will likely lead 10 dev elopment of more
successful targeled therapy.
One of the challenges in this revision has
been how to incorporate important and/or
recently acquired genetic information into
a classific ation scheme of AMl and yel
adhere to tile WHO principle of defining
horoogeneOuS, biologically relevant entities
based not only on gene tic studies or their
prognostic value, but also on clinic al,
morpho logic and/or immu nophenotypic
studies . This was particular ly prob lematic
for the most frequent and progn ostically
impo rtant mutat ions in c ytogenetically
normal AML, mut ated FLT3 , NPM 1 and
CEBPA. They have few or variably consistent mor phologic, irrwnunophenotypic
and clinical features reported to dale , and
the mutation s are not mutuall y exc lusive.
For the most par t, the framework coostructec in the 3rd edition proved flexible
enough to incor porate the new entities
propo sed by membe rs of the WHO c0mrmttee and the CAC (Table 107). The entities initially described in the subgroup
AML with recurring genetic ab normalnee' remain with only minor mod ifications
(Table 1.07) and three more entities, characterized by chromosomal transtocatioos
associated with fairly unilorm morphologica l and cl inic al features have been
added . Cases with muta ted NPMl and
CEBPA are added to the same subg roup
as ' provisional entities' ind icating that
more study is needed 10 lully characterize
and estab lish them as unique entities
Although mutated FLT3 is not includ ed as
a separa te entity because it is found to be
associated with a number of other entities,
Class I mutations
Class II mutations
FLT3-ITD
FLT3-TKO
KIT
RAS
PTPN11
JAK2
PML-RARA
RUNX1-RUNX1Tl
CBFB-MYH11
MLL fusions
CEBPA
NPM11
Proliferation and/or
survival advantage; not
affecting differentiation
its siqrsbcance should not be uoderestmated, and it is essential that it be tested

for in all cytog enetically normal patients,
including those who demonstrate NPM 1
and CEBPA mutations.
Modifications have been made in the
subgroup previously ter med "AM L wi th
multilineage ovsprasta." Initially, it was
envisioned that this g rou p would encompass biologically unique AML charac terized by MD$ -like fea tures, in cl ud ing
unfavourable cytogenetics, a higher lnc toence of ove rex pressfon 01 multidrug
resistance gfycoprotein (AS CS 1 or M DR-1)
and an unfavou rable respo nse to therapy.
Dysplasia in ~50 % of ce lls in tw o or m or e
heematop oienc lineag es w as used as a
universally-ap plic ab le surrogate m arker
for the myelodysp las iare late d featu res .
Although the c linical sig nificance of th is
grOl.lp has been verified in so me stud ies ,
it has been d isputed in othe rs in w hic h
multivariate anal ysis showed tha t m ultilin eage dyspla sia had no independent significance in predi c ting clinical outcome
wen cytogenetic findings were mc orporated in tne analysis 169, 869, 2356,
24651. Accordingly, in this revision, this
group has been renamed as "A ML with
myelodyspl asia- related changes," Patientsmay be assigned 10this ca tegory if
they evolve Irom previously documented
MOS. have specific myelodysplasiarelated cytogenetic abnormalities. or lastly,
if they exhibit mo rphologic mu ltilineage
dysplasia as def ined above. Pat ients in
Ianer group with a normal karyotype
to their g enetic a bno rm alities, but until

more data are available, we recommend
thai such c ases be classi fied as AM L with
m yelodysplasia-related c hanges (multilineage dysplasia) with the muta tional status
of the gene appended,
Therapy-related myeloid neoplasms (t-AMLJ
tMDS and t-AMlIt-MDSlMPN) remain in

the revised classificatio n as a distinct
subgroup. How ever, most patients who
develop therapy-related neoplasms have
Impaired haematopoietic
differentiation and
HqUent .poptos~
.ub-
should be evalu ated for FLT3, NPM I and

CEBPA rnutanons. Cu rrently, however, the
clinical significance of a mutalion of one
or more of these genes in the setting of
mo rpholog ic multilineage dysplasia is not
clear. Future studies may well prove that
such cases are better classifie d according
received therapy with both alkylating

agents as well as with topo isomerase II
inhibitors, so that a division according to
the type of the rapy is usually not pr actical
and not recommended in this revision. It
has been argued that 90% or more 01
cases with I-AMLIt-MDS or t-AMl/t-MDSI
MPN have c ytog enetic abnormalities
similar to those seen in A ML with recurrent genetic abnormalities or AML with
myelodyspiasia-relaled features and could
be assigned to those categories. However,
except for patients w ith t-AML who have
inv(16Xp 13.1q22), t(16;16XP13.1;q22)or
t(15 :17Xq22;q 12), in most reported series
those w ith therapy-rel ated myeloid neop lasm s have a significantly wor se c lin ical
outcome Ihan the ir de novo counte rp arts
with the same genetic abnormalities 136,
Table 1.07 Acutemyeloid leukaemia andrelatedmyeloidneoplasms,

Atutt myeloidIeukaemi,with recurrent gtllllIlIt Ibnormalitles
AMLwith ~8;2 1 )(Q22:Q22): RUNXt-RUNXm
AML with inv{16)(p13.1q22} c. \(16:16Kpl3.1:q22); CBFB-MYHIt
APl with \(15;17)(q22:Q12); PML-RARA
AMLwitht(9:11){p22:q23}: MLLT3-MLL
AMl with t(6:9)(p23;Q34): OEK-NUP214
AMl with inv(3KQ21Q26.2) ort(3:3J(Q21;q26,2); RPN1EVl l
AML (megakeryoblastic)with 1(1;22)(p13; q13): RBMI5-MKL 1
Provisional entity:AMl with mutated NPM1
Provisional entity: AML with mutated CEBPA
Acutemyeloid leukaemia with mye!ody,plilil-related changes
Therapy-related myeloid neoplil5m,
Acutemyeloid leukaemia, no! otherwl$l spec;lrted
AMLwith minimal diffe!lll1tialiorl
AML without maturation
AMLwith mallJ"aUon
Acute m~ leukaemia
Acute roonoblasticJmooocytic Ieukaemla
Acute ~ IeukaelBas
PIse erythroid leukaemia
EIythroleukaemia, 8I')1hroidfmyeloid
Acute megakaryoblas.lic Ieukaetnia
Acute basophl1ic Ieukaen'Ha
Acute panmyeIosis with myebfibrosis
Myeloid sarcoma
Transaent abnormal myelopoiesis
Myeloid leukaemia ISSOCiaIed with Down syndrome
Blastic plil5maC}'loid dendritic u1llll1oplalms
Introduction and overview of lhe classification 01 the myeloid neoplasms
29
227 , 1886~ 2034 , 204 1}, suggesting some

biological differences between the two
groups. Fur thermore, the stu dy of therapy-related neoplasms may provide valuable insig ht into the pat hogenesis of de
novo d isea se by p rov id ing c lues as to
wh y a few pat ients de ve lop leukae mia
wher eas most p atients treated with the
same therapy do not. Therefore, patients
with therapy- related neoplasms should be
de sig nated as suc h, but the specific c ytogenetic abnorma lity shou ld also be
listed, for example, "therapy-related AML
with s,11}(p22;q23)".
Acute myeloid leukaem ia , not otherwise
specified, encompasses those cases that
do not fu lfil the spec ific criteria of any of
the othe r entities. This g roup accounts for
only 25-30% of a ll AM L that are not assigned to one of the mo re specific ca tegories. As more genetic subgroups are
iden tified , the num ber of pa tients that fall
into the AMl , NOS c ateg ories w ill cantmoe to diminish . Of note is that infor mation used to characterize the subgroups
within this c atego ry, suc h as epidemic-logic or clinical out come , is oft en ba sed
on older stud ies tha t inc lud ed patients
now assigned to d ifferent diagnostic ca teg or ies. and may not be reliable. Althou g h the p roposal to collapse th is
category into fewer subgroups has bee n
made. the notion that some of these may
yet be found to be associated with spec ific genetic or b iologic abnormalities
argued to maintain this category.
Myeloid sarcoma, an extramedullary
tumour mass consisting of myeloid blasts,
is inc lud ed in the classifica tion as a d istinc t pa tholog ic entity. How ever, wh en
mye loid sa rco ma occu rs de novo, the
d iagnosis is eq uiva lent to a d iagnosis of
AML . and fu rthe r evaluation , including
genetic analysis, is necessary to determine the approp riate cl assific atio n of the
leukaemia 117421. When the PB and BM
is concurrently involved by AMl. mese tissues may be used for ana lysis and furthe r
30
classification . However, when the myeloid

sarco ma precedes ev idence of PB or BM
invotvement. the irrvnunophenotype should
be ascertained by flow cytometry and/or
irrvnunohi stoc hemistry, and the genotype
determined by cytogenetic analysis, or in
the absence of fresh nssue. by FISH o r
molecular ana lysis for recurrent g enetic
abnormalities. Myeloid sarcoma may also
be the initial ind ic atio n 01 relap se in a
pat ient previously d iagnosed With AM L or
may indicate disease progression to a
blast phase in pat ients with a pr ior d iagnosis of MDS, MDS/MPN o r MPN.
Lastly, the unique featu res of Down synd rome- related myeloid neoplasms has
been rec og nized in a separate listing that
incl udes transient abnormal myelopo iesis
and mye lo id leukaemias (MDS/A ML )
assoc iate d with Down synd rome.
Summary of major changes In AML

1. AML with recurrent genetic abnorma lities,
a ) AML w ith t(8;2 1)(q22;q22), AMl w ith
inv( 16}(p 13 .1q 22 ) or I( 16; 16}(p 13. 1;q 22),
and APL with t(15;17}(q22 ;q 12) are considered as AM L regard less of bla st count;
for all othe rs, b lasts 2:20% of P8 or of all
nucleated BM ce lls are req uired .
b) In API... with1( 15;17)(Q22;q12); FM..-R.AR4,
varia nt RARA uenslocaucos with other
partner ge nes are recognized separately ;
not all hav e typica l APl featu res a nd
some have ATRA resistance .
c ) The termer cat egory, AM L with 11q23
(MLL) abnormalities has been re-defined
as -AML with 1(9;11)(p22;q23); MLLT3-MLL".
Balanced transtocanons other than that
involving MLLT3 should be specified in
the di agn osis. Ot her abn or malities of
MLL , such as partial tande m du p licatio n of
MLL should not be placed in this categ ory.
d) Three new cytogenetically delined entities are ad ded : AML with t(6;9)(p23;q23);
DEK-NUP214, AML with inv(3)(q21q26.2)
or t(3;3)(q21 ;q26 .2); RPN1-EV/1; and AMl
(megakaryoblaslic) with t(1 ;22)(p 13;q 13) ;
RBM15-MKL t.
Introduction and ove rview of the classification of the myeloid neo plasms
e) Two p rovi siona l ent ities are added:

AML with mutated NPM1 and AMl with
mutated CEBPA. Although not included
as a distinc t entity, examination lor mutations of FLT3 is slron gly rec orrwnended in
all cytogenetically normal AM L.
2 . AM L with mye lodysplasia-related
changes .
a) Name changed from AML with rru llilineage dysp lasia".
b ) Cases of AML are assig ned to this categ ory if 1) they have a previous history of
MDS and have evol ved to AML , 2) they
have a myelodysp las ia-related cytogenetic abnormality, or 3) if ;<:50% 01cells in
two or more myeloid lineages are dysplastic ,
3. Therapy -related myeloid neoplasms.
Cases are no longer subcategorized as
"alkyl ating agent related " o r ' tccoisomerase tl-intubttor related " or "other",
4. AM L, NOS.
a) Some c ases previously assigne d to the
subcategory of AMl. NOS as acute erythroid leukaemia may be re-classihed as
AML with myelodysplasia-related changeS.
b ) Cases previously ca tegorized as AML
NOS. acute megakaryoblastic leukaemia
should be placed in the appro priate
ge netic category il they are associa ted
With inv(3)( q2 1q26 .2) or t(3:3)(q21 ;q26.2);
RPN1-EVlf, or AM L (megakaryoblastic)
with t(1;22)(p 13;q 13); RBM15-MKL 1.1JcM'n
synd rome related cases are excluded
from this ca tego ry as well .
5 . Myeloid proli ferations related to Down
syndrome.
New ca tegory to inc or porate trans ient
abno rmal mye lopoies is as we ll as myeloid
leukaemia that is Down synd rome related
MDS related to Down syndrome is conside red biolog ically identical to AML
related to Down syndrome.
/~
Chronic myelogenous leukaemia,

BCR-ABL 1 pos it ive
Definition
Chronic myelogenous leukaemia (CMl)

is a myeloproliferative neoplasm thai
originates in an abnormal plur ipotent
bone marrow (8 M) stem cell and is consistently associated with the BCR-ABL1
fusion gene located in the Philadelphia
(Ph) chromosome {154. 1455 . 1607, 18841.
Although the in.tial major finding is neu trophilic leW<ocytosis, the BCR-ABL 1 is found
in all myeloid lineages as well as in some
lymphOid cells and endothelial cells . The
natural history 01 untreated CML is bi- or
tripha sic : an initial indolent ch ronic phase
(CP) is followed by an accelerated phase
(AP), a b last phase (BP) or both.
ICD-O code
9875/3
(WBC) count performed at the time of a

routine med ic al exa mination is found to
be abnormal 1486 . 755, 1942/. Common
findi ngs at p resentation inc lude fatigue.
wei ght loss, nig ht sweats, splenomegaly
and anaemia 1486. 19421. Atypical presentations include marked thrombocytosis
unaccompanied by a significantly elevated
WBC count as well as initial presentation
in BP without a previously detectable C P
134 ,486. 17301. In the absence of curative
treatment most patients progress from CP
to BP either suddenly or through a transitcoat AP. although some die in AP without
progression. The transformed phases are
generally accompanied by worsened performance status and by symptoms related
to severe anaemia, throm bocytope nia or
marked sp lenic enla rgement 17551.
J W _Vard iman
J ,V. Melo
M . Bacc arani
J . Thiele
for less than 5% of the marrow cells in CP

and 10% or more indicates disease progression 14821- Erythro id precu rsors vary
but erythroid islan ds are usually reduced
in number and size {222 11 . The megakaryocytes of CML are smaller than normal
and have hypolobated nuclei ("dwarf
megakaryocytes"). Althou gh they may be
normal or slightly decreased in number.
40-50% of patients exhib it moderate 10
extensive megakaryocytic proliferation
1296.775,22 15.222 1). The initial biopsy
Synonyms
Ch ronic gr anulocytic leukaemia ; ch ronic
myeloid leukaemia
Epid emiology
CM L has a wo rldwi de annual inci dence of
1- 2 cases per 100 ,000 po pul ation. The
disease can occur at any age, but the

median age at diagnosis is in the 5th and
6th de cades of life There is a slight male
oreoorno ance 1755, 1053 , 1826 1.
Etiology
Factors p red isposing to CML are unknown.
Rad iation exp osure has been implica ted
in some c ases 1226, 4791. There do es not
appear to be an inherited di sp osition.
Sites of Involvement
In CP, the leukaemic
are minimally
invasive and the proliferat ion is la rg ely
confined to naerocoieuc tissues, primarily b lood . BM an d sple en although the
liver may be infiltrated as well . In BP, extramedullary tissues, including lymph nodes,
skin and soft tissues may show infiltration
by blasts 1486,1029,15341.
cens
Clinical featu res

Most patients are diagnosed in CP which
usually has an insidious onset. Nearly
20-40% of patients are asymptomatic and
are diagnosed when a white blood cell
32
Myelop",lile"tive neoplasms
Morphology
Chronic phase (CP)
In CP the peri pheral blood (PB) shows
leukocytosis (12-1 000x 1()lI1L. median
- 1OQx1CPIL) d ue to neutrop hils in different
stages of maturation wit h peaks in the
pe rcent of mye locyt es and seg mented
neutrophils 1486, 755, 1164, 1942, 20671 .
There is no significant dysplasia 11 89 ,
2458 }. Blasts usua lly account tor less than
2% of the wac 1189, 206 7l. Ab solute
basoph ilia is invariab ly pr esent and
eosinop hilia is common (2067l. Ab solut e
monocytosis may be p resent but the frac tion of rnonocvtes is usua lly <3% (189 1.
except in rare c ases assoc iated with the
p 190 BCA -A8 L 1 tsoto rm. in whi ch case
monoc ytosis is nearly always present and
con fusion with c hronic myelom onocytic
leukaemia is possib le 114581 The platelet
co unt usually rang es tram normal to
gre ater than 1000 x1()91L and thrombocytopeni a is uncommon 119421. The 8 M cellular ity is incr eased due to g ranulocytic
proliferation with a maturation pattern similar to that in the blood 1486, 1534 1. In
biopsy sections the paratrabecutar Cuff of
imma ture neutrophile is often 5- 10 cells
thick in contrast to the normal 2-3 cell
layer and 1he mallie neutroph~s are situated
in the intert rabecutar areas. Eosinophils
may be prominent. Blasts usually account
F""i-2.o1 CML. ctvoricphase. A ~ blood SlTlllit"

showing Ieukocy1osis and neu1rophiIic eels at varyI1g
stages d malnIKn 8asqJIiIia is ~ ttl dyspIasiI
iii ~ B Bone marrow biopsy $I'lOw$marked hypeIc:eIIuIanty due to granulocytic prolderabon. C The
megaka/yOC)1es in CMl are c:harac:leilsbcaly ~
ItIan ~ megakaryocyIes.
stoNs moderate to marked reticulin fibrosis

in approximately 30% 0 1 cases wh ich
often correlates with inc reased numbers
01 megakaryocytes, larger spleen size
and reportedly. a worse p rognosis 1293 ,
540, 1217.2215. 222 11. Pseudo-Gaucher
cells and sea-blue histiocytes are commooly observed secondary to inc rease d
cell turnover and are de rived 'rom the
neoplastic clone 135. 22271. More than
80% of patients have sign ifican tly redu ced
or no iron-laden macrop hag es 120451.
In CP the spleen is enl arge d du e to
inliltration of the red pulp co rds by g ranulocytes in differe nt mat uration sta ges ,
A similar infiltrate may be seen in the
hepatic sinusoids and port al areas.
Disease progressionltra nsformed
phases in CMt
The recognition of di sea se prog ression
from CP to the transfo rmed stages of AP
and BP is impo rtant for prog nosis and
treatment, but the c linica l and mor phologic boundaries between the se stag es
olten overlap and the parameters used to
identify them have va ried among di fferent
investigators [118, 293, 481 , 482, 829 ,
1100.194 11 . Furthermore, there are only
scant data relevant to d isease pr ogre ssion in the era 01 protein kinase inhibitor
(PTKI) therapy. Bone ma rrow c hanges
following short and long term PTKI trea tment have been extensively stu died
showing a reduction 01 g ranulocytic eelkJlaflly. normalization of megakaryopoiesis,
regression of fibrosis and inc rease in
eccctosis associated with decrease in
proIilerative act ivity 122191.
Acce lerated phase (AP)

In the 3ld ed ition of the WHO Classifica tion
110391, it was suggested that the d iagnosis
of AP could be made if any of the follOwing
paramete rs were present: 1) persistent or
inc reasing WBC (> 10x1()9!L) and /or pers istent or increasing splenomegaly
unres ponsive to the rapy, 2) persistent
mrontocvrose [> 1000xlcYlL) uncontrolled
by therapy, 3) pe rsistent thrombocytopen ia
100xl()9!L ) unrelated to therapy, 4)

clonal cytogenetic evolution oc curring
afte r the initial diagnostic karyotype. 5)
20% or more basophils in the per ipheral
biooo . and 6) 10-19% myeloblasts in the
blood or 8M. Criteria 1- 4 are more likely
10 be ass oc iated with transition from CP
to AP, whereas c riteria 5 and 6 more
frequently indicate a transition between
AP and SP. Although modifications to
Fig. 2.04 CUL dVonicphase, "Pseudo-GaiI:: eels in CML.. A Pseucb-Gauchef cells In COITIllOl'Ily obsenoed i'l
the marTOW aspIate$ aI pabents WIth CML. B They Ina)' also be ~ as loamy or strialed eels in ITIlI"I'OW
biopsy sedions. TheseI'listo:)"es are seaJndary " increased celllm::Ner. <We del'ived from the neopIaslic dln and
easily ~ from the &mal rnagakaryoc:yte tt-" rn8f9I").
Chronic myelogenous leukaemia. BCR-ABL I positive
33
Fi9. 2.05 Splenomegaly 11 CML A The gross appearara of Itle spleen is solid and uniIonnIy deep red, although areas of inlartt IlI8)' appear as IlghIer aIloured regions, 8 TIll
red pljp disbibubon of!tie infiltrate usually (XIll1lfesse5 alldobhlefates lhe while pulp. C The leukaemiC cells are present in!he SInuses as wei asin!he spleniccools of lhe red pulp.
these criteria have been suggested and

different criteria proposed by others
[4821. it is recommended tha t the paramete rs liste d abo ve sti ll be conside red as
evide nce of d isease pr ogression. Whether
they or other parameters, such as drug
resistance, necessarily ind ica te shortened
survival times or imminent blast nanetorma hon is not c lear in view of the efficacy
of current trea tment strategies, and more
studies are needed to accurately identify
criteria for AP in the face of PTKI therapy.
Often in AP the BM is hypercellular and
myelodysplasia is seen 11534, 24581. The
increase in myeloid lineage blasts may be
readily appreciated with stains for CD34
performed on the biopsy 116501. large
clusters or sheets of small , abnormal
megakaryocytes associated with marked
reticu lin or COllagen fibrosis are commonly
34
Myeloproliferative neoplasms
observed and may be considered as

pres umptive evidence of AP. although
these find ing s are almost always associated with one or more of the othe r c riteria
listed ab ove 1289, 293,15341. The find ing
of lymphoblasts in the blood or ma rrow is
unusual in AP and should raise concern
for lymphoblastic BP 15571.
cases the blasts are Iymphoblasts 1557.

1138. 1558, 1706. 1913,24541. In BP the
blas t lineage may be ob vious morpho logic ally bu t often the b lasts are p rimitive or
heterogeneous and cytochemical and

immunophenotypic analysis is recommended.
If accumulations of bl asts occupy focal
but significant areas of the 8M , e.q. an

Blast phase (BP)
The BP may be d iagnosed when 1) blasts
equal or are greater than 20% of the PB
WBC or of the nucleated cells 01 the BM,
or 2) when there is an extramedullary
blast proliferation. In approximately 70%
of cases. the blast lineage is myeloid and
may inc lude neutrophilic . eosinophilic. besophilic . monocytic, megakaryocytic or
erythroid blasts or any combination thefeof.
whereas in approxi ma tely 20-30% of
entire intenrabecular region, a presump-
tive dtaqrosrs of BP is warranted , even if

the remainder of the 8M biopsy shows CP
12891. Immunohistochemical studies lor
CD34 andlOf terminal deoxynucleotidyl
transferase (TdT) may help in distinguishing such foci of blasts in BP from the loci
01 promyelocytes and myelocytes thal

often are prominent in paratrabecutar and
perivascular regions during CPo
Extramedullary blast proliferations most
v- --
0 0
II
c:orrvnonly present in the sk in. lym ph

node, spleen. bone or central nervous
system, but can occur anywhere, and may
be 01 myeloid or lymphoid lineage 110291.
Irrm.oopheootyp
The oeutrophils in CP have markedly

decreased neutroph~ alkaline phosphatase
{16401. In myeloid BP the blas ts may have
strong. weak or 00 myetoperoxidase
activity but express antigens associated
withgranulocytic, monocytic , megakaryoblastic and/or erythroid differentiation. In
the majority of c ases the myeloid b lasts
will express one or more lymp ho id an tigens as well {557. 1138 , 1558 , 19 13 1.
Mos1 cases of lymphoblastic BP are precursor B in origin but cases of T lym phoblastic origi n also oc cur p 138 , 1558 ,
19131. In lymphoblastic BP, one or more
myeloid antigens are co-expressed on the
nphoblasts in the majority of c ases, Ap proximately 25% of BP cases fulfill c riteria
for mixed phenotype acute leukaemia
(MPAL) 1557. 1138. 1558, 19 131, but these
are considered as exa mp les 01 BP and
are different from de novo MPAL,
Genetics
At diagnosis. 90-95% of cases of CM L
have lt1e characteristic t(9 ;22)(q 34 :q 11,2)
reciprocal translocation tha t resu lts in the
Ph chromosome [der (22q)] 11607. 18841.
This translocation fuses sequences of the
BCR gene on ch romosome 22 with
regions of the ABL 1 gene from c hrom osome 9 11541. The remaining cases either
have variant trens'ocauons that involve a
third or even a fourth chromosome in
addition to ch romo somes 9 and 22 . or
neve a cryptic translocation of 9q34 and
22<;11.2that canno t be identified by reotile cytogenetic ana lys is. In suc h cases,
'tie BCR-ABL 1 fusion gene is present and
Cl be detect ed by FISH analysis . AT-PCR
Of Southern blot tec hniques 114541. The
site of the breakpoint in the BGR gene

may influence the phenotype of the e nsease 11454) . In CML, the breakpoint in
BGR is a lmost always in the major breakpoint cluster region M ~8C R . spanning
exons 12-16, (previously known as b1-b5)
and an abnormallusion protein, p2 10. is
formed wh ich has increased tyrosine
kinase activity {1454 1. Rarely, the breakpoint in the eGR gene occurs in the
1J-8CA reg ion , spanning exons 17-20
(p reviou sly known as C1-C4 ) and a larger
fusion prote in, p230, is encoded . Patien ts
with this fusion may demonstrate prominent
neutrophilic maturation and/orconspicUClUS
throm bocytosis {1454 , 1685 1. Although
breaks in the minor breakpoint region,
m-BCR (BCR exons 1-2) lead s 10 a
shorter fus ion p rotein (pl90) an d is most
freq ue ntly associ ated with Ph positive
ALL , small amounts of the p190 transcript

can be detected in >90% of patients
with classical p210 CML as well, due to
alternative splicing of the OCR gene 11907,
23061 . However, this breakpoint may also
be seen in rare cases of CML that are d istinctive for having increased numbers of
monocytes and thuscan resemble chronic
myelomonocytic leukaemia 114581.
The enhanced tyrosine kinase activity of
BCRABL 1 is responsible for coosntunve
activation of several signal transduc tion
pathways 15391. This resu lts in the
leukaemic phenotype of CM L ce lls which
encompasses deregulated proliferation ,
red uced adherence to the 8M stroma and
defective apoptotic response to mutagenic st imuli . The understand ing of the
abnorma l signaling in CML cells led to
the design and synthesis of small
F"tg. 2.08 0r.I... myeloid bla ~ ptlase. A ~ l:tlodofl pllientWllh myeIoidbllst phase . Tht ma;onty oftle "'*
l:tlod oats<n blasts. B.C Sheetsof ~ in' " bin! ITWTtM bqIsy. D Myeloperolidase del8cllId Imu'oo
tvmchei,U1. pIWng ee myetoid lineage of hi blasl P'~lIlul.
Chronic myelogenous leukaemia, BCR-ABL 1positive
35
A Penphetal blood smear. 8 Bone malTOW biopsy C Mam:lw aspirate smear.
Fig. 2.10 0Al.. myeloid bIasI phase , in 8Ile~ site . A,8 l~ node biopsy obtained from iI pabent with a tIiStor'y 01 CML lor 3 ~_ The lymph node d1iteclln is
Iatgely eIIaoad by a proIrfefatlon 01 medir.Jmkllarge Sized cells. C l~ im~ confirms the myeloid lineage ollhe blasts,
molecules that target the tyrosine kina se

ac tivity of BCR -AB L 1, of which imatinib
was Ihe first to be successfully used to
treat CML 1616, 6 171. lmatinib competes
wi th ATP lor b ind ing to me BCR-ABL 1
kinase domain thus preventing phosphorylation of tyrosine resid ues on its substrates, Interruption of the oncogenic
sig nal in this way is very effective for control of the d isease , particularly when used
early in CPo However, the eme rg ence of
sub-c lones of leukaemic prog enitor c ells
with point rrutations that prevent the bnding

0 1 the inhibilOf to the kinase domain of
BCR-ABL 1 can lead to d rug resistance,
p articularly in AP and BP 11103. 23731.
The second generation compounds nilotmib and d asatinib can circumvent this
form of d rug failure in the case of most but
not all kinase domain mutations assoc iated
with imatinib resistance 11103, 2373} .
The mol ecu lar ba sis of d isease tran sformation is still large ly unknown . Progression
is usua lly associated w ith clo nal evolu tion
1657, 1487, 14881, and at the time of
transformation 10AP or BP, 80% of patients

demonstrate cytogenetic changes in additlOO to the Ph ch romosome, such as an
extra Ph, . 8, . 19 , or i(17q). Genes shown
to be altered in the transformed staqes include TP53, RB1, MYC, p1 f7'"""" {CDKN2Aj,
RAS, AML 1 and EVil , but their role in lhe
transformati on , if any, is currently unknown
1821 , 1455 , 14871- The recent introduction
of gen ome -wide expression profiling by
mrc roarray tech nolog y has started to reo
vea l othe r cand idate genes assoc iated
with the ad vanc ed stages , and has also
revealed similar gene expression patterns
betwee n AP and BP, suggesting that the
genetic even ts lead ing to transformation
in AP and BP occur in late CP or early AP
11608, 1624 , 18031.
Postu lated celt
of origin
It is curren tly accepted that CML-CP

originates from a plu ripotent 8M stem eel.
However. disease progression may originate in more corrvn itted precursors lhan
previously supposed, as myeloid BP has
Fig. 2.11 Fluorescence il SItu hybAckzalion (FISH) with dual color and dual fusion probe on a normal metaphase eel
(A) 8Ild metaphase preparaOOn (8) from a patient witht(9-,Z2)(q34;q11 .2~ AWal alia' anddual fusion InInsloc:aIion probe
is used (VysisR corporatlon). The ABL I and BCR probes are labeled with SpectrumOrange and SpectrumGreen
respecIJYeIy. In J'lOfmllI eels (A) two orange Signals represenbng the ABL 1 gene al 9q3.4 and two green SIgnals representing the BCR at 22(111.2are &hown. In the pall&nl's CMl cells (8) one orange (J'lOfmllI 9q34), onegreen (normal
22q11.2) andtwo orangeJgteen(yelOw) signals, repl"esenOOg derivative 9q3.4 and 22q11 ,2, respedively, are detected.
36
Mye loproliferative neoplasms
been repor ted to involve the g ranulOcytemac rop hage prog enitor pool rather than
the naerroooletc stem cell pool 114741.
Whether the same applies to lymphoid BP
is not know n,
L-
AlP-bind ing com etitors
\m t?9;22)(q34 ;q11.2)
---.J
BCR.ABL1
813a2
.1402
p210
A
rig. 2.1 2 ... SC1lemabc representabDn of !he U:9:22) chromosomallranslocabon, me fusion mRNA ~ encoded by !he BCR..-&.1 tl)trid gene geoeqted in !he 22q. or
F'IlIacletiIlia (PIli chi OliiOJmll , and hi nnslated BCR-ABL1 kl5ion protOO, ...nose oncogenic ptqlllrties I'e/y pl'lIl'IiIdy' on ts conslllUOVely actrvaled tyrosne U1ase en:xlded bytie
s..:~ I ISH1)domain i'llicatedby ltle red Orde. Some of It1e oltlef ~ UlcWlaI don'IaI'S CQ'1tnlluted by tie BCR andABLl pcnons oIlhe Oi iCClPi oceifl n sI'lowfl.
These n 1Ile dMnensaliOn domain (00): Vl n wtlich is !tie allloptlosphoryllion s<1e crucial lor binding to 008-2; the ptIospho-Ser and -Thr SH-binding dorr'I<Wl; a region
turdogaIs tI Rho guarlIdne ru:Ieoticle exet.ange laclots (Rho-GE.F): ee ABll regoJa1o"y SH3 and SH2 domains; Y412 as !he map Slt8 r:I ~ wiltlillhe StU
IrNse dcrnarI; ru::i8ar kx:att:alitw, J9IaIs (tt.S) and lhe DNA- and adn-I:imng danains.. B Mectllnsm 01 adIion 01 acR-A8I..l \yrtliW1e kNse ~ 'M1ereas h physdogicaI
tning rJATP III its poDelllbn BCR-ABLllO phosphorylate seIeded tyrosWle residues onrts SI.tIslrales (left <iagam). a synlheIicATP rrmc such lIS inalinlb fits t1ls poct.et
Iiaopm),lluliXles nol prOYide Ihe esseoIiaI phosphate ~ lO be transfem!d k11he SI.tIslraIe Thedownstream d1aIn 01 reactions is lhenhaAed because,lfII'iltI irs tyrosines i'llhe
~ form. ee subslrate does not assume the necessary ronJoonabon 10erlSlH associabon WIlh itS efleclor.
t,..
~ and predictive factors
Based on historical data prior to any

effective therapy, median survival times in
CML ranged bet ween 2-3 years {7671_
With conventional c hem othe rapy (bus ulfan, Hydroxycarbami de) me dian survival
was about 4 years, but progression to AP

and BP was only slightly delayed w ith 10year overall survival (OS) less than 10%
1767, 1948, 2022). Interfe ron-u -based
regimes delayed prog res sion signilicarttly, with median survival of approximately 6 years and to-yea r OS of - 25%
1115l. With allogenic stem ceutransotant.
1O-year OS ranges between 10 and 70%,
depending on d isease phase, patien t age
and donor ty pe 1116 , 828, 20221. Thre e

pr ognosl ic models ba sed on baseline
pr ognostic variables including age ,
spleen size, p late let count , the percentage of mveiobrasts in PB as well as the
percentage of basophils and eosinopnns
in the PB allowed the c alc ulation of rela tive risk, hence of the life expectancy, of
patients treated with conventional chemotherap y an d inte rferon 1905, 1101 , 2044 1
and w ith im atinib { 116, 6 15), b ut not those
treated wi th all ogene ic stem ce ll tra nsp lant. Som e stud ies have show n that the
p redictive va lues of these models can be
fur ther improved by the inclusion of morphologic parameters, particularl y the
pres ence or abse nce of m ye lofib rosis

1292 , 293, 12 17, 12 181. Pretra nsplant
myelof ibrosis ha s been reported to be
associat ed wit h a delayed or failure of
naematoooenc reconstitution 1293, 22071.
How ever, in the current era of PTKI
therapy, the most important prognosti c
ind icator is the response to treatment at
the haematologic , cytogenet ic and molecular level 1116/ Cu rrently the comple te
cytogenetic response rate to ima tin ib is
70-90%, with a 5-year progression free
survival and OS between 80 -95% 1116,
6151
Chrooc myelogenous leu kaemia, BCR-A BL 1 po sitive
37
B.J . Bain
RD. Bru nning

JW. Vardiman
J . Thiele
Definition
Chronic neutrophilic leuk aemia (CNL) is a
rare myeloproliferative disease . cha racterized by susta ined peripheral bloOd (PB)
neut rop hilia. bone marrow (8M) hypercellulanty d ue to neutrophilic granu locyte proliferation. and hepatosplenomegaly. There
is no Philadelphia (Ph) chromosome or

BCRABL 11usion gene, The diagnosis reo
quires exc lusion of reac tive neutrophil ia
and other myeloproliferative neoplasms,

ICD.Q cod e
996313
Epidem iolog y
The true incidence 01 CNL is unknown ,
but only about 150 cases have been

reported. In one study 01 660 cases of
chronic leu kaemias of myeloid origin. not
a singlecase 01 CNL was observed 120031.

CNL gene rally affects olde r adults. but
has also been reported in adolescents
1909, 2474, 2504}. The sex distflbulion is
nearly equal 1231 . 640, 2474, 25041.
Etiology
The cause of CNL is not known. In up to
20% of reported c ases, the neutrophilia
wa s associated with an und er ly ing neoplasm , most usua lly multiple my e loma
1355, 58 4, 20761. To dale, no cases of
CNL as sociated with myeloma have been
rep orted in wh ich a clonal c hromosomal
abnormal ity o r evid enc e of cronauty by
molecular tec hniques has been co nvinc ingly d emons trated in the neutroonns
120771. II is thus likely that most cases of
CNL associated w ith mye lom a are not
autonomous prolif erations of the neuuophi ls , but are secondary to abnorma l
cvtokme release from the neoplastic
plasma cells or othe r cells regulated by
the plasma cell population . The same
may be true of C NL associated with other
neoplasms. However, it should be noted
that evolution to acute myeloid leukaemia
(A ML) occurred in one pat ien t with CNL
associated with multip le my eloma {5841 .
Sites of involvement
The PB and BM are always involved, and
the splee n and liver usually show leukaemic
38
Myeloprol iferat ive neoplasms
..
. :t
Fig. 2.13 Ovtnc newophIc ~ _ A The neutrophiia dIatac:IeristIc oIltie ~ t*:xx1 il CNL B The. .
granUatiolllXlr!JTllldy obset'o'ed. Reproduced from Anastasi and ~ (3SAJ. C The bone rnatfOW asprDt SI!W
der!lcmIrates neutrophil proWerabOn from myebcytes to ~ forms 'Mlh toO: granu/abOn, 1M no olIW"
s9'ificant abnormaibes. D The bone marrow biopsy specimen is hyperceWar, showing a markedly eIevMld
myeIoicI:erylM:lid ratio WI!h increased IIJrmers of nNrophk, partK:tarly maturesegmented bms.
infil trates 12257. 2474 . 2504 1. How ever,

any tissue may be infiltrated by the rectrophils 12257 , 2474, 25041.
Clinical features
The most constant c linical feature reported
is sp lenome ga ly. whi c h may be symptomatic . Hep atomeg aly is usu ally present
as we lt 12474 , 2504 1 A history of b leed ing
from mu cocutaneous surfaces or from the
gastrointestinal tract is reported in 25-30%
of patients 1909, 25041. Gout and pruri tus
are other possi ble symptoms 12504 1.
--
The PB smear shows neu trophilia w ith a

wh ite b lood celt count ~25x l ()9/L.. The
neutrop hils are usuatty segmented, b ut
there may be a substantial increase in
band for ms as we lt. In almost alt cases,
neutrophil precursors (pn::rnyeIocytes, myeiocytes. metemyetocytes) account for
fewe r than 5% of Ihe white cells, but oc casionally, they may account f()( ~p to 10%
1231 ,640 , 909 , 2474. 25041. Myeloblasts
are almost never observed in the blood

The neutrophils often ap pear toxic . with
abnorma l, coa rse granules, but they may
also a ppear normal. Neutrop hil dysplasia
is not present. Red blood ce ll and platelet
morphology is usually normal. The 8M
b iop sy shows hypercel lular ity w ith neutrophilic p roliferat ion. The myeloid:e rythroid rat io may reac h 20 : 1 or greate r
Myelo blasts and p rom yeiocytes are not
inc reased in percentag e at the time 01 diagnosis, but the percent of mvelocvtee
and mature neutrophils is inc reased. Erythroid and megakaryocytic prol ifera tion
may also occur 1231, 24741. Sig nific ant
dysplasia is not present in any 01 the cell
lineages and, if found , another diag nosis.
such as atypical chronic myel oid
leukaemia . should be considered (See
Chapter 4). Retic ulin fibros is is uncommon 1231, 640 , 2474, 25041. In view of the
reported frequency of CNL in association
with multip le myeloma, the BM should be
examined for evi dence of a pl asma ceu
neoplasm 1355, 584, 2076, 20771. If plasma
cell abnormalities are p resent, clona lity 01

the neutrophil lineage should be supported by c ytog enetic or molecular tec hniques
be fore
making
a
diagnosis of CNL. Splenomegaly and
hepatomegaly result from tissue inliltration
by the neutrop hils. In the spleen , the infiltrate is mainly confined 10 the red pulp; in
!he liver. the sinusoids, portal areas or
both, may be infutrated 12474, 25041.
Cy\ll(:hen>stry
The neutrophil alkaline phosphatase score
IS usually norma l or inc reased. but no
OCher cvtocoencarabl"l()(mahty has been
fepor1ed
"""""'"
Table 2.01 Diagnostc criteria lor chronic neu troph~ iC Ieu ~aemia.
Peripheral blood leukocytosis, wac <:25xW/L
5e9meflted neutrophils andband folms Bftl >80% of wtlite bloodceas
ImmatlKEl granu~es (promyelocytes, myebcytes, metamyelocytes) <10%ofwtllte bloodcells
Myeiotllasts<1 %of I't11ite blood cells
2.
HyperceftlJar bone matTllW biopsy

Neutrophilicvanuloc)1es increased II'l pen;enlage andnumber
Myeloblasts <5% 01 rWeated IT\CIl'ltI'IIf' cetIs
NeutmplVliC maluration paneronormal
Megaka ~ normal or left shifted
3.
Hepatosplenomegaly
No ideflt!f.able caJ5e lorptrysioIogic neutrophika or. if presanl, denw:lnslration 01 donaIiIy ofmyeloid eels
by cytogenelic or molllo.I* studies
Noinfecbous or J1lIarnmaIory JlItlC8SS
NoPtlitadelphia cMlmo5ome or BCR-ABL 1 Mlon gene
6.
No ~ d PDGFRIo , PDGFRB or FGFR1
7.
No ~ of polyc'y1tlaenia vera. pti'Tlaty A'I)'elofibmsis or essential ~
8.
Noevidence 01 a myebcIysplaSllC ~ or a myeIodyspIasIicImyeloproleraliw neop(asms

No gtafUcqtc dysplasia
No myelodysplaslic changes II'l olher myeloid hages
MonocyIes <hl O"IL
1909. 2504 1.
CytogenetIC studies are ooemat in nearly

00% 01 patients. In the remaining patients,
clonal karyotypic abnormalities may
include +8, +9 . +2 1, del(2Oq ), del (1 1q)
andde~12pl l 566. 640 , 736, 1415, 24661.
Clonal cytogenetic abnormalilies may
appear during the cou rse of the disease .
There is noPh chromosome Of BCR-ABL 1
fusion gene. A vana nt of chronic myelogenous leukaemia, BCRABL 1 positive
(CML) has been repo rted that demonstratesperipheral blOOd neutrophil ia stmilar to that seen in CNL 1168 51. In such
cases, a variant BCR-ABL1 fusion protein ,
p230, is found. Cases with this molec ular
variant of the BCRABL 1 fusion gene
should be considered as CMl , not CNL.
Occasional patients with a JAK2 rnutation
have been reported [1083, 14351and this
bassometimes been homozygous 110831.
Ccrnplete cytogenetic remission with imatnib was reported in a patient with CNl
No_.. . .
and 1(15; 19)(q13:P13.3), suggesling the

possibility of an unident ified fusion gene
in some cases 1433 J.
Postulated cell of origi n
Cell of origin is unknown. It is most likely
a BM stem cell with limited lineage ooten tiaI 1736, 2466 1.
Prognosis and predictive fac tors
Although generally regarded as a slowly
prog ressiv e disord er, the survival of
pa tients wi th CNl is variable , ran gin g
from 6 months 10 more than 20 years.

Usually the neutrophilia is p rog ressive.
and anaemia and thrombocytopenia may
ensue. The development of myelodysplastic
features may signal a translor mation of
the disease to AML, which has been reported in some patients 1909, 2504 1. It is
not clear whether the transformation was
relate d to previous cytotoxic therapy in
the cases rep orted.
Chronic neutrophrlic leukaemia
39
Polycythaemia vera
Definition
Poiycvtbaemra vera (PV) is a chronic
myeloproliferative neoplasm (MPN) characterized by increased red blood cell
production independent of the mechanisms
that normally regu late erythropoiesis.
Virtually all pat ients carry the somatic
ga in-ol-lunction mutation 01 lhe Janus 2
kinase gene, JAK2 V617F or anothe r
functionally similar JAK2 mutation thai
results in proliferation not only 01 the
erythroid lineage but of the granulocytes
and megakaryocytes as well , t.e "panmyelosi s". Three phase s 01 PV may
be recognized : (1) a prOdromal, prepo lycythaemic phase c harac terized by
borderline to only mild erythrocytosis; (2)
an overt poIycythaemic phase. associated
with a significantly increased red cell mass ;
and (3 ) a "spent" or post-oo'vcvtnaemic
myelofibrosis phase (post-Pv MF) in
which cvtooeruas. including anaemia . are
associated with ineffective haematobone marrow (8M) fibrosis. extramedullary haematoooesrs (EMH) . and
hypersplenism, The natural progression
of PV also includes a low incidence of
evolution to a myelodysplastic/preleukaemic phase and/or to acute leukaemia
(AML). All causes of secondary eryth rocytosis, inheritab le po lycythaemia and
othe r MPN mus t be excluded. The d iagnosis requires integration of c linica l, laboratory and 8M histolog ica l features as
outlined in Tab le 2,02 .
J. Thiele
H ,M , Kvasnicka
A,Orazi
A TeHeri
G , 8irgegard
Evolution _
...10"Jl,,;15'Mi
....21 Idl!!!9-U-
Manifestation
- - - - - - - Transformation
Post -polycythaemc
myeIokl metaplasia
(post-PV MF)
1
t
. - -_ _ 20 %
~.Iy
L.._ < 10 %
definite increase In
red cell mass
I
Post-PV MF WIth
biasbc transformation
11
II
Tennin.J1 sage
Fig. 2.14 SdJematic presentabOn of ee 8YOIuliOn of 1hedisease process ., ~ vera.
poese.
ICD-Ocode
9950/3
Synonym
Polycythaemia rubr a vera,
Epidem iology
The reported annual incidence of PV
increases with advanced age and varies
from 0.710 2.6 per 100 000 inhabitants in
Europe and North America. but is much
Iavver in Japan 110591. Most reports indicate
a slig ht male predominance, with the M :F
ratio rang ing from 1- 2:1 ISO. 1389 1. The
median age at d iag nosis is 60 years . and
p atients you ng er than 20 years old are
only rarely reported 117001.
40
Etiolog y
The underlying cause is unknown in most
cases. A genetic predisposition has been
reported in some famil ies 11778 , 20321.
Ionizing rad iation and occupational
expo sure to toxins have been suggested
as po ssib le causes in occasional pa tients
1312}.
Sites of involv eme nt

The blood and 8M are the major sites 01
involvement, but the spleen and fiver are
also affected and are the major sites of
EMH in the later stages, However, any
organ can be damaged as a result
of the vascular co nsequences of the
increased red cel l mass .
Table 2,02 Diagnosticcriteria lor poI~emia vera (PV). Diagnosis requires the presence 01 bottl major criteria and
onemM criteriOn or \he presence of the firstmajor cri tel'\orl togeth&r with two minor criteria.
Majorcriteria
t. Haemoglobin >18.5gJdL., men, 16,5g!<ll
in 'Io'OfT'l8l1 orother evidence of eceeseo red cell voll,lTlEl'
2. Preserce of JAK2 V617F or otnerfunctionaly slnVlar mutiltion sudl as JAKZe_on 12 rl'lI.ltalion
Minor criteria
t . Bone marrow biopsy shoWing hypercellularily lor ageWIth lJirIeage growttl (panmyelosis) wiltl prrITWIefll
erytIvoid, granulocytic aodmegakaryocytJc proMerabon
2. serum erylhl'ClPClie'n levelbelowthe reIerenc:e range lor normal

3. EI'IOOgenous eryttvoid colony Iormabon II'l VItto
Haemoglobin Of haematoall >99th pertentile of rneIIlod-speofJ reference range lor age. sex, albtude of
resideool a hael,qJobiI. >11 gill. 10 men. 15 Wdl in women assoaaled WIth a doI:menled iIfld sustaned
Mease of alleasl 2 gldL from an indMdual's baseline value Il\al tarl nol be attnbuted 10 correctlOn 01 irOn
defDency, or lll&vated red c:eI f'lIa$$ >25% llbove mun normal predicIer:l value
Clinical features
The major symptoms of PV are related to
hypertension or vascular abnormalities
causedby the increased red cell mass, In
nearly 20% of patients an episode of
venous or arterial thrombosis, such as
deep vein thrombosis, myocardial ischaemia or stroke, is documented in the
medical history lSOI and may be the first
manifestation of Pl/lSO, 197, 1389.20711.
Mesenteric, portal or splenic vein thrombosis and the Budd-Chiari syndrome
should always lead to coosideration of PI/
asanIJlderlying cause and may precede
the onset 01 an overt polycythaemic
phase ISO, 2701. Headache, dizziness.
visual disturbances and paraesmeses
are major complaints, and pruntus. erythromelalgia and gout ere also common.
In the full-blown polycythaemic stage
physical findings usually include plethora
and palpable splenomegaly in 70% and
hepatomegaly in 40% 01 patients 11445,
20711.
Clinical laboratory studies that aid in
confirmation 01 the diagnosis of PV
include subnormal erythropoietin (EPO)
levels [223. 15271. endogenous erythroid
c:oklny (EEC) formation 15951. and oetectoo
at the JAK2 V617F or functionally similar
mutations, e.q. JAK2exon 12 mutations
Fig. 2.15 F'dycylhaemiaveta, ~stage. A I.WcIy hyperc:eWa' bone If\ilIJOIIWsI'oIro'rIga ~01

large megakaryocytes in ee bone mafI'OW secUon. B Many large ld gianttlyperIobuIated ( ET~ ke) megakyotytes
in a pa\leIIl dilic:ally mrrickJng ET, because 01 a platelettxUlt in excess 0I 10D0xlO'1t- Note ee my dIy inaeased
~ lnf ef)'tt"ropoiesi (panmyelosis), beUerdlImDl ostraIed by ~ esterase f9ClCtiOrL
the morphological findings are of sufficienl

specificity to allow distinction of PV from
secondary poIycythaemla as well as other
subtypes of MPN 122031,
Pre-polycythaem ic phase and

overt poIycythaemia
Generally, in the pre-polycythaemic and
polycythaemic phases of PV the major
features in the peripheral blood (Pal and
8 M are attributable to effective proliferalion
in the erythroid , granulocytic and megakaryocytic lineages, Le. there is pannweosrs.
The PB shows a mild to overt excess of
normochrcmie, normocytic red blood cells.

If iron deficiency due to bleeding is present. the red cells may be hypOchromic
and microcytic. Neutroptufia and rarely
basophilia may be present. Occasional
irrmature granulocytes may be detectable
in the overt polycyttlaemic phase, but circulating blas ts are generally not observed ,
Because of prominent thrombocytosis, up
to 15% of cases of early phase PV
may clinically mimic essential thronbocvthaerma (Ell 122101 but such cases
eventually evolve into an overtly polycvmaemc stage 11047, 2007, 22101.
11 981,2168. 21771.
Occasionally. patients may present with
clinical symptoms suggestive of PV b ut
WIth a haemoglobin level and/or red cell
volume not sufficiently e levated to substantiate the d iagnosis. Such patients
may be in the pre-oo'vcvtbaemrc phase,
wtlich was previously refe rred to by some
authors as "latent PV' or as ' p ure id iopathic erythrocytosis" 1197,1559, 1715,
1697,2224), The detection of a sub normal
EPO level, a JAK2V617F or funct ionally
similar mutation andlor abnormal EEC
lcmaton. in combination with the typ ical
morphologic features described below,
will allow the diagnosis of this phase of
PV; these features are not found in
secondary or spurious polycythaemia.
The ore-ooivcvtnaemc phase may be
expected to become overtly poIycythaemic
at a later time.
Maphology
The morphological lind lngs in BM biopsy
specimens at patients with PV must always be correlated with other clinical and
taboratory fmd ings in order to firmly establish the diagnosis 121771. However,
eYen n the earty pre-po/ycyttlaemi stage
PoIycythaemia vera
41
FIg. 2.11 AcuteIeukaen'ilWl poIycyth8emia WlflI . Blood

a pabenl M1h. ~ Ilist:Iy of PII.
The patient had been treated with a/kyIabng agents
!bing !he poIycyIhaemic stage. The blasts
C013. C033. C0117 alld C03-f. and had a compleJ
karyotype. COf1SISlenl wrIh Il'lerapy-related aalte myeloid
~ from
eeeseee
.......
Bone marrow cellular ity has been reported

to range from 35-100%, with a median
cellularity of about 80% [641 1, but c haracteristically the BM biopsy is hyperceuular for the pa tient's age. A finding that is
especially noteworthy is increased ce llularity in the subcortical marrow space, an
area which is nor mally nyooceuurar (775 ,
2203] Panmyelosis accounts for the inc reased ce llularity b ut an increase in the
numbe rs of e ryth roid pr ecursors and of
meg akary oc ytes is often most promin ent
{641, 775, 22031. Erythropoiesis is normobl astic, and granulopoiesis is mor p holog ica lly no rmal. The pe rcentage of
myeloblas ts is not increased. Mega karyocvtes are increased in number. particularly in cases with an excess of platelets,
and display characteristic morphological
abnormalities, such as hyperlobated
nuclei, even in the early phase of the
disease , The presence 01 the panmyelosis, which although less prominent in the
pre-poivcvtnaenc than in the overt polycythaemic phase, is nevertheless detectable and helps to distinguish early PV
from ET, whi ch it may otherwise resemble
clinically 1221 01 As in the pre-pdycythaefr
phase, megakaryocytes seen in the
poIycythaemic stag e 01 PV are clearly
di st inguishable from those seen in ET.
42
MyeloproliferatIve neoplasms
They typically tend to lo rm loose c lusters

or to lie close to the bone trabeculae, and
often show a significant degree 01 pleomorphism with a mixture of different sizes .
The major ity of the megakaryocytes
exhibit normally folded or deeply lobulated
nuclei, and usually lack significant cytologica l abnormalit ies, alt hough a minori ty
show bul bous nucle i and othe r nuclear
ab norma lities, pa rticularly when assoc iate d with a minor incr ease in ret icu lin
{22 111. When taking the c ha racte ristic
histological pattern of PV into account,
d iscr imination of PV from ET and PMF as
well as the distinction from reactive erythrocytosis and thrombocytosis is feasible

{2211 , 22221. Reticulin stains will show a
normal reticulin libre network in about
80% 01 patients . but the remainder display
inc reased reticulin and even borderline 10
mild collagen fib rosis {297 , 641 , 775,
1189,221 1] de pen d ing on the stage 01
disease at first dia gnosis, Reactive nodular
lymp hoid agg regates are found in up to
20% of cases {22031. Sta ina ble iron is
lack ing in the 8M as p irate and biopsy
specimens in mo re than 95% of the cases
1641, 22221 .
Tabl.2.03 Diagooslicaileria fOf postiJOlycythaemic myelofibrosis (posl-PV MF )
Required criteria
1. Documentation ofa previous diagnosis of'MiQ.defined PV
2,
Bone mallOlll1ibl"os4s grade 2-3 (000-3 $C8Ie) orgr-ade 3-4 (000- 4 scale)
Additional criteria (2 art rtquiredj

1.
Anaemia' Of sustained km of ei1hef pl1Iebotomy r~ the abseoce of ~ therapy)orcytoreduc:M
lrealmenl requilKnent b~s
2,
Leukoel)1hroblaslic penpheral blood picbQ
3.
Incteasll1g spIenornegllIy defIOlld as .rther aninaeasein palpable SPleoomegaIy of >S an from baseIint
ldistanee from the left costal marg.n) Of Iht 1pp&afaflC8 of newly palpable spleoomegaly
Development of >1 of 3 consblulional symploms: >1 0%weighlloss i'l61'1'lC11'1\tts, iWJhI sweats.

6
unexplained Ie'o'eI' (>31.S C)
"Spent phase"and postpolycythaemic

myelofibrosis (oost-Pv MF)
During the later phases of PV, e rythropoiesis progressively decreases. As a
consequence, the red blood cell mass
normalizes and then decreases, and the
spleen further enlarges. Usually these
Changes are accompanied by corresponding 8M aneranons 1641 . 20711. The most
common pattern of disease progression
is posf-Pv MF accompanied by myeloid
metaplasia which is characterized by a
Ieukoerythroblastic PB smear, poikilocy'
ioss wil h teard rop-shaped red blood
cells. and splenomegaly due to EMH , as
defined in Table 203 {143A). The morphological hallmark of th is slage of the
disease is overt reticulin aOO collagen
fbrosisofthe BM 1641 . 775 , 2203, 22221,
The CelkJarity varies in this terminal stage.
tu: h'y1:loceIIular specimens are coreroo.
CUsters of megakaryocytes, olten with
hyperchromatic and very dysmorphic
nuclei, are prominent Eryth ropoiesis and
granulopoiesis are decreased in amount.
and are sometimes foun d . along with
megakaryocytes, lying within dila ted marrcw srcsocs 12203 1. Osteosclerosis may
also occur 164 1, 775 1, The splenic enlargement is a consequence of EMH ,
....nich is characterized by the presence of
erythroid. granu locylic and megakaryccvnc elements in the splenic sinuses
and cords of Billrot h. An increase in the
number of immature cells may be observed in these stages, butme finding of
) 10% blasts in the PB or 8 M or the pre sence of signific ant my e lodysp lasia is
unusual, and mosl likely sig nals tran sformation to an acce lerated phase and/or a
myelodysplastic synd rome (MD S), Cases
inwhich 20% or more blasts are found are
AML 11701, 2071, 2203, 2222).
cnsoerec
""""phenotype
No abnormal phenotype has been reo
"",eo
Go'o'"
The mosf frequent genetic ab normality in
PV is the somatic qam-ot-tuncnon mut atoo JAK2 V617F. Altho ug h il occurs in
>95%of patients with PV, it is not specific
and is found in other MPN as well. but in
splerJedoi"r
Fig. 2.19 ~ Ylll'a, ~ rnyelofbosis (pos&-PV MF) and"lbd metaplasia ,

specinen. The splenic enlarvement in the ~ ptIase isdue IlIMlIy b eJb"ameOJlary Ilaema!DpoIesis
!hat Cll:X:ln II1 It1e splenic sftlses , as wei 11$Iibrosis.-.d lll1trapmenl d platelets and tIaernalopoieli eels II1lhe splenic
coos
iower freq uencvltea. 1044 ,1 186 , 12881.
The mutation occurs in a haematopoielic
stem cell , and is found in all of the
myeloid lineages. Hence cells that utilize
JAK2 kinase in the intr acellular signaling
path way may be hyp ersen sitive to g rowth
fa ct ors a nd other cvtokmes. inc lud ing
EPO . A fun ct ionally similar mutat io n in
exon 12 of JAK2 has also been reported
11981/. so that virtually all patient s with PV
have a JAK2 aber ration , St ill, no ge ne tic
defect enti rely specif ic to PV has been
ide ntified . At diagnosis, c yto ge ne tic
ab normal ities are detectab le in ab out
20% of pa t ients. The mo st c ommon
rec urring abnormalities inc lude +8, +9,
del(20Q), de l( 13q) and de l{9p) : sometimes +8 and +9 are found tog ether 142,
2394/. There is no Philade lphi a c hromosome or BCR-ABL 1 fusi on g ene . The se
c hromosomal ab normalities are seen with
increasi ng frequency with d isea se progression and in near ly 80-90% of those
w ith post-PV MF 1421, Almost 100 % o f
those wh o develop MDS or AMl have
cyt ogenetic abnormalities. inclu ding those
commonly o bserved in the rapy-related
MD S and AMl (See Chapter 6 ).
Postulated cell of ori gi n

Heemetopoteuc stem cel l.
Prog nosi s and pred ictive fact ors
With currently available treatment, median
survival li mes > 10 ye ars are commonly
repor ted {SO, 1215 , 1548,2071/ . although
controversy persists about the risk factors
other than olde r age {1215, 1389, 17021 .
Most p atients d ie from thrombosis or
haemorrhage , but up to 20% succumb to
myelodysplasia or acute mye loid leukaemia
ISO, 1389, 207 11,
The factors tha t p red ict the risk of thrombo sis or haemorrhage are not well
d efined 11389, 1700,20711, The incid ence
of MDS and ac ute leukaemic transformation is only 2-3% in patients who hav e not
been treated with cy totoxic agents , but
increases to 10% or more follow ing
ce rtai n types of c hemot hera py {704 ,
1389 , 1548 , 170 1, 1702 1_
PoIycythaemlCl vera
43
J . Thiele
H M . Kvasnicka
A. Tefferi
G. Barosi
A. Orazi
JW. Vardi man
ICD-O code
Definition
Primary myelofibrosis (PMF) 11464 1 is a
clonal myeloproliferative neoplasm (MPN)
characterized by a proliferation of predominantly megakaryocytes and granulocytes in the bone marrow (8M) that in fully
developed d isease is associated with
reactive deposition of fibrous connec tive
tissue and with extramedul lary haematopoiesis (EM H) . There is a step wise evolution from an initial prefibrotic phase
121771 cha rac terized b y a hypercell ular
BM wit h absent or minimal reticulin fibrosis
to a fibrotic phase with marked reticulin
9961 /3
Synonyms
Chronic idiopathic myelofibros is (CIMF);
Agnogenic myeloid metaplasia (A MM);
Myelofib rosiS/scl erosis with myeloid metaplasia (MMM) ; Id iopathic myelofibrosis .
or collagen ubrosrs in lhe 8M and often
Epidemiology
The overt fibrotic pha se is estimated to
oc cur at 0.5- 1,5 per 100 000 persons per
year {1060,21671. It occur s most C()fTV'TK)ll1y
in the sixth 10 seventh decade of life, and
both sexes are nearty equally affected
121671. Children are rarely affected 136n
osteosclerosis. This fibrot ic stage of PMF

is characterized by ieukoervtbrobiastosis
in the booo witll teardrop-shaped red cel ls.
and by hepatome galy and sp lenomegaly
(Tabl e 2,0 4 ).
Etiology
Exposure to benzene or ionizing radi ation
has been documented in some cases
{5881 Rare familial c ases of 8 M fibrosis
Table 2.114 Diagnos1ic crilefialor primary myelofibrosis: <iagnosis requires meeting all 3 mator and2 miroof crileria
MaiOI' eritltria
t . Presence d
~ ........... 1
atypiI", usuaIylaXllTlpalied byllitlerreIla*l inlier a:tagen ~
'"
nile absenat d sig1Icat /W)Jin Iibrosi:s, tle ~ chat'gesIl'LISI be llCClJI'llliDed by a'l 1lcJeaged
bone ITI8fTOWcelIularrty characlenzlld by granuIol:yIic pn:jferabDn and often deaea:Sed erythn;lpooesis
~ e. p!VftlroIic ceItEr-pllase disease ).
2. Not meeting WHO Criteria lor poIy<:ythaemia~. BCRABLt+ chronic myeIogeoous leukaemia'.
myelodysplaslic syndrome'.fJ( other myejoid neoplasms
in yo ung chil d ren have been reported

How often this represents an MPN is ~
known. but at least some cases appear 10
represent an autoscmal recessive imented
families with a
oondilioo 118731 In
somewhat later age of onset . the leal1.Xes
havebeen consistent withan MPN, suggesting a familial predisposition to PMF 13691.
oee-
Sites of involveme nt
Blood and BM are always invo lved. In the
later stages of the d isease , EMH (also
kno wn as myeloid metaplasia) becomes
prominent, in particular in the spleen
117731. In the initial stages. randomly distnbcted C034+ prOlJenitors are slightly increased in the 8 M. but not in the
pe ripheral b lood {PBl Only in the tate
stag es they ap pear in large numbers periphe rally (1592, 22091 This increase of
CD3 4 + ce lls in the PB is a ph enomenon
large ly restric ted to overt PMF and is not
seen in non-fib rotic po lycythaemia vera
(PV) or essential thrombocythaemia (ETl
141 ,1 45,17031 . It has been postulated
that EMH is a consequence ot me peculiar ability of the spleen to sequestrate the
numerous ci rculating CD34+ cells 122081.
Liver. lymph nodes. kidney ad renal gland.
dura mater, gastrointestinal tract, lung
and ple ura. b reast skin and sott tissues
are other possible sites of EMH 1216n
3. Demonstration of JAK2 V6t7F or other donal marker (e,g. MPL W515K!L),
'"
in the absence 01 a clonal marker. 00 evidence lhatlhe bone marrow fibrosis et otherc:Nlnges aresecondary
kl mecoon.autorr1rrone dison:ler r:K0lIlerchronic I1ftarnnatory t'a'llIIJon hairyC8lI ~ et OCher IyrnJ:tMjd
neoplasm, metasta1ic mal9'ancy. et klxiC (etvonic) myeIopaltlies"
Minor aiteril
1 .l~ '
2. Increase on serum lactate deIlydrogerIase level'

3, Ar\aemIa.
,
I
S""""""",,
Small to largemegakaryocyteswith an aberrant nuclearlcytoplasmic ratiO and hyperchromatic, bulbous, or
irregularly loIded nuclei and dense clustering
Requires !he lailure 01 ironrnpiacemenllherap)'to increasehaemoglobin level 10 tile potycythaem~ vera
range in the presence 01 decfeased serum fembn. ExckJsion of poIycylhaemia vera is based on haemoglobin
and haematocrit levels.n red eel massmeasurement is not required,
< Requns the absence oIBCR.ABL.1 ,

" Req!.ns atlMnce01 dyW)'ltliopoiesi$ and:~.
Patients WIth an:libons associaled wilhreactve Ill)'IlIofitlro llfe not
be COIlSide1 lld n std1 cases ~ olhercntena are mel
I Degree of abnorrnalIIy could be borderline or martell .
44
Myeloprolifera tive neoplasms
mn.one kl PMf. ;rod . . ~ stxUd
Clinical featu res

Up to 30% of patients are asymptomatic
at the time of diagnosis and are d iscovered by octcctco of splenomegaly during
a routine physical examination or when a
routine blood count discloses anaemia .
leukocytosis and/or thrombocytosis. Less
commonly. the dia gnosis results from
d isc over y of une xplained teukoervmrobtastosis or an increased lactate dehydrog enase (LDH) {366 . 2 16 7, 2 1771. In the
initial p refib rol ic phase of PMF. the only
find ing may be marked th rombocytosis
mimicking ET 12177, 220 11. Therefore. a
sustained thrombocytosis cannot. by itself,
discriminate between prenbrotc PMF and
ET 12201, 2202. 22041. Constitutional
symptoms may include fatig ue. dyspnoea.
weigh l loss, night sweats. Iow-grade fever
and bleeding episodes, Gouty arthritis

and renal stones due to hyperuricaemia
may alsooccur. Splenomegaly of varying
degee is detectedin up to 90% of patients
and may be massive: nearly 50% have
t'epa!l:megaty 1143, 366. 367, 1635, 2 1671.
The JAK2 V617F mutation may be found
n ~50% at patients in the fibrotic pha se:
its incidence in the prefibrotic stage has
no! been well studied. Althoug h helpful in
disllnguishing PMF from react ive condiboos thaI may result in 8M fibrosis, the
mutation is not speci fic for PMF but is
tound in PV and ET as well 121721.
The classical pic ture of advanced PMF

includes a PB smear that shows leukoerythroblastosis and anrsopo'knocvtosrs
(particularly with teardrop-shap ed red
cells) associated with a hvp oceuura r BM
with marked reticul in andlor c ollagen
fibrosis and organomegaly caused b y
EMH, However, the morp holog ical and
clinical findings vary c onsiderably at
diagnosis depending on whether the
patient is first encountered during the
prefibrolic or the fibrotic stage of the
disease (2177, 22041. Bec ause the pr ogressive accumulation of fibrous tissue
parallels diseaseprogre ssion, it is impo rtant to reproducibly and sequentially
grade the amount of BM fibrosis semi~ntitatively by using a sCOfing system
122141(Table 2.05).
PreffJroticandearly stage PMF:No registrybased prevalence ligures are available
b" the incidence otme prehbrotic pha se
ol PMF, but series der ived from various
'llfereoce centres reveal that 30-40% of
patlerlIs arefirsl detected in a prodromal,
preltbmllC phase without a significant increase in reticulin and/or collage n fibres
1297.775.2202,22041 _In these cases the

BM biopsy is nvperceuotar with an increase in the number of neutrophifs and
atypical meqaaarvocv tes . There may be
a mild "left shin- in granulopoiesis, bu t
usually metamyeloc ytes. bands and seqmented forms predominate. Myelob lasts
are not increased in percentage. and conspicuous clusters of blasts or of CD3 4+
progenito rs are not obse rved {2202 ,
22041_ In most cases, erythropoiesis is
red uc ed in qua ntity. but early erythroid
precur sors are promi nent in some patients 122281_ The megakar yocytes are
markedly ab normal, and their ntstotocography and morphology is the key to the
recognit ion of the prefibrot ic stage of PMF,
The megakaryocytes often form den se
Evolution _
clusters of variable size that are frequently

edrecent tc 8M vascular sinuses and the
bone trabeculae 1297.775,2204 .22161 .
Most megakaryocytes are enlarged, but
small megakaryocytes may also be seen,
and theif detection is greatly facilitated by
the use of immunohistochemistry with antibodies react ive with meg akaryocytic
antigens 12201, 22041 . Deviations from
the normal oucrear.cvtoptasmc ratio (an
expression of defective maturation). annormal pa tterns of chromatin clumping with
bulbous, "cloud -like" or "balloon-shaped"
nuclei , and the frequent occurrence of
bare megakaryocytic nuclei are all typical
findi ngs, Overall in PMF the megakaryocvtes are more atypic al than in any other
typ e of MPN. Vascular oronteeanon is
Manifestation - - - - - Transformation
initiat
Biage
GJ
~
CD
e;,.",d
~_I
MF-O
MFo I
11
Mf.2
Mf.]
Prefibrotic:-early PMF AdYilnced PMF (MMHJ
Fig. 2.21 ~ oI lhe disease process 11'1

(rr'IllCWI values) arid associaIed fibre ~
PfWnarY lIlJ8lDIiblosis (PMF) withassocialed ~ (lata

Primary myekllibrosis
45
usual in the 8M 11 214 1, and lymphoid

nod ules are found in about 20% to 30%
1220 1, 22041 . Careful 8M morphological
examination is particularly crucial in distinguishing pretiorotrc PMF with accompanying thromb ocytosis from ET 1712.
796,2 177.220 1.22161. Reticulin fibrosis
is minimal or even absent (corres pon din g
to grades 0 and 1)during this stage 122141;
if present. It is usually foca l and tend s to
be concentrated around vessels . The rnajority of cases with pretrbrotic and early
(reticu lin) fibrot ic stages of PMF even tually transform into overt ubronczscrerotrc
myelofi brosis associated with EMH 1295.
775. 1189 , 2204. 22 181.
Fibrotic stage: Most pat ients with PMF are
initially diagnos ed in the overt fib rotic
stage 1143, 366. 1635, 2 1671. tn this stage
the 8M b iopsy demonstrates clear-cut
reticulin or collagen fibrosis (fibrosis
grades 2 and 3) . The 8M may stilt be
focally nvpercenurer, b ut more often is
normocellular or hypocellular. with patches
of active naerretopoeers alterna ting with
hypocel1ular regions of loose connective
tissue andlor fat. Foci of immature cells
may be more prominent. although myelob lasts account for < 10% of the 8M cells
{297, 775. 22041. Atypical megakaryocytes
are often the mo st conspicuous find ing ;
these oc cur in large c lusters or sheets,
often within dilated vasc ular sinuses 1295,
2204). Sometimes lhe 8M is almost devoid
of haematopoi etic c ells, showing ma inly
d ense reticulin or collagen fib rosis, with
small islands of haematopo ietic precursors
situated mostly within the vascu lar sinuses.
Associated with the de velopmen t of
myelofibrosis is a sign ifica nt proliferation of
vessels showing marked tortuosity and luminal dis tension, often assoc iated with
conspic uous intras inusoidal haemato(1214, 1347, 1463). Osteoid seams
or eooossionarnew bone formatioo in budlike endop hytic plaqu es may be ob served
{775, 22041. In this osteoscl erotic phase.
the bone may form broad , irregular trabeculae that can occupy >50% of the 8 M
space. With exception of allogenei c stern
cell transplan tation 11592. 22131, develop-ment of myelofibrosis in PMF is not significan tly influence d by treatment modalities.
an d is obviously related to disease p rogression 1295. 22 17, 22181 In patients with
a previously established diagnosis of PMF,
the finding of 10-19% bl asts in the P8
and/or 8M and the oerectco by immunohistochemistry of an increased number of
CD34+ cells With cluste r formation and/or
Tlble 2.05 SemiQuanlitati~ grading of bone marrow fibrosis (MF).

GflIding
08$criptlon'
MF 0
Scatlemd ftar reticulin WlItl ro IOte~ (CIOS$-OWlI'S), CO!reSpCJnding to normal booemarrow
MF- 1
loose networt of reliaJlin wl\tl many i'ltersections, especiallyin perivasa.dar ereas
MF- 2
Diffuse arr:l dense increase In rebaJlin wrtll eJ:tenSlYe intersedtons. occasionally 'frilh local
burr:lles 01 coIagen and/or local OSleosderosis
MF- 3
0l1fuse and dense II"lCl'eaSe IIIreticulin 'M!tl extensive II'IIer$edIons ilIICl coarse bundles of
collagen, often associated 'frilh ~
coese
46
~~~) ..
Fig. 2.23 Primary myelofibrosis, fibrotic stage, WlIIl ellrameduallary haemalopoiesis in Iivet. A In the Mr, tie
sirtUSOids are prominenUy involved by bilineage prolilerallOll. B Megakaryotyles are the hallrnart. 01 abnonnll
irltrasinusoidal haematopoiesis.
an a normal endosteal loc ation in the 8M

12204. 22091. ind ica te an accelerated
p hase of the disease, whereas ~%
b lasts is consid ered as acute uanstometeo. Patients with PMF may also present
initially in an accelerated phase Of an
acute phase . In cases with 20% Of more

blasts in the PB and/Of 8 M at presentation
in which other find ing s may suggest PMF,
the diagnosis 0 1 acute leukaemia shOOd
be made with only mentiOnof the possible
derivation from PMF.
Extramedullary baenatoooleeta
The most common site of EMH is the
spleen , followed by the liver 117731. The
spleen shows an expansion of the red
pulp by erythroid, granulocytic an d
megakaryocytic cells. Their identification
can be aided by immunohistochemistry
[ 16 13, 2 1991. which also allows an appreciation of an increase in neoanqioqenesis / 144\ . Megakaryocytes are often the
most conspicuous component of the
EMH. Occasionally large aggregates of
rreqakeryocytes. growing COhesively. can
ooocce macroscopically evident tt.mOUral
lesions. In the presence of nodular lesions
and , in general. in any advanced stage
disease with large amounts of EMH, the
PQS&bility 01 a myebd sarcoma should be
c:onsidefed and carefully excluded by perlaming irrmunohistological studies with
CD34 117731. The red pu lp cords may
exhibit fibrosis as well as pooling 01
platelets. Hepatic sinuses also show pr0minent EMH. and cirrhosis of the liver may
occur /21671.
Immunophenotype
No abnor mal phenotypic fea tures have
been reported .
Fig.2.24 PrWncwy myeIoIilrosis. 6brollc stage . A ThIs penrtIerBl bloodsme<I" shows dac:ryotytes. occasionalnu::MaIed
red bloodeels <n:I irrrnalJ..nI grarUocytes ~l . BA dilaIed sinus corrtans inmaIIft tIaerrI.1qloiet
elements, most notably megakaryocytes (p,f,$ stain) . ThiS intrasinusoidal haematopoiesi$ together oMth VilSClAr
pn:iIeralJon is charadetisbcbutnot liagl'105bC of PMF WIth myeloid rneIapIa:sia. C Megakaryocytes are ol\en the IOO5t
conspicuous haemalopoielic element il the marrow Often !he cells appear to "'s1ream"1I'rough themarrow due 10 the
In:lerI)tlg fitrosis. 0 Mcrled retJctjn and o:tagen Mln:lsII aSD:iated witha srreanHke arrargemenI of megakMyocytes
arld initial osteosclerosis is $hoIrm (slYerstaIn).
Genetics
No ge netic d efec t specific for PMF has
been ide ntified 11832AJ. Ap proximately
50% of pat ients with PMF exhibit the JAK2
V617Fmutation. Althou gh the presence of
the mutation confi rms the croneltty of the
proliferation, it is a lso found in PV and ET
and thus does not dis tingu ish PMF from
these MPN {163 , 1044 , 1064, 1186, 1288J.
A funct iona lly similar ga in-o f-f unc tio n
mutation of MPL (MPL W5 15K/l ) has
been repo rted in up to 5% at PMF cases.
but in occasional cases of ET as
/16891. Cytoge netic abno rmalities occur in
up to 30% of patients (630, 1832, 21 741.
There is no Philadelp hia chromosome or
BCRABL 1 fusion gene. The presence of
either del( 13)(q 12-22 ) or der(6) t( 1;6)
(q21-23 ;p2 1.3 ) is strongly suggestive b ut
not diagnoslic of PMF [5861. The most
common rec urring abnormalilies inc lude
del (2Oq), and partial trisomy 1q , allhough
+9 and/or +8 are also reported {63O.
1832A, 21741. Deletions aNeeting the long
arms of ch romosomes 7 and 5 occur as
'Nell. but may be associated with prior cytotoxic therapy used to treat the myeloproliferative p rocess.
wen
Postulated cell of orig in

Haematopoi etic stem cell
Prog nos is and p red ict ive fac tors
The time of survival in patients with PMF
ra ng es from month s to d ecades. The
overall p rog nosis de pends on the stage
in wh ic h PMF is firstly di agnosed 11215.
22041. The median survival time is approximately 3 to 7 years in patients diagnosed in the fibrotic stage {142 , 366 . 367 .
630, 2 167/. which contrasts with a 10and ts-vear relative survival rate of 72%
and 59% respectively, in patients diagnosed in the early prefibrotic phase
11215. 12191. Factors at presentation that
adversely affect pro gnosis include age

>70 years . Hb <10 g/d l , platelet count
<1 00x l ()6/l , and an ab normal karyotype
11 42 , 143.366,630, 12 15 , 12 19, 1832A,
2105 ,2174,22041 . The major causes of
morb idi ty and mortality are 8M fa ilure (in.
tecnon . haemorrhage). thromboembolic
events , portal hypertension, cardiac failure
and acute leukaemia (AMl) {21671. The
repo rted frequency of AMl ranges from 5
to 30% 1366, 630 , 21671. Although some
cases of AMl are related to prior cytotoxic the rapy. many have been reported
in patients who have never been treated,
confirming that AMl is pa rt of the natural
history 01 PMF
47
Defin ition
Essen tial thrombocythaern ia (Ell is a
chronic myeloproliferative neoplasm (MPN)

that involves primarily the megakaryocytic
lineage. It is characterized by sustained
thrombocytosis <!:45Ox l()1'A.. in the periph-
eral blood (PS), increased numbers of

large. mature megakaryocytes in the bone
marrow (8 M), and c linica lly by ep isod es of
thrombosis and/OI' haemorrhage, Because

there is no known genetic or biological
marker specific lor ET. other causes for
thrombocytosis must be excluded , including other MPN, inflammatory and
infectious disorders, haemorrh age and
other typ es of haematopoietic and nonhaemat opo ielic neop lasms. The presence
of a BCR- ABL 1 fusion gene exc ludes the
diagnosis of El
IC[).() code
9962/3
bocytose, haemorrhagic thrcrnbocythaemia.
Sites of inv olvement

Bone marrow and blood are the principal
sites of involvement. The spleen does not
show signilicant extramedullary haematopoesrs (EMH), but is a sequestration site
for platelets 1705. 902. 21751.
EtiOlogy
The etiolog y of ET is unknown.
1. SllSIairled' platelet count ~45Ox 10"1t

2. Bone marrow biopsy specimen showing proliferation mainly of the megakaryocytic lineage with increased
nlll'11bers of9l1larged. matul'tl megakaryocytes. No signllical1t increase Of Iefl-sMtofOOlItrophiI glanoopoiesis orer,1IWOpoiests
3. Not meetlng WHO atSerialor poIycyIIlaema vera, P'JI'Nf'Y myelofIbrosI$.< BCR-ABL f posiWe ct.ror.:
myeIogenouIlMaetnia' ormyeIodysplaslic syndrtml" Of oIher myeklid ~
4. Demonstration 01 JAK2V617F orolher donal maricer. or in !tie absenteofJAK2V617F, no e-.1dence lor
reeceve thrombocy1osls'
Sustatned ooring the W(ri.-up process.

Requires Itle fcMure of iron repIaoement ItIefapy toincrease IIaemoglcOf1 level10I!'oe polyc)1IIaemia "'llfa
fange Illhe presence of deaeased serum lerTilin. Ex<iJsion ofpo/ytyltIiIllfllia vera is based on haemoglobin
rod hilemiIIocrtIeve!s and red eel mass meiISl.Ifement is not required.
Req.wes!he absence 01 relevartre!iQjn Ibosis. coIagen fitll&s, ~ ~~ ,
Of markedly hyperceIuIar marrow aetOll"C'3ried by megakaryocyte IIUphoIogyIhat III lypicaI for primary
myelofibrosis ifIcludtng smaH 10large rnegakaryocytes WIth an aberranl nuclearl~smic ratio iIfId
hyperchromatic. bulbous Of irregularlyWed noc~ and dense dusterirlg.
Requires the absence of BCRABL 1.
Requires abser'loe ofdyserythlopoies and llysgranulopoiesis.
, Causes of reactive thrombocytosis iIdude I/'Ofldeficiency. splenedomy. StJfgefY. nedion. inllammation.
alM8CtIVe!lssue disease . melastIticcancer. and ~trve disorders However. the presence of
a cendIOOn iIS800ated wllll reactiveborrtlocyt)sis may noI edJde fie possility d ET 't!he fnl wee
criteria are met
48
Myelopro liferative neop lasms
H M. Kvasnicka
A.Orazi
A. Tefleri
H. Gisslinger
Epidemiology
The true inc idenc e of ET is unk now n, bu t
when di ag no sed according to the g uidelines of the Polycythaemia Vera Stu dy
Group (PVSG)115491. it is estimated 10 be
06-2.5 per 100 000 persons per year
{1055. 10591. Most cases occur in patients
50-60 yea rs 01 age , with no major sex
predil ect ion. How ever, a second peak in
frequ ency, pa rtic ularly in women , oc c urs
at about 30 years 01age 1705. 902 . 10551.
ET can also be seen in ch ild ren , albeit infrequently 118151, but must be distinguished from rare cases 01 hereditary
thrombocytosis 1585. 24011.
Synonyms
Primary thrombocytosis: id iopathic mrom -
J . Thiele
Cli nical features

More than one half of patients are asvrrptomauc when a markedly elevated platele!
count is discovered lortUitously at the tJml!
of a routine PB count 1705, 802 , 9022 1751. The remaining patients preset
with some manifestation of vascular
occ lusion or haemorrhage 1210, 4581
Microvasc ular occlusion may lead to trarlstern iscnaemc attacks, digital ischaemia
with paraestheeias. and gangrene 1210.
458 . 1473. 18291. Thrombosis of map
arteries and veins also occur. and ET may
be a cause 01 splenic or hepatic veil
thrombosis as in the Budd-Chiari syndrome . Bleedi ng occurs mos t comrrow
from mucosal surfaces. suc h as the gastrointestinal trac t or upper airway passages 1379. 802, 1549. 19551. If h
criteria established by lhe PVSG 101 E1
are used. mild splenomegaly is present
approximately 50% of pa tients at diagnosrs
and hepa tome ga ly in 15-20% 1705, 802.
902, 1549 , 2 175 1 How ever, when !he
WHO classification is applied and patients with thrombocytosis associated
the p relibrotic stage 01 primary myeIcj.
brosis (PMF) are excluded. spIencrneg<I,
is seen in only a minority of patients
ET112151. Rare pa tien ts who meet the
terra for ET have been repo rted to half
noncronat meqakervoc vtoootests eoe I
tower incidence of thrombo tic epi
19011. kry relationship of such cases 10
vast majority of cases 01 ET that
clonal haematopoiesis is not clear.
In ee past, the platelet threshold for the

diagnosis of E'r was :!:600x109/l115 49J,
but some patients have haemorrhag ic or
ltuombolic episodes at lower platelet
cents 11272, 1829, 19031. In order not to
C01lprcmise the diagnosis in such cases,
a number of investigators convincingly
argued tOl" a lower platelet thresho ld for
ee diagnosis of ET. and the WHO has
adopted the recommenda tion of a platelet
COltlt ~450 x 1 l)l'IL, a value that exceeds
!he 95th percentile for normal platelet
counts adjusted for gen der and rac e
(1272. 1897, 1903.21771. Although this
llYeshoid will encompass more pat ients
1Io'!lh ET, it will also include more pat ients
'I4lCCflditions that mimic ET. It is therefore
essential that all Criteria listed in Table
200 for the diagnos is of ET be met to exewe olher recotastc and non-neoplast ic
causes 01 thrombocytosis 12 1771. The 8M
bi:psy is particularly helpful in exc luding
ere myeloid neoplasms associated with
excessive platelet counts. such as myelodysplastic syndrome (MDS) associated
wltrl isolated del (5q). the prov isional
'l'r)'eIodysplasticlmyeloprohferative entity
refractory anaemia with ring sioerobras ts
and thrombocytosis (AAAS-T), and the
cetoronc phase of PMF. Althou gh the
JAK2 V617F mutation is fou nd in only
40-50% ot cases of ET and is not specific
b' ET, when present it does exclu de reectve mrorroocv tosrs 121771. Similarly, in
eeo enocqeroue erythroid and/or meg akaryocytic colony formation, althoug h not
specrlic tor ET, also exc ludes reactive
ltYombocytosis 15941.
a normocel lular or moderately hypercellular 8 M {775, 22161. The most striking abnormality is a marked proliferation of
megakaryocytes with a predominance of
large to giant forms displaying abundant,
mature cytoplasm. and deeply lobulated
and hyperlobu lated (stag- horn like) nuclei. The rnegakaryocytes are usually dispersed throughout the BM but may occur
in loose clusters. Bizarre, high ly atypical
megakaryocytes, such as those observed
in PMF, are not found in ET and if present.
the diagnos is of ET should be ques tioned
1712, 796 , 2200 , 22051. Proliferation of
erythroid precursors may be found in a
few cases, p articularly if the pat ient has
exper ienced haemorrhages. but granuloc ytic proliferation is highly unusual; If
present. the increase in granulopoiesis is

usually only of mild degree. There is no increase in rnvetobtasts nor is myelodysplasia observed, The network of reticulin
fibres is normal or only minimally increased in ET. and the find ing of signif icant retic ulin fibrosis or any collagen
fib rosis excludes the diagnosis of ET
1712, 775, 796, 2177, 2205, 22161. Bone
marrow aspirate smea rs also reveal the
markedly increased numbers of megakaryocytes of large size with hyper lobutared nuclei and . in the background. large
sheets of platelets. Emper ipoles is of BM
elements is frequentl y observed in ET. but
is not a spec ific find ing. Stainable iron is
present in the aspira ted BM specimens of
40-70% of patients at diagnosis 116491.
f ig. 2.27 Essential ttwombocylhaerma, bone marrow aspl'ate smear. AAll increase in the nurrtler and size of the
megailaryocyles. B NoIe the deeply Iobutaledmegaka'yocytic ~, as well astarge pools01 pla te~_ Note that the
aspirate smears fail to reveal the overall marrow archilecture anddistribution of the rnegar.aryocytes thatcan be (Illy
seen in the biopsy,
Mo'phology
The major abnormality seen in the PB is
marked thrombocytosis, The plate lets
often display anisocytosis, rang ing from
tiny torms to atyp ica l large, g iant
platelets. Bizarre shapes, pseudopods
and agranular platelets may be seen, but
are rot common. The white bloo d ce ll
(WEq count and Ieueocyte differential
~e usually normal, although a borderline
eevaton in the WBC count may occur
(705,802.902, 21751. Basophilia is usuaMy absent or minimal 115491 _ The red
blOOd cells are usually normocytic and
rcerccnrcnc unless recurrent haerrormage has caused iron deficiency, in
W"Mch case they may be hypochromic
and microcytic. Leckoervtnrobleetosts
d teardrop-shaped red blood cells are
IQ seen I'l ET 121751.
~ rrosl cases, the BM core biopsy shows
49
react ive thrombocytosis , An abnormal

karyotype is found in onl y 5-10% of patients with ET when d iagnosed according
to lhe previou s PVSG criteria {15491. There ;
is no consistent abnormality. but those
reported include +8, abnormalities of 9q,
and del(2Oq) {939, 1682 1. Ahhoogh isoIatoo
del(Sq) has also bee n reported in ET. cerelui rrorphologic examination is required 10
distinguish such cases from MOS associated with this abnormality 116821.
Postulated ce ll of ori gin
Haematopoetc stem cell.
Prognosis and predictive factors
ET is an indolent disorder characterized
The lTIOfphological findings in the 8M

biopsy are essential to distinguish ET from
other MPN. myeloidosooes and reactive
may initially present wittl thrombOCytosis

without leukocytosis and can mimic ET cl~
conditions tha t p resen t with sustained

ttlrcmbOCytosis , The finding of even a mild
degree of combined granulocytic and erymroo proli feration should raise consideration of prodromal stage poIycythaemia vera
(PV) 122101. and the finding of granulocytic
proliferation associated with biza rre. hig hly
atypical megakaryocytes should p rom pt
concern lor the prefibrotic slage of PMF
12201,22231 . Significant dyserythropoiesis
or dysgranulopoiesis sug gest a d iagno sis
of MOS rather than ET. The large me gakaryocytes with hy per lobulated nucle i of ET
contrast with the medium-sized monoioba ted megakaryocytes associated with de l
(Sq ) as an isolated ch romosom al abnormality in MDS and with the small. dysplastic megakaryocytes associated with the
inv(3)(q21q26 2) or t(3;3)(q 21;q26.2) chro mosomal abnormality. Lastly, some patients
with c hronic mye logenous leukaemia (CML)
ET can be easily distinguished from the

sma ll -dwarf" megakaryocytes of CML. cytogenetic and! or
genetic analysis to exclude a BCR-ABL 1 fusion gene is
recommended for all patients in whom a diag nosis of ET is considered 11841 1.
;cany. AJ1hough !he ""90 rnegaJ<ao,ocytes of
rroecuer
Immunophenoty pe
No aberrant pherotype has boon described

Genetics
No mol ecular genetic or cytogenetic abnormality specific for ET is known. Approxim ately 40-50% of cases ca rry the JAK2
V617F or a functi ona lly sim ilar mu tation
1163. 1044,1064.1186.1 2881, Thesemutatoos are not specific for ET and are found
in P\I and PMF as well, A gain -of-Iuncti on
mutation of MPL. MPL W515K/L , has been
reported in 1% of cases of ET {16891. None
of these mutations are found in cases of
Table 2.07 WHO diagnosbc cnleria lor posl~ssenlial thrombocythaemia myelofibrosis (postET MF),
R.quired criteria
1. Documenlatiol'l of a prevklus diagnosis of WHQ-defined essential ttlrombocythaemia
2. Bonfl marrow fibrosis grade 2-3 (011 0-3 scale) or grade 3-4 (oo 0-4 scale )
Additional crittril (2 are ~j..-cl)

1. Anaemia' 22{1dl decrease from baseline haemoglol*1leve1
2. A leukoefythrobla pe~ bloodpiclufe
3. Incr&aSingsplenomegaly defiMd as &$ler an Increase in palpable splenomegaly of>5 emfrom baseIne

(lislance Ircm ltIeleft C05laI margin) orIle appearance 01 newly p.alpable splenomegaly
4. Increased LDH (atloYe reference level)
5, Development 01 >1 of3 CXlIlSlrtlllional s~ : >10% weight bss in 6 month$. right sweats, I,Il8lplBined
illver{>37.5-C1
50
MyeloproliferatIVe neoplasms
by long symptom-free intervals, inter,

ruptec by occasional ute-mreaten
thromboembolic or haemorrhagic episodes 1705, 802, 902, 12 15, 154 9, 2175
Although after many years a few pat
with ET may develop 8M fibrosis associ-ated w ith mye loid metaplasia (EMH
such progression is uncCll'TYTlOl1 1297, 775.
1189.22201. Precise diagnostic guidelines lor diagnosing post-Ef MF are given
in Table 2 .07 . Strict adherence to
and other WHO c riteria 1143A . 21771
necessary to prevent diagnostic comus
associated with early PMF accompa
by thrombocytosis 1365}. Transformation~
ET to ac ute myeloi d leu ka emia or MOO
occurs in <5% of patients, and when
does occur is likely related to previous
cytotoxic therapy 1705 , 802, 90 2, 1800
M ed ian survivals of 10-1 5 yea rs are
common ly rep orted . Beca use ET usu al~
occurs late in midd le age. the [,Ia
ex pecta ncy is near normal for m an~
patients {1215. 1702 , 2200 . 2430}. Fi nal~
it is noteworthy that the maj ori ty of c lini
stud ies are based on prev iou s d iag l10stic
gu id eline s 11 549 } that fail to d ifferentiate
clearly between the early prefibrot
stages of PMF wit h accompan ying thr
bocvtosrs an d ET ac cordi ng 10 the
classification 11215, 2200, 2205} . A su
stannat d ifferenc e in ove rall prognosis
been reported w hen these two di ffer
ctessmcanon sys tems are ap plied to
same pa tien t population 112151.
Chronic eosinophilic leukaemia,

not otherwise specified
Ctwooic eosinophilic leukaemia (CEL) is a
myeloproliferative neoplasm (MPN) in
which anautonomous. clonal proliferation
01 eosinophil precursors results In perSistently increased numbers of eosiroptliIs in the peripheral blood (PS), bone
(BM) and penooerarnssoes. with

being the dominant baemak*lgical abnormality. Organ damage ccClSS asa result oueceaemc infilt ration or
ee releaseof cytokines, enzymes Of other
proteins by the eosinoctas. Chronic
matrON
eoSKlOPh~ia
eosinophilic leukaemia . not otherwise
specified, (GEl. NOS) excludes patients

WIth a Philadelphia (Ph) chromosome,
BCR-ABL llusion gene or rearrangement
01 PDGFRA, PDGFRB or FGFR1.
In eEL, NOS the eosinophil count is
n5xl ~1L in the blood. There are fewe r
than20% blasts in the PB or 8M . To make
adiagnosis 01CEl. there should be evidence/or clonality of the eosiropbus or an
ecreese in myeloblasts in the PB or 8 M.
In many cases however, it is impossible to
proyeclonalrty 01 the eosoo ptuls. in w hich
case, if there is no inc rease in blast
cells, the diagnosis of "id iopathic hypereosinophilic syndrome" is made . The
idiopathic hypereosinophilic synd rome
(idiopathic HES) is de fined as eosi nophilia (~1.5~ 1CfJ/L) persisting for at least 6
months, for which no und erlying ca use
can be fou nd , and w hich is associated

with sig ns of organ involveme nt and dysfunction 1443, 23821; there is no evidence
for eosinophil clonality. It is a diagnosis 01
exclusio n. and may inc lude some cases
of true eosinophilic leukaemia that cannot
currently be reccqnrzeo. as we ll as cases
01 cytokin e-d riven eo sino philia that are
due to the ab normal release of eosinophil
gr owth fa ctors, e.q . interleukin (IL) 2. 3
and 5, fOf unknown reason s (128 , 443 ,
1971. 2072 , 238 21.
ico-oeeee
9964/3
Synonym
Hypereosinophilic synd rome (not recommend ed) .
Ep idemiology
Due 10 the p revious dilfic ulty in d istingu ishing CEL f rom idiopat hic HES. the
true inc id enc e of these di seases is
unknown, althou g h th ey are rare . Many
patients wh o wou ld until rec ently have
bee n c lassified as hav ing idiopathic HES
ca n now be show n to have C El assoc iated w ith a FJPtL 1-PDGFRA fusion gene
{466 1. Since this co ndition oc cur s mainl y
in ad ult me n, the male dominanc e and the
peak inc ide nce in the four th decad e
prev iously descr ibed in "HES" {443 , 1971 ,
2072, 2382 ) are now exp lained , at least in
BJ. Bain
D.G. Gi lliland
J W , Vardiman
H .-P. Horny
pa rt. The epidemiological features of

cases of HES that rema in idio pathic have
not vet been c learly d efined.
eEl
is a multisystem disorder. The PB

and BM are alwa ys involved . TIssue infiland release of
tration by the
cytokines and humoral factors from the
eosinophil g ranules lead to tissue damage in a number of organs, but the heart.
lungs , central nervous system, skin and
gastrointestinal tract are commonly invoiveo. Evidenc e of sp lenic and hepatic
invo lvement is p rese nt in 30-50% of
patients 1443. t97 1. 2072 , 23821 .
eos.roonns.
Clinical features
Sometimes eosinophilia is detected
inc identally in patients who are otherwise
asymptoma tic . In othe r pa tients, co nstitutiona l symp toms , such as fever, fatigue ,
cough, ang ioed ema . musc le pa ins, pr uritus and d iarr hoea are found . The mo st
serious clinical findings relate to endomyoc ardi al fibrosis . with ensu ing restrictive
ca rdiomeg aly. Scarring 01the mitralltricu spid valves leads to valvula r regurgitation
and formation of intrac ard iac thro mbi,
w hich may embouze to the brain or elsew here, Perip heral ne urop athy, cen tra l
nervou s syste m dy sfu nction, pulmonary
symptoms due to lung infiltration, and
Chronic eosinophilic leukaemia. not otherwise specdied
51
rheoma toroptcar findings are other frequ ent ma nifestations (443, 1971 , 2072 ,
2382 1
In CEL, NOS the most striking feature in

the PB is eosinophilia, there being mainly
ma ture eosinophils with only small numbers of eosi no p hi lic myelocytes or
promyelocytes {443. 710, 12OJ. 1971, 2072,
23821. There may be a range of eosinophil
abnormalities, including sparse granulation
with clear areas of cytoplasm, cytoplasmic
vacuolation, nuclear hype rseg men tation
or hyposeg me ntati on, and enlarg ed size,
These c hanges ma y be seen in cases of
reec uve as well as of neoplastic eosinophilia, however, and are thus not very
he lpful in deciding whether a case is likely
to be CEl {1281. Neutrophilia often accom pani es the eosinophili a , an d some
c ases have monocytosis, M ild basoph ilia
has been reported 17101, Blast cells may
be present but are less than 20%.
The BM is nvoercenotar due in part to
eosinophilic proliferation 1289, 443. 710,
1200, 2382 1 In most cases, eosinophil
maturation is orderly, w ithout a d isp ro portio na te inc rease in m ye loblasts. Ch arcotl eyden crystals are often present.
EryttTopoiesiS and megakaryOCytopoiesis
are usually normal. The finding of inc reased num bers of m yelob lasts (5-19%)
supports a di agn osis of CEl, as does the
ob servation of dysp lastic features in other
cell linea g es. M ar row fibrosis IS seen in
some cases 1289, 7101. Any tissue may
show eosinophilic infiltration and Charcotleyden crystals are often present. Fibrosis is a common find ing . an d is caused by
the d egr anu lati on of the eo sin op hile wit h
the release of eosinophil basic protein
and eosinophil cationic proteins {443,
1931 ,2382} .
Fig. 2.31 Ch ron ic~oop/l i l ic ~uk.aem ia . Peripheral blood smear from a patient With ahistory ofpersjstent eosi1c?*
Immatureaswell as mature eosinophilsarepresent CyloQenebc arlalysis showed trisomy of chromosome 10,
disease 1128. 19311. In addition, a number of neoplastic disorders such as

lym phoma, Hodgkin lymphoma, sys tem ic
ma stocytosi s, acute lym p hob last ic leuk
aemia and other MPN may be associated
with abnormal release of Il2, 1l3, ILS or
GM-CSF and a secondary eosinophilia
tha t mimics CEll 128 , 1168, 1172, 1450,
1616. 1924, 1931,246 11: in systemic mas tocytosis there can also b e eosinop hils
be looging to the neo pl astic clone. The BM
should be carefully inspected for any
process which might explain the eosinophilia as a secondary reaction, such as
vasculitis, lymphoma, acute lymphoblastic leukaemia , sys tem ic m as toc ytosis o r
gran ulomatou s d isorders. Some cases of
persistent eosinophilia are due to the abnormal release of cvtocnes by t-eens that
t-een
are immunophenotypical1y aberranl an:!

tha t mayor may not be clonal 1286, 1156.
202 41. When such an aberran t T-c ell pop.
ulati on is presen t, the case is not CEl00
is it idiopathic HES. If the monocyte con
is > 1x1r:P1L a diagnosis of chronic mye;o.
monocytic leukaemia with eosinoptlU
may be more appropriate, but if there are
dysplastic features and> 10% neutrophl
precu rsor s in the PB and no rnonccytoss.
a d iag nosis of atypical chronic myebd
leukaemia with eosinophilia should Sifn.
larly be considered.
The distinction between GEl. NOS. arc
idiopattuc HES is important. Idiopattlc
HES can be diag nosed onl y in fUlly investigated pa tients and on ly when (i) there,
an eosinophil count of <!:1.5x 1()l11l perse
ing lor at least 6 months; (iil reaclM
Differential diagnosis
D iag nosis re qu ires posi tiv e evidence of
the leukaemic nat ure of the co ncnton and
exclusion of cases of MPN with rearrangement 01 PDGFRA. POGFRB or
FGFR1. The diagnostic process often
starts wi th exclusion of reactive eosinophil ia. A d eta iled histor y, physical exam ina tion, b loo d count an d blood film ar e
essential. Conditions to be excluded
include parasitic otectoo. allergies, pulmonary d iseases such as Loetner's syndrome. cyclical eosinophilia. skin diseases
such as anqictymphoid hy perplasia, colla gen vascular d isorders and Kimu ra 's
52
1. There iseosinophilia(eosinophil count <!:1,5x1(ll1L)

2. Thefe is no Ph chrorrosome or BCR-ABL 1 fusion gene or oItIer myeloproliferative neoplasms (PV. ET. PMF)
orMD5ItolPN (CMULIX ICML)
3. There is nott.5;12)(q31-35.p13) ohIr ream1l9B"*~of PDGFRB

-4
There is no FlP1l1-PDGFRA fusion gene crotherrearrangement 01 PDGFRA
5, There is noI'88rrangemerlt of FGFR1

5. Theblast cell count in the peripheral blood and bone marrow is less than 20"10 and there is 110
'l\'(15)(p13Q22) IX 1(16;16)(p13;q22) IX oIher lealureGagrlosbc ofAML

7. There is a cbIaI cytol}eneIiC or rnolecaar genetic abnormaIrty, IX bIasleels aremore lhan ~ in !he
~ bk:Jod men than 5% in !he bone marn:ow
If apatient haseoiil"lOPhilia bul lhese mlenaare not met !he dial;Joos4S may be reactive eosinopt1ilia,idiOpa1tMc
hypereosinophilia or idiopathic hypereosinophilicsyndrome,
,.
e
tiC
1m
Nc
m,
G.
No
"'"
;d
a,
Fa
lu
ca
wit
GEl
con
maO
as
eosinophilia is excl ude d by appropriate

h:lrcxJgh investigatoo ; (iii) AML. MPN, MOS.
MPN/MDS and systemic ma stocytosis are
excluded; (iv) a cytokine-prod ucmq.
~icalty-aberrant. t-een pop ulation is excluded; (v) and there is tissue
damage as a result of hyper eosinophilia .
Hcnteria i-iv are met but there is no tissue
damage. the app rop riate d iagnosis is
ocoamc hyperoosinop hilia .
Patl8rlts in whom a diagnosis of idiopathic
Itypefeosinophilia or id iopalhic HES is
made should be kepi und e r reg ular
review since evidence may su bsequently
Emel'g8 that the con dition is leukaemic in
!'laue, Treatment may also be necessary
e,tlchemstry
Cytochemical stains c an be used to
identify eosinophils bu t they a re no t
essential for diagnosis , Partial degranulaeco can lead to eosinop hils ha ving
reduced peroxidase con tent.
No specific immuno p henotypic ab nermalily has been reported In CEL.
Geretics
No single or spec ific cytogenetic or
molecular genetic ab normality has been
identified in CEl. NOS . Cases with rearrangement of PDGFRA, PDGFRB or
FGFRI are spec ific ally excluded , The
detectOO d a Ph cbrcroscre or BCR-ABL 1
fusion gene ind icates one of the rare
cases of chronic myelogenous leukaemia
wnh dominant eos inoph ilia . rather than
eEL. Ellen when eosinophilia occurs in
conjunction with a ch romosomal abnormality that is usually mye loid neoplasmassociated, it may be difficult to decide
_.-
F"l9- 2.32 kiopaltiC HES. Ablood smeard a pabertWlth ca-dIaclai.n,1eukot'yt:lsi$ and~ .
whether the eosinop hils are pa rt of the

clonal process. since react ive eosi nophilia
can occur in patients with myeloid neo-pla sms 17111. However, the linding of a
recurring ka ryotypic abnormality that is
usually ob served in my elo id d isord er s.
suc h as +8 or i( 17q), does suppo rt the d iagnosis of CEl 1128, 1692 ). Occasiona l
pat ients have a JAK2 mutat ion 1106 41.
x-unkeo polymorphism ana lysis of the
PGK or HUMARA genes c an oc ca sionally
be used in fema le patients to dem onstrate
cionautv 1392, 13501.

Survival is quite varia ble. In some series
in which pat ient s with idiopathic HES as
well as those with probable eosinophilic
leukaemia were incl uded. 5-year survival
rates ap proached 80% 1443. 19 71,2072,
23821. Marked splen ome g aly. as well as
the find ing of b lasts in the b lood or
inc reased b lasts in the 8M , cvtcqeneuc
abn ormalities and dysplastic features in
othe r my eloid lineages have been reported to be unfavourable prognostic
find ings [443, 1971. 2072 ,2382].
Postul ated cell of or ig in

The ce ll of orig in is a haemopoietic stem
cel l, b ut the lineag e potential of the
affec ted cell may be var iab le.
Chronic eosocobtc leukaemia. not otherwise specified
53
Mastocytosis
H ,-P' Horn y'
n.o. Metc alfe

J.M . Bennett
B,J . Bain
Definition
Mastocytosis is due to a c lonal, neoplastic
prolife ration of mast cells thai accumulate
in one or more organ systems. It is characterized by the presence of mult ilocal
compact clustersor cohesive aggregates!

infiltrates of abnormal mast cells. The d isorder is heterogeneous. ranging from skin
lesions that may spontaneously regress to
highly aggre ssive neoplasms associated
w ith muttiorgan failure and short survival
(Table 2.09). Subtypes of mastocytOSis are
recog nized mainly by the distribution of
the disease and cli nical manifestations . In
cutaneous mastocyt osis (eM), the mast
cell infiltration remains confined to the
Solitary mastoc ytoma

of skin
Indolent systemic
mastocytosis
withAHNMO"
Aggressive systemic
mastocytosis
Mast cell leukaemia
Mast cell sarcoma
Extracutaneous
mastocytoma
skin, whereas systemic mastocytosis
Synonym
Mast cell d isease .
IC[)..() codes
Cutaneo us mastocytosis
(urtica ria pigmentosa)
Diffuse c utaneous
mastocytosis
9740/1
9740/ 1
Table 2.09 Classification of mastocytosis.

, Cutaneous mastocytosis (CM)
2, Indol&nt s)'5t&mic mastocytoSis (ISM)
3. Sy5temic mastocytosis wittl associatedclonal

haematological non-mast-celliineage disease
(SMA.HNMDj
4 AggressiwSy5temic masklc)'toSis (ASM)

5, Mast cellleul<.eemia (MCl)
6. Mast c:eII sarcomlI (MCS)

7. Ertacutaneous meslocytoma
For the partlClpl!lms 01 the Vear 2lXXl Wortung Group

ceeeeece on Mes\OCytOllS .....no ~ flo.ooIved in the
def,r1llJOIl 01 cr<terlll and WHO cIassohcllllOll 01rrestoC)'lOSIS' C Alr,1'l . KF Auslen . Jt,4 Bernett. AD BrI.roning.
l Elicr lbano. H-P Horny. I( lerI'lerI. CVI.J. JB Longley,
G Marone. 00 MelC8Ne. A Nunez . MA P_aresch.
LB Sct>warU. I( Sollar. ~ $perl. P V8Ienl. .IN 'laid..
man. K WOlIf
54
MyeloproliferatIVe neoplasms
9740/1
974 1/ 1
97 41/3
97 41/3
97 4213
974013
974011
"AHNMO, ass oc iated naematoioqrce!

c lonal non-mast cell d isorder
(SM) is characterized by involvement of at

least one extracutaneous organ with or
without evidence 01 skin lesions . Mastocytosis shoul d be strictly separated from
mast cel l hyperplasia or mast cell activation
slates without morphological an dJor m0tecuer ab normalit ies that characterize the
neoplastic proliferatio n.
C. Akfl
L Escribaro
P. Valert
Fig. 113 Cutaoeoos maslOCytosiS. Darier"s '91- TIl

skit lesions 01 III bms 01 0Jtane0us II'\a:Stlc)t::s
~ wI'len stroked A. palpable wileaI ~. IN
moments afterhlltJysical sllrIUatIon, lkJe" hi,..
0I1t1slamnt from !he mastcells,
Epidemiology
Mastoc ytosis may occur at any age Cutaneous mastocytosis is most common in
c hil dren and may be present at birth.
About 50% of afflic ted chil dren develop
typical skin lesions before 6 months of age .
In adults. CM is less frequently diagnosed
than in ch ildre n 12055 . 2436 1. A slight
male predominance has been rep orted in
C M. SM is generally di ag nosed after the
second decade of life ; the ma le to female
ratio has been report ed to va ry from 1:1
to 1:31 181, 1465, 1694).
Approximately 80% of patients with mas toc ytosis have evid ence of skin involvement
{16871 . In SM the bone marrow (BM) is almost alwa ys involved, so morp hological
and molecula r anal ysis of a BM b iop sy
specimen is stron gly rec ommend ed 10
con firm or exclude the diagnosis [287.
290, 971, 12751. Rare ly. the pe riphe ral
blood (PB) shows leukaemia due 10 significant numbe rs of circulating mast ce lls
{972. 14841. Other organs that may be involved in SM inclu de the sp leen. lymph
nodes, liver and gastro intest inal tract mucosa, b ut any t issue may be affected
1287,966.968.973, 1275, 1334. 1466.

1694 1. Skin le sions occur in more than
50% of SM pat ients, and are more often

observed in those with an indol ent course.
Fig. 2.34 Cutaneous mastocytosis, Numeroos typi:;i
eac nar and maCtllop.apular pigmented eseu ct

urticaria ~gmentosa in a young child "
Fig. 2.35 Ditluse artaneous mastocytosrs. T'I'OenC.

reddlSh'peau ~' 1esic:In$ d'Ia'acteI'isbc oIlilta
cutaneous mastocytosis This variant ocan

exdusiYely in d*\'eIl
am:..
In contrast. aggress ive va riants of SM

often present without skin lesion s [97 11 .
However, some SM patients withou t skin
escos may on occasion present wit h an
indolent form of SM, most often isolated
8M mastocytosis.
CIricaI features
Cutaneous mastocyt osis includes several
cetrct cmco- nistocettoicqcar en tities.
l esions of all form s 01 CM may urticate
when stroked ("Darier's sign 4 ) and most
snow intraepidermal accumulation of
melanin pigment. The term 'wtcana
4
ptgmentosa mac roscop ically describes
two clinical features. Blister ing
("b.bJs mastocytosis") does n:lI represent
a separate subtype but rather an exaqgeralion 01 urticaria. Blistering is usually
seen IrIpatients less than 3 years of age.
m may be assoc iated with all forms of
CM 11 68 7, 2055, 24361.
Symptoms in SM at presentation have
beefl grouped into 4 c ategor ies: 1) conSbtUtIOO8! symptoms (fat igue, weight loss,
Mr, diaphoresis). 2) skin manifestations
(prurituS, urticaria, dermatographism).
31mediator-related systemic events (abdcminal pain. gastrointestinal d istress ,
Dushing. syncope, headache. nvpoienson.
tachycardia. respira tory symptoms) and
4) musculoskeletal complaints (bone
pain. oeteoceora'osteoporoers. frac tu res,
<JltIralgias, myalgias) {181, 22901 . These
symptoms range from m ild in many
pabents to severe, life-threatening med iatorrelated events in othe rs, Sym ptoms ma y
also be related to orga n impa irme nt (du e
10 mast cell infiltrates), pa rticularly In
patients with high-grade ag g ress ive or
eukaernic disease variants,
Physical findings in SM at d iagn osis m ay
InClude splenomegal y (o ften minimal).
\lltile~dooopalhy and hepatome galy
are foond at signif ica ntly lower trequencies !966,968, 973. 1275, 1466 1. Organornegaly is often absent in the m ost
rormon variant. indolent systemic mastocytOSis(ISM). but is usuall y p resen t, alo ng
w impaired organ function, in aqq resSNesystemic mastocytosis (AS M) an d in
leukaemic variants. Severe systemic
~s may occ ur in patients w ith ISM
bbwIg eceosve release and generatIOn
rJ bcctemcar mediators including tustaI'!'f'e. eicosanoids. poteases and heparin.
For example, gastrointestinal symptoms
S\.d1 aspeptic ulcer disease Of diarrhoea
n more corrmonly attributed to release
rJ biologiCally active mediators than to
Fig. 2.36 Indolent syslelTllt mastocytosis. Dense

infiltrate conSisting mainly 01 spind~ sti\tJ1Iy
~nUar
mast eels.
sese
ceeoanc
Fig. 2.38 Indolent systel'lic mastoeylOSis. A loo5eIy scattered spmd\Hhaped tlypograrlular mast cells WJlhooI
tendency III awegate. Diagnosis is lacihlatedI'fhen addibonal imrrI.rnostaHWI and moIeaJIar analysis n performed.
B IrrITlIA'lOSlain withCD25 shows an atypical ~ 01 mast eels with rnentlralle assooated reactivity.
Fig. 2.39 Systemic mastocytosis, Skeletal lesions ate common in systemic masloc,1OSiS. This X-ray shows paldty
osteosclerosis, osteoporosls WId multiple IyIiclesions mille lemur,
infiltration of the g astrointestinal trac t by
excessive numbers of abnormal m ast
cells P8 1. 1334 , 2288 1.
Ha ema tologica l abnormalities in 8 M
include an aemia , leukocytosis, blood
eosinophilia (a frequent f inding). neutropenia . and thrombocytopenia 1130,
287.7 13.971 , 1162 , 16871. Bone ma rrow
failure is encountered only in patients with

aggressive or leukaem ic disease varian ts.
Significant numbers of circulating m ast
celts are rarely observed and are suggestive of mast cell leu kaemia 122901. In
up to 3)% of cases with SM. an associated ,
clonal haematological. roo-mast cellileage

d isease (AHNMD) is d iag nos ed before.
MasfOCytosis
55
T~ble
2.10.Criteria lor cutaneous end systemic maslocytosis
Cutaneous mastocytosis (CM)"

SIOO lesions demonslrebng!he typical dinicallindlng5 ofUPIMPCM. diffuse cutaneous mastocytosis or soIttary
mastocytoma, and lypiCBltlistoIogical i1filtrates 01 masl cells in a lTlJltJlocal or dlfIuse ceeem in anadequate skill
biopsy. Inaddition. a tiagnosbc prerequiSIte b thediagnosis of CM is theabsence 01 features/aliena
sufficiant toestablish the ~s 01 SM
l/p(laled and &I9llly modified cnteliab skin i1YO/YemerJt in mastoey!OSiS have recetlUy been suggested {<t7A}.
S)'Itemic mastocytosis (SMI
The diagnosis 01 SM CBl be made when the IIIaJOI' critenon and one IIIir'Ia criterion or at least Ihnle mnor
crrteIia are prMel'll
lIIajor crilerion;
t.UlrfocaI, dense rliIlrates rJ mast eels (::!:15 mast celI$ n ~) deleded i1 sections of bone I'IllIITOW
and/or OCher eltraaAaneous organ(s)
Minor criIW:
1. In biopsy sedJons rJ bone nwrow orOlIlItel1raCUlaneOuS organs, :>25%ollhe mast eels r11he
infihle are ~ orhaveatypocaIlll(llllI1CJIog or, d aI mas! eels n bone m.arrtM'asprate
smeaR, :>25% aremnalln oratypical.
.........
2. Deleclion of an ICtiYaII'lg poI"It rnuta\lI:Wl at c:odor1816 of KIT~ bone manow. blocdor anolher eJ:lraCula.
3. MastOBIs itI bone marrow. blocdor oItler eJhcutaneous organs express CO2 and'orC025 in adl;1itlOII ~
nonnat mast 011 maR-eB.
<t 5enJm tolaI tryptase pet1istetllly exceeds 20l'lgIml(unless!here is an associated daIaI myeloid dIsordar, it
wtictI caselhisparamet9f 1$ not valid).
simultaneously with. or after the diagnosis of SM. In princi ple, any defined
myeloid or lymp hatic malig nancy may
occur as the AHNMD. but myeloid neoplasms predominate, and chronic myelomonocy tic leukaemia (CMML) is most
common 197 1, 9 75. 2056, 2066, 2095,
22901. In patient s with SM-AHNMO, clinical sympt oms and disease course relate
both to the associated baematoioqrcat disorder and to SM 11977, 2290).
Serum tryptase levels are used in the
evaluation and monitoring of patients with
mastocytos is, The finding of a pers istently
elevated serum total trypta se > 20 ng/mL
is suggestive of SM and is used as a
"minor" criterion for diagnosis, unless there
Fig. 2.40 Typical skin lesion of a d\Ild WIlh ur1icatia

pigm&nIosa. Aggregales of mast cells Iil Ihe papIIafy
demIII a'ld edllnd as 5he8ls into Ile f'8tJCWr clemis.
56
Myeloprol!ferative neoplasms
is an assoc iated clonal myeloid non-mast

cell disorder, in which case this parameter
is not valid. Serum trypta se levels are normal to slightly elevated in mos t pat ients
with CM and have also been found to be
independent of the patient's tryptase
hap lotype 11977, 2290).
Morphology
The diagnosis of mastocyt osis requ ires
demonstration of rnultifocal clust ers or
co hesive aggregates/infiltrates of mast
cells in an adequate 8M biopsy specimen
(Table 2, 10), The histolog ical pattern of
the mast cell infiltrate may vary according
to the tissue sampled 1130, 290 , 7 13, 966,
968 ,973, 1162, 1466 1. A d iffuse interstitial
infiltration patt ern is def ined as loosely

scatte red mast cells in the absence of
compact aggregates. It must be noted.
however, that this pattern is also observed
in reac tive mast cell hyperplasia and in
cases of mveromastccvnc leukaemia. a
term used for cases with advanced
myeloid neoplasms in whom elevated
numbers of immature atyp ical mast cess
are found , but criteria for SM are not met
120651. In patients with the diffuse infiltration pattern it is therefore impossible to
establish the diagnosis of mastocytosis
Without ad ditional studies including the
demonstration of an abe rrant illYT'lUfl(}
phenotype and/or detection of an acliva!
iog point mutation in KIT1977, 978 , 1196
2056,20571 , In contrast, the presenced
rruttifocal compact mast cell infiltrates ora
diffuse-compact mast cell infiltration pattern
is highly compatible with the diagnosis d
mastocytosis during first inspection. H0wever, additional immunohistochemical a'Id
molecular studies are strongly reccnmended even in these cases.
In tissue sections stained with H&E, ~
reactive mast cells usually are loosely
sca ttered througho ut the sample, and
display round to oval nuclei with clumped
ch romatin, a low nuclear/cytoplasmic
ratio. and nucleoli that are absent CI
indistinct. The mast cell cytopl asm is
abundant and usually filled with small
faintly visible granules. Dense aggregates
of mast ce lls are only very exceptionalfy
detected in reactive states or in patere
treated with stem cell factor (SCF) 11 275
1694. 22901. In smear preparations, mast
ce lls are read ily visible in Romanowsky
stains as med ium-sized round or oval
cells with plentiful cytoplasm , con ta in i~
densely packed metachromatic granules
and round or oval nuclei. In norrnarreao
tive states, mast cells are easily dislil'\o
guished from the smaller metactvonac
TIIbIt 2.11 SubdaSSlf?tiOn 01cutaneous mastocy1osis,
1. ~ pioJnenIosa (UP V~
ewneous mastoeylosis (MPCM)
1.
2 DIuse l:lJWoeou$ mastocylO$ls

3,
Sl*arI mamcytomaof skin
basophils which have segmented nuclei,

and larger and fewer granules. With enzyme cytochemistry. mast cells reac t
strongly wrth naphtholASD-chlofoacetate
esterase (CAE) but do not express
rnye!operoxidase In mastocytosis. the
cylOIogy of mast cells vanes, but aboor'!'tal cyIo1ogic features are almost always
oetected. nckJdlllQ marked spindling and
hypOgrarJJlarrty 122901.
Cytanorpnoiogical atypia is pronounced
1'1 higtl-gfade lesions 01 mastocytosis.
ee occurrence of metachromatic
ees cells being a usual feature 01 mast
celleukaemia 122901. The finding of treQUeft mast cells with bi- Of multi lobated
I\dei rpromastocytes") usually indicates
if! aggressive mast cell proliferation.
aIItOJgh these cells may be seen at low
IreQuency in other subtypes of the disease 122901. Mitotic figures in mast cells
Ii) occur, but are infrequent even in the
aggressive or leukaemic variants of SM.
Kl assess mastcell numbers with cowenlO"aISlalning procedures, Giemsa or toiuidine blue are employed 10 detec t the
metachromatic mast cell g ranules and
CAE IS alsohelpful 122901. However, the
roost specitc methods lor ide ntific atio n of
nmature or atypical mast ce lls in tissue
sectons utilize immunohi stoch emic al
staimng fortryptase/chymase and CD 117
and, for neoplastic mast ce lls. C0 2 and
CD25, The morpholog ic features of th e
common subtypes of mas toc ytos is are
tescnoeobelow.
~dk19nosis of
eM requires the d emon-
strahon of typical clinical find ing s an d

'VSlOIogical proof of abno rma l mast ce ll
atoo ol the dermis (Table 2.10). In
cases a isolated eM. there is no evide nce
~ systemiC involvement using such oa1I'l"ell!fS as elevated levels of total ser um
ryptaSe or organomegaly. Recently, consnus craeria for the diagnosis of CM
Il8've been further relined. and three
vanants of CM are now recogniZed
1atIIe 2111122861.
IndolentsystemicmlStoeytosis(ISM)
Meets arteria b" SM. No"C" findings (see below). No evldence of afl associated non.roastc:elli'leage cJonaj
I1aematOOgicaI mali\1laflc.yldlsonlel" (AHNMOI In !hisvanant. !he mast cellMOefllS low and skin
lesions areaWnosI i'lVaria ~ present
1.' BDnemarrow mastocytosis

As above (ISMI wiIIl bone marrow involvement. but noskin lesions.
1.2 Smouldering systemicmastocytosis
As above (ISM), but wI\tl 2 oc ITIOl'e "8' fn:l1l'lgS but no "C" ffldings.
2. Sptemie mastocytosis with n soeiBted clonal hMmaI~ norHnUt c:.Illl. . . . disease (SMAHNMO)
Meets CriIeria torSU and cntenalor an assoaaled. donIlIl'IIemaloklgicI flOIloITIaII eel lineage disorder.
AHNMO !MOS, MPN .AJ.IL,~ . oc ott. ~ neopasm tIal meets !he aliena b" a
disbnd~ " tie WHO cIasslticaIm).
3.
AggrlSSivt systemic: mastocylosis (ASM)
......
Meets c:nena b SM. <n oc IOOf8 "'C" Indings. No ll"o'lci8rOI of maslceI-..aema. UsuaIy ri'1oU: sm
Cutaneous mastocytosis (eM)
Table 2.12 Criteria lor variants 01 systemic mastocytosis
3.1 l~hic mastocylOiIs with t<l5ioophilil

Progessive ~ wCh penphefaI bloodeoswlOphIa. orten Wllh extensrve borle
irlvoI'o'emeol. and t\ep<l~ . butusuaIy II'IIlnJI skin lesions. CasesWIltII'NI~~
......m~.'"
of PDGFRA weelCkJded.
.t. Mast c:elileukaerrlia (MCl)

Meets cnteria lor SM. Bone marrow biopsy shows a ~ lrlfiIIrabOn. usualy oompacl. by aIypicaI,
immaturemast cells. Bone IT1arnl\lr aspirate smears snow 2O"It or more mast eels In typitaI Mel . mast
cells aa::ountfor 10%oc more of~ blood wtIIte eels. Rarevanllfll: aleukaenK mast c:el leukaernla
- as above. but <1 0% ofwlile bloodcells aremast cells. Usualy wiIhouI sbl lesions
5
6.
Mas. c:ell 5MComa (MeS)

. lJfIifocaI mast celllurr'OJr. No evidence 01 SM. Oesll'uClive grow\tl pattern. HiQh1lrade cytology,
Extl'illcutaneous mastocytoma
UnilocaJ mast cell ltl'TlOU', Noevidence 01 SM. Noskin lesions. NoOOestruetiYe !1owth pattern, Low-grade
-8" findings
1.
Bone marrow biopsy showing >30% infinratkin bymast cells (focal, ceose aggregates) andlor serumlolal
lryptase level >20 nglmL.
2. Signs of dysplasia or myeloproliferation. in ten-mast ceil lineage(s). but insufficient criteria for definitive
diagnosis of a haematopoietic neoplasm(AHNMD), with nonnal or only slightly abnormal bloodcooors
3. Hepatomega ly withoutimpairment 01 ~v&r function , andlO!" palpatlle splenomegaly without hypersplenism,

and/or lymphadenopathyon palpalfon or imaging
"C" findings
1_ Bone marrow- dyslunction mal1lfasted by ooe Of more cy\OI)a!1ia (ANe <1.Ox10'1l.. Hb <10 gJdl, lX
platelets <1 Clli10"Jt). but noobvious noo-mas! ceU haematopoielic malignancy
2, Palpahla !lepatDmagalywiltl impairment oI ~ver 1uncIlon. ascites and/or portal hyperterlSior1.
3. Skeletal i1'o'Oi'o'eman1 withlarge osteolytic lesions d Ol' palhologtcallractures.
.t. Palpablesplenomegaly With hypetSJlielVsrn.
S. Malabsorption WlIh we9Jl loss due 10 GI mast cell infiftrates,
Urticaria pigmentosa (UP)lmaculopapufar

cutaneous mastocytosis (MPCM)
This is the most lre q uent form of CM. In
child ren,1he lesions of UP tend to be larger
and papular. Histopathology typically reveals agg regates of spindle-shaped mast
cells filling th e papilla ry dermis and extending as sheets and ag gregates into
the retic ular dermis, et ten in per ivasc ular

and pena dnexar pos itions 124361. A subvariant. usually occurring in young children.
presents as non-pigmented. pl aqu e-forming lesions. In adul ts . the lesions are d isseminated, and tend 10 be red ex brown-red
and macular or maculopapul ar. Histopathology of adult UP tends to reveal
Mas tocytosiS
57
Rg. 2.43 A Booe marrow smear of a patJenI WIth indolent systemiC masUytosi$. The eel is atypical. witIlan indenled nucleus in an eccentric Iocabon, and cytoplasm ... ....
an ~ emson WIt1 ~ dIslr1buIim of ~ 8 Sysl8rlIc rnastlc)tlsIs. The eels may haw bland ru:lel WIIIl moderate ~ of 1* tyqllasm , spinIed _ _ ..
I'MeITtlle fibroblasts. or IctllAated nuclei WIth ab.nln dear C)'kIpIasrn The Ialler eels mayresermle rnonoc:ytes or his/ioq'Ies. and ant more oommooly seenin aggnssift
"' .....
fewer mast cells than observed in children. The numb er of lesoner mast cells
may sometimes ove rlap with the up per
range of mast cell number s found in normal or inflamed skin. In some cases,
examination of multiple biopsi es and
immunohistochemical analysis may be
necessary to establi sh the diagnosis of
e M 12286, 2436).
Diffuse cuta neous mastocytosis

This clin ically remarkable subvanent of
CM is much less frequent than UP and
presents almost exclusively in childhood .
Here the skin is diffusely thickened and
may have a peau chag rine or peau d'aange (orange peel) appearance. There are
no individual lesions. In patients with cl inica lly less obvious infiltration 01 the skin,
the biopsy usually shows a band-like
infiltrate 01mast celts in the papillary and
upper reticu lar dermis. In massively

treted skin , the histological picture !Tll'f
be the same as that seen in solitary mas
cytorna 12055, 24361.
Mastocyt oma of skin

This oc cu rs as a single lesion, almost
exc lusively in infants. without predi lecl~
of site. The histolog ic picture is one ~
sheets of mature-appearing highly metachromatic mast cells with abundant C'/'I>
plasm that densely infiltrate the oa
and reticular dermis . These mast eel
trates may extend into the suocoteoece
tissues (11541 . Cytological atypia is na
detected . This allc:M's separation 01 mas
cytoma from an extremely rare mast eel
sarcoma 01 the skin 119581.
n
s
Cl
Systemicmastocytosis (SM)
sa
The prerequisites for the diagnosis of So\!

are outlined in Table 2.10. In most cases.
ag greg ates 01 atypical mast cells a1
readily found in tissue sections. The crtt9'll
lor variants 01SM are given in Table 2.12.
di,
He
Fig. 2.45 SystemiC mastocytosis, booe marrow bklpsy. A The local lesions01 mast cellschenconsist of a central core
ol lymp/lOCyles, surrourldlld by polygonal mast cells with pa~ . faintly lJ"iJrlUlarcyIOplasm. WIth reactive eosinophils at
the outer margirl ol lhe lesion. 8 The lesiOns are often well-circumscribed. and may OCCIJ" irl parauabecular or
perivascular Iocabons, but may be I'lV'ldorTWy dislnbuted in the interll'abeclAar regionsas wei.
58
Myeloprol!terative neoplasms
Bone marrow
In most cases of SM, multifocal . sllar~
demarcated compact infiltrates 01 rna;
cells are the most common and easily ce
tect able feature in the BM bio psy. The
infiltrates are found pred ominantly If
paratrabecutar and/o r perivascular locations 1290, 965, 971, 977, 978. 11981. The
focal lesions are co mprised 01 varyiOj
numbers of mast ce lls. intermingled w
varying numbers of lymphocytes , eoere
phils , tusnocytes. and fibrob lasts. These
diagnostic "mixed" infiltr ates are o/tell
ex
era
fr
of
s
my
pl.
my
00<
d isl
0'
qUE
148
'he
seen in ISM and generally show eithe r a

central core of lymphoc ytes surrounded
bymastcells, or a central compact mast
eel aggregate with a broad rim of lymphocytes 19651 In other cases , the lesions are mot e rronorooptec and are
many composed of spindle-shaped
mas! cells that abut Of stream along the
bony trabeculae 1977 . 9781 . Significant
relJCulin fibrosis and thickening of the
adlacent bone are frequently Observed .
ScrnetIITles. the 8 M space is d iffuse ly replaced by compac t mast cell infiltrates ,
which may resemble sheets of fibroblasts
19711. Marked reticulin or even collagen
fibrosi s is frequentl y observed in such
cases 1971 , 977, 9781. Usu ally, there is a
mixture of both spind le-shaped and round
mast cells. Rarely, co mpac t infiltrates may
exclusively consist of round hype rgr anu'af mas! cells, which meets the criteria for
so-called trvptase-c ostnve round cell
l'lfiltratioo 01 8 M (TRDCI-8 M) 19761. In
cmrest to spind le-shaped tryptaseexpresSing cells that are alw ays mast
cells, the round nvptase-posmve cells in
TROCI are either mast ce lls (coexpres9IOl'l li C0111 and c hymase), neoplastic
!laSl:ViIS (primary or secondary basoIt1k leoIo:aemial or myeloblasts in the
should be classified according to established WHD criteria . II is important to note

whether the re is inc reased cellularity of
the marrow or d isturbed maturation of
haematopoietic cell s, because. even if
c riteria lor a coexisting myeloid neoplasm
are not completely fulfilled , hypercetlutarity
Of abnormal myeloid maturation patterns
cou ld be associated w ith an unfavourable
out come (progression to ASM or SMAHNMD) or with a smouldenng variant of
SM in which the out come is uncertain
122901. Inter pretation of findi ngs must include consideration that reac tive , nonclonal mast cell hyperplasia may
accompany a var iety of haematolog ical
disorders, including myeloid and especially

lymphoid neoplasms, such as lym phoplasmacytic lymphoma or hairy c ell
leukaemia 122901. In such reactive states ,
the predom inantly round mast cells lac k
major" cytological atypia. and are almost
always loosely sc attered throughout the
tiss ues. a find ing that c learly contra sts
with the compact aggregates 01 reooiastc
spindle-shaped mast cellsfound in mastocyt os is 122901.
The d ocumentation of 8M involvemen t
accompanying SM is usually established
by examination 01 a 8M trephine biopsy
specimen. However. the analysis of marrow aspirate smears does provi de useful
Fig. 2.46 Systen'ic masb;ylosls, spleen, A Sl)Ieen tom a pa\letIt 'lII'i01 systen'ic maslIXylosls. B Aggregates rJmast
eels may be seen II \tie red orwliIe pulp, orbolh. ~ his case, mast eels ate seen II a penloIi::IJNlocation.
sett.ng of a trvotase-oosmve acute
'l'IyflIOId eokaene.
CaretlJ inspec tion of the 8M no t
at!ected by mastoc ytosis is of crucial
ecctarce. Often, the una ffected 8M is
II1remarkable with a normal distribution of
tal cells and haematopoenc p rec ursors .
Such cases usually eithe r belong to ISM
o\'lthinvOvemen! of skin and 8M , or re preSMt isolated mastoc ytosis of the 8M ,
However, in othe r c ases th e 8M not
drectly infiltrated by mast cel ls may be
extremely hypercellular due to the prolifescoof cells of non-mast cell lineages,
tduding neutrophils, rnonocytes. or less
frequently, eosoopbns or b last cells. DePQ"Ong on the type of proliferating cells,
lindlngs may be reactive (myeloid
~ ), or may indica te the presence
d acoexisting naematoooeuc neoplasm
ll.d! as acute myeloid leukaemia , a
~ollferatiYe neoplasm, a myelodyssyndrome or myelodysplasliC/
~ferati ve neoplasm, Of chronic
...""llc ~. Lymphoproliferahve
diseases, such as plasma cell myeloma
~ malignant lymphoma. are less Ire(JJllfl\Iyseen 1110, 969 , 971, 975.1 147 ,
1484 2056,2066, 20951. In all such cases,
~ associated naematoroorc d isea se
eese
I
t
e
9
~
Fig. 2.43 SM-AHNUD (acutemyeloid Iel.Jkaemia). A The streaming, spindled eels of a largemast eel aggregate can
be seen on one side rJ lhe booy lrabecUkJm (arrow), weeeas a rTlCIllOIonoUs J)Opljabon of blast cellsis seen onlhlI
opposite side . B The spiodledcells of mastcell disease abut on a large aggregale of blasts.
Mas tocy tosis
59
granulomatoid lesions in the caranececular and paratoucurar areas. or within the

lymphatic follicles, or as diffuse infiltrates
within the red pulp. As in other tissue
sites, eosinophilia and fibrosis are frequently observed in areas of mast eel
infiltration. In some cases. an associated
haematolog ical disorder may be present,
but this is often difficu lt to diagnoseusirg
splenic tissues alone 1973, 14661.
...C
Liver
Liver involvement in SM usually presen
With disseminated small granulomat
foci of mast cells within the periportal
tracts and as loosely scattered mast eels
within the sousoos . Severe liver i~
rrent is only rarely seen in SM. WiderWg
and fibrosis 0 1 periportal areas is cctmonly found . but fully developed cirrhosis
is rare 1966, 14661.
f~ 2,49 SystemicmastlcyloliswiltI associ8led hl*yt:ell Waerria. A Bone marrow aspi'a'B smear Wllh hairycels
and al)1liCal mast eels B The spirded mast cells M pteSel11 adjacentto the hairy eel i'lfiItJate il lhe intersbbaI
regions oI1he IT\il'I'OW Although hairycelleubemia may occasioRaIy assume a spindledlTW)IJlIlology, in Ihis case lhe
mast eel tryplase lustrated in (e ) dearly demonslrales !he masl eel origin 01 ltle spindled tens. alll! an
imuIostaIn for C020 idenlifles ltle IIaify eels in (D).
additional information and is c rueial lor the

diagnosis of mast ce ll leukaemia and 01
some suovanante of $ M-A HNMD 122901.
In ISM, most mast ce lls are found within
the thicker regions of the aspirated

crushed fragments. Mast cells in ISM,
which should always be assessed in the
thin region s and at a fair di stance from
8 M part ic les , usually com p rise < 1% of all
nucleated marrow ce lls. This is in contrast
to mast ce ll leukaemia, where mast cell
numbe rs b y defini tion equal or excee d
20% of all nucleated cells in aspirate

smears 1290, 977, 978, 2290},
Lymph node
Lymph nodes appear to be rarely involved in 8M in that significant lymphadenopathy is unusual. The mast cell
infiltrates within lymph node s may involve
any of the anatomical compartments but
particularly involve the paraooncat areas.
Mast cell infiltrates can be either foca l or
diffuse, but rarely totally efface preexisting
archi tecture. Hyperplasia of germina l
ce ntres, evide nce of angi oneogenesis,
tissue eosinophilia, plasmacytosis and reticulin/coll agen fibrosis usually accompany
the mast cell infiltrates 1968. 14661. In a
few patients, lymphadenopathy is marked ,
with a progressive clinical co urse mimick ing malignant lymphoma . II Sig nificant
blood eosinophilia is present. such cases
60
have been reported 10 belong to a defined

subset of ASM, namely "Iymphadenopathc SM with eosinophilia" 11484, 22901.
In such cases, studies for rearrangement of
PDGFRA are recorrmeoded, and if present,
the cas e should be reassigned to the category of myeloid neopla sm with eosinophilia and rearrangement of PDGFRA.
Spleen
The white and red pulp of the spleen may
be involved in SM, with rare case s showing preferential infiltration of the lymphoid
follicles of the wh ite pulp (9731 . Here.
mast ce ll infiltrates often present as focal
Gastrointestinal (GI) tract mucosa

Involvement 0 1 the GI tract mucosa bf
mastocytosis is frequently suspected ctnically but may only rarely be assessed
morpholog ically. As in omer tissues,
least one compact mast cell infiltrate isrequireo to support the diagnosis of SM. IfI
typical cases. these mast cells shOw an
abnormal immunophenotype with expression of CD25, and an activating poirt
mutation of KIT is present. Due to the Irequency of CD25- positive lymphocytes.
careful examination of the tissue is recessary to avoid false positive results. To
eva luate a GI biopsy for mastocytosis,
both antt-trvotase and anti-C0117 anti'
bod ies should be applied in order to
avoid false positive results due to strong
bac kg round staining when only ant~
tryp tase ant ibodies are used. A lew
exceptlOl'l3l cases exhibit a diffuse compact infiltration of the lamina p ropf"ia mu cosae by atypical mast cells , and this
'f'B1 reseroe inlIanTnatory bowel disease
r:1 malignanl lymphomaat first glance . AIklgelher, lour patterns of involveme nt of
theGI tractmucosa by mastocytosis can
be dlscnminaled 1171 1: 1) Loosely scattered mast cellswithout dense ag gregates
W wrth an atypical immunophenotype
and an activating point mutation of KIT,
usual~ in the settinq 01 SM of some duraioo and involving the 8M, 2) Slight increase in loosely-scattered mast c ells
withoccasional dense aggreg ates and an
atypical rrmoopterotvce with expression
ct CD25. usually associated with an actr~ating point mutation of KIT, 3) Diffuse
Cl:lmpaCI infill ralion 01 the mucosa by
atypiCal mast cells, resembling the ag~ive variant of SM in other tissu es
171 1and 4) Localized mast cell sarcoma
(based on one published case with in'OteTlerC oIlhe ascending colon) 111761.
_ 1esK>ns
Of osteoporosis is another frequent find-
ing in patients with mastocytosis, and

may occur in any variant.
Mast eel/leukaemia (MCL)

In mast cell leukaemia , mast cells equal
or exceed 20% of all nuc leated cells in
aspi rate smears 1290 , 977, 9 78, 22901. In
this rare and hig hly ag gressive lorm of
SM , the BM reveals a diffu se, compac t
infiltrate with marked redu ction of fat ce lls
and normal haematopoietic precu rsor s.
The mast ce lls often show sign s of
marked atypia with hypogranu lar c ytop lasm, irregularly shape d monoc ytoid or
b ilobated nuclei (p romas tocy tes), and
may even pr esent as me tach romatic
b lasts 122901. In some cases, the nucleoli
may be prominent. In typ ical cases , mast
cells ac c oun t for 10% or mo re of the
c irculating nucleated cells . If mast cells
comp rise less than 10% the circulating
cens. the diagnosis of an "a'eukaem.c"
variant of MCL is appropriate 122891.
The lfequency of bone changes varies
ee subtype of disease. \-\'hile pu re

tduse ceteoscerosis is unusual in ISM
Iil(:U 6%0), it is observed in about one
Mast eell sarcoma (MCS)
dWl:lol patients with ASM. The most comradlOlOglcallinding associated with

ISM crests of concurrent osteosclerotic
andOSleolytic lesions (45%). Osteopenia
Ma st cell sarcom a is extremely rare and

cha racterized by a localized and destruc tive growth of highly atyp ical mast
cells, which c an be id entif ied only after
llO'I
application 01 appropriate immunohistochemical markers, particularly anti-tryptase

and anti -CD l17 . AlthOugh initially localized , distant spread followed by a terminal
phase resembling MCl is seen alter a
short interva l. Mast cell sarcomas have
been report ed to occur in the larynx, large
bowel, meninges , bone and skin 1265,
970, 11761 .
This localized tumour consists of an
ac cumulation of mature-appearing granulated strongly metachromati c mast cells ,
in contrast to the hig hly atyp ica l mast
cell s observe d in a mast c ell sarcom a.
Extra cutaneous mastocytoma is exception ally ra re, and the reported cases
involved the lung {3981.
Irrm.mopheooIype
Mast cells co-express COO, CD33, CD45 ,
CD68 and CD 117 but lack severa l
rnyelomonOCytic ant9S"S, including CD14,
CD15 and CD16, as well as most T- and
B-eell related antigens 1974, 977 , 978 ,
1073, 1292, 1687, 22901, Virtually an mast
cells , irrespective of stage of maturation
or neoptasnc state , react with antibodies
against trvp tase . a cell not expressing
tryp tase ca nnot be id entified as a mast
cell immunohistoc hemically. Chymase is
Mastocvtose
61
expressed in a subpopulation 01 mast

cells. Chymase is highly specific but
much less sensitive for the identification
of atypical and immature mast cells than
C0117, whereas COl17 expression is a
highly sensitive but rather nonspecific
marker of mast cells. Neoplastic mast
cells show a similar antigen profile to that
of normal mas t cells, but in con trast to
normal mast cells. they also coexpress
C02 or C02 and C025, These latte r
observanons are of considerable value in
the diagnosis and in the differential diagnosis of mastocytosis and related tumours,
and can be applied in immunohistochemical as well as in flow cytometry studies
j650, 1655.
The application of antiC025 enuoooree has been found particularly useful in the histopathological
evaluation lor suspected SM. Howeve r.
C02~posilive T-cells are usually present in
tissues and must be taken into account
before an atypical C02-positive mast cell
population can be properly iden tified . p.J.
together, it can be assumed in the routine
diagnostic evaluation 01 mastocytosis that
cells expressing uvptaserctrsmase and
C0117 are mast cells, and cells coaxpressing tryp tase/chymase, COl17 and
C02/C025 are neoplastic mast cells
120571. C025 expression may be inconstant or even unde tectable on mast cells
in some rare subvartants of the disease,
such as welt-dilt erentiated SM or in a subgroup 01patients with mast cell leukaemia
.. ." .
~
. e
205n
1141.
Genetics
Mastocytosis is frequently associated with
somatic activating point mutations within
K IT 121761. In most cases, co don 816
mutations in the tyrosine kinase domain
are detectab le. Rare familial cases with
qecmune mutations of KIT have bee n
repo rted [ 14,15, 1331,1332, 1333, 1557,
21761. In patients with SM-AHNMO additional genetic de fects are det ec ted,
depending on the type of AHNMO,
Somatic point mutations of the KIT protQoncogene that encodes the tyrosine
kinase recept or for SCF are de tected as
recurring abnormalities in mastocytosis
11 4,15, 1331, 1332, 1333, 1557, 1656,
21761 _ The most commonly observed
mutation shows substitution 01 Val for Asp
at codon B16 (D816V). This mutation
results in ligand-independent activation 01
KIT tyrosine kinase and provides relative
resistance to the prototypical tyrosine
kinase inhibitor imatinib 1995, 15571.
62
Fig. 2.53 Mast celleull.aem&a A ~ blood smear. Note lhe biIobed ru:tel and relatively ~
cytoplasmoften seen in Itll5 awessive form of rnastIcykIIas. B Theborle marrow biopsy is li1IuseIy inIiIlr.*ldby
~slJC mastcells, C derronslriIles !he 'dear aIr appearance !hat is due ~ !he poorgratlJIalion of the
ltIatis typical of inmature mast eels ofmast eelleukaernia. 0 All irmI.JnohisD::h slainbr masteel ~
""""' .......
The DB16V mutation is identified in the

mast cells of 95% or more of adults with
SM when sensitive methods are used, inclu din g nested PNA-PCR or PCR on
poo led micro-dissected single mast cells,
Other activating point mutations of axon
17. such as DB16Y, D816H and 08 16F
are rarely seen {756. 1332, 1333, 20561 .
The DB16V mutation is seen in only about
one third 01CM in paediatric patients 114,
1331, 1332) and the frequ ency of point
mutations other than 08 16V is significantly
higher in CM than in SM, In patients with
SM-AHNMO, add itional ge netic defects
may be detected, depending on the type
of AHNMO. For example, in SM associated
with AML, the RUNX1-RUNX1T fusion
gene may be found , whereas in cases of
SM associated with myeropronteratse

neoplasms. JAK2 V617F may be found
The de tection of the FIPIL 1-PDGFRA
fusion gene has been reported in patients
with mast cell proliferation and eosinophilia
122861. Although patients presenting wlt'I
elevated serum trvptase levels. clonal8M
eosinophilia with a F/P1L1PDGFRA
fusion ge ne and a few scattered atypical
mast ce lls have been described as having
an unusual variant 01SM {130, 713, 11621
most of these patients do not fulfili 8M
criteria, particularly as compact mast cel
infiltrates are missing , and they are best
classified as a mye loid neoplasm With
eosinoph ilia and rearrangement 01
PDGFRA (See Chapter 3) 122871.
Postulated C~ II of oriQin
Haematopoietic stem cells.
In children, CM usually has a favourable
outcome and may regress spontaneously
before or during puberty. In adul ts, cu taneous lesions generally do not regress
and are. in contrast to a previous belief,
oI1en associated with SM, usually the
ocoient variant. One study identified
predictors of a poorer prognosis as rate
onset of symptoms , absence of CM.
ttrembocytopenia. elevated lactate dehyciogenase (lOH). anaemia. 8 M hypercelk81ty. qualitative PB smear aboorrehtes.
elevated alkaline phosphatase and hepatosplenomegaly. The perce ntage and morphology of mast cells in 8M smears have
been ide ntified as additional important
and independent pred ictors of survival in
mastocytosis 122901Currently, there is no cure lor SM. and the
prognosisdepends on eediseasecategory
1228 7, 22881. Patients with high-grade
(agg ressive) disease inclUding mast cell
leukaemia may survive only a few months,
whereas those with indolent SM usually
have a normal life expectancy 12287.
22881. SM patien ts with cutaneous
invotvement usually also follow an indolent
course, whereas patients With aggr essive
disease often have no skin lesions 122901

However. isolated 8M mastocytosis as a
sobvanant of ISM with excellent prognosis
also presents without cutaneous lesions.
If there is an associated baematoroqrcet
malignancy, the clinic al course and prognosis are usually domina ted by this related haematological malignancy 19751_
Patients with aggressive SM generally
show a rapid cl inical course with a survival of only a few years. MCS shows a
prog ressive course with death within
months . Patients with ASM, Me l and
MCS are thus candidates lor cvtoreduc tive therap ies.
MastocytosiS
63
Myeloproliferative neoplasm,
unclassifiable
Definition
The designation. myeloproliferative ne0plasm. unctassmaore (MPN . U) should be
applied only 10 cases that have definite
cl inical, labora tory and mor pholo gical
fea tures of an MPN but that fai l 10 meel
the criteria for any of the specific MPN
entities, or that present with featu res that
overlap two or more of the MPN ca tegories. Most cases 01 MPN. U, will tall into
one of three groups: 1) Early stages of
poIycythaemia vera (PV), primary myelofibrosis (PMF) or essootial thrcmbocythaemia
(El) in which the c harac teris tic featur es
are not vet fully d eveloped: 2) Advanced
stage MPN, in wh ic h p ronounc ed myelofib rosis. osteosclerosis. or transformation
to a more aggressive stage (r.e . increased
blasts and/or dysplasia) obscures the
underlying disorder 1775, 1216, 2206,
22 16,22221 : or, 3) Patients with convincing
evi de nce of an MPN in whom a coexisting
neoplastic o r inflammator y d isord er obscures some of th e diagnostic c linic a l
and/or morp hological featur es , The presence of a Philadelphia (Ph) ch romosome,
BCR-ABL 1fusion gene or rearrang eme nt
of POGFRA, POGFRB or FGFR 1 genes
excludes the diagnosis of MPN ,U.
The diagnosis MPN,U shou ld not be used
64
wren clinical data necessary for proper

c lassification are insufficient or not available, when the bone marrow (BM) specimen is of inade q uate q uality or size for
acc urate evaluation (1216, 22 16 , 22221, or
w hen there has bee n rece nt cy totoxic or
growth factor therapy - p rob lems that account for the ma jority of the unclassifiable
cases encountered in routine practice . In
such cases it is often preferable to describe the morphological findings, and to
sug gest additional cl inical and laboratory
p rocedures tha t are nee ded to further
classify the p rocess, inClud ing ad eq uate
pe riphe ral blood (PB) and BM biopsy and
aspi rate specimens. When a d iag nosis of
MPN, U is made, the repo rt should summarize the reason for the difficulty in
reaching a more specific diagnosis, and.
if possible, specify which of the MPN can
be excluded from consideration .
If a c ase does not have the features of
one of the we ll-d efined entities, the possibility that it is not an MPN must be
strongly consi de red, A reac tive 8 M response to infection and inflammation, loxins, chemotherapy, and administration 0 1
growth tactors. cvtokmes and irrmunosuppressive agents may closely mimic
MPN and must be exc luded, Furthermore,
H.M. Kvasnicka
B.J . Bain
J , Thiele
A. Orazi
H.P. Horny
JW , vardiman
a number 01 other naenatopoeuc and

rco-neenatcooenc neoplasms, suchas
lymphoma or metastatic ca rcinoma , may
infiltra te the marrow and cause reactive
changes, inc lud ing dense fibrosis and
osteosclerosis that ca n be misconstrued
as an MPN 122061. Dete ct ion of a clonal
cytogenetic abnormality, a JAK2V617F a
othe r functionally similar JAK2 mutatIOn,
or an MPL IMP/.. W515K1L) rrutation
distinguish an MPN from such reaclrve
conditions, although not all cases of MPN
U express a currently recognized aeretc
marke r 12171, 21771. In add ition, thedefining c harac teristics of each MPN must be
considered with the realization that, as with
any other biological process, variations 00
occur, and they may progress thrt:llJ!1l
different stages so that the c linical 31"(1
morphological manifestations of the disease will change with time 12177, 22161
ICD..Q code
997 513
Epidem iolog y
The exact incidence of MPN, U is ur*~
but some reports indicate that the pelcentage of unclassifiable cases ecccn
for as many as 1~ 15% of all cases Ii
MPN 1775, 2222 1, The frequency varies
significantly aCGord ing to the exper ienc e

l1lhe diagnostician and the specific erassfication system and criteria utilized to
dassifyMPN 11216, 22161.
ElOOgy
The cause is unknown.
Sites 01 W1voIvement
5mlar to the other MPN
cncaJ leatures
r-e dI1icaI features 01 MPN. U are similar

Iltoseseen in the other MPN, In pat ients
, . early, tn:: lasgjfjable disease, organo-regaly may be minima l or absent. but
sclen:lmegaIy and hepatomegaly may be
'T'8SSNe i1 those with advanced d isease
" "IIto'n 8M scecerees are characterized
0, ~ myek)flbrosis and/or increased
rurtlers of blasts 122161. The baemato~ valles are also variable , and range
\rem mild leukocytosis and moderate to
'I'.arlo:ed thrombocytosis, with or without
~nying anaemia, to severe cvtoPfJ'8S ae 10 8M failure. Some patients wilt1
1IlN. Upresent WIth otherwise unexplained
p:fIai or splanchnic vein thrombosis.
Iil<pI<JI<lgy
'krrtcases that are diagnosed as MPN. U
tJemQ to very early stage disease in
iI'tlCJ the differentiation between ET, the
p"elibrOlic stage of PMF, and the preJ:dycythaemic stages of PV is difficult
11216, 2223, 22241. Often, the PB smear in
li.dI cases shows thromboc ytosis and
Ia'iatlle neutrophilia. The haemog lob in
concentration may be normal, mildly d eeeasec or borderline incr eased . The 8M
bqJsy specimen frequently shows hyperterlJiarityand often prominent megakaryoClI'= proliferation, with variable amounts of
Q'a1\Jlocytic and erythroi d prol iferation
12216,2223,22241, If the guid elines suqgested in the previous sections for each
specdic MPN are carefully applied wi th
ti:lSe attention paid 10 the megakaryocy' morpholog y and histotopography,
'lOSt cases can be accurately assigned
1I 8spedic subtype; but if not. the des."a1OO ot MPN, U is preferable until
follow-up data or adomonar lebo'By studies provide evidence leading
1)8 precise diagnosis.
lJe-stage disease. the BM specimens
-eseal dense fib rosis and/or os teo~, indicating a terminal or
...m<lA stage, and distinction between
oost-polycylhaemic stage of PV
(post-Pv MF) or rarely ET (post-ET MF)

1143A1 and lhe overt fibrotic-osteosclefotic
stage of PrlAF may be impossible if there is
no previous history or histology for review
12203, 22CX'i, 2216, 22221 Although Chrc:K1ic
myelogenoos leukaem ia (CMl) may also
be accompanied by marked myelofibrosis, the sma ll size of the megakaryocyt es
will alert the morphologist to the correct diagnosis, and cytogenetic and mole cular
qenetc demonstration of the Ph chromosome or the BCR-ABL 1 fus ion gene will
con firm the di agnosis of CMll775, 2216.
22221.
More than 10% b lasts in the PB or 8M
and/or the findin g of significant myelodysp lasia gen erally indica tes a transition of
the disease to a more agg ressive, often
terminal b last phase. If the initia l diag nostic speci men has features of a myeloproliferative proces s that cannot be
spec ifically ca tegorized , but shows
10-19% b lasts in the PB or BM, the diag
nosis of an accelerated stage of an
MPN, U, is appropriate, Irrmu notlistochemical staining of the 8M biopsy sec tions for
CD34 ma y be of diagno stic value in these
cas es by demonst rating increased number s an d/or clusters of blasts 12216,
22221. If bl asts account for 20% or more
of the perip heral white blood cells or nucleated 8 M cells in the initial specimen ,
then the diagnosis is acute leukaemia ,
and the suggestion that the case may be
a bl ast transformation of a previous but
uncl assifiable MPN is appropriate, Myelodysplastic features may appear dur ing
the natur al p rogression 01 an MPN even
without prior cytoreoucuve therapy. How ever. if the initial pretreatment specimen
demonstrates myelodysplasia , the diagnosis of a myelodysplastic syndrome or of
a myelod ysplaslictmyeloproliferative reoplasm, incl uding the provisional entity, refractory anaemia with ring sidercblasts
and thrombocytosis, should be considered
11 27,1 29,865.1 245,1406.2082,2169/.
Inwrunophenotype
No abnormal phenotype has been
ported for this group of patien ts.
re-
Genetics
There is no cvtcqenetc or molecular
genetic finding specific for this group.
There is no Philadelphia chromosome,
BCRABL 1fusion gene , or rearrangement
of PDGFRA. PDGFRB or FGFR1. Some
cases with a mutation of JAK2 as a sole
genetic abnormal ity do not meet the criteria for a specific MPN or any other speci fic disease ca tegory, and are thus best
ca tego rized as MPN, U.
Postulated ce ll of origin
Haematop oietic stem ce ll.
Prognosis and predi ctiv e factors
In patients with the initial stages of an
MPN that is urctassmabie. follow-up studies performed at intervals of 4-6 mon ths
wilt etten provide sufficient information for
a more precise classification {2216, 2222/.
Such patients in the early stages of disease will have a prognosis similar to those
of the group into which their disease
eventually evolves. Patients with advanced
disease in whom the initial proc ess is no
k>nger recognizable due to 8M fibrosis or
bla stic infiltration wou ld be expected to
have a poor prognosis.
Myeloproliferative neoplasm, unciasSlfiable
65

with eosinophilia and abnormalities of
PDGFRA,PDGFRBorFGFR1
Myeloproliferative and lymphoid neoplasms
associated with rearrangernenl of PDGFRA.
PDGFRB and FGFA1 constitute three rare
B,J . Bain
D,G Gilli land
H.-P. Horny
JW. Vardiman
specific disease groups, which have

sore sha red features and some that differ. All result from lormalion of a fusion
gene encoding an aberrant tyrosine ki-
nase. Eosinophilia is characteristic but not

invariable. II has been established that, in
the case 01 POGFRA and FGFR t-related
neoplasms. the cell of origin is a mutated
plu ripotent (lymphoid-myeloid) stem cell.
It is possible that this is also true for

PDGFR~relaled
neoplasms, but this has

yet to be established.
All three disorders can present as a

chronic myeloproliferatIVeneoplasm (MPN) ,
but the frequency 01 manifestation as a
lymphoid neoplasm varies . The clinical
..
4,,
.'. ..
. '.'
and neen ercoocer features are also influenc ed by the partn er g ene involved . In
the c ase of PDG FRA-related disord ers,
prese ntation is usua lly as c hronic eo sinop hilic le ukae mia (CEl) with promi nent
involve ment of the mast cell linea ge and
sometimes of the neutr oph il lineage. l ess
often , pr esent ation is as ac ute my eloid
leuka emia (AMl ) or precur sor-T lymp hoblastic lymphoma (T-LBL), in both instances
with ac companying eos ino philia , In the
c ase of PDGFRB-related disea se, the features of the MPN are more va riab le but are
often those of c hronic myelomonocytic
leukaemia (CMML) with eosinophil ia, Proliferation of aberrant mast c ells can again
be a feature. Acute tran sformations that
have been d escribed to date have been
myeloid . In the case of FGFR r-reteteo disease, a lymphoma tous presentation is COOlmon, pa rticularly T-18L with accompanying
T~" 3.01
""
f ig. 3.01 FIP1L 1-PDGFRA-ffllaled etvonic ~leu kaerlia. A PenpheraI blood IilmstIOlWIg Ihree rrlllder*f
degranulated eosinopl'lils. Romanowsky stain. B Trephine biopsy section. Abundanl eosinophils and eosI'q)lli
precursors, Giemsa stain. C Trephine biopsy S&ClIOO. Abundalll mast cells. many of wI\it:tI are spindle-shaped,
Iormingsmalloose dosleB, Masteel tryp\lIS8 staining, 0 Trephinebiopsy section. CD25expression in tilemast CIk
eosinophilia, Other patients have had CEL,

precursor-B lym phoblastic leuka emia /
lymp homa or AML.
The importance of recog nizing these di so rde rs is that the aberrant tyro sine
kinase activity can make the d isea se
responsive to tyrosine kinase inhibitors,
This hope ha s already been reali zed for
MPN with rearrangemen t of PDGFRA o r
PDGFRB, whic h are resp onsive to imatin ib and some related ty rosine kinase
inhibitors . Similar specific therapy has not
yet been de ve loped for FGFR 1-relale d
disease. Rele va nt c ytogenetic analysis,
Diagnosticctitena of an MPN' wilt1 eoslnophilia associated witt1 FIP1U -PDGFRA.
AmyeloproIlferatMl neoplasm .",111 promnenl eosmoph~ia
molecular genetic analysis or both should

be car ried out in all patients in whom MPN
w ith eosinop hilia is suspected and also
in pat ients presen ting with an acute
leukaemia or lymphoblastic lymphoma
with eosinophilia. Recognition of PDGFRA
related disease usually requires molecular
genetic ana lysis, sinc e the majority of
cases resu lt from a cryptic deletion,
whe reas c ytogenetic anal ysis will reveal
the ca usative abnormal ity in the case of
PDGFRB- and FGFR1-related d isease.
Myeloid and lymphoid

neoplasms with PDGFRA
reanangement
AND
Presence of a FIPILl-PDGFRA fusion gene'
Definition
Patients preserUlg witt1 aculemyekidledaema or tyr1lJhDbIastic ~ with8CJSinOPt*l and

a FIP1L1.f'OGFRA lusion geneare also aSSlgfllld tobs categoIy.
! II appropnate OI)IeaJar.-.alysis is not 1IYIilable.lhisliagnosis slJ:ll*S be suspected ilU1ere is. Pt\-negalrve
MPN lIiIlIh Ihe ~ teahns of chronic eosirq:lhIc leukaemia assooateeI WIfI ~,
marked ~ of 58I0OI YltaJfWI812. eIeYaliort of serum tryplase and incteasecI bone Il'llWI'lM mast llllI!.
The most common MPN assoc iated wll1l

PDGFRA rea rrangement is that asSOCIated with F1PIL l-PDGFRA formed as a
result of a cryptic de letiorl at 4q 121466l
(Table 3.0 1). Presentation is generally as
eEL but can be as AM L, TLBL or bon
68
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities 01 PDGFRA . PDGFRB Of FGFRI
smcuaneously (14691. Acu te transformation can follow presentation as GEL.Organ

damage occurs as a result of leukaemic
infiltration or the release of cvtokines. en zymes or omer proteins by the eoeropnns
and possibly also by mast cells. The peripheral blood (PB) eosinop hil count is
markedly elevated (in cases reported to
dale it has almost always been ~ 1.5x1rPlL)
atthough it should be noted that. in some
series of patients . investigation was confined to patients with eosinophilia. There is
no Ph chromosome or BCR-ABL 1 fusion
gene. Except when there is transformation
kl acute leukaemia, there are <20% blasts
fl the PB and bone marrow (8M),
roo _ a
The provisional code proposed for the
fourth edition of IGOoO is 996513
---
~".
~opi . .. . ,
1',...... eEL_
_c:,.........,
nptIine
---, --I
I~"!.-
-=Iya&.
b60CIaY Met
1n,"tiglClonb
Synonyms
~~
I
Chronic eosinophiliC leukaem ia: chron ic

eosinophilic leukaemia wilh FIPIL1PDGFRA; myeloproliferat ive var iant of
the hypereosinophilic syndrome.
Epidemiology
The FIP1Ll PDGFRA syndrome is rare. It
is considerably more common in men
than women; the M:F ratio is - 17:1. Its
peak incidence is bet ween 25 and 55
years (median age of onset in late 40s)
with reported cases ranging in age from 7
10 77 years 1131).
Etiology
The cause is unknown, althoug h several
cases have been reported following c ytotoxic chemotherapy 11 625, 2157) and a
case of chronic myeloid leukaemia with a
BCRPDGFRA fusion gene also followed
combination chemotherapy 119061 .
GEL associated with FIP1L1-PDGFRA is
a multisystem disorder, The PB and 8 M
are always involved , Tissue infiltration by
eosinophils. and release ot c v tokmes and
humoral factors from the eosinophil granuleslead to tissue damage in a number of
organs, but the heart, lungs , central and
peripheral nervoussystem. skin and gastrointestinal tract are commonly involved .
The spleen is enlarged in the majority of
patients.
Cinical features
Patients usually present With fatigue or
pruritus, or with resp iratory. cardiac or
eel
~~~
.,
t,G
--_.......... @ e
--,
r.::==:=:::'::-l
~
(lncludiog
f _ I ...u..tI.1(11 nut
....
Hoi
~\I.
....
idiopathic HES
Fig. 3.02 Flow diagram showing the diagnostic process in hypereosinophilia, e EL, chronic eosinophilic leukaem ia
The definitivediagnosis is shown within blue circles/ovals,
gastrointestinal symptoms 1466 , 139 1,

2309 1. The majortty of p atients have
splenomegaly, and a minority have hepatomegaly. The most serious cl inical findings
relate to endomyocardial fibrosis, with ensuing restrictive cardiomyopathy. Scarring
of the mitral/tricu spid valves leads to
valvular regurgitation and formation of in
tracardtac thrombi, which mav emtonze.
Venous thromboembolism and arteria l
thromboses are also observed . PulrTl()l1ary
disease is restrictive and related to fibrosis; symptoms inc lude dyspnoea and
cough; there may also be an obstructive
element. Serum tryptase is increased
(> 12 ng/mJ). usually to a lesser extent
than in mast cell disease but with some
overlap. levels of serum vitamin B12 are
markedly elevated (2309). FIP1L 1-PDGFRAassociated GEL is very responsive to imatinib , the gene prod uct being 100-fold
more sensitive than BCR-ABl 1 1466J.
MorphOlogy
The most striking feature in the PB is
eosinophilia. the eosinophils being mainly
mature with only small numbers of eosinophil mveiocvtes or promyelocytes . There
may be a range 01 eosinophil abnormalities,
inclUding sparse granulation with clear
areas " cytoplasm, cytop4asmc vacuolation,
smalle r than norm al granules , immature
granules that are purplish on a
Romanowsky stain . nuclear hypersegmentat ion or hyposegmentation and
increased eos inophil size 1466, 23091.
Myeloid and lymphoid neoplasms associated with POOFRA rearrangement
69
These chanQes may, however, be seen in

cases of reactive as well as 01 neoplastic
eosinophilia 11281 and, in some cases, of
FIPIL I-PDGFRAassociated CEL, the
eosinophil morphology is c lose to normal.
Only a minority of patients have any
increase in peripheral blast cells 123091.
Neutrophils may be increased. while basophil and monocyte counts are usually
normal 118541. Anaemia and thrombocytopenia are sometimes present. Any tssue may show eosinophilic infiltration. and
Charcot-leyden crystals may be present.
The 8M is hypercellular with ma rkedly
inc reased eosooprars and precursors. In
most cases . eosinophil maturation is orderly, without a d isproportionate inc rease
in blasts. but in a minority the percentage
of blast cell s is increased. There may be
necrosis and Charoot-leyden crystals. particularly in those cases where the disease
is becoming more acute 14661. Bone marrem mast cells are often but not always increased on trephine biopsy 11163. 1688}
and mas t cell proliferation should be rec ognized as a feature of FIP1L 1-PDGFRAassociated MPN. The mast cells may be
sca ttered Of in loose noo-cot1esive clusters
orin cohesive clus ters {1163. 16881. Many
cases have a marked increase in C025+
spindle-shaped atypical mas t cells , and in
occasional c ases morpho logical features
are indistinguishable from those of systemic
mastocytosis. Aeticulin is increased 111631.
Patients presenting with AMl or T-l Bl
have had coexisting eosinophilia (PB counts
1 4- 172x 109/l ) and in the majority of
cases ore-extsunq eosino p hilia was also
documented (1469 1.
Cyt ochemi stry
Cytochemical stains are not essen tial for
diag nosis. The reduced g ranule conten t
of eosinophils can lead to reduced pe roxidase con ten t and inaccurate automa ted eosino phi l counts.
Immunoph enotype
Eosmcptuls may show immunophenotypic
evidence of ac tivation such as expression
of C023, C025 and C069 11163}. The
ma st cells in this syndrome are usually
C02-negative
11162} but
some times are C02-negative C025
negative 114691 and occasionally C02
positive C025-poSitive 11469J. In conpanson , the mast cells 01 systemic mastocytosis are almost always C025-positive
and are C02-positive in about two thirds
of cases.
cozs-coense
70
Fig. ] .03 Myeloid neoplasm with eosinophilia associated WIlt! PDGFRB rearrangement Penpheral blood lWn d
a palienl 'MIh 1(5;12) showing numerous abnoImaleosiIlOphis; eosmphis were 40% cIleukoc)1eS.
Genetics
Usually cytogenetic ana lysis is normal,
with the FIPIL I-PDGFRA fusion gene
resu lting from a cryptic del(4)(q12).
Occasionally there is a chromosomal
rearrangement with a 4q12 breakpoint
such as t(1:4Xq44:q12) 14661 or 1(4;10)
(q12;p1 1) /21631. In other patients there
is an unrelated cytogenetic abnormality.
e.g. trisomy 8, which is likely to represent
disease evolution. The fusion gene can
be detected by AT-PCA, nested ATPeR
often being required 14661 The causative
deletion can also be detected by fluorescence in situ hybridization (FISH) analysis,
often using a probe lor the CHIC2 gene.
which is uniformly deleted , or using a
b reak -apa rt probe that encompasses
FlP tL 1 and PDGFRA. Since the maiontv of
patients do not have an increase of blast
cells or any abnor mality on conventional
cytogenetic analysis, it is usually the detection of the F/P 1LI -PDGFRA fusion gene
that per mits the definitive d iag nosis of a
myeloid neop lasm . Cytoge netic ab no rma lities ap pear to be more com mon when
evolut ion to AML has occurred (1469 1
Postulated cell of origin
The c ell of origi n appe ars to be a p luripotent haemopoietic stem cell able to give
rise to eosmophtts and in some pa tients
neutrophils. rronocytes, mast cells. T cells
and B cells {18541 . The detection 01 the
fusion gene in a lineage does not necessarily correla te with morphological evidence 01 involvement 0 1 that lineage .
lymphocytosis. for example . is not usual,
even in those with apparent involvement
of the B or the T lineage 118541. In
chronic phase disease, involvement is
predominantly of eosinophils and to a
lesser extent mast cells and neutrophils.
Acute phase disease may be myelOid or
T lymphoblastic 11469}.
Prognosis and pred ictive teeters

Since FIPtL 1-PDGFRA-assoc iated GEL
and its imatinib responsiveness were
recognized lor the first lime only in 2003
14661. the Iong-Ierm prognosis is not yet
known . However. prognosis appears
favourable if cardiac damage has not
already occurred and imatinib treanre
is available. lmatinib resistance can develop, e.g . as a result of a T6741 mutation
(which is equivalent to the T3 151mutation
that can occur in the BCR-ABL 1 gene)
1466. 844} . Alternative tyrosine kinase
inhibitors such as PKG412 and sorafenib
may be effective in these patients 1468.
1297. 2 103}. Patients presenting as AMl
or T lymphoblastic lymphoma can achieve
sustained complete molecular remission
with imatinib 114691.
Variants
A number of possible mo lecula r variants
of F/P1L 1-PDGFRA-associated GEL have
been recognized in wh ich there are
other fusion genes inco rpo rating part of
PDGFRA. A ma le patient with imatinibresp onsive CEL was found to have a
K /F5B-PDGFRA fus ion gene assoc iated
with a com p lex ch romosomal abno rmality
invol ving chromosomes 3. 4 and 10
119 79 1. and a female patient had a
CDK5RAP2-PDGFRA fusion gene associated with ins(9:4)( q33:q 12Q25) 123541. A
male patient with t(2;4)(p24:q 12) and a
STRN-PDGFRA fusion gene 14971 and
ano ther with t(4; 12)(q2?3;p1?2) and an
ETV6-PDGFRA fusion gene, both with the
haematological features of CEL responded
10 low-dose imatinib 14971.
Patients with t(4 :22)(q12;q1 1) and a
BCR-PDGFRA fusion gene, four cases
which have been described, have deease characteristic s intermediate betweer.
those of FIPIL 7-PDGFRA-associaled
eosinophilic leukaemia and those
BCR-ABL t-poseve chrcnic myeIogenec:l.lS
Myeloid and Iymphotd neoplasms With eosinophilia and etoomannes of PDGFRA. PDGFRB 0' FGFR 7
,
(
E
T
n
"
rr
/:
leukaemia; eosinophilia mayor may not

be prominen t 1162 , 765, 1906, 22661. Accelerated phase 11621 and T 11 621 and B
lymphoblastic transformation 122661 have
been report ed . The condi tion is imatinibsensitive 11906, 2266/ .
Myeloid neoplasms with

PDGFRB roanangement
Table 3 02 Diagnostc criteria of MPNaSsoclated witll ETV5-POGFRB tusioo gene oroItIer rearrangement of PDGFRB
fn:I ecreeres witt1 ~ orflUlX)'tlsis
AND
f'ntsence of 1(5:12)(q31""Q33;pt2)or a variant translocatiOn' or,demonstrabor1 of an ETV6-PDGFRB fusion
gene or of reBlfBngememof PDGFRB
A~~ , often -MIl ~eosilqlhIa
, Because t(5;ll)(q3t""Q33;p12) does IIOl always INd 10 an ETV6-PDGFRB fusion gene, rnoIei::uIM conlirmation
is ~ (lesjrable If I'lJClIe(Uar ana/ySiS is not avaiable. Ihis dtagnosJs sho\j:j be suspected if there IS a f'Il.
negative MPN asscrialed wi1tI eosirqIhiIiIlnd witha ~sIocaborl Wllh I 5q31-33 brealqloint.
Table 3 03 f.Aljecu1ar variants of MPN associated WIth ETVU'DGFRB Modified from It31)
FUIlon V&I1t
Definition
A distinctive type of myeloid neoplasm
occurs in association with rearrangement
~ PCXiFRBat 5q31-33 (Table 3 .02) . UsuaIy there is t(5 ; 12XQ31 - 33 ;p 12) with formalion of an ETV6-PDGFRB fusion gene
1812. 11341. In l/OCOITITlOfl variants. other
"ansIocations with a 5q31-33 breakpoint
lead to the formation of other fusion genes,
incorporating part of PrX;FRB (Table
3.03). In cases with t(5 ;12) . and in the
variant rransiocatcne. there is synthesis
~ an aber rant, consti tutively activated ty!OSine kinase. The haematological features
are most often those of CM ML (usually
With eosinophilia) but some patients have
been charac terized as atypical ch ronic
myeloid leukaemias (aC ML) (usually with
eosinophilia), CEL and MPN w ith eosinophilia 1131. 20851; Single cases have
been reported of AML. probably superimposed on ch ronic idiopathic my elofibrosis
12245). and of juve nile my elomon oc ytic
eukaemia 115 13J, the latter associated
/jith a variant fusion gene . Eosino philia is
usual but not inva riab le 12085 1 Acute
sensiorrnaton ca n occur, ofte n in a relatively short period of tim e . MPN with
PDGFRB rearra ng eme nt is sensi tive to
tyrosine kinase inhibitors such as imatinib
sse
t(1;3:5)(p36J)21;q33)
WDR48-POGFRB
ca
d8r(1lll1 ;5)(p34:q33).
dert5)1(1:5)(p34:ql5).
der(11 )ils(11;5Xp12:ql5q33)
GPfAP1-PDGRFB
ca
1(1:5)(q21;q33)
TPMJ.POGFRS
ca
1(1:5)(q23:q33)
POE4DII'POGFRS
l(4;5;5)(q23:q31;q33)
PRKG2-PDGFRB
l(3;5)(pll25;q3t-35)
GOtGA4-POGFRB
l(5:7)(q33;q1t .2)
HIP1.pf)GFRB
CMML WIth eosirloptlia
l(5:10l(q33:q21)
CClJC6.PDGFRB
aCMLWllh eosinoph6a, MPD with eosinophN
t(5;ll)(q31.J3;q24)
GIT1.p()GFRB
eEl
l(5;14)(q33:q24)
NIN.PDGFRB
Pl'H'lega1ive CML (13% eoV1ophils)
t(5;t4)(q33;q32)
KlAA1S09-POGFRB
CMML wrlh eosinophilia
1(5;15){q33:q22)
TP53BP1-PDGFRB
Ph-negabveCML with prominent eosinoptlIa
t(5:16)(q33:p1J)
NDE1-PDGFRB
CMML
t(5:17)(q33:pt 3)
RABEP1 -PDGFRB
CMML
t(5;17}(q33: pl1.2)
SPECC1 -PDGFRB
JMML
aCML. alypical chronicmyeloidl6ukaemia; CEl , chrooic eosinophilk:leukaemia: CML, chronic myeloid

leukaemia: CMML, chronic myelornonotybc leukaemia: JMML, juvenile myelomonocytiC leukaemia: MPOIMOS,
myeloproliferativeJmyeioctysplastic syndrome: MPN, myeloproliferative lleOpIasm.
;64).
ICD-O code
The provisional code pro posed for the
foorth editio n of ICO- O is 996613.
Syronym
Chronic mvetomonocvnc leukaemia with
!IOSinophilia associated with t(5 ;12) .
-"'ogy
T!'IIS neoplasm is considerab ly more com~
in men (M :F.,2:1) an d has a wide
age range (8-72 yea rs) with the p eak
rcoerce being in mi ddle-aged ad ults;

reoen age of onset is in the late 405
00lS1.
rl
Fig. 3.04 Myeloid neoplasm wI\tI ~ associa1ed wilh PDGFRB ~ Trephine biopsy sedion In:lm
a pa\llll'It WIth 1(5;12) showing a mar1o.ed increase in eosWlclphiII.
Myeloid and lymphoid neoplasms associated
W Ith
PDGFRB rearrangement
71
Sites of involvem ent

MPN associated with t(5; 12Xq31-33;p12)
is a mul tisys tem disorder, The PB and BM
are always involved, The spleen is enlarged in the majo rity of pa tients. Tissue
infiltration by eosmoctats and release of
cvtounes. humoral factors or granule
contents by eosinophils can contribute to
tissue damage in a number of organs.
Clinical features
Patients often have splenomegaly, with
hepatomegaly being present in a minority.
Some patients ha ....e skin infiltration and
some have cardiac damage lead ing to
cardiac failure . Serum tryptase may be
mildly or moderately elevated The great
ma;ority 01 patients who have been
treated with erenmo have been found to
be responsive.
M<Kphology
The white cell count is increased . There
may be anaemia and thrombocytopenia
There is a ....anabre increase of neutrophils . eosooonne. rrooocvtes and eosinophil and neutrophil precursors. Rare ly.
there is a marked increase in basophils
{23551. The 8M is hype rcellu lar as a result
of active granulopoiesis (neutrophilic and
eosinophilic). Bone marrow trephine b iopsy
may show, in ad d ition , an increase 0 1 mast
cells and these may be spindle-shaped
1503,23551. Bo ne mar row reticulin may
be inc reased 123551. In c hro nic p hase
di sease, the blast cell co unt is less than
20% in the PB and 8 M.
Cytochemistry
The eos inop hils, neut rophile a nd mono c ytes show the expecte d c ytoc hem ical
reacti ons for ce lls of these lineages,
Immunoph enotype
Immunop henotypic analysis of the mast
cells has show n exp ression of C02 and
C025, as is also obse rved in the majori ty
of cases of ma st cell disease [23551.
Geneti c s
Cytog enetic analysis usually shows t(5;12)
(q 31-33 ;p 12 ) with the translocation
result ing in formatio n of an ETV6-PDGFRB
fusion gen e {8 12/ (p re viously known as
TEL-PDG FRB), In one patient ETV6
PDG FRB resulted from a four-way translocation, t( 1; 12;5 ; 12 )(p 36 ;p 13;q33;q24)
{489J, and in anomer occurred in
association with ins(2 ; 12)(p21;q?13q?22)
15121. The 5q breakpoint is sometimes
assigned to 5q3 1 and sometimes to
5q33, although the gene map loc us of
PDGFRBgene is 5q3132.
Not all translocations characterized as
t(5 ;12)(q31 ;p13) lead to ETV6-PDGFRB
fusion . Cases without a fusion gene are
not assigned to this category of MPN and.
importantly. are not likely to respond to
imatinib; in such cases an alternative
Ieukaemogenic mechan ism is upregulation
of mterleukin 3 (IL3) 146 71. AT-PeA. using
primers suitable for all known breakpoints, is therefo re rec om me nd ed to
confirm ETV6PDGFRB {498 / but if
molecular analysis is not available a Irial
of imatinib is justi fied in patients with an
MPN assoc iated with 1(5; 12).
Variants
A number of molecular variants of MPN
with ETV6-PDGFRB fusion have been
reported 1131, 20851. In addition, a patie!t
who acquired eosinophilia at relapse (j
AML was found to have acquired 1(5:14
(q33;q22) with a TRIPl1-PDGFRBf
gene. A number of other patients ha",
rearrangement of PDGFRB but With
second gene involved being unl<.novo1l.
Complex rearrangements appear to be
common (e .g. a small inversion as~.
translocation) 120851. Because of the
apeutic impl ication s, FISH (break~
FISH with a PDGFRB probe) is indicaled
in all patients with a presunptive
of MPN who have a 5q31-33 break
particularly. but not only. if there ,
eosinophilia. However, FISH analysis
not always demonstrate rearrangemercd
PDGFRB, even when it is detectable
Southern Blot analysis 120851. MoIect.iJ
analysis is not indicated if there is
5q31-33 breakpoint on classical
genetic analysis since all cases re
to date have had a cytogenetically delectable abnormality.
Postulated cel l of origin

The cell of origin appea rs to be a multipo tent baemocorenc stem cell , which is
able to give rise to neutrophils, monocytes.
eosinophils and probably mast cells,
Myeloid and lymphoid

neoplasms with FGFRI
abnonnalities
Progn osis and predi c tive factors

Pre- imatinib, the med ian survival was less
than 2 yea rs, Ther e are not yet re liab le
data on surviva l of imatini b-treated
pat ients, but in a small series (10 patients)
the med ian surviva l was 65 mont hs 15121 .
Med ian survival is likely to im prove as
patients are recog nized and sta rted on
approp riate treatment at d iag nosis rather
than when c ardi ac d ama ge or transformati on has alread y occurred
Table 3.04 Diagnosbc 0'Itetia of MPNor actIIe leuk.aerria associated withFGFRf rearrangement
A myeIoproIlleralive neoplasm lMlh promIfIent eosmpI1E and sometines withneutrophilia or rTW:IAClC)'Iosi
OR
Acute myebd leukaemia or preanor T<eIIor preanor EkeII tymphoblasliC ~ {~

associated with periphetaI blood or bone JTIilITlI'W eosonophIia)
AND
Preseoce r:A .8;13)(P11;q12) or. v;nnl\Jallsb..aboil!eadlng kl FGFRf~ delrorkStJaIed in
ITI)'8Ioid eels, ~sts or boItl
72
Definition
Haematoroqrce! neo plasms with FGFRJ
rea rrangemen t are hetero geneous.They
are de rived from a pluripote nt baemaio
poietic stem ce ll, altho ug h in differet'l
patients or at d ifferent stages of the disease
the neop lastic ce lls may be precursa
cells or mature ce lls. Presentation call be
as an MPN or, in tra nsfor mation, as AML
T or 8 lineage lymphoblastic lympt'loo'lQl
leukaemia or mi xed p heno type acute
leukaemia (MPAL) (Tabl e 3.04).
ICD-O code
The provisional code proposed fOf tl"E
fourth enuon of ICO-o is 996713.
Synonyms
8p 11 myeloproliferative syndrome, 8p11
stem cell syndrome, 8p1 1 stem eel
leukaemiallymphoma syndrome.
EpklemKllogy
This neoplasm occurs across a wide age
range (3-84 years) but most patients are
young . with a median age of onset iJi
Myeloid and lymphoid neoplasms With eosooobne and abnormalities 01 PDGFRA. PDGFRB Of FGFRI
aroun d 32 yea rs {1354 1. In contrast 10

MPN with rearrangemen t of POGFRA and
PDGFRB, there is only a moderate male
predominance ( 1.5:1)
Tissues primarily involved are 8M , PB,
lymph nodes, liver and spl een. lymphadenopathy is the result of infiltration
byeither Iymphoblasts or myeloid c ells.
Clinical features
Some patients present as lymphoma with
mainly lymph node involvement . while
others present with myeloproliferative
leatures. such as splenomegaly and
hypermetabolism. and yet others wilh
features of AML or myeloid sarcoma 13.
1006. 13541. Systemic symptoms such as
fever. weight loss and night sweats are
otten present 11311.
~
Presen tation may be as CEL, AML,
T-LBL or. least often. precursor B lymphoblastic leukaemiallymphoma . Cases 01
acute leukaemia/lymphoblastic lymphoma
may be of mixed phenotype . In patients
who present with CEL. there may be subsequent transformation to AML (including
myeloid sarcoma), T or B lineage lymphoblastic leukaemiall ymphoma or MPAL.
Lymphoblastic lymphoma ap pea rs to be
rrore common in patients with t(8;13) than
in those with variant transiocatons 113541.
Patients who present in chronic phase
usually have eosinophil ia and neutrophilia
and, occasionally. mono cyto sis. Those
who present in tran sformation are often
also found to have eosinop hilia, Ove rall,
about 90% of pat ients have PB Or BM
eosinophilia (1354). The eosinophils belong to the neop lastic clone, as do the
Iymphoblasts and myeloblasts in cases in

transformation. Basoph ilia is not usual but
patients with BCR-FGFR1 fusion may
have basophilia {18791. An association with
polycythaemia vera has been observed in
three patients with t(6;8)1FGFRIOP I-FGFRI
fusion 11770, 23401 .
T precursor lymphoblastrc lymphoma
charact eristically shows eosinophilic
infiltration within the lymphoma.
Cases should be classified as leukaemia!
lymphoma assoc iated with FGFR1
rearrangement, followed by further details
of the specific p esenatco. e.g. "~
lymphoma assoc iated with FGFRI
rearrangement/chronic eosilophilic IelJ<ae.
mia, T precursor IyrrVlobIastic lymphoma.
or "leukaemia/lymphcma associated with
FGFRI rearrangemenl/myeloid sarcoma".
Cytochemistry
Neutrop hil alkaline phosphatase score is
often low, but cytochemistry is not important in the diag nosis.
Immunophenotype
Immuno phenolypic analysis is not useful
in chronic phase disease, but is importa nt
to demonstrate the T or B lineage 01
precursor Been or pr ec ursor
leukaemiallym phoma.
r-ceu
Genetics
A var iety of transloca tions with an 8p 1 t
breakpoint ca n underli e this syndrome,
Secondary cytogene tic abn ormalities
occu r, among wh ich trisomy 2 1 is most
often obser ved. Dependi ng on the partner
chromoso me, a variety of fusion gene s
inco rpo rating part of FGFR1 are formed .
All fusion genes encode an abe rrant tyrosine kinase (Tab le 3,05)
Table 3.05 Chromosomal rearrangements and fusion

genes reported in MPN associated wiltl FGFRt
rearrangemenl. Modrtied from (1311.
Cytogeoetica
M~laf
geoetic:s
1(8; 13)(pl l;q12)
ZNFI98-FGFR'
t(8:9Kp11 ;q33)
CEPf1O-FGFR1
t(6:8l(q27:pl1-12)
FGFRIOP1.FGFR1
1(822l(pl1;ql1)
BCR-FGFR1
(l' .8l(q34:pl1 )
TRJN2.f.FGFRJ
1(8.11)(pl1:Q23)
lrlY018A-FGFR1
1(8:19)(pl2;q13.3)
HERVK-fGFR1
n(12:8)(p11;pl1p22)
FGFR10P1-FGFRf
N'
"
tI adclillon, FGFRJ fl!IilfTiIl'iQt!ilelt has been ku1d II

iISSfJciaIio'. will ~: 12l(p11;q151aocl.8:17XP1l;q25)
but h suspected IwoIYement d FGFRt 1I1(8:tl )
(p11,pt5) wasnot confrmed.
I rvrtln ~ tern MaI::OoniIId iIl"Il Cross (1354).

The cell of origin is a pluripotent tymphoidmyeloid naema topoietlc stem cell.
Prognosis and pred ictive factors
The prognosis is currently poor. There is
no estab lished tyrosin e kinase inhibitor
therapy for MPN with FGFRI rearrangement. althou gh PKC 142 was effect ive in
one case 14001. Interferon has induce d a
cytogene tic response in several pa tients
11354. 14021. Until specific therapy is
develop ed. haematopoietic stem cell
tran splantation should be considered .
even in those who present in chron ic
phase.
Myeloid and lymphoid neoplasms associated WIth FGFRI abnormalities
73
CHAPTER 4
Myelodysplastic/Myeloproliferative
Neoplasms
Chronic mye lomonocytic leukaemia
Atypical chronic myeloid leukaemia. BCR-ABL 1 negative
Jwenile myelomonocytic leukaemia
Myelodysplasticlmyeloproliferative neoplasm. unclassifiable
Chronic myelomonocytic leukaemia
A. Orazi
J. M. Bennett
U. Germi ng
A.D. Brunning
B.J. Bam
J . Thiele
Definition
CIvLric~ IeU<aenia (CMML)
is a clonal baematopoletrc mal ignancy
that is characterized by features of both a
myeloproliferative neoplasm and a mye lodysplastic syndrome. It is characterized
by : 1) persistent monocytosis >1x 1()9/L in
the peripheral blood (PBl; 2) absence of
a Philadelphia (Ph) ch romosome and
BCR-ABL 1 fusion gene; 3) no rearrangement of POGFRA or PDGFRB (should be
specifically exclude d in cases with
eosinophilia); 4) lewer than 20% blasts
(promonocyles are considered as blast

equivalents) in the PB and bone marrow
(8M) ; and 5) dysplasia involvi ng one or
more myel oid lineages. Howe ver, II c onvinc ing myelodysplasia is not pre sent, the
diagnosis of CMML can still be mad e if
the other requ irements are mel, and an
acqu ired. clonal cytog ene tic or molecular
genetiC abnormality is present in the 8M
cells . or if the monocytosis has per sisted
for at least 3 mon ths and all other c auses
of monocytosis. such as the presenc e of
malignancy, infection or inflammation,
have been excluded, CMML is further
subdivided into two subsets. CMML 1
and CMML2 , depending on the number
of blasts plus promonocytes in the PB and
BM. The clinical, haematological and morphological features of CMML are heterog eneou s, and vary along a spec trum from
predom inantly myelodys plastic to ma inly
myeloproliferative in nature. In contrast with
the BCRABL 1negative myeloproliferative
76
2.
No ~ cf1romosomeor BCR-A8L11usion gene
3,
No rearrangement of POOFRA or POGFRB (sllouldbe spealicaRy e~duded 11 cases Wlth eosinophial
Fewer than 20% blasts" in the blood al'(j in ee bone marrow
5.
Dysplasia In oneor more myeloid lineages. If myelodys~asia is absent or minimal. the diagnosis of CMM,.
may stil l be made iflhe other requirements aremet. and'
anacquired, ctooa l cylogenelic or moleculargenetic abnoonality is present in thehaemopoietic cells. r:r
the monocytosis hasp&rSisted forat east 3 months and
aijother causes 0( monocytosis have been e~duded
Blasts irl<:IWe myeloblasts. monobIasts and prornotlOC)'le5. Promonocytes owe monocytic precursors WI1Il
ab\.IIdallt light grey or sIif1Iliy besophilic cytoplasmwitha lew scattered. h liIac-<::oIoIJ-ed p1UIes. finelydislrtluled. sWied nudear etwomabn. variably prominent nudeoIi. WId delicale nud8arloIding oroeasilg. rd
in tIIisdassilicaliorl are equivalenl lO~. AbnormaIITIClI'IOCy1eS wnen can be present baCh ti the ~
blood and bone marrow are excluded from lhe blastCCUIIl
neoplasms. JAK2 V617F mutation is uoccmmon in CMML 11058. 20821
ICD-Ocode
9945/3
Epidemiology
There are no reliab le inc id enc e data for
CMML. because in some epidemiolog ica l
surveys CMML is grouped with chronic
myeloid rewaemras and in others is
rega rded as a myeioovsptasnc syndrome
(M OS) \108] In one stud y in which CMML
accounted for 31% of the cases of MOS.
the incidence of MOS was estimated to
be approximately 12,8 cases per 100 ()(X)
pe rsons per year (2414). The median age
Myelodysplastic/myeloproliferative neoplasms
at dia gnosis is 65--75 years. with a male

predominance of 1.5-3:1 148. 683. 777
2047.21021
Etiology
The etiology of CMML is unknown. 0CCupenona t and environmental carcinogens
and ionizi ng irradi ation are possible
causes in some cases 1108. 20261 .
The PB and BM are always involved. The
spleen. liver. skin and lymp h nodes arethe
most common sites of extramedu llary
leukaemic infiltration 148. 683, 777).
Clinical features
Inthe majority of patients, the white blood
cell (WBC) count is increased at the time
of diagnosis. and the disease appears as
an atypical myeloproliferative neoplasm.
Inother patients, however, the WBC is normal or slightly decreased with variable
neutropenia and the di sease resembles
MOS. The incidence of the most common
presenting comp laints of fatigu e, weight
css. fever and night sweats is similar in
re two groups 01pa tients. as is the rate of
otectooand of b leed ing due to thrombocytopenia 148, 683 , 777, 2047 , 2 1021. AI
ilough splenomegaly and hepatomegaly
rn'irf be present in either gr oup, they are
more frequent (up to 50%) in patients with
leukocytosis 177n
Morp/loklgy and cytochemistry

Peripheral blood monocytosis is the hall mark of CMML. By definitIOn, monocytes
are always >lxl Q91l and usually range
from 2 to 5 x10~/L, b ut may excee d

8Ox 1()91l [48. 683, 1396, 14711. Monoc ytes
are almost always > 10% of leukoc ytes
\ 189.20031 . The monocytes generally are
mature. with unremarka ble mo rphology.
bu t can exhibit abnormal granulation, or
unusual nuclear lobation or chrom atin
pattern 111851. The tatter cells are best
termed abnormal monocvtes -a designation used to describe rronocvtes that
are immature, bu t. in com parison to
promonocytes (and monoblasts). have
denser chromatin, nuclear c onvolu tions
and folds, and a more gre yish cytoplasm ,
Blasts and promonocytes may also be
seen , bu t if the sum of blast s plus the
promonocytes is 20% or more , the d iagnosis is AML rather than CMML. Other
changes in the PB are variable . The
may be normal or slightly decreased . with
neutropenia, but in nearly one half of
patients it is inc reased due not only to
monocytosis bu t also to neu troph ilia
wac
(777, 1396. 164 51 . Neutrophil precu rsors

(promyelocytes, myelocytes) usually account for < 10% of the leukocytes 1189,
2003 1. Dysgranulopoiesis. including neutrophils with hypolobated or abnormally
lobated nuclei or abnormal cytoplasmic
granulation . is present in mos t cases , but
may be less prominent in patients with
leukocytosis than those with a normal or
low wac 1'185, 13961. It may be difficult
in some c ases to distingu ish between
hypogranular neutroph ils and dysp lastic
moooc vtes. Mild basophilia is sometimes
present. Eosinophils are usually normal or
slightly inc reased in number, but in some
cases eosinophilia may be striking. CMML
with eosinophilia may be diagnosed when
the criteria lor CMML are present. but in
addition the eosinophil count in the PB is
2: 1.5xlQ1JIl. Patients in this category ma y
hav e complication s related to the
degranu lation 01 the eosinophils. These
"hypereosinophilic " cases of CMML may
f1. U 2 Chn:nc myeIomonocytic IeukaenU-l. The degree of ~s, neutrr.optMia and dysploIsia is YiWiabIe .. CUt.4L. A The ..... bIoocI eel Cl:Ullis eIINaIed wiIh rnirImaI
~
in !he ~ series. B A noonaI wtJIe bIoocI eel axn WIth absokJte monocytOSis. ~ and dysgrarUopoiesls. C A bone marrow biopsy splDnen Inlm a
CJM..1. Oftsn, " grarUoqIlc WI.-u"" ~ is mosl obYil::lIJs lin se biopsy ~, iW'llI monocyI8S may nol be rNliIy appreoaIed. D The tllded ru:IeIlnl dek:aIe
.... c:t'ttInRn em..... iiIic fA monocyI8S CM be appreciated IIIIO'IQ 1he~.
..,.. .
Chrorllc myelornooocylic Ieuka8ffila
77
closely resemble cases of myeloid neoplasms with eo sinophilia associated with

specific cytogenetiC/mol ec ular genetic
abnormalities involving POGFRA or
PDGFRB genes. for which suc h c ases
should always be exam ined . These d isorder s are con sidered sep arately from
CMML. Mi ld anaemia . etten nor mocytic
but som etimes mac rocytic. is c ommo n.
Platelet counts vary, but moderate thrombi>
c yto pen ia is often pre sent. Atypical , large
platelets may be ob served 148. 13961
The BM is hyperc e llular in ove r 75% of
cases. bu t rorrrcc enorer and even hypoc ellula r sp ecimen s also occur (1471,
21021. Granu loc ytic prol iferation is often
the mos t striking find ing in the BM biop sy
but an increa se in erythroid pr ecursor s
may be seen as well (189. 14711. M0nocyt ic proliferation is invariably present. but
can be d ifficu lt to appreciate in the biopsy
or on 8M aspirate smears. Cytochem ica l
and immunohistOChemicalstudies that aid
in the identificatiOn of mcoocvtes and their
less mature term s a re strong ly recommended when the d iagn os is of CMML is
suspected 121701 Dysqranulcpoiests.
similar 10 that found in the blood. is present in the 8M of most panent s with CMML.
and ovsevmroooesrs (e.g. megaloblastic
changes, abnormal nuclear contours. ring
srderoblasts) is observed in over one ha lf
of patients 177 7, 1396 , 147 11 . Micromegakaryocytes and/or meqekervccytes
with abnormally lobated nuclei are found
in up to 80% of patients [1396. 1471 1.
A mild to moderate increase in the amount

of reticulin fibres is seen in the 8M of
nearly 30% of patients with CMM L 114061.
Nodules c omposed of mature p lasma cytoid de ndritic c e lls (plas mac yto id
monocytes) in the BM b iopsy have been
reported in 20% of cases 116491. These
cells have round nuc lei. finely d ispers ed
chromatin, inconspicuous nuc leoli and a
rim of eos inop hilic cytop lasm. The cytop lasm ic membrane is usua lly d istinc t.
with we ll-defined cyto plas mic borders.
This imparts a c ohe sive ap pearanc e to
the infilt ratin g c ells. Apoptonc bodies.
often within star ry sky testrocvtes. are
frequently pre sent. The rela tionship of the
plasmacytoid dendritic cell proliferation 10
the leuka emic ce lls has been consider ed
uncertain 1120, 655 , 895 , 9671. A recent
study. however. has show n that they are
c lon al. neo pl astic in nat ure , and closely
related to the associated myeloid neoplasm 123351.
The splenic enlargement in CMML is
usua lly due 10 infiltration of the red pu lp
by leukaemic cells. Lym phadeno pa thy is
uncommon, bu t when it occurs. it may
signal transfor mation to a more acut e
phase. and the lym ph node may show
d iffuse infiltration b y mye loid blasts.
Sometimes, there is lymph node and (les s
commonly) sp len ic involveme nt by a
diffuse infiltration of plasmacytoid dendriti c
cells. In some patients generalized lymphadenopathy due to tumou ral prol iferations
of plasmacytoid dendritic ce lls may be
the presenting manifesta tion of CMML

Blast cells plus oromonocvtes usually
account for fewer than 5% of the periphera;
b lood leukocytes and fewer than 10% ci
the nucleated BM cells at the time of
d iagn os is. A higher number of blasts
(p lus promonocytes) than this may ident4y
pat ients who have a poor prog nosis or a
greater risk of rap id tran sformation to
acut e leukaemia {48. 682, 683. 833. 2102.
2 170. 24431. Thus. it is recommelldecl
that CMML be furt her d ivided into two
subcategories. dependil"lQ on the runt:lEJ
of blasts (plus promonocytes) found i'l
PS and 8M . as follows :
CMML- 1
Blasts (including promonocytes) <5% r:
ee PS , <10% in the BM ;
CMML2
Blasts (incl uding promonocytes) 5-1 9\
in the PB or 10- 19% in the 8M . ex I'tte1
Auer rod s are present irrespective of the
b last p lus p romonocyte cou nt.
The value of this approach has been recently con firmed 17801.
Cytoc hemic al or immunop henotypic studies are strongly recommended whenever
the d iagnosis of CMML is c onsidered
When performed on P8 and 8M aspirate
smears. alpha naphthyl acetate esterase
or alpha naphthyl butyrate esterase, used
alone or in combination with naphtt'dASD-chloroacetate esterase (cbioroacetae
I
A;. 4.03 Chronic myelomonocytlc teokaemia-2. A Blood smear from a newly ~ patient. 0C:casi0naI bl9:sls W8f1l noled.,!he perVleIaI blood smear. B Bilpsy~ ..
same palJefW. The Im\aIJ.ny of !he ba1e fllamlW BIemenIs c:ar1 be rea:iIy appreciated. C BIasts.-.d pI'Ofl'IOf'IOC) ICCOU'IC lor 12".110 of !he I'fllIm)fr eels (~ ~
78
Myelodysplasticlmyeloproliferative neoplasms
esterase, CAE) is extremely useful to assess the monocytic component.

Inmunophenotype
The PB and BM cells usually exp ress the
expected myelomo noc ytic antigens, suc h
asCD33 and C013, with variable exp ression of C01 4, C068 and C064 1243,
1377, 24421. The PB and BM monocytes
often express aberrant phenotypes with
:...oar more aberrant features by flow cvtometric analysis. Some, such as decreased
expression of C0 14 , may reflect relative
rronocyte immaturlty_ Other aberrant
characteristic s include overexp resscn of
C056, aberrant expression of C02 or
cecreesec expression of HLA-OA, C0 13,
C015. CD64 or C036. There may be aberrn phenotypic features on maturing granulocytic cells and neutroonas may also
stlCM' aberrant scatter properties . An
percentage of CD34 + cells or
emerging blast population with aberran t
.rrrnunophenotype has been associated
tilth early transfor mation to acute
eukaerma (AML) 1626. 2442 , 24591.
Irrmunohistoc hem istry on tissue sec tions
b the identi fication of monocytic cells is
-etanvelv insensitive as compared with
cytochemistry or flow cytometry. The most
reliable marke rs are CD68R and CD l63
11649J. Lysozyme used in conjunction
with cytoc hemistry for CA E can also faci l~ate the id entifica tion of monocytic cells,
...nich are lysozyme- positive but negative
lor CAE, in contrast with the c renulocytrc
precursor ce lls, wh ich are pos itiv e for
bolh, An increa sed perc entag e of C0 34 +
cells detected by immunohistochemistry
has also been ass oc iated with tran sfo rmation 116491 .
The plasmacytoid d endritic cells associated
\II'ithCMML have a c haracteristic immunopeeootype. They are positive for C 0 123,
CD14, C0 43, C068, C 068R, C 0 4SAA,
C033 (weakly) and CD4. Granzy me B is
also regularly exp resse d. but TIA 1 an d
perforin are not. Variable C056 expression
is seen in a minor ity of the cases, whi le
tceu-assoctateo an tig ens suc h as C02
!'Id CDS can also be present.
rceaseo
F"tg.4.04 Onncmyelomooocylic leukaemia, Some dl9'8801fibrosrsmay beseen in upb3O"1i 01 cases. A,8 These
pl1oklmicrographs 1ustra1e retiaJIin fibnls$ in a mafTllW blopsy specimen 01 a pabefIl WIIt1 CMML.
an
,8
Fig, U 5 CI.-onic myelornonocytIc leukaemia ANodI.*s COfl'IPOMd 01 pIastr1ac:ybd tter'01tiC eels in the bone R'IiIrrow 01 a patient WIIt1 CMML. B com is posilMIin pIasmaqtid dendriIic eels
mutations of RAS genes at diagnosis or

dunnq the d isease course {1686, 2 118,
24171- The approp riate categorization of
baematoroqrcat neo plasms associated
w ith isolated isochromosome 17q is uncertain at this tim e. Although a p roportio n
01c ases meet the crite ria for CMML, others
may be more ap propriately ca tegorize d
as MDS/MPN , uncrassmabre {708 . 14371Abnormal ities of 11q 23 are unc ommon in
CMML, and instead suggest the diagnosis
01 AML.
Cases of MDS/MPN with eos ino phi lia
associated with t(S;12)(q31 -33;p1 2) and
an ETV6-PDGFRB fusion gene, whic h
were formerly incl uded in the CMML
c atego ry, a re no w co nside red a d isti nct
en tity, Cases resembling C MML may
express the p1 90 BCR-ABL 1 Isotorm and
should be c lassified as ch ronic myelog enous leukaemia (CM L). Thus, if a
t(9 ;22)(q 34 ;q 11) is not detec ted by cytog enetic analysis it is insufficient 10 use
only PeA analysis for the presence of
p 210 to exclude CML.
is 20-40 months {48. 682 , 683. 777 , 779.

833,2047,2102,2170.2443 1_Progression
to A ML occurs in approximately 15-30%
of cases. A num ber of clinical and
haematological pa rameters, includi ng
splenomegaly, seve rity of ana emia and
degree of leukocytosis, have been reported to be important factors in predicting the cou rse 01the di sease . However, in
virtually all studies, the percentage of PB
and BM blas ts is the mos t important factor in de term ining survival j48 , 480 , 682,
683 , 777 , 780, 833, 2047, 2102 , 2170 ,
2443 ).
Genetics
Cb'lal cytogenetic abnormalities are found
in 20-40% of pat ie nts w ith CMML, but
rme is specific 148, 683 , 684 , 777 ,867,
2102, 2170, 2260 1_ The most frequent re:urng abnormalities include +8. -7/deI(7q)
ind structural abnormalities of 12p. As
many as 40% of patients exhibit point
Postu lated cell of origin

Heerropoeuc stem cell.

Survival of patients with CMML is reported
to vary from one to more than 100 months,
but the median survival time in most series
Chronic myeklmonocytic IeukaerTlla
79
Atypical chronic myeloid leukaemia,

BCR-ABL 1 negative
Def inition
BCR-ABL 1negative (aCMl) is a leukaemic
disorder with myelodysplastic as well as
myeloproliferative features at the lime of
initial diagnosis. It is characterized by
principal involvement of the neutrophil lineage with leukocytosis resulting from an
increase 01 tnOfphologically dysplastic
neutrophils and their precursors. However,
mullilineage dysplasia is common and
reflects the stem cell origin 01 aCML. The
neoplastic cells do not have a BCRABL 1
fusion gene.
ICD-<l code
Synonym
987613
Epid emiology
The exact incidence of aCMl is not krlOWn,
but is reported to be only 1- 2 cases for
every 100 cases of BCRABL 1 positive
C ML 1200 31. Patients with aCMl tend to
be elderly. In the few series repo rted to
dat e, the med ian age at di agnosis is the
seve nth or eighth d ec ad e of life bu t th e
d isea se has been reported in teen ag ers
as we t11266 , 928, 1208, 1396,20031 , The
report ed maie.temare ra tio var ies , b ut
based on the larger series reported , is
approximately 1:1 1266 ,928 , 1208,1 3961.
The pe riph eral blood (PB) and bone ma rrow (BM) are alwa ys invol ved: sp lenic and
hep atic invo lvement are also common.
Table 02 Dl3QOOSoc critenalor at)1Ial dlronic myeloid leuUemIa, BCR-ItBL nega!lYe (acML).
~ t*;lod
Ieukocylosi$ (WBC 2: 13alO'1l) cl.Ie 10IllCtlliIsed runbers 01 neutn;lp/'iIs arKI their
prewrsor5 WIth prominent ~
NoPh dlromosome or BCR-ABI..1 fIlSIOIl gene

NorearrMgBI'IlllI 01 PDGFRA or POGFRB
Neulrophi prectJS(n {pfomyelocyles, myeIocyles,~) ~1 0% 01 leukocytes
hh'naIlIbsokIIe ~ : b9soptlis USUIIy 4"4 0I1IIukocyles
Ncor II'III'IirrIClI absoUe~ ; lMl'lOC)1eS <10'1t oI~
pi" . '
~arbone mafTtM'wiII~
and ~~. W!ltl or wrtloul
dysplasia n h etyflroict and megakaryocyIc Irl9Iges
less than m bIiIsts n fie blood and n h bone rr8lUW
counts in excess 01 3OOx1091l 1266, 928,

1208, 1396 ,20031. Blasts are usually less
than 5% and always less than 20% 0I1eu~
cvtes. Neutrophil precursors (promyelocvtes. rnveiccvtes and metamyelocytes)
usually comprise 10 - 20% or more of the
leu kocyte d ifferent ia l. Although the absolute monocyte count may be increased,
the perc entage of rnonoc yte s ra rely exceeds 10. Baso p hilia may be observed
but is no t prominent 1189 . 266. 928. 1396 .
20031. The ma jor feature that characterizes aC ML is ovsqranctoooese. which is
often pronounc ed , Ac qu ired Pelger-Huat or
othe r nuc lear abn or malities, suc h as abnorm ally clumped nu c lear c hroma t in or
bi zarrely seg me nted nuclei, and abnormal
cytop lasmic granu lar ity m ay be obse rved
in the neutrop hils. Mod erate anaemi a is
frequ ent and the red blood cells may show
c hang es indi ca tive of dysery th ropoiesis,
inc ludi ng macrcovaiocvtosrs. The platelet
cou nt is variab le, b ut thrombocytop enia is
Cl inic al features
There are only a lew reports of the clinical
featu res of pa tien ts with aC ML. Most patients have symptoms related 10 anaemia or
some times 10 thrombocytopenia. whereas in
others the chief complaint is rela ted to
spleromega" 1266. 928 .1206. 1396.20031.

Mor phology and cytochemistry
The white blood cell (WBC) count is
always ~ 13x 1r1fL 11891 but median values
ra ng ing from 24-96x1Ql'1L have been
reported and some patients have WBC
80
JW, Vardiman
J.M. Bennett
B,J, Bain
R D , Brunning
J , Thiele
MyekldysplasticJrnyeloproliferative neoplasms
common 1189 , 928,1396,20031 .

The BM biopsy is hypercellular due to an
increase 01 neutroph ils and their pecesos
Blasts may be modestly inc reased 111
number, but are always less than 20'%:
large sheets or clusters of blasts are rICK
present. Dysgranulopoiesis is a constant
find.ng and the changes in the neutroptil
lineage observed in the 8M are similar to
those described for the blood, Megakaryocvtes may be decreased. no rmal or increased in nu mber, but in most cases
some oysmeqakarvopoiesrs is present
including sm all me gaka ryocytes and
mic rorreqakarvocytes and/or megakaryo.
cvtes with hy po lobu laled or non-lobulated
nuclei 1266, 9281. Usually the M:E ratio is
g reater than 10:1, but in some cases ery
th roid p rec ursors ac count for ove r 30% 01
the 8 M ce lls, Dy serythropo iesis is present
in at leas t 50% of c ases 11 89, 266, 9281_
Inc rea sed reticu lin fibres are seen in some
c ases at the time of d iagno sis , or may
.
-,
.
- .....
~
Fog. ' .07 Atypical chrOIlIt myeloid leukaemia. A Bone IT\lIITOIfI'biopsy shows 1Iypetc:eIIWnty. 0Je to~ proMerabon B NcJ(e anncrease "' Ihe l1JITtler of rnegak.afyocytes,
... smal abnonnallorms From the biopsy alone. !he fT'OlIhology wWd be dlfliQjt to tjft'erentlale from BCR-ABl. po5IbYe chronic myelogenous leukaen'ia C Bone marrow
. . smear. Oysplasia in !he ~ and the megakaryo:;ybC lineages is eWlenI.
appear later in the course of the disease.

Most cases reported as the 'syndrome of
a~mal chromatin clumping " can be
considerec:l as a ....ariant of aCML 1276. 680,
10071. These are characterized in the P8
.nt 8 M by a high percentage 01 reuno:tits and precursors that exhibit exagger
eeock.mping of the nuclear chromatin .
'> specific cytochemical abnormality has

been reported 10 date, although stains to
detect a significant rnoncx:ytic component
can be use ful to exclude chronic myelomonocytic leukaemia (C MML) . A nonSPecific este rase react ion performed on
a BM asp irate may identify sign ific antly
more monocytes than are ap prec ia ted by
routine stains. l e ukoc yte alka line phosphatase scores may be low, normal o r
elevated. and thus are not useful for

diagnosis 11208. 13961 .
Immunophenotype
No speci fic imm unop henotypic c haracteristics have be en reported to date, A s
with cytoc hemistry, immunohistochemical
studies for CD 14 o r CD68R on biopsy
sections may he lp to id entify monocytes:
fnding a significant 8M monocytosis
sllould call the di agn osis of aCML into
coesnon.
Genetics
Karyotypic abnormalities are reported in
up to 80% 01 patients with aCML. The most
CCfTITlOlI abnormalities are +8and del(2Oq) ,
but abnor malities of chromosomes 13, 14,
17,19 and 12 are corrvnonly repor ted as
'Nell 1266, 928.13961. Rarely, patients whose
neoplastic c ells have an iso lated isochromosome 17q may have features of aC ML
although most will fulfill the cr iter ia for
CMML 11437f.
There is no BCRABL 1 fusion gene.
Cases with rearran gement of PDGFRA or
PQGFRB gen es are also specifica lly
excl ude d. The ac tiva ting JAK2 V617F
mutation has been reported in some c ases
of aCML {1064, 12871. Approx imately 30%
of cases are ass ociated with acquired
mutat ions of NRASor KRAS1 2311 1,
Some c ases of t(8; 9)(p22;p 24 ) with the
PCM1..JAK2 fusio n gene have bee n
reported as "aCML" 1259, 18331 but d ata
cu rrently ava ilable suggest they hav e
eosinophilia and lack mye lody sp lasia and
may be better regarded as chronic eosinoph ilic leukaemia. Meticulous description of
the morpholog y of atypical mye loid proutera tions associated with var ious geneti c
defects will be necessary to assign them
to appropriate ca teg orie s,

Bone ma rrow haematopoietic stem cell.
Prognosis and predi ctive factors

Patients with aCML fare poorly, The series
reported to the present time include only
small numbers of patients, but median
survival times range from 14 -29 months
1266, 928, 1208 , 20031. Age >65 years ,
female sex. W8C >50x 1Q91l thrombocytopenia, and Hb <10g1dL have been
repo rted to be adverse prognostic findings {266. 9281. Howeve r, pa tients who
rec eive 8M nansptantanon may have an
improved outcome 111781. In approximately
15- 40% of patients, aCM L evolves to
acute mye loid leukaemi a. wherea s the
remain de r die of marrow fail ure {266.
12081,
AtypIcal crvooc myeloid leukaemia. BCR-ABL 1 reqanve
81
Juvenile myelomonocytic leukaemia
Definition
Juvenilemyel:m:>nocyt<; ""-'<aemia (JMMLI
is a clonal haematoocietrc disorder of
childhood characterized by proliferation
p rinci pally of the gr anulocytic and m0nocytic lineages. Blasts pius promonocytes
account for <20% of cells in peripheral
blood (PB) and bone marrow (8 M). Erythroid and megakaryocytic abnomaunes
are frequently present 132. 303, 14771.
BCRA8L , is absent, whereas rrctato-s involving genes althe RASIMAPK pathway
are cha rac teristic .
ICD-Ocode
994613
Epidemiology
The inci dence of JMMl is estimated to be
approximately 1.3 per millio n ch ildren
0- 14 years of age per year. It accounts
for less than 2-3 % of altleukaemias in
chi ldren, but for 20-30% of all cases 01
mye lody splasl ic and mye loproliferative
disease in patients < 14 years of age 1907.
17041. The age at diagnosis ranges from

one month to early ado lescence, but 75%
of cases occur in child ren <3 years of age
1345, 1346 , 1595 1, Boys are affec ted nearly
twic e as freq ue ntly as g irls , Ap proximat ely 10 % of cases occur in c hild ren
with the c linica l diagnosis of neurofibromatosis type 1 (NF l) 1345 , 1595,2 10 11.
Etiology
The c ause of J MML is not known . Rare
c ases have b een repo rted in identical
twins \17051. The association between NF 1
and JMML has long been established 1345.
1595 , 2 1011. In contrast to adults who
hav e NFl . children with NFl are reported
to have a 2OQ. to 5(X).fold increased risk
of developing myeloid malignancy, mainly
J MML 115951.Occasionally young infants
with Noonan syndrome develop a JMML-like
disorder, which resolves without treatment
in some cases and behaves more aggressively in others 11211 , These children carry
germhne motanons in PTPN11,lt1e gene
encocting the protein tyrosine phosphatase
SHP2121621 or in KRAS 119741 .
The PB and BM always show evidence of
myerononccvnc p roliferation. Leukaemic
in filtra tion of the liver and spleen is found
in virtually all cases, Although any tissue
may be infilt rated, lymph node, skin an d
t he resp iratory t rac t are other co mmon
sites of invo lvem ent 1345, 134 6 , 15951.
Clinical features
Most patients p resent w ith constitutio na l
sym ptoms o r ev idence of inf ect ion \34 5 ,
1346, 1595l . There is generally ma rked
hepatosplenomegaly, Oc casionally sp leen
size is no rm a l at di agn osis but rap id ly
inc reases thereafter, About half the patient s
Table 4.03 Diagoosticarteria of juveoile myelomonocytic leukaemia"
1. F'eflpheralblood ~ >b lO'IL

2. Blasts (ird.Jdlng ~)" In <:!(l%of lie leUor.ocyles II eeblood 1Rl of !hermeated beneITI8ITtlW eels
3 No Ph d\lomosome or BCR-ABL1 fusion gene

.4
Plus two ex more dille loIowing:

- HaemogIoI:lln F irocrea&ed lor age
- Irm'Iature granulocyles in the peripheral blood
- WBC counl >10J;10"/l
Clonal d1I01TC1SOm111 abrlormIldy (may be monosomy 7)
GM.csF hyper'5enIIbviI of myeIold progerIIIor5 on I'itro
"McOfled from 11596}.

."In IIliScialslkalJon. protI'I(lllCICy In equivaIer( 10 bIa5ts.
82
Myelodysplastic/myeloproliferative neoplasms
I Ba umann
J ,M. Benn ett
C.M. Niem ey er
J , Thiele
K , Shannon
<)
.~
FIg.4.111
..hJyrie myek:m:lnocytlc IUaeITia I.MU

PenpheraI blood smeal" shoWn;l abnornIaI ~
wotrl C)t:IpIasmic vacuolesand two oormoblasl5.
have lymphadenopathy. In addition , Waemic infiltrates may give rise to markedy

enlarged tonsils . Signs of bleeding are
frequent and about a quarter of the caress
have skin rashes. Cafe au tait spots are
noted in patients with NFl .
A remarkable feature of many JMML cases
is a ma rke dly increased synthesis 01
haemoglobin F, specifically in cases WIth
a normal ka ryotype 1345. 1595 1. AddrtiClrl!
fea tures include polyclonal hyp ergammaglobulinaemia and the p resenc e of autoantibodies 1345, 159 5 1. The cl inical and
laboratory featu res of JMML sometimes
clos ely mimic infectious diseases, including
those du e to Epstein-Ba rr virus , cytomegaloviru s, human herpesviru s 6 and others
11 376, 1596, 17511, Ap p ropriate laboraicv
testing inc luding mo lecu lar stud ies and if1
vitro c ultures may be requ ired to exclude
infec tions as a c ause for the clinical arc
haematoroqc find ing s
In vitro, there is ma rked hy persensitivityol
myeloid progeni tor cells to GM -CSF 16441;
this has become the hallmark of the d isease
and represents an important diagnostic lo:t
Morphology and cytochemistry
The PB is the most important specimen III
proving the d iagnosis. It gener ally stoes
leukocytosis, throm bocytopenia and
anaemia 1345.1346. 15951. The median reported .....tIile blood count ('NBC) varies lrcm
25-30x1Ql1Il, but rarely is >l00xll1i\.
The leukocytosis is comprise d mainly aI
neutroohns. with some immature ceus
such as promyelocytes and mveocytes.
oae-
as well as of roonoc ytes . Blasts (includ ing

promonocytes) usuall y account for fewer
than 5% of the white cells, and always less
than 20%. Eosinophilia and basophilia are
ooseved in a minority of cases, Nucleated
red blood cells are often seen . Red blood
cell changes include macrocytosis, partieularty in patients with monosomy 7, but normcx:ytic red cells are more common, and
recrocv tosrs due to iron deficiency or acQOired thalassaemia phenotype 1961} may
be seen as well Although platelet counts
are variable , thrombocytopenia is usual and
may be severe 1345, 1346, 1595, 17051.
Bone mar row f indings are not by themselves diagnost ic . The 8M aspi rate and
biopsy are hyperce Uular with gral'lUloCytic
proliferation , although in some patients
erythfoid p recursors may p redominate
\1595, 17051. Monoc:ytes in the BM are
often less impressive than in the PB .
generally accounting lor 5-10% 01 the
BM cells. Blasts (including prorooocytesj account tor <20% 01 the 8 M cells.
and Auer rod s are neve r seen . Mos t often
dysplasia is minimal. However, dysgranuccorese. including pseudO Pelqer-Heet
neutrophils or hyp:>granularlty may be noIed
n some c ases and eryt hroid precursors
may be enlarged, Meg akaryoc ytes are
cnen reduced in number, but marked
rregakaryoc ytic dysplasia is unusual 1345,
1595, 17051 . Reticulin fibrosis has been
noted in some patients 13451.
Leukaemic infiltrates are common in the
skin where myelomonocyt ic ce lts infiltrate
the superfic ial and d eep der mis , In the
IUl"Ig, leukaemic cells spread from the capillaries of the alveo lar septa into alveola e .
ld il"l the spleen they infiltrate the red pulp ,
and have a predilect ion for trab ecular and
central arteries , In the liver, the sinu soids
the portal tract s are infiltrated ,
~ specific cvtocterracai abnormalities have
been repor te d in JMML. In 8M as pirate
smears. c ytoc hem ical sta ins for alpha
naphthyl acet ate esterase Of butyrate
esterase, alone o r in combin ation wi th
naphthol-ASD-chloroacetate esterase,
may be helpf ul in detection of the monocytic compone nt . A lthou g h leu kocyte
all.aline phos p hatase scores are reported
to be elevated in about 50% 01 patients,
this test is not helpful in establishing the
diagnosis 113461.
Fig. U t Juvenile myeIomooocytlc leukaemia, A The bone marrow- aspole &IM3f usuaty refIecls thed\afIge$ noted
in the blood. buI !he monocyle ~ lllIlI is dmft10 appreciate, 8 ACOlTiw'oed alpha naplhyI acela1e eslefase and
naptl~ esterase ' eaclion idenblies the vanulocytlt (blue reaction product) and the ITIOflOCYlIC
component (brown feacbon product). A lew eels contain bolh pnxIuct$
Fig. 4.10 Juvenile ~ lOCytJc leukaemia, A The b<:Jre marrow is ~ wrlh g~pn:lilefabon.
B The megakalyocytes are reduced in IlUfTlbef, but appear rTlOIphologlcally IlOffIIII in Ihe biopsy Blasts are not
substantially ineteased in rvnber.
foC~
eoo
- type
"' speo!ic ~abroonaJ'"

rave been reported in JMML. In extra~ 1JSSUeS, the monocytic COflXIl8llI
Fig. 4.11 JU'.'OOile rnyeIofnoncq1ic leukaemia. The leukae ~ infiltrate in the Iivef isin the portalregiOns (AI as wei as
in !he hepalic sinusoids (8) , C The leukaemicI1filtrale in !he red pulp of !he spleen encroadles ~ !he gemiIIaI ten.
Int. 0 The infiltJale is compfised mainly of immalufltand maluflt neutrophils and fTIOflOCY\es.
is best detected by irTVTlunohistochemica l

techni ques that detect lysozyme and
CD68 R. However, individual cases may
show almost excluswetv infiltration by
myeloperox idase-positive granulopoietic
precursor ce lls .
Gene tics
Karyotyping studies show monosomy 7 in
about 25% of patients, other abnormalities in 10%. and a normal karyotype in
65% 115951. Philadephia chromosorneand
the BCR-ABL I fusion gene are absent.
JlIVenile myebnonocytic leukaemia
83
There is evidence that JMML is, at least in

part. due to aberrant signal transduction
resulting from mutations of components of
the AAS/MAPK signaling path way, Somatic mutations in PTPN 11 occur in 35%
of patients 11329, 21621. and oncogenic
mutation of the RA$ genes, NRAS and
KRAS2, and of NFl are each seen in appro ximately 20% 121621. Mutations in
PTPN1' , the RAS genes and NFl are
largely mutually exclusive, suggesting
that pathOlogical activation of AAS dependent pathways plays a central role in
the pathophysiology of the disease.
In JMML cells of children with NF 1, unrparenteral dlsomy results in dUplication of
the mutant NFJ allele 1714, 20961 . Since
the NFt gene product, neurouoromo. is a
negative rroourato- 01 AAS function, the
loss of the normal NFt allele is associated
with AAS hyperactivity 119971,
Haematopoietic stem cell.
Prognosi s and pred ictive factors
Although JMMl rarely trans forms into
acute leukaemia. it is a rapidly fatal diso rder for most children If lelt untreated . The
median survival time Without allogeneic
stem cell transplantation (HSCT) is about
one year. Low platelet co unt, age above 2
years at diagnosis and high haemoglobin F
at diag nosis are the main pred ic tors of
short survival 1345. 1595. 17051. In the absence of effective treatment, most children
GM~SF
SO~
She
G, b2
Ga b2!
SHP-2 - -
R a s -GDP
~ --.......r-,
Neurofibforrin
.-I
"..,""'"""~
GM~SFR
PTPNU Mutation
(-35%)
I EttK tor Path ways

Fig.4.12 Molecular lesions ~ Ras sir'*'!l prOWlS in JMM.. GM-CSf normaIy binds kI its rec:epD". in1al
I'IeterIXlin1er d asserrbIes 8 ~. d S9'*9 mclIo.JIes a'ld adaplets flat i'le1.I::les She: and GttI. ThesI
proieln$. " un. ftICI"Uit Gab2. SHP-2 and 505. 1IltliCh eataIyzeI ~ IWJd80lIde ~ lllI Ras and iwnases
oee
irr.IoeI.D"leYeIs d Ras-GTP.
aetvaaed, Ras-GTP ~ ..... rurtJerd ~ elfectIrs, The Gw.
lIdMI\log proB1s pt2OGN' and net.6OIibn:mn brld kIRas-GTP and aoc:eIerate lXlfI'o'eIWn d Ras-GTP kI Ras-W'
~ kI GM-CSf is a ceIlW haImart. d JtAt. ltIal resulls from a rurtJer d lisln::l genetic ~
t.lJtaIioI1s in PTPNfl increaseSHP2 phosphatase acIYlty a'lderNIce Ras SigrlafrIg. SiTI1arIy. cancer-associaled . . .
acid Slbsl.iluIiCI'I in NRAS or KRAS2 red in /TJJlarIl: Ras prol8in:s IIaIlICO.Il1Jiate " ee acINe. GTP-b:u1d c:onbmalion. FnaIy. inacIivaIiorI ofllle NF l ~ ~gene ~ Rassigoahng ItlrtXJgh loss ofneurofib'orm
die from organ failure. such as respiratory

failure. due to leukaemic infiltration .
Haernatc poietic stem cell transplant
(HSCT) from a related or unrelated HLA
com patible donor c an cu re about half the
patients 113261. Relapse is the major
ca use of treatment failure, There is clea r
evid ence that graft versus leukaemia
effect plays an impo rtant role, since a

substantial proportion of children can be
cured alter a failed HSCT by donor 1ymphocvte infusion and immunomodulatory
therapy 117871. The role of anti-leukaemic
eeaov prior to HSCT is currentlyu-ceten
s
(
s
ti
T
o
84
MyelOdysplasticJmyeloprolilerative neoplasms
Myelodysplastic/myeloproliferative
neoplasm, unclassifiable
JW. Vardiman
J.M . Bennett
B.J, Bam
I. Baumann
J , Thiele
A. Orazt
Definition
Myelodysplastic/myeloprohferative neopIasm. lI'lClassifiabie. (MDWPN. U) meets
!he criteria lor the MDSIMPN category in
lhat, at the time of irntial presentation ,
eee are clinical, laboralOf'y and rrceprobgicaI features that overlap both MOO and
MPN. Cases classified as MDS/MPN, U

00 not meet the criteria lor chronic
myelomooocytic leukaemia . juvenile
myelomonocytic leukaemia or atyp ical
d'rlnc myeloid leukaemia The finding 01 a
oc:R-ABL , fusion gene or of rearrangement
11 PDGFRA, POGFRB or FGFR' excludes
tie diagnosis of MDSlMPN , U .
It is important that the designation

UDSnvtPN, U not be used for patients with
aprevious, well-defined MPN who develop
Oysplastic featu res in ass oc iat ion with
eans'ormeton 10 a more aggressive
rrase. HoNever, MD5'MPN, U may inc lude
sere patients in whom the c hronic phase
01 an MPN was not previously detected.
:rld who initially present in Iransformalion
MIh myelodysplasticfeatures. If the under~ MPN c annot be identified . the desigration of MDS/MPN , U is appropriate. If
there has bee n any rece nt cytotoxic or
arowth fact or therapy, follow-up clinical
and laboratory observations are esse ntia l
kl demonstrate that the peripheral b lood
(PS) and bone marrow (BM) c hanges are
'lOt due to the treatm ent.
ICD-O code
9975/3
Synonyms
\lIXed myeloc routerawe/myelocysptastc
syndrome , unctasstnebre : "overlap" synacme, unclassilia ble .
&las of involvement
The BM and PB are always involved:
spleen, liver and other extramedullary
':ISSUeS may be involved.
The case has dirucaI, laboratory and ~ IN!ufes rJ onerJ !he ca1egories rJ MDS (reifacklry
~ WIItl unineage: dysplaSIa, relraalryaJla&mia WI\IlI'IIgSiCIerObIasIs. reIracIory tyqlenia 'MIhIlUbIileage ~. relradory anaemia -.ilh elC8SS 01 blasts) and <20"4 blasts in the blood and bone marrow
""
no ""
Has proITWlenI mye!oploilelalMlleatLres, e.g. pIMeleIaut a 45OJ;10'lt associaIed -.ilh megakaryotytlc

proIileration, or WBC COld~ 1 h1 l1'lt , MIh or WI1hOul P'tJn*Ienl spIeIlllfTIllgaIy
tia$ preceding tGlfy rJ In ~ W'N or rJ KlS , no hlst:lryrJ n!CeflI L)'k*JXlC or ~ Iador
\hel'apy ~ ccokl e.'(j)lain !he ~ or 1ll)eIopi00000llti.. feaUes , IIfId no F'hiadelphia
chCfl'CSOlII8 BCR-ABL1 k.tsion 98"8, no realral'9lll,.ltrJ PDGFRA. PDGFRB or FGFRf,1IfId no
isolated del(5q},l(3:3)(Q2I;(l26) or1fI'l'(3)(Q21q26)
The palienlhas de rICM) disease WI\tl nned myeIoprolilnlrt'8 and myelodyspIastIc features IIfId eatnlt
be assigned to i1It'/ olhercategory rJMOS, MPNrJMDSIMPN.

These disorders are charac terized by proliferation of one or more myeloid lineages
that is ineffec tive, dysp lastic or both and
simultaneously, by effective pro liferation .
with or without dysplas ia, in one or more
of the other mye loid lineages, l aboratory
features usually include anaemia of variable
severity, w ith or without mac rocytosis and
ofte n d imor ph ic red blood c ells o n the
per ip heral smea r. In addition, there is evidence of effec tive proliferation in one or
more lineages, e ither as thrombocytosis
(platelet count ~ 45Ox1Q91l) or leukocytos is
(w hite b lood c ell c ount ~ 1 3 x 1 09/l ) , Neutroph ils may show dysplastic features and
the re may be g iant or hypog ran ular
pl ate lets, Blasts ac count for <20% of the
leukocytes in the PB and of the nucleated
cells of the BM , and a find ing of > 10%
bl asts in the PB or BM likely indicates
tranetoenetoo to a more agg ressive staqe.
The 8M bio psy specimen is hypercellular
and may show proliferation in any or all of
the myeloid lineages. However, dysplastic
featu res are simultaneously present in et
least one ce ll line .
Cytochem ica l find ing s may be similar to
lhose seen in MDS or in MPN,
~icaI featu res
The c linical features of MDSlMPN , U
IrrmJnophenotype
OYerlap those found in d iseases of the

l.tOS and MPN categories 1129. 1588.
23111.
May be similar to findings in MDS and/or

MPN .
Genetics
There is nocvtooeoetc or rooIecular genetic

finding specific tor this group. A Philadelphia
c hromo some and BCR-ABL 1fusion gene
should atways be excluded prior to making
the diagnosis of MDSlM PN, U. Cases with
rearrangeme nts of POGFRA, PDGFRB or
FGFRI or w ith iso lated de l(5q) or 1(3 :3)
(q2 1:q26) or inv(3Xq21q26) are excluded
from th is category as well. In diff icult
cases . the p resence of a JAK2 V617F
mu tation may help to confirm a haematopoietic neoplasm. thoug h the significance
of such mutations in this entity is unce rtain.
Occasional cases w ith isolated del(5q)
and JAK2 V6 17F mutation have been repo rted to have features that overlap MDS
and MPN 110051.
Haematccoretrc stem cell.

(RARS) associated with marked
throm bocytosis
Definition
In the third editionof the INHO Ciasetcaton

RAR$- T, previously also referred 10 as
essentia l thrombocythaemia (ET) with ring
sioerobiasts . was proposed as a provisiona l entity to encompass pat ients who
have the cuncat and morphological features of the myelodysplastic syndrome,
MyelodysplasticJmyeloproliferative neoplasm, uoclassifiable
85
AARS, bu l who also have marked thrombocytosis assoc iated with abnormal
megakaryocytes similar to those observed
in the BCR-ABL 1 nega tive MPN, such as
ET or eartv-staqe primary myelofibrosis
(PMF) 1865,1077,21091. However, some
investigators have suggested that MAS- T
is not a unique entity but instead rep resents cases of other subtypes of MDS or
well-defined MPN that have acquired ring
sidercbtasts as a secondary form of
dysplasia 119661. It is not clear whether
AAAS-T is a distinct entity, one end of the
spectrum of AAAS . a progression of
AAAS due to an addrtiooat acquired
genetic abnormality. or less likely. Ihe
occurrence of two rare diseases in the
same patient. Therefore . until these questions are more ctearly answered . AAAS-T
remains a provisional entity
In support of a myeloproliferative component to this neoplasm, the majority of
cases reooeted as RAAS- T have shown
the JAK2 V617F mutation, or much less
commonly. the MPL W515KIL mutation
1234. 354 , 762, 1835. 1839. 1969. 2081 ,
2 139. 2358 1_ On the other hand. the few
reported cases with this mutation that
have been studied for endogenous colony
form ation in vitro have demonstrated a
pattern mo re akin to that of MDS 1234.
18351 . Thus it may be that the provisional
design ation of an MDS/MPN accurately
reflects the underlying biology in a substantia l pr oportion of the p atients 1762J;
more stud y is neede d to further ctarify this
diso rder.
Cases with isolated del(SQ),t(3;3)(q21;q26)
or inv(3)q 2 1q26) are exc lude d from this
ca teg ory, as are cases with a BCRABL 1
fusion gene, In ad dition, if there has been
a prior d iagno sis of an MPN without ring
sioerc otasts. or there is evide nce that the
ring stoerotsasts might be a consequence
of therapy or represent disease prog ression in a patient wi th features tha t meet
the crite ria of another well-de fined MPN,
this designation should not be used.
IC().() code
9982/3
Morphology
These cases have features of AAAS
(anaemia With no blasts in the PB and
dysplastic , ineffective erythroid prolif8fation
often with megaloblastoid features, ring
sideroorasts :2:- 15 % 01 the erythroid precursors. and <5% blasts in the BM) and
thrombocytosis With a platelet count
:2:- 450x1CJ1Il associated with proliferation
86
..
Fig.' .13 Refractory eneema WIth ring SideI'Ob~s andlhfombocylosis This sequence of rnitrophotogriljtls AtsIr3lt
blood and bone marrow 01 a 62-year-old man who presenled with severe anaemia anda plateletcount oI85lb:10"l
A Abnormal red cells and Ihrontlocylosis. B El)'lhroid proliferation and abnormal megakaryocylll$ reserrtIing megNyccytes seen in ET. C Mild dyserythropote$is. 0 The majority01 erythroid pIlICllfSOrS were ring sicleroblasts.
of targe atyp ical mega karyocytes similar

to those observed in BCR-ABL 1negative
MPN (See Chapt er 2).
The minimum plat elet co unt requ ired for
inclusi on has been lowered to 450xl CY'/L
from 600x 109/L for consis tenc y with the
d efining criterion for ET, and because
severa l studies have demonstrated that
pa tients with platelet coun ts lower than
6OOxlCY'/L may have biological features,
includ ing JAK2V6 17F mutations, similar
to those with coun ts ~x1Cf1A..1354I . It is
importan t to note that the criteria for
AAAS-T includes morphologically abnormal meqakarvocytes similar to those
observed in ET and in PMF. This criterion
should aid in distinguishing AAAS-T from
those cases of RAAS commonly reported
to have a modest increase in their platelet
count. Nevertheless, we recommend testing for JAK2 V6 17F when the platelet
count is elevated in patients with AARS
until the borderline between AAAS and
AAAS-T is more clearly defined
MyelodyspiastiC/myelop rollferallVe neoplasms
Genetics
The recent discovery that up 10 60% of
pa tients with AARS-T harb our the JAK2
V617F mutation (an inc idence similar to
that found in ET and PMF) or less cornmon ly, the M PL W515KjL mutation, not
only elucidates the reason for the proliferative aspect of AARS-T but also woold
seem to move it closer to the MPN catego)
1234, 354. 762. 1835, 1839, 1969,2081,
2139, 23581. Thus. studies for JAK2V617F,
and. if ind icated, for the MPL W515M
mutation should always be performed in
such cases .
CHAPTER 5
Myelodysplastic Syndromes
Myelodysplastic syndromes/neoplasms. overview
Refractory cytopenia with unilineage dysptasia

Refractory anaemia with ring siderobtasts
Refractory cytopenia with multilineage dysplasia
Myeladysplastic syndrome with lsoleted del(Sq)
Myelodysplastic syndrome, unclassifiable

Childhood myelodysplastic syndrome
Myelodysplastic syndromes/neoplasms,
overview
Definition
The mve'oovsptasnc syndromes CMOS)
are a group of clonal haematopoienc
A.D. Brunning
A.Orazi
U. Germing
M .M . Le Beau
APOfWit
I. Baumam
J .W. Vardiman
E. Hellstrom-Lindberg
stem cell diseases characterized by

cvtopeorats). dysplasia in one or more of
the major myeloid cell lines. ineffective
baematopoesis. and increased risk of
development 01 acute myeloid leukaemia
(A ML) 1190. 353, 23101. There is an enhanced degree of eoootosrs which contributes to the cytopenias 12601. The
thresholds for cytopenias as recommended in the International Prognostic
SCoring System (IPSS)
lor risk stratification
in the MDS are haemoglobin < lOgJdL.

abso lute
reurroptut
count
(ANC)
< 18x l(Jl/l and platelets <l00xl(JlL 1833.
833AI. Values above these thresholds
are. however, not exclusionary for a diagnosis of MDS If delinitive morphologic
and/or cytogenetic findings are present
123271. The dysplasia may be accompanied by an increase in myeloblasts in the
pe ripheral blood (PB) and bone marrow
(BM) b ut the numbe r is <20% , wh ic h is
the req uisite thres hold recommended for
th e di ag nosis of A ML. It is important 10
recognize that the threshold of 20% b lasts
in the PB or 8M for the d istinction of A ML
from MDS does not represent a therapeutic mandate for treat ing pat ient s w ith 20%
blasts as acu te leukaemia . A treatment
dec ision 10 manag e the patient as AML or
MDS mu st be b ased o n seve ra l fa ct or s
including age, prior history of a mveoovsplast ic syndrcrne, overall clinical assessment
and tempo of the proc ess, wh ic h are the
same determi nant factors for patients w ith
30% bla sts. Althoug h progr ession to AML
is the natural course in many cases of
MoS, the perc entag e of pa tien ts who
p rogr ess varies substantially in the various
subtypes; a higher percentage of MDS wittl
increased myelo bla sts transforms to AML
178 1.1 3 711 Althoughthemajorityof MOS
are c haracterized by prog ressive 8 M Iailure. the b iOlogiC course in some patients.
e.q. refrac to ry anaemia with unilineage
dysplasia (RA) and refrac tory anaemia
wit h ring sroerobtests (AA AS). is p rolonged and indolent with a very low incidenced evokJIi:rI toM1L 1781. 1370. 2327 1.
88
Myelodysplastic syndromes
:.
.It
Fig. 5.01 Bone mamJIIIII smear from a pa\lel1t 'Mlh

~s B19 irltedlon showing mal1<.ed eryttvoid
hypoplasia wiltI occasional pi eryttYoblasts 'Mlh
dispetsed dwomalin and line cyIqllasmic YlICUllIM.
Fig.5 .02 Bone marrow smear from a . 1.year-d:l

'Mlh pancytoperia being cIYooic:aIy poiscWled
lneIic. There is ma'ked ~
Fig. 5.03 Bone marrow smear from a 57-yeaf-okl woman

r1'Io received several dl&molh&rapetJtlC ageots lor breast
carcinoma ir.clooing loIic acidantagonists.
Ep ide miology
Myetodysplastic syndromes occur princ ipally in olde r adu lts with a median age of
70 years . with a non-age corrected annual
incidenc e of 3-5/100 000 p ersons bu t
rising to >20/ 100 000 amo ng tho se ove r
the age of 70 years {109, 7831. App roximately 10 300 inciden t cases of MOS
were d iagnosed in 2003 in the USA
{1351 1. There is a male predominance .
Thera py-related mveioovsptasuc syndromes are discussed in Chapter 6.
Cli nic al featu res
The major ity of patients present with
symptoms related to cvtooentats): most of
the patients are anaemic and transfusiondependent. less frequent are neutropenia
and/or thrombocytopenia. Organomegaly
is infrequ ently observed.
Etiology
Prima ry or de novo MOS oc cu rs without a
know n history of c hemotherapy or race
expos ure. Possible etiolog ies for pre
ma ry MOS Include benzene exposure at
levels well abo ve the m inima allowed by
most government age nc ies. cigarette
smoking, exposure to agricultural cherricats or solvents an d family history ci
heematoootenc neoplasms 121131. Some
inherited haematolog ic al d isorders. SUCll
as Fanconi anaemia. dyskeratosis Cl)f\o
geni ta. Shwachmann-Diamond evnocre
and Diamond-Brackten syndrome are
also associated with an increased risk
MOS.
non
M"",hoIogy
The morphological classitication 01 MOO
is principally based 00 the percent
blasts in the 8M and PB. the type an:!
degree of d ysplasia and the pr esence of

ring sideroblasts {1 90 I. The cy topen ias
generally co rrespond to the d ysp lastic
lineage. but discordance may be present
(Table 5.0 1) 123271. To determi ne the
blast perc entage in the BM, a 500-ceU
differential of all nucleated cells in a smear
ortrephine imprint is recommended and in
the PB, a 2QO.leukocyte cnnerentrat In
severely cvtooenrc patients, butfy coat
smears of PB may tacuuare performing the
Odferential.
The charac teristic s of the d ysplasia are
relevant when diSlinguishing between the
various types 01 MOS and may be important in predictmg biology. In addition ,
some cytogenetic abnormalities are
associated with characteristic d ysplastic
features, e.g isolated del(Sq) and hypolobated and non-lobated megakaryocyte
nuc lei and det( 17p ) with hypo lobe ted

neutrophil nuclei / 12371
Assessment 01 the deg ree of dysp lasia
may be pr ob lematic depending on the
quality of the smear preparations and the
stain. Poor quali ty smears may result in
misinterp retation of the presence or absence 01 dysplasia particularly in assessing
neutrophil granula tion . Because of the
critical importance 01 recognition of dys pl asia to the diagnosis of an MOS, the
necessity 01 high quality slide preparations
cannot be overemphasized. Slides for the
assessme nt of dysplasia should be made
from freshly obtained specimens ; specimens exposed to anticoa gulants for more
than two hours are unsatisfactory
As a general precaution, no patient
should be diagnosed as having MOS
without knowledge 01 the clin ical and
"'ReIrDIlyq10perIIas 'III\I1lriineage dysplasia (RCOO)

Refraclory anaemia (RA); Relracloryneutropenia (RN);
_ _ IRT)
Retacklry anaemiI WIth nngsidetobltsts (RARS)
drug history and no case of MOS should

be reclassified while the patient is on
growt h teeter therapy, inclu ding erythropoietin. In add ition, cytopenia(s) in the
absence of dys pl asia shoul d not be
interpreted as an MOS. A presumptive
diagnosis of MOS may be made in the absence of dysplasia il certa in cytogenetic
abnormalities are present (See Genetics).
Persistent cytopenia without dysplasia and
without one of the specific cytogenetic
abnormalities c onsidered as presumptive
evidence of MOS should be viewed as the
recent ly described "idiopathic cytopenia
of undetermined siqrufcance" ( leUS),
and the patent's haematologic and cytogenetic status should be cerefuny monitared 124221 .
In an attempt to more accurately pred ict
chnical behaviour, cases of MOS without
8100dMdinp
~ or bicytopenia'
tI or rareblasts 1%)1
No "''''
Cylopenia(s)
No or fare blasts 1'10)2
NoAlIeI'rods
<'~10"11. monocytes
IJn*Ieage dysplaSIa. 2:10% dille cells Ifl onemyebd i1eage
<5%_
<15'10 01 eryIhrOId precursors are nngSlderobIasts
2:15% 01 eryIhroid precursors on rilg SlderobIasts

Erylhmid dysplasia only
<5%blasts
Dysplasia i'I 2:10% 0I1I'le cells in 2: two myeloid Iil'le<tges

(neutrophil and/or erythroid prealrsOfS and/or megallaryocyles)
<5'10 blasts in marrow
NoAuIM rods
1;15'10 ringsideroblasls
Refradory anaemia With e~C8SS b1asts--1 (RAEB-1)
Cytopenia{s)
<5%blasts'
NoAutlr rod s
< 1 ~1O"fl mooocytes
Unilineage or ml,lttl l~age dysplasia

5-9% blasts l
NoAuerrods
Refractory ana&mia with excess blasts-2 (RAEB2)
Cytope nia(s)
5-19% blasts
Auerrods t 1
Unilineage ormullilineage dysplasia

10-1 9"1o blasls
Auer rods 1;1
<1~10'J1. mooocytes
M)'elodj'Splastic syndrome - undaSSifJed (MDS-U)
Cytopeflias
5:1% blasts '
"""""
UsuaRy J'M)n1I3I or
we.ased pIaIeIet COUI1l
Noor rareblasts ,%)
Uoequivocal d~sia in less \Il<In 10% 01 eels ill one

or moremyeloid cell joes v.t1en a<:compaflied by a C)'\ogene~c
abnormallt)' considered as presun1pIlve evideflCe fora diagnosjs
01 MDS (see Table 5.(4)
<5%blasts
Normal 10increased megakaryocytes WJ1h
tJwoIobated fIUdei
<5% blasts
Isolated _
del{5q) cytogenetic al:inl:lrmlliTy
No_
8q'qlenIa may 0CCiI5i0naIy be obseMld cases Wl1l'I pancytopenia should be classified as t.I05--U.
myeloblast perc:entBge is <5% bul1tlEWe ere 2--4% myeIoblasls nee blood, ee liagnosticdass1Iic:aticrl is RAEB 1. Cases 01 RCUO and RCMDIIo'ilh I %Il)'IlIoblasts IIIlhll blood shoUlIbe dassifled as MOS, U
I . . . JIlafl'DW
Cases W1111wfII rods nI <5% myetlbIasls III 'lie blood arw3 0(10% inee I'!llll1tIW sInJId be d8s$lIied ... RAEB 2.
,--
--""
-.
Fig. 5.05 A Blood smear from a pa\J8I"It on grarUocyte COOny sbmulating!acttJr. A neutrophil W'IIh a bIlobed nucleus
and naeased azuror:I* grClruabon. B The same SI)Itinen as (A) showing a myeloblast.
an increase in blasts are recognized as

manifesting ei ther unilineage or multilin-
eage dysplasia In RA and RAAS. the

dysplasia is generally confined 10the erythroid lineage. Unilineag e dysplasia may
also occur in the neutrop hns. refrac tory
neutrop enia (AN), an d megakaryocytes.
refrac tory thrombocytopenia (AT), but
these processes are much less frequ ent
than unilineage dysplas ia invo lving the
erythroi d cells. In refractory cytopenia

with mul lilineage dysplasia (RCMD) with
or without ring sioe robleete. significant
dysplastic features are rec og nized in two
or more of the major myeloid cell lineages.
The reco mmended req uisite percentage
of cells manifesting dys plasia to qualify as
sig nific ant is ~ 10% 11864J in the erythroi d
p rec ursors and granulocytes, Significant
megakary ocyte dysplas ia is defin ed as
Tab le 5.02 Summary of cytopenias anddysplasia characteristics in MOS without an illCfease of marrow blasts.
Cytopenia(s)
Oysplasla
Categories
Unicytopenia
Bicytopenia
Unilineage
Refractory cytopel1ia with unilineage

dysplasia (RCUD)
Refractory anaemia (RA)
Relfactory I'le(Jtropenia (RN )
Relfactory tnrombocylcpenia (RT)
p- -"---...
Biq10penia
UflIinelIge and
""","",
(2:2 myeloid eels Ines)
"'"'-
90
Relr<lclory aI1aerTlla with ring SIIiIroblasts (RAAS)
2:15"" ringSideroblasts
Myelodysplastic Syndromes
MyelodysplaslJc syndrome. uocIasS/fled (MD5-U)

Retractory cyIOpenia Wllh mullilneage d:y$plaSiII
(RCMO)
~ 1 0% dysplastic megaka ryocytes basec

on evaluation of at least 30 megakaryo.
cvtes in smears or sections, Future snoes
may result in modification or this reccomendation 114201. Mcromeqakaryocves
and mullinucleate megakaryocytes are
the most reliable dysplastic findings inttl
megakaryocyte series 11420. 23271.
Although the majority of patients w
MDS and unlineage dysplasia pre
with a single cytopenia. this revised
etcatoo allows lor bicytopenia in refracb'y
cytopenia with lXlilineage dysplasia (00,.q
and RARS (Table 5.02). The majority ~
patients with RCMD have 2 cytopeMS
118641.
Ch.aracteristics of dysplasia
Dyserythropoiesis is manilest prine
by alterations in the nucleus ine
budding, internuclear bridging , karyCIrhexis , mu/tinuclarity and megalobla
changes; cytoplasmic features .
ring siderobIasls. vacooIisalion and penxk
acrd-Sctnf positivity. either diffuse (I
granular (Table 5.03). Dysgranu!opoiesl
is characterized primarily by nudelJ
hypolobation (pseudo Pelqer-Hoetj a~
hypersegmentation. cytoplasmic hypogranularity. pseudo Chediak-HigaS'J
granules and small size. MegakaryocytP
dysplasia is characterized by micromegakaryocytes with hypolobated nuclEi,
non-lobated nuclei in megakaryocytes Ii
all sizes, and multiple, wrderv-seoaraiea
nuclei, Megakaryocytic dysplasia maytlt
more readily app recia ted in 8M secncs
than smears and both types 01 specimers
should be eva luated
The cha racteristics of the dysplasia maj
be relevan t in pred icti ng biology of a
mveicoysorastc d isorder and the relatcoship to specific cy toge netic abnormalities,
ego Sq-syndrome {2327}, Unilineagedysptaaia is o bserved in RCUD and RARS
Multilineage dysplasia involving two c.
three of the myeloid ce ll lines is rTlOfe
frequently observed in the high-graClt
MDS an d is used to distinguish ReM!)
from ACUD 118641. Similarly, the presence
01 multilineage dysplasia is used
separate RARS from RCMD with n
sroerobtasts. the latte r of which has a
similar clinical course to RCMD_
increased number of ring sioerotnasa
occasionally> 15% of the erythroid precursors. may be observed in refract
anaemia with excess blasts (RAEB). TIt
defining criteria of RAEB- l or RAEB-2
dictate the classification in such cases
of AAEB-2 o r CM ML-2 in the con tex t of

MOS or MOS/MPN rega rdless of the blast
perc entag e. This concept is reta ine d in
the p resent classification. Cases of MOS
with <5% blasts in the 8M and < 1% in the
P8 may rarely have Auer rods. These
cases have be en reported to be associated with an adverse prognosis 124151.
Fig. s.ar A AtmrmaI bcaizaIon 01 inmaIu'e~.

Bone marrow sectJon lI'om I ease 01 RAE&-l
allIlain$ I locus 01 immature myeloid preo.nor$.
SAlocus 0I1nmnJrec:eIIs in. bone rnatTOW biopsy from
aesse 01 RAE&-2 reacted wl1t1 I nbbody kI C034. A
lI'Iap:II'Ity oIlhe mmature eels are posilMl.
The relationship betw een cvtopenras.

type of dysplasia. and classification is
summarized in Table 5.02 .
The significance of the Auer rod in
myeloid disorders has histo rically been
sonewttat uncertain. For severa l d ecades
Its detection was viewe d as virtually di agnestle of AML. There was no specificity
applied to it with the introduction 01 the
concept of MDS by the FA8 gr oup. In the
revised FAB c lassi fica tio n of 1982 it was
veweo as evid ence of a high -gr ade MOS.
refrac tory anaem ia with excess of b lasts
in transformat ion , (RAEB t ), irresp ectiv e
of the blast perce ntage in the PB or 8 M
11901. In the pri or WHO Class ification of
the MDS it was considered as evidence
Differential diagnostk: considerations

A majo r problem in the diagnosis 01 MOS
is the determination whether the presence
01 myelodysplasia is due to a clonal disorder or is the result of some other factor.
The presence 01 dysplasia is not in itsell
definitive evidence of a clonal disorder.
There are seve ral nutnnoner. toxic and
other factors which may cause myelodysplastic changes, including but not limited
to vitamin 8 12 and folic acid deficiency,
essential element deficiencies and exposure to heavy metals, parncutarts arsenic
and several commonly used drugs and
biologic agents 12601. The antibiotic
cotreroxezoie may cause marked neutrophil nuclear hypolobation indistinguishable from the changes observed in MOS.
In some patients on multiple d rugs it may
be d iffic ult to id entify the causative agent
of the neut rophil changes 11136. 2 1411.
Congenital r eematoioqcat disorders such
as conge nital dyseryth ropoietic anae mia
must also be considered as a cause of
dysp lasia when it is con fined to the erythroid cells. Parvovi rus B 19 infection may
be assoc iated with ervtn robreetopente
wil h gi ant megaloblasl oid eryl hrob lasls:
the imm unosu p p ress ion age nt mycophe nolate mofetil may also be associated
with erythrob lastopenia. Chemotherapeutic
age nts may resu lt in mar ked dysp lasia of
al l mye loid ce ll lineag es. Granuloc yte
colony- stimu lating fact o r res ult in mo rp holog ic alteratio ns in the neo trophns.
incl udin g m arked hypergranularity and
:-
--
f.. 5.01 M~a stJc dysery1hropoIeSil. Bone

MlIo ~ Inm., ao:Ul JT8B -Mlh fefracUy ~
.. rrUl*leage dysplasia (RCMD) and complex
~ 8t:n:lnnIIlItle N:tdng del(17p) and del(Sq).
A.
...
Fig. 5.09 Dysplasbc megakaryocy\eS. Bone n'llWl'OW as-
pirate smear from a 37-yearl male WIIh ~

stIotMg megaka-yocyleswithdysplaslic features.
Fig. 5.10 Neutn:lphi WIlll a r'lOI'Hlbaledru::Ieus (pseuclo

PeIger-HuiIJ in. bbXI smear from a paIienl on ~
mol3ZOle. ApproXllTlalely 50 percent 01 the neuIrtlpt*
had a simiar appearance.
FIg. 5.11 BtnucIeate mega~ in a bone marrow

smear from a pabeflt with ~ history 01 refrackIry
1hrontlocytopen There is a central !13f1JIOt'nere and a
peripheral hyalomere.
striking nuclear hypolobation 11968): blasts

may be observed in the PB and may
reach levels of 9- to% and rarely higher
in p atients with no evidence of AML or
MOS. The 8 M b last perc entag e is generally normal, but may be inc reased as well.
Paroxysmal noct urna l hae moglo binuria
may also present with features similar 10
MOS. As a result 01all these possibilities.
it is extremely impor tant to be aware of the
c linical history including expos ure 10
d rug s or c hemica ls and cons ider nonclo nal d isorde rs as possible etiologies
when evalua ting cases with myelod ysplasia, particularly those c ases with no increase in b lasts. Repeat ed 8 M biopsies.
including cytogenetic studies, over a period of severa l months may be necessary
in d ifficu lt cases.
Histopatho logy
The value of the BM biopsy in MOS is well
established 116471. It may aid in confirming
a suspected diagnosis by excluding
reactive conditions in which ovsnaematopoietic changes may also be observed: it
can also increase the diagnostic accuracy and helps in refining the IPSS score
123281. Assessment of 8M cellularity and
strcmal reactions, e.g. fibrosis. B!eadditi:Jrl<W
Overvrew-
91
cases of MDS with inadequate aspirates,

the blast determination requires a aM
biopsy and immunohistochemical studies
for C034 may prove invaluable.
Fig. $.12 A Bone marrow bI:lpsy from a case of MDS (RAfB) WIth /I'I)'eIOfb'osi 5everaI ~ iIIe
presenl B Retio.anstain ona marrow bclpsy from a case of MDS wilh myelofibrosis. There is a marked inaease II
retia.Wl MIres.
important diagnostic features of the

biopsy. The 8M in MDS is usually hypercellular ex oormocenutar: the cvtopenras
result from the ineffective reenatcooese.
Histologically, aggressive MDS may be
characterized by the presence of aggregates (3-5 cells) ex clusters (>5 cells) of
blasts in 8M biopsies usually localized in
the central portion of the 8 M away from
the vascular structures and endosteal
surfaces 01 the bone trabeculae. These
are frequently present in RAEB. The blasts
can also be identified by immunohistochemistry with an libody to CD34, an antigen expressed in p rog enito r cells and
Table 5.lJ3 Morphologic marule$tabons 01 ~

Oyserylhropolesll
N....er
Noclear budding
Int&rTll.lClear bridging
Karyorrtlexis
Mll ~inuclearity
Nuclear hyperlobation
Megaloblastic changes
Cytoplasmic
Ring sideroblasts
~izaliOn
PeriodiC acid-SChiff positvily

~granulopoie. l.
SmaI or oousually largesize

Nuclear hypoiobaliOn
(pseudo Peiger-Huet: peIgeroid)
IrT9{PJIar hypetSl:lgmentation
Decreased granules : agrarWrity
PseucIo QledIak-HtgastH ~arws
.... """
--
~l)'ocytopoiIs ls
NudNt hypoklbllJon
~ (normaI .,..katytq1es in
I.lI'W'IJl:illI wilh kltdaled nudeI)
92
Myekxtysplaslic syndromes
early p rec ursor 8M cells in lhe majorIty of

cases. Antj-C034 can be used to demonstrate pathologic accumulations of blasts
both singly and in clusters in aggressive
subtypes of myeloid neoplasms 120501.
With some fixatives, CD34 will also immunoreact with megakaryocytes in MOS ,
IrTYTlunohistologicanalysis with anti-C034
may be especially useful in cases 01 MDS
with fibrosis or hvpoceuuiar marrows as
well as therapy-rela ted cases to assess
b last percentage. In these instances the
p resence 01 fibrosis ()( fany changes in the
8M may make accurate cbaractenzanon
of the process very di fficult.
Hypoplas tic MDS

In a minority of the cases of MDS, approximately 10%, the 8M is hypocellular. These
c ases have been referred to as hypoplastic
MOS. This group , which has
independent prognost ic signific ance per S8,
may lea d to d iffic ult ies in the d if/eren lial
d iag nos is w ith aplas tic a naelT)i~ 1
834.
1648 1. In add ition, anti-thymocyte g lobulin
and other therapies used for aplastic
anaemia have been used with some deg ree
of success in this sub group 1260, 1302,
2477, 24781. It is also impo rtant when consid ering the diagnosis of hypoplastic MDS
10 excl ude toxic myelopathy and au toimm une di sorders .
no
MDS with myelofibrosis

Sig nilicant degrees of myelofibrosis are
o bserved in ap proximately 10% o f the
cases of MO S. These cases have been
referred to as MDS w ith fibrosis (12461.
Most of the cases with fibrosis have excess of blasts and an aggressive clinical
course. Such cases may erroneously be
consid ered low-grade MOS if only the
blast count determined from the 8M aspirate, which is usually diluted With P8 , is
evaluated. In the fib rotic group, as in other
1l1VTlUnophenotyping
Published studies on immunophenotyprg
by flow cytometry in MOS have focused CI'l
several stra tegies, including determrwg
the size and immunophenotype of ee
blast population and assessing the maturation pattern 0I1he myeloid cell popUatol
More specifically. these studies included
immunophenotyp ing of CD34+ cells, ap.
plication of SCOfing systems, and pattern
recognition strategies uSing muttiCOO
analysis and comparison with norrn;iI
reactive PB and 8M.
There is generally good correlation between the percentage of blasts as ceremined by morphologic examination iJ
fOJtine smearor irr'pV'ltor ~
preparations and percentage of CD34.
cells determined by flow cytometry ( FC~
However. in some cases there may be
significant discordance due to signilicart
myelofibrosis and haemodilute samples
As a result, Fe percentages 01 CD34+ eels
cannot replace differential counts 00
smears, However, Fe may be informal1Ye~
abnormal phenotypes of C034+ cells are
detected: this could be additional evidence
dysplasia. In addition, an emerging
athological population of CD34 IJ
01 17 cells in low-grade MDS could Sl.I9"
gest evolution of the d isease 116221.
Ma tu rat io n pa tte rns of erythropoie tic
g ranuloc ytic, and monocytic difterentiatcn
in the normal/reac tive 8 M, as well as the
immuno phenoty pe of the mature cells in
PB have been thorough ly desc ribed using
fou r-co lor FC. Erythroid abnorm alities as
de termined by the pattern of exoressce
of H-ferritin , CD7 1 and C010S in gly
cophorin A (GPA) posi tive nucleated cells
reportedly ca n pred ic t morphological erythroid dysplasia with 98% sensitivity [5501,
A be rran t maturation patterns in granulopoiesis could pred ict morphological
dysplasia and abnormal cytogenetics in
ap proximately 90% of cases 112121. ThJs
flow cytorretrv results co rreiate well with
morphology and cytogenetics in MDS
However, in cases with borderline dys.
plasia by morphology and no cytogenetic
abnormalities. FC results are highly suggestive for MOS only if there are three IJ
more aberrant features in erymropoietc.
g ranulocytic or monocytic maturation;
single aberrant features by FC are na
f:
signific ant. .Cases with inconclu sive

morphologic an d cytogene tic find ing s
and three or mo re aberrant fea tures by
flow cytometry should be reeva luated
over seve ral mon ths for definitive rrorprologic or cytogenetic evidence of MOS,
Genetics
Cytogenetic and molecular studies have
a major role in the evaluation of patients
with MOS in regard to prognosis, determnaton of clonality {833, 16411, and the
'ecognltion of cytogenetic , morphologic ,
m clinical cor relates . Clonal cytogenetic
abnormalities are observed in - 50% of
I,()S cases. Myekxtysptastic syndromes
associated with an isol ated del(5q) occur
orinarity in women, are c ha racterized by
megakaryocy1es with roo-ocetec Of hypoklbated nuclei, refractory macrocytic
anaemia, normal or increased platelet
Cl:lOO t, and a favourable clinic al c ou rse,
and are recccneec as a scecinc type of
MDS in this c lassification , The oc c urrence
(j 17p loss is assoc iated wi th MOS or
AML with pseudo Pelger-Hu6t anomaly.
small vacuol ated neutroohlrs. TP53 mutation and unfavourable c linical course: it is
rest common in therapy-related MOS
(12371 Complex karyotypes (2:3 abnormalities) typically include chromosomes 5
andfOf 7 [-S/del(5q), -7/del(7q )), and are
generally assoc iated with an unfavourable
clinical course . Several olher cytogenetic
lindings ap pear to be assoc iated with
characteristic morp hologic abnormalities
such as isolated del(20q) w ith involve ment of eryt hroid ce lls and meg akaryocvies. and abnormalities of c hromosome
3 (irw (3)(q2 1q 26 ,2) or t( 3 ~ 3)( q 21 :q26,2 )].
which are associated with MOS and AML
withincreased abno rma l meg akaryoc ytes
1289, 866, 1207j.
Some clonal cytogene tic abnor mal ities
occuring in MOS are not definitive evidence for this disorde r in the absence of
morpholog ic al crtterte. e.q . -Y, +8 or
ool(2Oq) as the sale abnormali ty, The
other abnormalities listed in Tab le 504 in
presence of a refractory c ytope nia ,
but no morphologic evidence of dysplasia,
are considered presumptive ev idence for
MOS. It is recommended tha i tnese pallefllS be followed caretcuv lor emerging
roorphologi c al evidence of MOS. FISH
tJOVides increased senSitivity in monitoring
Sl.Ch pateots.once a recurring abnormality
res been identified ,
ee
Tabl. 5.04 ReCl.lning cluumosomal abnormalities and

their frequency in re myelod~aslic syndromes at
diagoosis.

Haematoooetic stem cell.
The morphological subtypes of MDS can
be generally categorized into three risk
groups based on duration of survival and
incidence of evolution to AM L. The Iow-risk
groups are RCUD and RARS. The intermediate-risk groups are RC MD with or
without ring srderobrasts and RAEB-1 , Patients with RAE&-2 constitute the high-risk
group. It shou ld be noted that patient s with
bcvtopema in RCUO and RARS have
been reported to have a shorter surviva l
tha n patients with one cyt openia 123271.
Pat ients with one cyt openia in the con text
of RCMD had a longer survival than patients with two cvtocenra s 123271
The importance of c ytog enetic studies as
a prognostic indic ator in MDS has been
recogniZed and c od ified by the International My ekxtysplaslic Synd rome Work ing
Group 18331 Three major risk categ ories
of cytogene tic findi ng s have been d efined : i) good risk -normal karyotype,
isolated del(5q), isolated del (2Oq) and -Y;
ii) poor risk ---com plex abnorma lities, l.e.,
2:3 a bnormalities, or abnormalities of
ch romosome 7; and iii) intermediate risk
- all other abnormalities.
A scoring system for predicting survival
and evolution to A ML based on percent
8 M blasts. type of cy togenetic abnormalities , and degree and number of cytcoentas has been pro posed by this g roup
(Table 5.05) 1833, 833A I, Four risk g roups
based on this sc oring system are recog nized : low, O' INT (inte rme diate) - 1,
0 ,5- 1.0; INT-2, 1,5- 2.0; and high , 2:2 ,5. In
general, the higher-risk groups are related
to higher 8 M bl ast percent ag e, mo re unfavou rab le c ytogenetic find ings and mo re
A_"
MO'
""""""""
' 0%
' 0%
' 0%
' S'
1 or del(7Q)
-5 or del(Sq)
. ..
- ,'
.r
S%
. S%
~ 17Q)
or l(17p)
.13 or del(13Q)
del(11Q)
del(12p)Of 1(12p)
-,
,-110,
""'
""'
'"'"
'"
' .2%
' .2%
dc(X)(Q13)
...
.
1( 11;16)(q23,p13.3)
1(32 1)(q262;q22.1)
1(1;3)(p36.3:~1.2)
1(2;1l)(p21:Q231
~3)(q21 q26.2)
1(6:9)(p23;q34)
'"
2%
, The ceseece of these at:JnormaIIies as the sc*l

~ abrmnaiIy 11 !he absence of rrupho-
logic aTlenais no! considered deMiIive evidence lor

1.40S, In !he seltlng of persistent eytapenias ol
~ origin. lhe oll'ler abnormahties shoWn
are IXIO~ ~ve evidence 01 MDS in the
absenc:e 01 defu'itive ITlCfPlIOIC9C features.
severe degree of cytopenia.

Constderatoo of age improves predict abilityof survival ; patients young er than 60
years of age have impro ved survival in the
ind ividual risk ca tegories compa red with
patients older than 60 years.
The cytoge netic subg rouping of the IPSS
system also has an independ ent value in
pred ict ing the outco me of allog eneic stem
cell transplantation in pati ents w ith MOS
15321.
Table 5.05 International Prognostic SC:or1'1g System(IPSSllor MDS (833,833Af. See Prognosis and pt'edidive faclQrs
lor interpretation,
,,~
Prognostic variables
" bone marrow blasts
Karyotype"
C~s -
<5.
5-1 0%
.-,
Intermediate
Good
,.s
11 - 19"110
20-30%'
Poot
2-3
"This ~ is ~ as AML in the wtK) classificabon.

- Karyotype:
Good" normal, -Y,del(5Q). del(2Oq).
Poor " ~l ~ lIbnormaIiIies) or ....~~mlTlOSOl""'m..
18 7...::ma1ies:
Intermecliate " otherIIbnormaIrt.oes
- Cylopenias:
Hgb<1llgk1.
NeutropIiIs <1.8xlll'11.
PIaWets <1 00x 1 ~

Overview
93
Refractory cytopenia with

unilineage dysplasia
Definition
Refractory cytopenia with unilineage dysplasia (RCUD) is intended to encompass
those myelodysplastic syndromes (MDS)
which present with a refractory cytopenia
with unilineage dysplasia and includes
refractory anaemia (RA) , refractory neutropenia (RN) and refractory thrombocytopenia (AT) . Although refractory anaemia
with ring sioercoiasts is also characterized
by unilineage dysplasia. it is considered
as a distinct entity of its own . Refractory
bicytopenia may be inCluded in the AGUD
category il accompanied by unilineage
dysplasia. It is recomnet ICIed that refractory
pancytopenia with unilineagEl dysplasia be
placed in the category 01 rnyelodysplastic
synd rome. unctassrnaore (MDSU). The
recommended level lor dysplasia is ~ 1 0%
in the cell lineag e affected. The recommen ded levels for defining cytopenias are
haemoglobin <10g/dL. absolute neutrophil count (ANG) < 1.8x1Ql1IL and platelet
count <100x1(19/l1833, 833AJ. However,
values above these levels do not exclude
MDS if definitive morphologic and/or cytoge netic ev idence of MOS is p resent. The
typ e of c ytopenia in the majo rity of cases
w ill cor respon d to the type of unilineage
dy spl asia , e.q. anaemia and eryth roid
dys plasia, although discordance between

type of cytopenia and cell lineage dysplasia may be observed 123271. Some of the
cases previously classified as M05-U may
be included in this category. e.q. RN, RT
All non-clonal causes tor the dysplasia
must be explored and excluded before
the diagnosis of MOS is established
These inc lude, but are not limited to, drug
and toxin exposure, growth factor therapy.
viral infections, immunologic crsorcers.
congenital disorders, vitam in deficiencies
and possible essential element deficiencies, such as copper deficiency 18371_
Excessive zinc supplementation has also
been reported to be associated with severe cytopenia and dysplastic changes
110 10 1. It a clonal cytogenetic abnormality
is not present, there should be a period of
observation of six months from initial
examination before a diagnosis of MOS is
established unless more definitive morprologic or genetic evidence eme rges during
the observation per iod .
The presence of pe ripheral blood (PB)
blasts esse ntially excludes a diagnosis of
RCUD although in an occasional case a
rare blast may be id entifie d: pa tients w ith
the find ings of RCUO and 1% blasts in the
PB and <5% in the bone ma rrow (BM) on
A.D. Brunning
A.P. Hasserjian
A . Porwit
J.M. Bennett
A. Orazr
J. Thiele
E. Heustrorn -Ltndberq
two successive evaluations should be

placed in the category of MOS-U because
of the uncertain biology of this constellation
of findings. Patients with 2-4% blasts 11"1
the PB and <5% blasts in the 8M should
be classified as refractory anaemia With
excess btasts-t (RAEB-1) if other cntere
lor MOS are present. The number d
cases with these findings is very low ana
these patients stoJd be careftAly coseoec
for increasing 8M blast percentage 111651,
Refractory cytopenia with unilineage
dysplasia should not be equaled wiVl
"Id iopa thic cytopenia of undetermined
signiftcance" (ICUS) which lac ks the
minimal morphologic or genetic criteria
requisi te tor a diagnosis 01 MOS and
should not be considered as such [24221.
Synonym
Refractory anaemia.
Epidemiology
Refractory cytopenia with unilineage
dysplasia comprises 10-20% of all cases
of MOS 1782, 1371/. It is primarily a dsease of older adults; the median age is
around 65-70 yea rs There is no signifi
cant sex pred ilection , The vast majorityo!
RCUD c ases are RA. Refractor y neutropen ia and refr actory thrombocyt openia
are rare an d extreme c aution should be
used in making either of these d iagnoses.
The P8 and 8 M are the p rinci pal sites 01
involvement,
Clinical feature s
In RCUO. the presenting symptoms are
related to the type of cytopenia, The cytoper nas are refracto ry to haernauruc therapy, but may be respo nsive 10 growth
factors 19831.
Mo<phology
Refractory anaemia
code 998013)
In the PB in RA, the red blood cells are
usually normochrcmic, normocytic or normoctYomic, macrocytic. Unusually, there is
anisochromasia or dimorphism with a
oco-o
Fig. 5.13 Refradory WIlIeIT'Iia, This bone IIWTt7W smear speomen shows dyspIasbc Jeatures criy in !he8f)1tVOld
preo.nors; octaSiOnaI erythrobIasl$ sI'lClW vacu:lIat8d c:ytopIasm Mel ~ megakXVst*! 1'oldBi.
94
AS
Fif!. 5.14 A Refraclory neuuopel'lIa Bklod smear m a 56-year-old male;!tiel'lIllAJq)hI in lhe bwer IeflIS normal aweamg with weI-grarIJIated cytJpIa$ITI and a namaIy M!1I'*'*I
1IJdIus. The A8IA"ophI inltle l4lP8l'
is dysplastic wiIh ~ ~ cyq:.Ia$mWld oc:casionaI 0CHe bode&. The I1.JdM; shows retarded MglIl8lI!alJOll. ApprounaleIy
IlIIf01 fie nMropI'Iis 'III'8l1l dyspIaslic. Cytogenetic S!I..des showed .. extra toP'I d cnomosome 8 lWld perlOlft'lc rNer1ion d ctvornosare 12. B A tIyspIastic megakaI)uyte in a
~ ItTl8al' from a ll-year-okl male WIlIl a two year hISlory oIrelradory II1rtlmbocyk:Jp Theie is ~ Ikdearcylopiastllc dewelopll.,1 '/IIllh a ~
~ and 8 norHobated mnaltn nucleus. CytIgeoelic slldIes ' I this !line stoNed a missing Y chromosome. There was SlbsequenC evokIIIon at which lime ~
-.oes shcMoed a rrWsSlI'lg Y, addltIonaI9 and deletion 13.
rv-
population of hypochromic red blood cells.

Anisoc ytosis an d po ikilocytosis va ry from
none 10 marked. Bla sts are rarely seen and,
if present, acc ount for <1% of the while
blood cells. The nectrocnns and p latele ts
are usually normal in number and rrorpno-
Neutropenia secondary to drug therapy,

toxic exposu re, infectious processes , immune mechani sms, or other causative factors must be exclud ed , The other myeloid
cell lines do not show signific ant dysplasia
10%).
logy. How ever, some degree 01 either

neutropenia or thrombocytopenia may be
present
The erythroid precursors in the 8M in RA
vary from decreased to rnatkedty increased ;
<tyseryltYopoie variestrern slight to mode ere. unequivocal evidence of dysp lasia
met be present in 10% or more erythroid
precursors. Dyserythropoiesis is manifest
principally by alterations in the nucleus

includ in g budding, internuclea r br id ging ,
karyorrhexis. multinuclearity and mecatoblastoid ch anges: cytoplasmic features in.

coos vacuolization and periodic acid-Schiff
positivity, either diftuse or granular. Aing
sideroblasts may be present but are <15%
iJ erythroid precursors. Myelob lasts acooun1 for <5% of the nucl eated BM cel ls,
The neutrophils and megakaryocytes are
'l:lm'IaI or may show rnnimaJ dysplasia, but
~ways < 10% in either cell line , The BM
biopsy is generally hypercellular due 10
rcreased erythroid precursors. but may be
rorrccenoiar or even hypocellular.
Refractory neutropenia
(lCD-O code 999 1/3)
Refractor y neutropeni a is ch aracterized
by~ 1 0% dysplastic neutrophils in the PB or
3M; the dysplasia is principally manifesl as
ru:::1ear hypoIobation and hypogranulation.
--
Refractory thrombocytopenia
(ICD-O code 9992iJ)
Refra ct ory thrombocytope nia is characterized by 2': 10% d ysplastic megakaryocv tee of at lea st 30 megakaryocytes
eva luated : hypolcbate megakaryocytes,
b inucleate and multinucleate megakaryecytes and mrcromeqakarvocvtes are the
most reliab le and reproduci ble featu res
of mega karyocyte dysp lasia , Dyspl astic
megaka ryocyles may be more eviden t in
sections than smea rs and usually well
exceed the 10 % threshold . The megakarvocvtes may be increased or decreased . The other myeloid ce ll lines do
not show sign ificant dysplasia (<10%).
Distinction frem chronic autoinvnune
thrombocytopenia is cntc at and may be
extremely difficult clinica lly and morphologi ca lly. Cytogenetic studies may be of
consi derable aid in this distinclion 18661.
Immunophenotype
In refractory anae mia abe rrant immuneph enotyp ic features of erythropo ietic
precursors can be found by flow cytometry
ana lysis 15501. There are no d ata on RN
and RT.
Genetic s
Cytogenetic abnormalities may be observed in up to 50% of ca ses of refractory
anaemia 1782J Several difterent acquired
clonal chromosomal abnormalities may
be observed. and although useful for
establishing a diagnosis of RA, they are
not specific. The abnormalities generally
associated with RA include del(2OQ), .8
and abnormalities of 5 aod/Of 7. The number 01 reported case s of AN and
is 100
low to allow for generalizations, although
del(2Oq ) has been reported in AT 1866.
19381.

The clinical course is protracted ; the
median survival of patients wilh RA in one
series was approximately 66 month s and
the rate of progression to AML at 5 years
was approximately 2% 17821 . In another
study, the median survival tor pat ients
over 70 years 01 age with AA, RARS and
MOS with del(Sq) was not sigml icantly
different frem the non-affected population
11371 1. Approximately 90-95% 01patients
with RA have low or intermediate International Prognostic Scoring System (IPSS)
scores 1833, 833AI. Approximately 80-85%
have good to intermed iate cytogenetic
profiles 1782, 13711, Most patients with AT
have tow IPSS scores and 90% of the patients live more than two years 119381.
Refractory cytopenia with unilineage dysplasia
95
Refractory anaemia with

ring sideroblasts
R.P. Hasserjian
N. Gatterman n
J.M. Bennett
A.D. Brunning
J . Thiele
Detinitioo
Refractory anaemia with nng stderoorasts
(RARS) is a myelodysp lastic syndrome
(MDS) cha racterized by anaemia. morpho-
may be symptoms related to p rog ressive

iron overload .
logic dysplasia in the eryth roid lineage

and ring eoercoteste comprising ~ 1 5% of
the bone mar row (B M) erythroid precursors , There is no signif icant dysplasia in
non-erythroid lineages. Myeiobiasis comprise <5% allhe nucleated 8 M cells and
are not present in the peripheral blood
(Pe) , Secondary causes of ring sroeroblasts must be excluded.
ICD-O cod e
998213
Epidemiology
RARS accounts for 3-11% of MDS cases.
It occurs p rimarily in older indivi dua ls with
a median age of 60-73 years and has a

simi lar freq uenc y in males and females
1267.782. 13711.
EIOOgy
Ring sideroblasls represent erythroid pre-
cursors with abnormal accumulation of iron

within mitochondr ia. includi ng some deposited as mitoch ondria l ferritin 1352, 82 7f.
Primary def ect s of haem synthes is (such
as the a-amlnolevonruc acid synthetase
defect in hered itary X-link ed srderoblastc
anaemia) ca n largely be exclud ed be cause p rotoporphyrin IX, the end prod uct
of po rphyr in synthes is, is not decreased
in RARS 11 2091. Furthermore , acqu ired
mutations in g enes of the haem synthetic
pathway have not been demonstrated in
AAAS {20841 Therefore. a pr imary defect
of mitochondrial iron metabolism is suspect ed . This de fect ma y be caused by

soma tic mutations or deletion s in nuclear
or mitochondrial DNA. Potentially analogous congenital d isorde rs inc lude the
Pearson mar row-pancreas synd rome ,
whic h features s.oerooiastc anaemia and
is caused by congenital large oeetcos of
mitochondrial DNA 1478/ . Somatic point
mutations 01 mitochondrial DNA have
been ident ified in the BM 01 some patients
with AA AS t7631 bu t it rema ins 10 be
established whether they cause the soeob lastic p henotype 11 4221. Clona lity 01
CD34-positive progenitor cells and
erythroid and granulocytic elemen ts has
been demon strated in RARS patients by
x-cbrorosome inactivation analysis {549.
2 1261. Stem cells from AARS patients
d isp lay poor eryt hro id colony formation
in vitro and manifest abnormal iron deposition at a very ea rly stage 01 erythroid
deve lopment {444, 2 1781 . This evide nce
suggests tha t RARS re prese nts a clonal
stem cell d efect that manifests as abnormal iron metabolism in the erythroid lineage
and results in ineffec tive eryt hropo iesis .
The PB and BM are the prin cipal sites of
involvement. The liver and splee n may
show evidence of iron over load.
Clinical features
The presenting symptoms are related to
anaemia. which is usually of mode rate degree; some pati ent s may additiona lly be
thrombocytopenic or neutrop eni c . There
""""hology
Patients typically p resent with norrTll'>
ch rom ic macrocytic or normochromic
normocytic anaemia. The red blood eels
in the PB smear may manifest a d imorphic pattern with a major population 01
normochromic red bkxxt cells and a
minor population 01 hypochromic cells
Blasts are not present in the PB. The 8M
aspirate smear shows an inc rease in erythroid precursors with erythroid lineage
dysplasia. inc ludi ng nuclear lobation and
megaloblastoid fea tures . G ranulocytes
and megakaryocytes show no significant
dysplasia 10% dyspl astic forms).
Haemo sid erin-Iaden macrophages are
often abundant. Myelob lasts are less mao
5% of the nucleated 8 M cells. On an ironstained aspirate smea r, 15% or more of
the red cell prec ursors are ring srceroblasts, as defined by 5 or more iron g ranules enci rcli ng one thi rd or more of the
nuc leus. The 8 M biopsy is norrnocellularto
markedly hyperceIlular. usually witha marked
erythroid proliferation. Meqakaryocytes are
normal in number and morphology.
Ring sid eroblast s are frequen tly observed
in other types 01MDS 1776, 10781. For examp le , c ases with ring sideroblasts that
hav e exc ess blas ts in the PB or 8M are
cl assifi ed as refractory anaemi a with
excess of blasts (RAEB). When ring stoero
bl asts a re 15% o r more of the eryth roid
precur sors but there are 10% or more dyspl astic cells in any non-erythroid lineage.
Fig. 5.15 RefratQy..aema WItl'l rtog siderobIasts. A Blood smear wilh dmorphic red bklod eels and macrocyIeS (WrJItII-Giemsa). B 8lnI 1l\WfOlf aspt'aIe smear stlowIWlg I
marked 8l)'ttlroid proIiferallon with a d)'5!JIBstlc Mderate bm (WrVrt-Giecnsa). C Ironslain d bone Il\WfOlf iISpQI8 sIll:JrMng I'U"I'letOUS ring sdetoblasts.
96
Myelodysplas!iC svnorores
and bla sts are < 1% in the PB and <5% in

the 8M with no Auer rods or mo noc yto sis,
the case is cl assi fied as refractor y cytopenia with mullilineag e dy sp lasia (RCMD ),
Such patients have infe rior surviva l to
patients with AARS.
tbHleoplastic causes 01ring sideroblasts .
includ ing alcohol. toxins (lead and benzene). dr ug s (isoniazid), zinc aorrurustraton. copper defic ienc y and congenital
sderootastc anaemia, must be excluded
1201.
Irrrnunopheootyp
In refractory anaemia with ring stderooests . aberrant immunophenotypic tealures of erythropoietic precursors can be
lound by flow cytometry analysis 15501.
100
eo
0;
.~ 60
---1....-
"~
RCMD with 2:15% RS
~RARS
40
Q.
20
0
0
100
200
300
Months
Genetics
Clonal chromosomal abnormalities are
seen in 5-20% of c ases of AARS and,
when presen t. typic ally involve a single
chromosome 1267. 776. 7781 .
FIg. 5.16 Stn;vaI Ctro'eS aller long-lenn ~oI' 161 patients WIth RARS and 318 RCMO patients WIltJ 2'15%mg
siderotlIasts (RSI. showing i'ltenor survival lor lIIe pallents WIth mg sideroblasts and nUtiIineage dysplasia
(p:O.ClCIOOS)(Datafrom ltIe Dusseldorf UDS regislry),
Postulated cell 01 orig in

Haematopo ielic stem cell.
Prognosis and p red ictive fac tor s
Approximately 1- 2% of cases of AAA S
evolve to ac ute mye lo id leukae mia. The
reported ove rall median survival is
69- loa months 1549, 7781.
Aefractory anaemIa with ring
soercoiests
97
Refractory cytopenia with multilineage

dysplasia
Definition
Refractory cytopenia with multilineage
d ysp lasia (ACMD) is a type 01 myelodysplastic syndrome (MOS) with one or more
cytopenias and dysplastic changes in t'NO
or rrore of the myeloid lineages: erythroid .
9mnulocytic. n-egaka<yocytjc 118641. rtere
are < 1 % blasts in the peripheral blood
(PS) and <5% in the bOne marrow (8M) ;
Auer rods ere not present and the mono-
cytes in the P8 are less than l xHJ'I\.. The

recommended levels for defining cytopenias are haemoglobin < lOgfdL absolute
neutrophil cocnt <1.8xl()9/l and platelet
count <100xl()11I\.I633. 833A1 . However,
values in excess 01 these thresholds are
not exclusionary of a diagnosis of MDS if
definitive morphologic and/or cytogenetic
findings are consistent with a diagnosis.
e.q. complex cytogenetic abnormalities .
The thresholds lor dysplasia are ~10% in
each of the affected cell lines. In assessing dysp lasia it is recommended that 200
neutrophils and precursors and 200 erythroid pre cursors be evaluate d in smear
and /or treph ine imprint preparations. The
neutr oph il dysplasia may be evaluated in
PB or BM smears. At least 30 meg akarycc ytes should be evaluated for dysplasia
in BM smears or sec tions, In some ca ses,
dysplastic meg akaryocyt es may be mor e
readily identif ied in sec tions than smears,
In particul ar the presenc e of micromegakaryocyte s should be noted . Cases
with multilineage dyspl asia and 2-4%
98
Myek:!dYSplastlC syndromes
R D. Brunning
J ,M . Bennett
E. Matures
A. Orazi
J.w. Vardiman
J. Thiele
b lasts in the PB, <5% in the BM, and no

Auer rod s should be classified as refrac tory ana em ia with excess of blasts
(RAEB)- l ; cases with 1% blasts or fewer
in the PB and <5% blasts in the BM, and
Auer rods should be classified as RAEB-2 ;
cases with 1% blasts in the PB and <5%
in the 8M and no Auer rods should be
classified as MDS-U. Some cases of
RCMD have 2:15% ring sideroblasts (782 .
137 11 .
ICD-Ocode
998513
Epid emiology
Refractory cytopenia With multilineage
dysplasia occurs in older ind ividuals: the
median age is approximately 70 years.
There is a sligh t predominance of males.
The peak incidence for males is 70-74
years, for fema les 75-79 years (7821. It
accounts for -30% of cases of MDS 1782.
137 11 .
Sites of involv ement
Blood and bone ma rrow
Clinical features
Most patients present with evidence 01
BM failure with cy topenia 01two or more
myeloid cell lines.
Morphology
The BM is usually hypercellular. Neu trophil dy splasia is cha racte rized b y
.......
Fig. 5.1' Refractooy ~ withrn.J~~
Bone marrow smear shows eviOenCe 01 dyspasia...bl:tl
ee erythroidprecursors andthe neutropnils. The maI\tt
neutrophils aresmall andMvallypolobulated rn.cIeI.
hypo granulation and/or nuclear hyposeq.

ment ation with ma rked clump ing of the
nuclear ch romatin (p seudo Pelqer-l-iuet
nuclei), The nuc lear hyposegm entation
may occur as two clumped nuclear lobes
con nec ted by a thin chromatin strand
(ptoce-nez type) Of marked ly clumped
non-lobated nuclei , Myeloblasts account
for <5% of the 8 M ceus. In some cases
there is a marked inc rease in erythroid
precu rsors . Erythroid p recursors may
show cytoplasmic vacuo les and marked
nuclear irregularity, inclu ding internuclear
chromatin bridging, multilobation, nuclear
bu dd ing, multmucleation and megalobrastord nuclei. The vacuoles are usually
poorly defined and dissimilar to the
sharply demarcated vacuoles observed
in toxic alterations such as alcoholism
The vacuoles may be pe riodic acid-Schlll
(PAS) positive; there may also be diffuse
cytoplasmic PAS positivity. In RCMD,
variable numbers of ring stoercorasts may

be identified Megakaryocyt e abnorma lities which may be obse rved inclu de nonlobated nuclei, nvpotonered nuclei,
binucleate or multinucleate megak aryocvtes and micromegakaryocytes; the micromegakaryocyte is defined as a
megakaryocyte approximately the size of
a promyelocyte or smaller with a nonlobated or bitobed nucleus and is the
most reliab le and reproducible dysplastic
feature in the megakaryocyte series
{1 4201_
Immunophenotype
See Chapter on mye lod ysplastic synoromesrneo otasms. overview.
Genetics
Clonal cytog enetic abnormalities including
trisomy 8, monosomy 7, del(7q). monosomy 5, del(5q ), and del(2Oq), as well as
com plex karyotyp es, may be found in up
to 50% of patients with RCMD {782, 8331.
Haematopoietic stem cell .

The clinical course varies. The majority of
patients wilh RCMD has International
Prog nostic Scoring System (IPSS) scores
in the intermediate category 1833, 833AI.
Prognosli c factors relate to the degree ot
cytopenia and dys plasia . The frequency
of acute leukaem ia evolution at two years
is - 10% in RMCD 17821. The overall median survival is approximately 30 rron ms.
Patients with complex karvorvpes have
survivals similar to patients with refractory
anaemia with excess of blasts (AAEB)
17821.
Refractory cvtooeoa With multJ!ineage dysplaSia
99
A.Orazi
R D. Brunning
R P. Hasserjian
U. Germing
J. Thiele
Definition
(RAEB) is a myelodysplastic syndrome
(MDS) with 5-19% myeloblasts in the
bone marrow (BM) or 2-19% blasts in the
peripheral blood (PB) Because of differences in survival and inc idence of evolution to acute myeloid leukaemia (AML).
two categories of RAEB are recognized:
AAEB-l, defined by 5-9% blasts in the
BMor 2 -4% blasts in the PB, and RAEB-2 ,
defined by 10-19% blasts in the 8M or
5-19% blasts in the PB 18331. The pres-
ence of Auer rods in blasts qualifies a

case as RAEB-2 irrespective of the blast
percentage 17811.
ICD-O code
998313
Ep;demkllogy
This disease affec ts primarily individuals
over 50 years 01 age . It accounts lor approximately 40% of all patients with MOS.
Etiology
The etiology is unknown. Exposure to environmenta l toxins, including pesticides,
pet roleum derivatives and some heavy
metals inc reases risk, as d oe s cigarette
smok ing 12113AI.
Sites of Involve me nt
Blood and bone marrow ,
Clinical features
Most p atients initially present w ith symptoms rela ted to BM fail ure , includ ing
anaemia, thrombocytopenia and neutrope nia.
"'"""",Iogy
The PB sme ar freq uently shows abnormali ties in all th ree myeloid cell lines.
including red cell anisopoikilocytosis.
large, giant or hypogranular platelets and
abnormal cytoplasmic granUlarity and
nuclear segmentation of the neutrophils.
Blasts are commonly present. The BM is
usually hyperceHular. The degree of dysplasia may vary. Erythropoiesis may be
increased with macrocyticlmegaloblastoid
changes . The erythroid precursors may
100
FIg. 5.19 Relractoryanaemia Wl1tJ excess b1asts-1(RAEB-1J. Bone rnatrOWsmear. The malJ.l'e ~ I'Ihsc.
show nuclear hypolobulabon (pseudo Pelger-Hll8I nuclei) and cytoplasmic hypograrnunty.
show d yserythropoiesis including the

presence of ab no rmally lobulated nuclei
and internucl ear bridging, Granulopoiesis
is frequently incr eased and shows var iable deg rees of dys p lasia. This is cha racterized primarily by sma ll size neutrophils
with nuclear hypo lo bation (pseudo
Pelq er-Hoe t nucl ei) or nucl ear hype rsegme ntation , c ytop lasm ic hypogranularity
and/or pseudo Chediak-Higashi g ranules.
Megakaryopoiesis is va riable in quantity
b ut is frequentl y no rma! to increased. The
megakaryocyt es often show a tend enc y to
c luster. Oysmegakaryopoiesis is a lmost
inva riably present and is usually cha racterized by the p rese nce of a bnormal
forms predomin antly of small size, incl ud ing micromegakaryocytes 122261. Howeve r, megakaryocytes of all sizes as well
as for ms wi th multip le widely-separated
nuclei can also occur. The BM biopsy
shows alte ration of the normal tnstctopography. Both erythropoiesis and
megakaryopoiesis appear frequently dis located towards the paratrabecular areas
that are normally predominantly occupied
by granulopoietic cells.
In a minority of cases the BM appears
normocellular or hvpocenuar. RAEBcases

with hypocellular 8M represent only a
small proportion of ca ses of hypoplasbC
MOS, since most of these cases do rd
show an increased numbe r of blasts ana
belong to the g roup of refractory cvtooere
with unilineage dys plas ia (RCUD) or less
common ly to refractory c yto penia witn
mu ltilineage dy sp lasia (RCMDl , The 8M
bio psy ca n be very useful in documenting
the presence of an exc ess of blasts perticula rly in cases w ith subo ptimal aspirate
smears such as those assoc iated wim a
hypocellular and/or fib rotic BM. Blastsi1
AAEB of ten tend to form cell clusters II
aggregates that are usually located a~
'rom bone trabeculae and vascular snc
teres. a histologic find ing formerly referred
to as abnormal localization of immature
precursors (AlIP). Immunohistochemical
staining for C034 may be particularty
helpful in their identification.
RAEB wilh fibrosis (RAEB-F):
In about 15% of patients with MOS, ee
BM stews a sign ificant d eg ree of re\lCl.irl
fibrosis . Such cases have been termed
MDS WIth fibrosis (MDS-F) (1246. 1400/.
MyelOdysplastiC syndromes
Since myelQfibrosis can be seen also in

cases otmerapv -rerateo MOS, myelop roliferative neoplasms, and, rarely, in reactive dyshaematopoietic con ditions (e9
HIVrelated myelopathy) these conditions
need to be excluded. Because of the lack
of consensus on the degree of fibr osis
necessary to characterize a case as
MDS-F, it is stilt unclear whether fibrosis
represents an indepe ndent prognostic
parame ter 12083 1. The cur rent wo rking
definiloo of MOS-F requires diffuse coarse
reticulin fibrosis with or without coocomilant
collagenizalion , associated with dysplasia
in at least two cell lineage s 12083, 23121.
Most of the cases def ined as MOS F
belong to the RAEB category (RAEB-F),
The presence of an excess of blasts in
these cases ca n usually be demonstrated
using immunohistoch emistry. particularly
for CD34. The BM smears are usually
inadequate. A cha ract eristic finding in
RAEB-F is an increased number 01meg akeryccv tes with a spectrum of cell size
(including micromeg akaryocytes) and a
high degree of dysplasia 112461. Cases of
RAEBF may morpholog ically over lap
acute paomveiosts with myelofibrosis
(APMF) previously referred to as acute
(malignant) myelofibrosis. APMF is d isne t from RAEB-F by its abrupt onset with
'ever and bone pa in 11651 , 22251.
Irrmunoph enotype
Flow cytometry in RAEB often shows
increased numbers 01 cells pos itive for
precursor ce ll assoc iated antigens CD34
and/or C0 117. These cell s are usually
positive for C038. HLA-DR and myeloidassoc iated antigens CD13 and/or CD33 .
Asynchronous expression of granulocytic
maturation antigens CD1S, C011b and/or
COOS can be seen in the blast population.
Aberrant expression 01C07 on blast cells
is seen in 20% 01 cases and C056 is
present in 10% of cases . while exp ression
of other lymphoid markers is rare {1210.
1623J,
In tiss ue sec tions, C034 immunoh istochemistry may be used to co nfirm the
presence of an increased number of
blasts; it allows the apprec iation of their
arrangement into clusters or agg regates,
a cha rac teristic finding seen in most of
the cases of RAEB 120501. Antibodies
such as C061 or C042b can aid in the
identification of micromegakaryocytes
and other small dysplastic forms. wh ich
are particu larly numerous in cases of
RAEB-F 11246, 22261_

Haematopoietic stem ce ll.
Prognosi s and pl'edictive factors
Refractory anaemia with excess blasts is
usually char acterized by prog ressive BM
failure with increasing cytopenias. Approximately 25% of cases 01 RAEB-l and
33% of pat ients with RAEB-2 progress to
AML; the remainder succu mb to the
sequelae 01 BM failure. The median survival
is approximalely 16 months for RAEB-1
and 9 months for RAEB-2 17811. CD7
exp ression has been assocrateo with
poo r prognosis {16231.
RAEB-2 patients with 5- 19% blasts in the
PB have a median survival of 3 months
similar to that of myelodysplasia-related
AML 121 t 41 , In contrast, cases defined as
AAEB-2 based only on the presence of
Auer rods . have a prognosis which is
similar to that seen in cases of RAEB-2
with 2-4% periphe ral blasts (median survival. 12 months) 121141.
Genetics
A variable percentage of cases of RAEB
(30- 50%) have clonal c ytogenetic abnormal ities, including +8 , -5, de l(5q ). -7.
del(7q) and del(2Oq). Complex karyotypes may also be observed 17821.
tOl
Myelodysplastic syndrome with

isolated del(5q)
RP. Hasse rjian

MM LeBeau
AF. li st
J.M . Bennett
J . Thiele
,.
,
Definition
Mveiccvsoiasnc syndrome with isolated
del(Sq) is a myelodysplastic syndrome
(MDS) cnaractertzeo by anaemia with or
without other cvtopenrasand/or thrombocytos is and in which the sole cytogenetic
abnormality is del(Sq), Myeloblasts conprise <5% of nucleated bone marrow (8M)
cells and < 1% 01 pe ripheral blood (PSI
leukocytes and Auer rods are absent.
Synonym
MyeIodyspIastic syndrome with 5Q deletion
(Sq- syndrome) .
EpidemK>logy
MDS with isolated del(Sq) occurs more
oflen In women, with a median age 0167
years.
Etiology
Pres umed loss of a tumou r suppressor
ge ne in the d eleted regioo . Possible ca ndi dates include the early g rowth respo nse
1 (EGR 1) and c -ceterm (CTNNA I) genes
and as-vet-untcennted genets) in 5q32
1256, 1075, 1324). The RPS14 gene that
encodes a ribosomal protein has been
propo sed as a can didate in the Sq- syndrome, raising the possib ility that a defect
in ribosomal p rotein func tion ca uses that
di sorder 1256. 635 , 1075. 1324 1.
Blood and bone ma rrow,
Clinicalleatures
The most common symptoms are usually
related to anaemia. whic h is often severe
and usually macrocytic. Thromboc ytosis is
present in one third 10 one half of patients.
while rnromcoocytopenle is uncommon
{794, 14171.
non-lobated and hypolobated nuclei. In

contrast, dysplasia in the erythroid and
myeloid lineages is uncommon 1257.
794}. The term "Sq- synd rome - has been
used to desi gnate a subset 01 cases with
macrocytic anaemia. normal or eleva ted
platelet count and BM erythroid hypoplasia
1257,23621. The number of blasts in the
BM is <5% and in the PB is < 1%.
Genetics
The sole cytogene tic abnormality involves
an interstitial deletion 01 chromosome 5;
the size of the del etion and the breakpoints
are variabl e, but ba nd s q 31 q33 are
invariab ly deleted . If any ad ditional c ytoge netic ab nor mality is p resent (With the
exception of a loss of the Y chromosome),
the case should not be p laced in this cateqoey 11 has bee n recen tly reported that a
small subset of patients with isolated del(Sq)
m ay show a concomitant JAK2 V617F
mutation. Until more data are collected for
such cases and their clinical behaviour and
respon se to therapy such as lenalidomide
are clarified. it is prud ent to classify lhem as
MDS with isolated de~5q) (rather than in the
MDS/MPN category) and to note the presence of the JAK2V617F in the diagnosis
110051.
Mo<phology
The BM is usually hypercellular or normacellular and frequently exhibits erythroid
hypoplasia 123621. Meg akaryoc ytes are
increased in number and are normal to
sfil.:t1tIy decreased in size withconspicuwsIy
102
MyelodysplastJc Syndromes
Postulated cel l of origin

Haernatoootetrc stern cell . FISH analysis
has confi rme d p resence of the del{Sq)
abnormality in differentiating erythroid.
myeloid. and megakaryocytic cells, but
generally not in mature lymphoid cells
139.2191.
Prognosis and predictive fact ors
This disease is associated with a rrecen

survival of 145 months, with transformatioo
to acute myeloid leukaemia occurring II
<10% of patients 17941. Patients with
del(Sq) associated with other chrorTlOSlmll
abnormalities or with excess blasts have
an inferior survival and are excluded frOOI
this diagnosis 17941. Recently. the thali a;
mide analogue lena fidomide has been
shown to benefit MDS patients with isolated
del(Sq) as well as d el(5q) with additional
cytogenetic ab normalities. Transfusion
inde pendence was achieved in two thirds
of p atients and was c losely linked to
suppression of the abno rmal clone (795,
13201
Myelodysplastic syndrome,
unclassifiable
Definition
Myelodysplastic syndrome. unclassifiable
(MDS-U ) is a subtype 01 MDS which init~1y lacks findings appropriate for classi-
fication into any other MDS category

Three possible situations which qualify
patents tor inclusion in this category are
listed under -morp hology.
9989/3
A.Orazi
AD Brunning
I. Baumann
R.P. Hasserpan
--
Genetics
There are no specific morphological lindiogs. The diagnosis of myerocvsplasnc

syndrome, unctasslnabie. can be made in
the followi ng instances:
1. Patients with the findings 01 refractory

cytopenia with unilineage dysplasia
(RCUO) or refractory cytopenia with rn.Jltilineage dysplasia (RCMD) but with 1%
blasts in the P8 qualify for MDS-U 111651.
Sjrooym
Uyelodysplastic syndrome, NOS.
EpOdemk>logy
The incidence of mvetodvscrasuc 5YO-
2. Cases of MOO with tXlihneage dySplasia

which are associated with pancytopenia.
In contrast. the RCUD category only allows
for a single cytopenia or bi-cytoperna .
cone. uoctassmame. is unknown.

Sites of irwotvement
The peripheral blood (PB) and bone mal1'C1W
(8M) are the principal sites of involvement.
Clinical featu res

Patients present with symptoms similar 10
n ose seen in the other myetcovsprasnc
syndromes.
3 . Patients with persistent cvtooemats)

with 1% or fewer blasts in the blood and
fewer than 5% in the BM , unequivocal
dysplasia (Table 5.03) in less than 10% of
the cells in one or more myeloid lineages.
and who have cytogenetic abnormalities
considered as presumptive evidence 01 MOO
(Table 5.04) are p laced in this category
MDS-U p atients should be carefully
fo llowed for evid enc e of evolution to a
more specific MDS type.
See Table 5 .04.

Haematopoietic stem ce ll.
Prognosis and predic tive factors

If characteristics of a specific subtype of
MDS develop later in the course 01 the
disease , the case should be reclassified
accordingly. In cases diagnosed as MOS.
U. it is unknown both the percentage 01
patients which translorm to acute myeloid
leukaemia as we ll as the disease survival .
Cases with features otherwise consistent
WIth a diagnosis 01 RCUD Of ACMO. but in
which 1% blasts are detected in the peripheral blood, have been shown to have a
prognosis which is intermediate between
ACUO (or ACMO) and that of refractory
anaemia with excess blasts (AAEB)
11 1651.
Myelodysptasttc syndrome. unclaSSiflable
t03
Chi ldhood myelodysplastic syndrome
Myelodysplastic syndrome CMOS) is very
UflCOrTlfl"lOf1 in children, accounting lor less

than 5% of all haematcooenc neoplasms
in patients less than 14 years of age
(Table 5 .06) 1908. 910 , 1595A, 2079AI .
The de novo or primary form of MDS in
children should be distinguished from
cases of "secondary MOS that follow
congenital or acquired bone marrow (8M)
failure syndromes and from therapy
related MDS that tollows cytotoxic therapy
tora previous neoplastic or rco-reootastc
condi tion. Furthermore. although MOS
associated with Down syndrome has
been reported to account lor 20-25% 01
cases of childhood MDS in the past

{2079AI, this disorder is now considered
as a unique biologic entity synonymous
with Down syndrome-related myeloid
leu kaemia and cnstmct from other cases
of chil dhood MDS (See Chapter 6).
Many of the morphologic. immonophenotypic and genetic features observed in MDS
in adults are also seen in ch ildhood forms
of the d isea se b ut the re are some signific ant d ifferen c es reported , part ic ularly in
pat ients who do not have increased
blasts in the ir pe ripheral blood (PB) or
Table 5.06 Ir.cKIence of haematoklgical malignancies in
children 0 - 14 years, Combined data from Dtlnmark.
1980-1991 and British Columbia 1982-1996(907, 908}.
N
% Incidence'
79
38.5
AU
AMl1
915
115
11
5.4
"lOS'
38
Myebd leuk.aemia of OS
19
1.8
0.9
JMMl
25
1,2
0,6
13
'VIET
Unclassified
o
o
0.1
0.1
1031
100
48.1
CMl
T","
ALl. acute IyrnpIlobIaSbC leukaemia; AML. acute

myeloid leukaemia; MOS, ~SbC s)'l'klrome;
JMML,;.wetiIe m~ leukaemia: CUl .
etworic myelogenous leukaemia. PII. poIytytllaeITia
vera; El essenbal ttvorrtlocyII'I
, Exdudng Down 5)'I'ome (OS)
I per n-.on poptAalJon peryear
104
BM. For example, the subtypes 01 refractory

anaemia with ring stoeroblaets and MDS
associated with isolated del (Sq) chromosomal abnormality are exceedingly rare in
chil dren 11595A1. Isolated anaemia, which
is the major presenting rnamtestatton of
refractory anaemia (RA) in adults, is unCOlTIllOO in chil d ren, wto are more likely
to present with neutropenia and thrombocytopenia 1908, 11091. In addition, hypocellularity of the BM is more commonly
observed in childhood MDS than in older
patients. Therefore, some chi ldren have
findings that do not readily fit into the "low
grade" MDS categories. To address these
differences, a provisional entity, refractory
cytopenia of childhood (RCC) is introduced and defined below.
For ch ildren with MOS in whom there are
2-19% blasts in the PB or 5-19% blasts in
the BM . the same criteria utilized for adults
with refrac tory anaem ia with excess blasts
(RA EB) should be ap pl ied . Cu rrently, in
contrast to adult MOS, the re are no availab le stu di es that have investigated the
prognos1ic sig nific ance of distinguishing
RAEB-1 and RAEB-2 in chil dren, bu t it is
rec ommended th at this distinc tion be
made for future investiga tion. Children with
RAEB generally have relativ ely stable PB
co unts for weeks or months , Some cases
d iagnosed in children as ac ute myeloid
leukaem ia (AML) with 20-29% blasts in the
PB and/or BM that have myelodysp lasiarelated c hang es. includ ing cases w ith
myelodysp lasia-related c ytogenetic abnormalities (See Cha pte r 6 ) may also
have slowly progressive d isease. These
c ases, co ns idered as refract ory anaemia
with exce ss blasts in transformation in the
French-Amer ican -British cooperative classification. may lack the cli nical features of
acute leukaemia and be have more like
MOS than A ML 19081. thus follow-up PB
an d BM studies are often necessary to
measure the pace of the d isease in such
c ases. Children who present with a PB
and/or BM disorder associated with
t(8;21)(q22;q22), inv( 16)(p13.1q22) or
t( 16; 16XP13. 1;q22) or t( 15;17Xq22;q 12)
should be considered to have A ML regardless of the blast count
I. Bau mann
C,M. Niemeyer
J .M , Bennett
K. Shannon
~IQ .
5J l
Relractory~dd'ikhxld(RCC~_
marrow smear showing abnormal nuclear IctUabcwl d
an twyttYopoietIc precursor eel alld a smaI megaQ"rocyle WItIl a IJi.lobed 1IUdeus,
Refractory cytopenia of childhood (RCC)

Definition
Refractory cytopenia of childhoocl (RCC}1S
a mveioovsotastc syndrome (MDSl char
by persistent cytopenia with <5%
blasts in the BM and <2% bla sts in the PB
{908) . Although the pre sence of dysplasia
is required for the d iagnosis, the cytological
evaluation of dysplasia by itself const itutes
only one aspect of the morpho logical diagnosis of RCC , The evaluation of an adeq uate BM trep hine biop sy specimen is
indi spensable for the d iagnosis 01 RCe in
c hildren, About 75% of ch ildren with RCe
show co nsi de rable hypocellularity 01 the
BM 117841. Conseq uently, it may be very
cha llengin g to d ifferentia te hypocellular
RCC from other BM failure disorders, especially from acquired aplas tic anaere
and inherited BM failure disorders. Down
syndrome-related myeloid neoplasms are
excluded from this diagnosis. The WHO
Working Group assigned RCC to a groop
of provisional entities.
actenzeo
ICD-{) code
998513
Synonym
Refractory anaemia of childhood.
Epidemkllogy
RCC is the most corrmon subtype 01 MDS

in childhood accounting for about 50%ct
<
f
..
.,
./
. I ....~
'~
..
1-'
ire cases 11704, 1784 /. II is diagnosed in
all age groups and affects boys and gi rls

with equal frequency 111091.
Stes of involvement
Blood and 8 M are alw ays affected. Gen efally. spleen. liver and lymph nod es are
rot sites of initial ma nifestation .
Clinical features
The most common symptoms are malaise,
bleeding , fever and infection /1109). lym-
Morphology
The classica l p ictu re of RCC is a PB
sme ar that shows red blood cell
antsopolknocytosts and macrocytosis.
Anisochromia may be present. Platelets
often di splay anisocytosis and occasionally g iant p late lets can be de tected.
Neutrope nia wit h pseudc -Pelg er-t-luet
nuclei and/or hypogranularity of neutrophil
Table 5.07 Minimal diagnostic criteria for reffactory cytopenia of childhood.
phadenopathy secondary to local or

systemic infec tion may be present, but
hepatosple nomegaly is ge nerally not a
feature of RCe , In up to 20% of p atients,
eocjrucal signs Of symptoms are reported
11 109/. Congenital abnormalities of different organ systems may be present.

Three Quarters of patients have a platelet
count be low 150 x10 9/L. whi le anaemia
with a haemoglobin concentration 01less
than 10 g/d L is noted in aboul half of the
affected children 111091. Mac roc ytosis of
fed cells evaluated accord ing to the
patient's age is seen in mos t The wh ite
blood count is generally decreased with
severe neutropenia not ed in about 25 %
11 1091.
Etiology
The etiology is unknown in most cases.
c ytop lasm may be note d . Blasts are

absent or account for less than 2% of the
white blood cells .
On 8M aspirate smears dysplastic
changes should be present in two ditlerent
myeloid cell lineages, or exceed 10% in
one sing le cell line (Table 5.07). Erythroid
abnormalities inc lude nuc lear budding ,
mcmnucreanty karyorrhexis , internuclear
bridg ing. cytoplasmic granules and macr0cvnc Changes . Cells of granulocytic lineage ma y extubtt hyposegmentation with
p seud o-Pelqer-Huet nuclei . hypo-fagranularity of the cyt oplasm , mac rocytic (giant)
bands and cyt oplasmic-nuclear maturation
asynchrony. Myeloblasts account lex" fewer
than 5% of the 8M cells. Megakaryocytes
are usua lly absent or very low in nt.rn ber.
The detection of micromegakaryocytes is
a strong ind icator 0 1 RCC . Ring sioerobla sts are not fou nd .
In RCC with norma- Of hypercetlular 8M
specimens there is slight to moderate
inc rease of erythropoiesis with accumulation o f immature precursor cells. mainly
proerymrootaste. Increased numbers of
mitose s indicate ineffective erythropo ies is. Granu lopoies is appea rs slightly
10 moderately decrease d and ce lls of
granulocytic lineag e are loo sely scattered. Blasts ac count for less than 5% of
the 8 M cells , and C034 staining on the
biopsy is useful for verification of the blast
percentage. Megaka ryoc ytes may be nor
ma l, decreased Of incre ase d in number
and display dys plasia with non-lob ulated
nuclei. abnorma lly sep arated nucl ear
Bone marrow
aspirate
Bone marrow
biopsy
Erythropoiesis
Granulopoiesis
Megakaryopoiesis
Dyspl astic changes'

andlor megaloblastoid
changes in at least 10%
of ery\tlroid PfeoJ~
Dysplasbc changes" in at
18ast 10%of granulocytic
precursors and neutrophils:

<5%blasts
Unequivocal
micromegakaryocytes,
othefdysplasticchangesl
in variable numbers
A lew dusttl'Sof at least20

erythroid precursors.
No minimal diagnostic cmeria
UnequiYocal
micromegakaryocytes:
Stoll in maturatiOn with
irnrl'lJnohistoctlemistry is
obIigab')' (COOl , CD41 ).
oltlerdysplasti: cIIange5t
ill variable I1lSI1bers
increased numbers of
1''''0'''''''''''
lncmased I1UIT'tlers of mitoses.
Peripheral blood
Dysplastic changes'
nat I8ast10%of neutrophis;
""
....
AbnormaII'IIdear lobulation, mutIirKIdear oeh. I'lUdear bfidge$.

r Pseu:Io-PeIger-HlJiit eels. tlypo-or agrardanly, IJ'if'l b8rlds (In cases of severe neutropenia lI's crilena may nol
be fuIIiIed ).
f Megakaryocytes of vanabIe see WIttl $&p8r31ed nuclei orround
emude refraclofy C)'IOPel'Iia of chitJlood.
IlI,dei.Theabsence of megakyIX:yIes
"not
Childhood myeocvsotasuc svocrore
105
bbl, 5.08
Comparison Of rnlIIphologicaI cnlefiaaI hypoplastic refracby cytopeoiaof childhood and aplasticanaemia inchildhood
R,1ractofy cytopenil of childhood
--- -_d_
lbIe m.tm::lW. . C)'tc*lgy
Pattry dcstrtluIion
lell shift
.......,..."
~-
Agranuiabon ofcytoplasm
Ni.dear<ytoplasmlc malurabondefects
Marked dea8ase
Dysplastic manges
Miaomegakaryocytes
M~
Lymphocytes
May be increased focally

or dispersed
May be increased
C034+ cells
Noincrease
MulI ~e
separated nuclei
Small round nuclei
Aplastic lNemia in childhood

BoN tIJafJDW' ISpI(BIe ~
--
l.Icting or single smaI bcus

WlIh Ie5slhat110cels W11tl
lICkflg or Y8IY lew eels, WIthool.

dysplasia or megalobIastlid change
I.JIc:UIg or ~ decrease,
Y8IY lewsmalloci 'NIth maturation
l.adUng orY8IY few, no dysplastlc
-""
May be increased bcally Of
C034+ cells
No increase
lobes and charact eristic micromegaKaryocytes. There is no incr ease in reticulin

fibres.
The majority of patients with RCC show a
marked decrease of 8 M cellularity, down
10 5-10% o f the normal age matched
veroe. The morphologic findings are similar to those observed in the normally
cellular Of hypercetlular cases. Immature
erythroid precursors form one or several
islands consisting 01 at least 10 cells . This
patchy pattern of evtreoooests is usually
accompanied by sparsely distributed
granulopoiesis. MegaKaryocytes are sig.
nilicantly decreased or absent. Although
micromeqakaryocvtes may be rare or not
always found, they should be searched
lor carefully as they are impo rtan t in
106
May be increased
establis hing the diagnosis, Multiple sections prepared from the biopsy may be
helpful in roermtcanoo of abnormal rneqakarvocytes and immunohistochemistry to
identify mictomegakaryocytes is obligatory.
Fatty tissue between the areas of haematopoiesis can mimic aplastic anaemia
(Table 5.08). Thereforeat least two biopsies
at least two weeks apart are recommended to facil itate the detection of
representative 8M spaces containing foci
of erythropoiesis.
Differential di agnosi s
In children, a variety 01 non-haematological
d isord ers such as viral mtecuons. nutritional deficiencies and metabolic diseases
can give rise to secondary myelodysplasia,
thereby mimicking RCC (Table 5.09). In

the absence of a cytogenetic marker the
clinical course of cases suspected lX
RCC has to be carefully evaluated before
a clear-cut diagnosis can be made. rte
haematological differential diagnosis ....
ciuoes acquired aplastic anaemia. riter
ited 8M failure diseases and paroxysrral
nocturnal haemoglobinuria (PNH). In ceotrast to RCe. acquired aplastic aneere
presents with adipocytosis of the 8M
spaces with few scattered myeloid cells
there are no erythroid islands wllh
increased numbers of immature erythroblas ts, no granulocytic dysplasia and no
micromegakaryocytes (Table 5.08). CO'\<
trary to wnat is sometimes reported in adUls
with aplastic anaemia, at presentation
acquired aplastic an aemia of childhood
does not have mega loblastic features; IQl.
lowing immunosuppressive therapy, the
histological pattern of acquired apiasic
anaemia can no longer be separated fnm
tha t observed in RCC. The inherited au
failure oeoroers such as Fanconi ereera
ovskeratosrs conqemta . ShwachmarDiamond syndrome, amegakaryocytC
thrombocytopenia or pancytopenia
radioulnar synostosis show overlap
morphological features with ACC, They
have to be excluded by medical hisl~
phySical exemoanoo and the appropraale
laboratory and molecular studies belen
a definite diagnosis of RCC can be made
The clinical picture of PNH is rare in C/"Ml(j.
hood. although PNH clones in the absence of naemoivsts or thrombosis may
be observed in children with RCe 122921
The relation between RCe with two (It"
mo re dysplastic lineag es and retractor
cy topen ia with mu llilineag e dysplasia
(RCMD) has not vet been evaluated,
Currently il is recommended that children
who otherwise fit the criteria for RCMD be
considered as RCC until such studies
cla rify whether the number 01 lineages
involved is an important prococsc
discriminator in childhood MOS.
Immunophenolype
Mlcromegakaryocytes can be missec
easily in H&E stained 8M trephine biopsy
sectcos but can be more readily aweciated by the expression 01 platelet g/y(
proteins like C061 (glycoprotein lila), C04I
(glycoprotein lib/lila) or von Willebrancl
factor. Myeloblasts do not account ta
more than 5% of the 8 M cells , and oetectton of 5% or more CD34, mvetooeroe
dase, lysozyme and CD 117 positive biaS!
cells may lnc ncate progression to high

grade MOS. Clusters of myeloblas ts are
-ot seen in ACC.
Genetics
The genetic changes predisposing to
!.lOS in childhood remain largely obscure.
The presumed underlying mechanism
may also give rise 10 subtle phenotypic
abnormalihes noted in many children with
MOS. Monosomy 7 is the most common
cytogenetic abnormality /1 109, 1704,
17841 . Other cytogenetic abnormalities
IlChJding complex karyotypes may also
be observed. Most cases of ACC show a
rnmal karyotype irrespective 01 8M eelltarrty. There is no difference in morpholOgy between cases with Of without
-oonosomy 7.
PtlstuIated cell of origin
saematopoenc stem celt with multihneage potential ,
Prognosis and pred ictiv e factors
(aryotype is the most important factor
'or progression 10 advanced MOS. Patents with monosomy 7 have a sign ificantly higher probability of progression
f an patients with other chromosomal abrcmannes or normal karyotype 111091.
Table 5.09
Dfsofders which maypresent witll morp hoj ogic.a lleal~ res indisbnguishable from refractory cytopenia ofct1ildhood,
Infectioos (e.g, c:ytomeo;lalovirus, herpes Wuses. parvovirus 819, YiscerailelsnmaniasiS)

Vrtamin detiOeocy (e,g.deficiency of vitamin B12,Iolale, Yilamln E)
Metabolic: disorders (e.g, mevalonatemase delk:iency)

Rhel.maliC disease
A.utoirmuIe I)mphoproIIferative dISOrders (e,g, FAS deftciency)
Mllochondrial deleloos (Pear9on S)YIdrome)
~ bone marrow laikJre disorders(e,g Fanconi anaema. dyskeratosis congeniIa, 5hwactmam-Oiarnond
syndrome , amegakaryocyIit~,1hrorTtlocytope WI1h absent radii, radioulnar syMSlO$lS.
Sedtel syndrome)
P~nochrnaI ~ (PM-I)
~ apIasbc anaemia
dlmg haemalologicall'llCOYllfy
Spontaneous disappearance of monosomy 7 and cytopenia has been reported

in infants, but remains a rare event I t3801.
In contrast to mooosomy 7, patients with
trisomy 8 Of norma l karyotype may experiencea long stablecourseof their disease,
Currently, haematopoietic stem ce ll transplantation (HSCT) is the only cu rative
therapy and is the treatment of choice for
patients with monosomy 7 or complex
karyotypes early in the course of their disease . In view of a low transplant-related
mortality HSCT can also be recorsrenoed
for pa tients with other karyotypes if a SUIt
able donor is available /1784 . 21041.
An expectant approach with careful observation may be reasonab le for patients

in the absence of transfusion requirements.
severe cytopenia Of infections. Because
early 8M failure can at least in part be mediated by t-een immunosuppression of
baenatoooese. irrmunosuppressive therapy can be a successful therapy strategy
for improving outlook in some children
with ACC 12033, 24711 .
Childhood myelodysplastlc syndrome
107
CHAPTER 6
Acute Myeloid Leukaemia and
Related Precursor Neoplasms
Acute myefoid leukaemia with recurrent genetic abnormalities

Acute myeloid leukaemia with myelodysplasia-related changes
lllerapy-related myeloid neoplasms

Acute myeloid leukaemia, not otherwise specified
Myeloid sarcoma
Blastic plasmacytoid dendritic cell neoplasm
Acute myeloid leukaemia

with recurrent genetic abnormal ities
AML with balanced

translocations/inversions
This group is characterized by recurrent
genetic abnormalities of prognostIC significance. The most commonty identified are
balanced abnormalities: 1(8;21)(q22:q22),
inv( 16)(p 13. l q22) or I(16:16)(p 13 .' ;q 22),
1(15;17}(q22;q12) and 1(9.11 )(p22;q23)
1306. 72 1, 848 , 20361 . Each 01 these
structural ch romosome rearrangements
creates a fusion gene encoding a chimaeric protein that is required. but usually
not sufficient. for leukaemogenesis 120631.

Many of these d isease groups have charac teristic morphological and immunop henotyp ic features 1651. The categories
of acu te mye loid leukaemia (AML) with
1(8 :2 1)(q22:q22), iov( 16 )(p 13. 1q22) or
1(16:16)(p 13 .1;q 22 ) or l(lS;17)(q22:q 12)
are considered as acute reukaermas

without rega rd to blast cell cou nt. It is not
yet c lear if all c ases with t(9; 11Xp22;q23) ,
t(6 ;9)(p 23 ;q34 ). inv(3 )(q2 1q26,2), t(3;3)
(q 21;q26 2) or t( 1;22)(p 13;q 13 ) shoul d be
c ate go rize d as AMl when the blast cell
count is <20%. Many of the trans loca tions
are dete cted by AT-PCA whic h has a
higher sensitivity (1x 10"5) than c ytogenetic
analysis (1x 10-2 ) . Cases of therapy- related
AMUmyel odyspla st ic syndrom e (MD S)
may also have the balanced transloc ations
and invers ions that are d escribed in this
section, but the se should be diagnosed
as therapy-re lated AMUMDS with th e
associated g enetic abnormality noted.
Acute myeloid leukaemia with

t(8;21)(q22;q22); RUNX1
RUNX1T1
Def inition
Acu te myeloid leukaemia. with t(8 ;2 1)
(q22;q22); RUNX 1-RUNX7 T1 is an AMl
gene rally showing maturation in the neutrophil lineage.
ICD-Ocode
110
9896/3
D .A, Arber
R D , Brunning
M .M. le Beau
B , Falini
J.w.
Vard ima~
A. POrNIt
J. Thiele
CD. Bloomfield
Epidemiology
The t(8 ;2 1)(q 22;q 22 ) is found in -5% of
cases of AMl and in 10% 01 the prior acute
myeloblast ic le ukaemia with matu ration
(M2) c ategory of the French -AmericanBritish cl assification. It occurs predominantly in younger pat ients .
Cli nical featu res
Tumour manifestations , such as myeloid
sarconas. may be present at presentation .
In such cases the initial bone marrow (BM)
aspiration may show a mis leading low
number of b last cells. but should be
diagnosed as AMl despite a b last percentage in the BM of <20,
The co mmon morphological features inc lude th e presenc e of large blasts with
abundant basophilic cytoplasm, often
containing nume rous azuroph ilic granules
and perinuclear clearing or bots . A few
b lasts in many cases show ve ry large
gra nules (pseu do-Chedrak-Hiqashi gran ules), sug gestin g abnormal fusion . Auer
rods are freq uently found and appear as a
sing le long and sharp rod with tap ered
e nds; they may be de tect ed in mature
neutrophns. In addition to the large bla st
c ells , some smalle r bla sts, pred om inantly
in the peripheral blood (PBj, may be found.
Promyeroc vtes, myeiocytes and mature
neutroph ils with var iab le dy sp lasia are
present in the BM. These ce lls may show
abnormal nuc lea r seg mentation (e.q.
pse uoo-Pelqer-Hoet nuc lei) and/or cy toplas mic staining ab nor malities, including
homogeneous pink colo ured c ytoplas m in
neutrophil s. Dyspl asia of othe r Cell lines,
however, is uncommon. Eosinoph il precutsees are frequently increased. but they do not
exhibit the cytological or cytoc hemical ab normalities charac teristic of AMl associated
with ab nor ma lities of c hromosome 16:
basop hils and/or mast cells are sometimes
present in exce ss. A monocytiC component
is usually minimal or absent. Erythrob lasts
and meg akaryocytes are morphologically
normal. Rare c ases with a BM blast percentage <20 occur, These should be
cl assifi ed as AMl and not as MOS.
Acute rnyelord leukaemia and related p recursor neo plasms
FIg. lOl /IoI/IIl myeloid IeUlaen'ia Wlltl .8 11XQ22:Q22'
Bone marrow tllasts s/'lowirlg abl.n:lant pUr

qtIpIasm WIlh ~deari'1g em Wge~
.........
Fig. 6.02 Myeloid sarcoma Biopsy of an orbitaIl'I'IaSl

from a child w;th AML with a ~ a;21)(q22;q22). There in
precursors scattered in !he preOominat1l lNs1
poplI lation.
eosinoph~
Immunop henotype
Most cases of AMl with the (8;21 )(q22;q22)
transloc ation d isp lay a characteristc
imm uno phenotype with a subpopulatioo
of blas t cells show ing hig h intensity expression of CD 34, together with HLA-DR,
myercoeroxidase (MPO) and CD13. bJ
relatively weak expression of CD33j114Q,
17751. There are usually sig ns of granulocyt ic differen tiation with subpopuianonsd
cells showing granulocytic rnaiuranco
demonstrated b y CD15 and/or COO
expression . Sometimes po pulations cI
blasts showing matu ration asynchrony
are present (e .g . co-expressing COOt
and CD15 ). These leukaemias frequen
express the lymphoid marke rs CD19 and
PAX5, and may express cvtoptasrre
CD79a 1996, 1155. 2236} . Some cases
are terminal deoxynucleotidyf transferase
(TdT) posi tive ; however, TdT exoresscoe
generally weak. C056 is expresse d in a

fraction of cases and may have adverse
prognostic significance {1231
Genetics
The genes for both reteroosreoc components of core bindll)Q lactor (CBF), RUNX I
(atso known as AML 1or CBFA) aOO CBFB
ere involved in rearrangements associated
WIth acute reukaemes {20631. The t(8 ;21)
(Q22;q 22 ) involves the RUNXI gene, which
encodes core- bi ndin g factor subunit
alpha and the RUNX 1T1(ETO) gene {608,
1294, 17331. The RUNX1 -RUNX1T1 fusion transcri p t is consistently detected in
patients with 1(8;21)(q 22;q 22) AML. The
CBF transcripti on factor is essential for
baematopolests. and tr ansformation by
RUNX 1-RUNX 1T1 likely results from transcriptional repression of normal RUNX1
target genes via abe rrant recr uitm ent of
nuclear transcription al co- repressor complexes. Over 70% 01pati ents show aooiIIQll3I chromosome abnormalities: e.q. loss
rJa sex chromosome or d el(9q ) with loss
rJ 9Q22. Secondary cooperating mutations
rJ KRAS or NRAS are common (30%) in
caedtamc CBFassociated leukaemias
~l. Mutations of KIT occur in 20-25%
01 cases (16961.
Postulated nor mal cout erpart
Myeloid stem cell wilh predominant reunophil differentiation.
Acu te myelo id leukaemia with t(8;21)
(q22;q22) is usually associated with a
16
inv(16)(pI3.1q22) or
t(16;16)(pI3.1;q22); CBFB
MYH11
Definition
Ac ute myeloid leu kaemia with inv(16)
(p1 3.1q22) or t(16: 16)(p13,1:q22); CBFBMYH11 is an AML that usually shows
monocytic and gra nuloc ytic differentiation
and characteristically abnormal eosinophil
component in the BM {1258. 1393, 20631.
ICD-O code
9871/3
Synonym
Acute myeloid leukaemia with abnormal
marrow-eosoconns .
Epidemiology
Either inv(1 6)(p 13.1q22) or t(16 ;16)
(p13. 1;q22) is found in 5-8% of all cases
of AM L. They can occur in all age grou ps
but are found predom inantl y in younger
patients.
Fig. 6.04 Acu1e myeloid leukaemia with associated

inv(16Kp13.1q22). AbnonnaI eosi~ . one VIlth Large
basophiliccoloured granules. aAl present
Clinical features
Myeloid sarco mas may be p resent at
initial diagnosis or at relapse and may
c onstitute the only evidence of relapse in
some patient s.
Morpholog y and cytochemistry
In these cases. in addition to the usual
morphological featu res of acute myelomonocytic leukaemia, the 8M shows a
variable number of eosinophils (usually increased. but soretrres <5%) at all stages
01 rretoratco without significant maturation
arrest. The mos t striking aboomantee involve the immature eosinophilic granules.
mainly evident at the promyelocyte and
myelocyte stages . The abnormalities are
usually not p resent at later stages of
eosi nophil maturation . The eosinophilic
granules are often larger than mose normally pr esent in immature eosmocnus.
p urp le-violet in colo ur, and in some cells
are so dense that they obscure the cell
inv(16)
--<>
goo d response to ch emotherapy and a

high com pl ete remission rate with longterm d isease-free surv ival when treated
with high dose cytaratnne in the consolidation phase 1228. 8481. Some factors
appear to adversely affect prognosis
including C056 expression aOO the presence of KfTmutations 1123. 16961.
--<>
XI
16
inv (16)
:~:>:
Fig. 1.03 Acute myeloid leukaemia with inv(16)(pt 3.1q22). A The inversion 16 results from breakage and rejoining of bands 16p13.1 and 1&;22. G-banded normal (nI)
linrTIosome 16 and irW(16) are shown. B Dual rolor ftUOfllSC6OC6 in situhybridizalion: !he 5' regll)llof CBFB is labeled in red; !he3' regionin pen Anonnal ettromosome 16 has
~ 5'and 3' regions ~ 10 e<lch otherresultiog in a siogle yellowOf oveOappiog IlldIgreen signals, The invefsion 16splits theCBFB locus resulting in separale red andgreen
sigla/$. 80Itl interphase ooIIs have one normal 16etvomosome andoneinv(16),
Acu te myeloid leukaemia with recurrent genet ic abnormalities
11 1
morpho~y. The mature eosinophils may

occasionally show nuc lear hyposegmenlal ion . The naphthol-ASD-chloroacelale
esterase reaction. which is normally
negative in eosinophils, is charactenstically
faintly pos.tive in these abnormal eosmophils. Such a reaction is 001 seen in eoerophils 01 AML with the 1(8;21)(q22;q22).
Auer rod s may be observed in myeloblas ts. At least 3% of the blasts show
mveioperoxioase (MPO) reac tivity. The
monob lasts and promonocvtes usually
show non-s peci fic esterase reactivity,
although it may be weak er than expected
or even abs ent in some c ases. In ad dition
10the predominant monocytic and eosinoph il compo nents, the neutroph ils in the
8M are usua lly sparse, with a de cr eased
number of matu re neutrc phils . The PB is
not different from other cases of ac ute
mveromonccvnc leu kaemi a; eosinoobus
are not usua lly increased. but an occasional case has been rep orted with abnormal and increased eosi nophils in the
PB. While the major ity of cases 0'
inv( l6)(p13.1Q22) have been identified as
having abnormal eosinophils, in some
cases they are rare and d iffic ult to lind .
Occasooar cases with this genetic abnormality lack the eosinophilia or show
cxty myeloid mansatcn wilhoul a I"ro"lOCytic
CCJITlX)IlE!lll or only rro-ocvtc d ifferentiation.
Not infrequently, the blast percentage is only
at the threshold level 0120%or oc:casionally
lower. Cases with inv( l6)(p13.1 q22) or
t(16; 16):( p l3. l ;q22) and less than 20%
8 M blasts should be di ag nosed as AML.
The BM treph ine biop sy is usually hyperce llular, but may occasionally be normoce llular.
Immunophenotype
Most of these leukaemias are c haracte rized by a complex immunop henotype with
the presenc e of multiple b last populations:
immature b lasts with high CD34 and
CD l 17 expression and pop ulations d ifferentiating toward s gran ulocytic (CD13,
CD33. CD l5. CD65. MPO positive) and
monocytic (CD 14. CD4. CDl 1b.
CD64. CD36 and lysozyme positive) lineages Mat urat ion async hron y is often
seen. Co-expression 01CD2 with myeloid
mark ers has been frequently documented
but It is not specmc for this di agnosis.
cone.
Genetics
The inv( 16)( p 13, 1q22) foun d in the vas t
major ity of this subtype and the less common t(16; 16)(p13, 1:q22) both resu lt in the
112
fusio n of the CBFB gene at 16q22 to the

MYH 11 ge ne at 16p 13.1 120061. MYH11
codes for a smooth muscle myosin heavy
chain 15061. The CBFB gene codes for
the core binding factor (CBF) beta subunit, a heterodimeric transcription tactoe
known to bind the enhancers of t-een
rece ptor (TCR). Cylokine genes, and other
genes. The CBFB subunit heterodimerises
with CBFA, the gene product of RUNXl,
one of the genes involved in AMl with
t(8;21 )(q22;q22). Occasionally cytological
features of AM l with abnormal eosropnns
may be pr esent without karyotypic ev id ence of a c hromosome 16 abno rmality,
the CBFB-MYH 11 being neverthe less
demonstrated by molecular genetic studies
(1533 , 1882) By co nventional cytogenetic
ana lys is, the inv(1 6)(p1 3,lq22l/t(16:16)
(p1 3 ,1;q22) is a sub tle rearra ng ement
that may be over looked when metaphase
pr epa rations are suboptimal. Thu s, at
dia gnosis, the use 01 FISH an d RT-PeR
methods may be necessary to document
the genetic alte ration . Secondary cytogenetic abnormalities occur in approximately
40% of cases, with +22, +8 (10 -15%
each), and del(7q) or +21(-5%) most
commonly observed 113901. Trisomy 22 is
fairty specific for inv( l6XPl3.lq22) patients.
being very rarely detected with other primary aberrations in AM l. whe reas +8 is
commonly seen in patients with other prtmary aberrations. Rare cases of A ML and
chronic myelogenous leukaem ia with both
inv(16 )(p 13 ,1q22) and t(9:22)(q34:q1 l.2)
have be en reported, an d this findi ng in
ch ronic myelog enous leukaemia is usually
assoc iated with accelerated or blast phase
of the disease 12454 J Mutations of KIT
occ ur in approximately 30% of cases 116961.
Acute promyelocytic leukBemia

with t(15;17)(q22;qI2);
PML-RARA
Definition
Acute promyelocytic leukaemia (API. or
AML with t(15 ;17)(q22;q12)J is an AMLII
which abnormal promyelocytes predcmnate. 8cttl hypergrarUar'or "l'ypil:3" APLcnl
microgranular (hypogranular) types emt
ICD-O code
986613
Synonym
AM l with 1( 15;17)(q22;qt2).
Epidemiology
Ac ute promyeloc yte leukaemia comprises
5-8% of AMl {20 78 1. The disease can
occur at any age b ut pati ents are predom inantly adul ts in mid-life.
Clin ical featur es
Typical and rricrograrlAar API.. are lrequerty
associated with disseminated inlravasoJa'
coagulation (DIG) . In microgranular API..
unlike typical API.., the leukocyte COlJ'lt IS
very high, with a rapid doubling time
Postulated normal counterpart
Haemetcooienc stem cell w ith potential to

differentiate into g ranuloc ytic and monocytic lineages .

Clinical studies have shown that pa tients
with AMl with inv(16)(p13 .1q22) or 1(16;16)
(p13.1;q22) achieve longer complete
remissions when treated with high dose
cytarabine in the consolidation phase
1848, 15301. j-owever. older patients have
d ec rea sed survival and tho se with KIT
mutat ion s have a higher risk of relapse
and worse survival 1546. 16961. Patients
with +22 as a secondary abnormality have
bee n reported to have improved ou tcom e
11390. 196 21.
Acute mye loid leukaemia and related precu rsor neoplasms
~
B
Fig. '.05 Acute promyeIocybc leukaema. A ~
~ type n bone marrow smear. Theft we IM'i
abnormal prornyelocyles wilhITIense amq:hIc,.....
lam. Sewr1lI ollhe promyeIocyles oontaillUl-.all
Auef rods(Iaggot oeIs). B M~ vWrt. 1'1 Ptripheral bloocI smear. There are several abnclmll
promyelocy!es 'Mthlobl,Jlaled. almostc:eretlnbm ru:Il
The cytoplasm coolains numerous small alI.tllPl*
granules: other ~Is appear sparsely ganlMr.
nl
15
d .~15 )
15
17
II
A
1(15 ;17XQ22;Q12)
~ U16 AcuIe prorll)'8locybc Ieuilaen'U WIIh 1(15;11Mq22;q12), A The D'lslocabon 15;11 t'&SUts from br9akage a'ld r-.nion of bands 15q22 a'ld 11q12. G-bMded normallnl) 15
111 17 dY\::Jnc:lsanes (Ieft.l a'ldthe derivatNe ldetl 151n:l11 reslAng from ee IransIocation are sIlOWl'I on hi fil1C. BOuaIlDorl'unscence" sill hybtidiZ.alion M1h probes Pf.C.
l'~ iIl'lll RARA(17ql2) derroostrate the presence of a Pl.UWtA.lusion ~ from the 15;11 transIoca1o'l. Eactlof hi fw'ee IlBphase eels has one sep;nte red (PK)
J9W. (W'II sepataIe ween (RARA) sigIaI, In:l one \'dOw or~ ~greet1 si!r.aI ronsislenl..,1Il1tle pttl5etIC8 of a PMJRARA gene Iusioo.
IbphoIogy and cytochemistry
The nuclear size and shape in the aboorrrel promyelocytes of hypergranular APL
ere irregular and greatly variable; they are
::tten kidney-shaped or bilobed . The cytoplasm is marked by densely-packed or
even coalescent large granules, staining
:Yight pink, red or purple in Romanowsky
stains. The cytoplasmic granules may be
solarge andior numerous that they totally
rescore the nuclear cytoplasmic margin .
In some cells. the cytoplasm is filled with
Ire dust-like granules. Characteristic cells
containing bundles of Auer rods ("faggot
cells") randomly dis tributed in the cytoplasm are present in most cases, Myeloblasts with sing le Auer rod s may also be
Observed, A uer rod s in hyper gr anu lar
APL are usually large r than in other types
rJ. AML and they may have a c haracteristic
rrorpholog y at the ultras truct ural leve l
'.vith a hexagonal arrangement of tubular
structures with a specific period ici ty of
aeoroxrnaterv 250 mm in contrast to the
6-20 lamina r periodicity of Auer rods in
erertypes of AML. The MPO reaction is
always strongly positive in all the
exaernc oromyeiocvtes . with the reaction product covering the entire cytoplasm
l"Id often the nucleus . The non -specific
esterase reaction is weakly positive in ao;>rQximately 25% of cases. Only occaSJOnaI obvious leukaemic prooweiocvtes
may be observed in the PB.
Cases of rracrcqranurar (hypogranular)
A.PI. arecharacterized by distinct morphoQJicaI features such as apparent paucity
CJ absence of granules. and predomiI'lafltly bilobed nuclear shape 18111.
The apparent hypogranular cytoplasm

relates to the submicroscopic size of the
azurophilic granules. This may cause c0nfusion with acute monocytic leukaemia on
Romanowsky stained smears; however, a
small number of the abnormal promyelocvtes showing clearly visible granules
and/or bundles of A uer rods (faggot cells)
can be identified in many cases. The
leukoc yte count is frequently markedly
elevated in the microgranular variant of
APL with numerous abnormal mcroqranular promy elocytes in con trast to typical
APL. The MPO reaction is strongly pos itive
contrasting w ith the wea k or negative reaction in monocytes. Abnormal promveocytes
w ith deep ly baso ph ilic cy toplasm have
been de sc ribe d ma inly in the rela pse
phase in patients who have be en p reviou sly treated w it h al l-tran s rettnoic acid
(ATRA), The 8M biop sy is usual ly hypercel lular, The abnormal promyelocyt es have
relatively abu ndant c ytoplasm with nume rous g ranul es: occasionally Aue r rods may
be identified in well-prepared specimens.
The nuclei are freq uently convoluted
Immunophenotype
Acute p rom vetoc vtrc leukaemia with the
t( 15 ;17)(q22;q 12) (hypergranular or "typical" variant) is characterized by low
expression or absence of HLADR. CD34.
leukocyte integrins CD11a, CD 11band
CD18. a homogeneous, bright expression
of CD33, and heterogeneous expression
of CD13_ Many cases show expression
of CD117, although sometimes weak .
The granulocytic differentiation markers
C015 and COO5 are negative Of only
weakly expressed 11654. 1678} and CD64

expression is common. In cases with
microgranular morphology or cera Iran.
scr ipt of the PML-RARA fusion gene there
is frequent expression of CD34 and C02,
at least on a fraction of cells 16531. Ap proximately 20% of APl cases express
C056. which has been associated with a
worse outcome 16901 Using enrourocvtoChemis try, antibodies against the PML
gene product show a characteristic nuclear multigranular pattern with nucleolar
exclusion, in contrast to the speckled relatively large nuclear bodies seen in normal
oromverocvtes or blas ts from other types
of AML (6621.
Genetic s
In ad d ition to its thera pe utic imp act, the
sensi tivity of APL cells to ATRA has led to
the d iscovery that the retinoic acid receptor
alpha (RARA) gene on 17q12 fuses with a
nuclear regulatory fac tor gene on 15q22
Fig. 1.07 Aone promyeIocytic Ieukaema. Bone IIIiWTtIW

biopsy. Abnormal prorrt)'eIotyIe wilIl abl.ndal'll hyper.
gran,Aated cytlpIasm. Thenudei are genefaIylWId tI
oval. SewlraI of !tie nudei llfll lfregU;w and I!YagrIaled
Acute myeloid leukaemia With reconenr genetic ebroerrautes
113
the p rognosti c signific ance of FLT3-JTO

mutations in this di sease remains unc lear
/690 , 1199 1.
Fig.6.08 PM!. anI1bod'y n aaM promyeIocybc Ieukaen'Ia

showing a etlaractetistic Ill.Ideaf mufbgrnular paltem
\MIll ru:leoIar exclusion.
(o ronvelocvnc leukaemia Of PML gene)

giving rise to a PML-RARA fusion gene
produCII506, 529 . 14521. Rare cases 01
APt. lacking the classic t(15:17)(q22;q 12)
on routine cytoqenenc studies have been
described with complex variant transiocations involving both chromosomes 15
and 17 with an additional chromosome Of
with submicroscopic insertion of RARA
into PML leading to the expression of the
PML -RAR4 transcript ; these latter cases are
considered as cryptic Of masked t(15 ;17)
(Q22;q12) /6471. Mor pho log ic al analysis
shows no major d ifferences be tween the
t( 15;17)(q 22 ;q 12) positive group and the
PML -RA RA positive p atients wi thout
t( 15; 17)(q22;Q12) , Secondary cytogenetic
abnormalities are noted in - 40% of c ases .
with +8 being the mos t frequen t (10- 15%).
Mutatio ns involving FLT3, including internal tand em duplic ation (ITO) and tyrosine
kinase doma in mutations (TKO) oc cur in
34-45% of A PL. FLT3-l TO mutation s are
mo st co mmon and a re associated with a
high er white b lood ce ll co unt. mlcrocranurar b last ce ll mo rph olog y and involvement of the bcr3 b reakp oint at PML 1318,
747 ,1 199).
Myeloid stem ce ll with potential to d ifferent iate to granulocytic lineage.
Prog nosis and pred ictive fac tors
Ac ute promyetocyttc leukaemi a ha s a
p artic ular sensi tivi ty to treat ment w ith
ATRA. which acts as a dilferentiating ag ent
1342. 2 152/. The prognosis in APt.. treat ed
optimally With ATRA and an anlhrac ycl ine
is more favou rab le than lor any other AML
cytogenetic subtype. and cases of relapsed
or refractory APt. show a generally good
respo nse with arsenic tr ioxide th era py
1607.6851. Expression of CD56 is associ ated with a less faVlJU(able prognosis while
114
Variant RARA transl ocations

in acut e leukaem ia
A sub set of c ases. often with mor phological fealures resembling acute ~
cvtc leukaemia. show variant nensocetcos
involv ing RARA . These variant fusion partners inc lud e ZB TB 16 (previously known
as pr omv eiocvtrc leukaemia zinc finger
gene or PLZF) at l 1q23; the nuclear matrix assoc iated g ene (NUMA 1) at l 1q 13;
the nuc leophosmin gene (NPM1)at5q35
and STATSB at 17q l 1.2 124881.
Some c ases with vari ant transiocanons
we re initially reported as having APL
morphology 119141. However. the t(l l ;l7)
(q23;Q12); ZBTB16-RARA subgroup shc1ws
some morphological d ifferenc es with a
predominance of cells with reg ular nuclei,
many granules . usual absence ot Auer
rod s. an increased number of Pelg eroid
neutroph ils and strong MPO activity {19141 .
The initial cases of APL associated With
t(5 ;17)(q35 ;q1 2) had a p redom inant population of hypergran ular promyeiocvtes
and a minor population of hypogranular
promyelocytes; Auer rods were not oennteo
by ligh t m ic rosc op y 147 6 1. Some acute
promyelocytic leukaemia variants. incl ud ing t( 11; 17)(q 23;q1 2) w ith ZBTB16-RARA
and cases wit h S TAT5B RA RA fusion s are
res istant to ATAA 114521, A PL with the
t(5 :17)(q35;q 12 ) appears to resp on d to
ATRA {1452].
Cases with these va riant transroc atlons
should be d iagn osed as AML w ith a
va riant RARA transloc ation.
Acute myeloid leukaemIa with

t(9;II)(p22;q23); MLLT3MLL
Definition
Ac ute myeloid leuk aemia with t(9; 11)
(p22;q23): MLLT3-MLL is usually associated w ith monocytic featu res .
ICD-O code
present in 9-12% of paed iatric and 2%rJ

adult AML 1306 . 721 1.
Cunicalteatures
Patients may pr esent with d isseminaled
intravascular coagulation. They mayhave
extramedullary myeloid (monocytic) serco
mas and/or tissue infiltration (gingiva, skn~
Morphology and cylochem;Sby
There is a strong association between
acute monocytic and myelomooocytlc
leukaemias and t(9; 11)(p22;q23). altho.ql
occasionally the t(9 ;11) is detected i'l At.(
with Of without maturation. MonobIaSlS
and promonocytes typically predominale
Monoblasts are large cells . with abt.r1ci<rf
cytoplasm which can be moderately to.,.
tensely basophilic and may shcwt
pod lormabon. Scattered fine azurophilo:
granules and vacuoles may be preset
The rrooobasts usually have round BJCIl'i
With del icate lacy chromatin, and one f1
more large prominen t nucleoli. Prorcoo
cvtes have a more irregular and delicat~
convoluted nuclear configuration; the evtr
plasm is usually less basop hilic ana
sometimes more obviously granulated,
with occasional large azurophilic grarUe!
and vacuoles. Monoblasts and proro-o
cvtes usually show strong positive f'lCJl'
specific esterase reactions. The rrcocoass
ofte n lack MPO reactivity.
osecco
Immu nophenotype
Cases 01 AML with the t(9: 11)(p22;q23) ir1
c hild ren are associated with strong
exp ression 0 1 CD33, CD65 , CD4 and
HLA-DA, while exp ression at CD 13, CD34
and CD 14 is usually low /491 1.
Most AML c ases w ith 11q23 abnormalities
express the NG2 homologue (encoded by
CSPG4j, a c hond roitin sulfate molecule
reacting with the Mab 7.1124561. MostacU:
AM l case s w ith 11q 23 ab normalities
exp ress some marke rs 01 monocac
differentiation including CD14, CD4, COlle
CO l lc. CD64. CD36 and lysozyme, v.tIire
variable expression of imma ture markers
suc h as CD34 and CD1 17 and of CD56
has been reported {154 11.
9897/3
Genetics
Synonym
Ac ute myeloid leukaem ia . 11q23 abnorma lities.
Ep;demk>logy
The t(9;11)(p22;q23) may occur at any
age. but is morecomnor I in child ren. being
Acute myeloid leukaemia and related precursor neoplasms
Molec ular studies have iden tified a t1t.rna'I

homologue of the Drosophila trithorax
gene design ated MLL (HRX), that results
in a fusion gene in translocations invo/Vllg
11q231 1141. The MLL p rotein is a histl)1!!
mettwnransterase that assembles in pro.
tein complexes tha t reg ulate g ene Iran.
scription via ctuomato remodel ing. The

~9:11)(p22:Q23) involving MLLT3 (AF9 ) is
toe most common MLL translocation in
AML and appears to represent a distinct
enhty. Secondary cytogenetic abnormalities
are common with t(9:11) (p22:Q23). with
+8 most commonly observed, but do not
appear to influence survival [306, 15311.
Postulated normal cou nterpart
aaenaiopoeuc stem cell with multiJineage
ootennar.
Acute myeloid leukaemia with the
. 9:11XP22;Q23) has an intermediate sur.....aI and one that is supefior to AML with
e:tner l1Q23 translocations 11531. 18911.
Cases with the t(9: 11) and <20% blasts
II'IJSt be monitored closely fOf development of more definite evidence of AML.
'fi1riant MLL translocations
in acute leukaemia
C>ief 80 different translocalions involving
MLL are now described in adult and
paediatric acute leukaemia, with over 50
eensiccato n partner genes now cnaraclenzed 11 470. 20081. rrensiccetcoe involving MLLT2(AF4). resuitmq predominantly
n acute lymphoblastic leukaemia (ALL).
end MLLT3(AF9). resuhing predominan tly
n AML, are the most common. Other MLL
eensccauons that commonly result in AML
rcuoe the MLLT1(ENL). MLLTIO (AF1O),
MLLT4 (AF6) and ELL as partner genes,
Other than the ML L-ELL fusion resulting
Irom the t(1 1:19)(q23:p13,1), which is
res often associated with only AML,
these fusions occ ur pr edom inantly in
AML, but may be seen in ALL as well. Up
10 one third of MLL transiocauons in AML
ee not detectable on co nventional karyotype analysis , and FISH or other
molecular stud ies may be necessary to
dentify these variant translocations 120081.
AML with these fusions usually have
myelomonocytic or monoblastic rro rpnobgic and immunophenotypic features
While in the p ast all of these translocali:lns were encompassed by the category
rj AML with 11q23 abnormalities. the diagnosis should now specify the specific
abnormality and should be limited to
cases with 11q23 balanced translocations
fI'o'OIving MLL. For example. a case of
AMl with an MLL-ENL fusion would be
dl8gnosed as acute myeloid leukaemia
dh ~11 ,19)(q23;p13.3): MLL-ENL.
40Jte myeloid leukaemia with cytogenetic
B
Fig. 6.09 AML (monoblaslic) WIth t(9;1'Xp22;q23). Bone marrow smears A 5evefall'l'lOl'lllblasts. some WIth very
allur'l<Ia1l cytoplasm and h myelopeloxidase,..1iYe azurophilic granules are present B Non-speciflc esterllse
reacbon showing I1lensely poslIiYe IrOlOblasts,
'"
..
Fig. 6.'0 Mt. (1TIOI'I:ltyIic) \Mlh 1(9;11)(p22;q23}. Bone tJWI(M ~ A ThenlarelilMlt8llfOIObIasts and ~
with very pale cytor*lsm containing numerous fine anrophiic ~_ The promonocyles have delicate rudear lolds.
B Noo-speci1ic esterase S\aII"I_ The pn::monocytes are intensely reactive.
abnormalities associated with prior therapy or myelodysplasia. such as t(2; 11)

(p2 1;q23) or t( 11:16)(Q23:p 13.3), should
be diagnosed as therapy- related AML or
AMl with myelodysplasia- related changes
(See Cha pter on therapy-related myeloid
neoplasms),
Clinical features
Acute myeloid leukaemia with t(6:9)
(p23 ;Q34) usually presents with anaemia
and thrombocytopenia, and often with
pancytopenia, In adults, the presen ting
white blood cell count is gener ally lower
than other AML types with a median white
blood cell count of 12x1()9/L 120351,

t(6;9)(p23;q34); DEK-NUP214
Morphology and cytoche mistry

The BM blasts of AML with t(6:9XP23:q34)
may have morphologic and cytochemical
features of any FAB subtype of AML other
than acu te promyelocytic leukaemia and
ac ute megakaryoblas tic leukaemia. with
AML with maturation and acute mveromonocytic leukaemia the most common
128, 1676,20351_ Auer rods are present in
approximate ly one third of cases, Blasts
are myeloperoxidase positive and may be
positive or nega tive for non-specific esterase . Therefore , there are no features
specific to the blast cell population in this
entity Marrow and PB basophilia. defined
as >2% , is generally uncommon in AML
but is seen in 44-62% of cases of AML with
t(6;9)(p23:q34). In addition. most cases
""'" evidence oIgarL<ocybc and _
dysplasia. with megakaryocytic dysplasia
possibly less common. Ring siderooiaere
Definition
Acu te myeloid leukaemia with the 1(6 :9)
(p23:q34); DEK-NUP214 is an AML with
or without monocytic features that is often
associated with basophilia and multilineage dysplasia {17 14, 20351 .
ICD-Ocode
fourth edition of IGO-D is 986513.
Epidemiology
The t(6:9Xp23;q34) is detected in 0.7-1 .8%
of AML, and occurs in both children and
adul ts with a median age 01 13 years in
childhood and 35 years in adults 1306.
2035,20361.
Acute myeloid leukaemia wIth recurrent genetic eoocereetes
115

a re presen t in a subset of cases, The per-
centage of 8M blasts is variable. and

some cases may present wi th less than
20% bl asts.
Immunophenotype
The blasts have a non-specific myeloid
immunophenolype with consistent expression of myeloperoxidase. CD13,CD33.
C038 and HLA-DA 128, 1676,20351 . Most
cases also express CDl17. CD34 and

C0 15 while a subset 01 cases express the
monocyte-associated marker CD64 and
approximately hall are terminal oeoxvoodeotidy1 transferase (TefT) positive . Other
Iymp/loid antigen expression is Ul'lCOlTITlOl1 .
Gene tics
The 1(6:9)(p23:q34) results in a fusion 01
DEK on chromosome 6 with NUP214 (CAN)
on chromosome 9. The resulting nocieoporin fusion protein ac ts as an aberrant
transcription factor as well as altering nuclear transport by binding to soluble transport factors 119491. The 1(6:9) is the sole
clonal karyotypic abnormality in the vast

majori ty of cases, but some patients will
have the t(6:9)(p23:q34) in association with
a complex karyotype 120351. FLT3-lTO
mutations are very common in AMl with
t(6;9)(p23;q34) occurring in 69% of paediatric cases and 78% of adult cases
11676. 20351. Fl.T3-TKO mutations appear
to be uncommon in this entity.
Postulated normal count erpart

Haematopoietic stem cell with mullilineage
potential.
Prognos is and predictive factors
Acute myeloid leukaemia with t(6:9)
(p23;q34) in both ad ults and children has
a generally poor prognosis. similar to other
AMl with unfavourable cytogenetic abnorm alities . Elevated white blood cell
counts are most predictive of shorter
overall survival and increased 8M blasts
are assoc iated with shorter disease-free
survival. Based on limited data. allogeneic
stem cell transp lantation may be associated with better overall survival compared
to patients with no stem cen vansptantatoo 12035ICases with t(6;9XP23:Q34) and
<20% blasts must be monitored closely
for development of more definite evidence
of AML.

with inv(3)(q21q26.2) or
/(3;3)(q2/;q26.2); RPN/EVIt
Definition
Acute myeloid leukaemia with inv(3)
(021026.2) '" 1(3;3Xo21;q26.2); (RPrvI-EVII)
is an AML that may present de novo or
arise from a prior MOS. It is often associated with normal or elevate d PB platelet
coun ts and has increased atyp ical BM
meoakarvcc vtes with mono- or bi-lobated
nuclei and assoc iated multil ineage dysplasia (225, 1983,2 131).
ICO-O code
The provisional code propo sed for the
fourth edition of ICD-O is 986913.
Epidemiology
Acute myeloid leukaemia with inv(3)
(q21q26.2) or t(3:3)(q21;q26.2) represents
1- 2% of all AML 1306 . 20361. It occurs
most commonly in adults with no sex
predilect ion.
Fig.S." AML. with t(6:9)(p23:Q3-t). The blasts are

adn...ed with dyspIastlc erythroid precursors and
Clinical features
Patients most co mmonly present with
anaemia and a normal preteret count .
although marked thrombocythaemia
occurs in 7-22% of patients 1845.19831.
Patients may present de novo or have a
prior MOS. A subset of patients present
with hepalosptencmegaty. but "",,",,deropathy is UllCOI' llllOlI11983. 2C04, 21891.
scallered ~ (centre. '9ll).
116
Acute myelOid leukaemia and related orecursoe neoplasms

Periphe ral bloo d chan ges may include
hypog ranular neutrophils with a pseudoPetcer-Hcet anomaly, with or without
assoc iated peripheral blasts. Red eel
abnormalities are usually mild withOOt
teardrop cells. Giant and hypogranulat
platelets are common and bare megakaryocyte nuclei may be present 12251. The
8M blasts of AML with inv(3)(q2 1q26.2l cr
t(3 :3) (q2 1:q26.2) may have morphologic
and cytochemical features of any FAa
SUbtype of AML other than acute promyeIlr
cytic leukaemia with acute myebd
Ieukaertia without maturation. acute myeIomonocytic leukaemia and acute mega.
karyobIastic leukaemia morphologies rn:lSl
cornrnon 1715. 19831. A subset of cases
has less than 20% blast cens at the tiTle
of diagnosis. including cases with fsallles
of chronic myelornonocytic leukaemia
Multihneage dysplasia of non-blast eel
BM elements is a frequent finding WII/1
atypical megakaryocytes most cQlTllTlCll
1715. 1054. 19831. Megakaryocytes may
be normal or increased in number WI
many small
IJm) monoIobed a
bilobed forms. but other dysplastic mega.
karsocvtc forms may also occur. Dysplasia
of maturing erythroid cells and neutroptws
is also corrrnon . Marrow eosooonss. teso
phils and/or mast cells may be increased
The BM biopsy shows increased sma
hyr:x>lobated megakaryocytes. Bone marnJo\!
cellularity is variable with some cases presenting as hypoc ellular AML Marrow
fibrosis is variable.
30
Immunophenotype
Immunophenotypic studies of AML with
inv(3)(q21q26.2) or t(3:3}(q21:q26.2) are
limited. The blast cells generally express
C0 13. C033. HLA-OR. CD34 and C03S
Blast cells of some cases also abe rranf
express C07 and a subset may express
meg akaryocytic markers such as CQ4t
and C06 1. Abe rrant expr ession of lym.
photo markers other than C07 appears
uncommon [20041.
Genetics
A variety of abnoemauties of the long arm
of chromosome 3 occur in myeloid rnalo(t
nances. with inv(3)(q21q26.2) and t(3:31
(q21 ;q26.2) being the most common. The
abnormalities involve the oncogene EVIl
at 3q26.2 . or its longer form MOS1-EV!
and RPN7 at 3Q21 APN1 may act as <WI
enhancer of EVIl expression resulting
increased cell proliferation , and impaireo
cell differentia.lion: it induces naen etoooreticcell transformati on ( 1236, 1609, 21251 .

Other cytog enetic aberrations involving
3q26.2, such as t(3:2 1)(q26.2:q 22) res~tting in an EVI1-RUNX 1 fusion and usually seen in therapy-related disease, are
not included in this disease ca tegory.
Secondary karyoty pic a bnormalities are
common with inv(3)(q21 q26.2) and t(3;3)
(Q21;q26.2) with monosomy 7 most common, occu rring in approximately half of
cases, followed by 5q deletions and com"'" ...",.",..1 1963/. These abroonalrties
may precede the development of the
3q262 abnormality 116091.
Patents with AMl with inv(3)(q21q26.2)
3:3Xq2 1;q26.2) show overexpression
d EV/1 and GATA2, bulthese fIndings do
ro appear to be specific for the genetic
aonormality 11236,16091 .
Patients with chronic myelogenous leu-.aemia may acquire inv(3)(q21q26.2) or
(3:3kq21;q26.2), and such a finding usually
portends accelera ted or blast pha se of
!heir disease , Cases with both t(9 :22)
(Q34;q11.2) and inv(3 )(q 21q 26.2) or t(3;3 )
(q21;q26.2) are best considered as ag g-essive phases 0 1 ch ronic myelogenous
leukaemia. rather than AMl with inv(3)
(q2tq26.2) or t(3;3)( q2 1;q26.2).
PosllJlated normal counterpart
tiaematopoietic stem cell with multilineage
POtential.
AML with inv{3)(q 2 1q26 .2) or t(3;3)
(q21:q26.2) is an aggressive di sease with
sort survival 171 5 , 1834, 1983 1. Two patients with AMl with inv(3)(q2 1q 26.2) were
reported to show a response to a rsen ic
trioxide with thalidomid e, w ith one act uevi'19 complete rem ission 11 824 j , Cas es
lI,ttl inv(3)(q2 1q2 6 ,2) or t(3:3)(q 21;q2 6 .2)
and <20% bla sts must be mo nitore d
ClOSely for development of more d efinite
evidence of AMl.

(megakaryoblast/c) with
~ 1;22)(p I 3;q I 3); RBMI5-MKL 1
ICD-O code
The p rovisional cod e prop o sed fo r the
fourth edition of ICD-D is 991 1/3,
Epidemiology
The t(1; 22)( p13:q 13) is an uncommon
abnormality in A Ml, repr esenting < 1% of
all c ases. It most commonty occurs in
infants without Down syn d rome, with a
female pred ominance .
Clinical features
Acute mye lo id leukaemia with t( 1;22 )
(p13;q13) is a de novo AMl restricted to
inf ants and young chi ldren (3 yea rs or
less) with most cases occurring in the first
6 months of life (median, 4 months). The
'last rnajonty of cases present with
marked organomegaly, especially hepatosplenomegaly. Patients alsohaveanaemia,
and usually have throm bocytope nia and
a moderat ely eleva ted white blood cell
count.
The PB and BM blasts 01AML with t( 1;22 )
(p13;q 13) are similar to those of acute
megakaryoblastic leukaemia of AM l, NOS.
Small and large megakaryo blasts may be
p resent and they may be admixed with
more mor ph olo gically und iffe rent iated
b last ce lls with a high nuclear-cytoplasmic
ratio resembling ivmorobrasts. The megakarvobtasts are usually of medium 10 large
size ( 12- 18 urn) with a round, sligh tly irrequrar Of indented nucleus with fine reticular ch romatin and one to three nucl eoli.
The cytopl asm is ba sophilic , often ag ranular, and may show d istinct ble b s o r
pseudopod formati on. Mic romeg akaryocvtes are common , but d yspl astic features of gra nu locytic and eryth roid c ells
are not usually p resent The 8 M biopsy is
usually normocellular to hyperce llular with
retic ulin and co llage nou s fib rosis usually
presen t. Cases may show a stromal pattern o f BM infiltration mimicking a metastatic tumour 120 5, 341 1. Cy toc hemical
stains for Sudan black B (SBB) and MPO
are cons istently negative in the megakaryob lasts. A subset of cases will have less
then 20% BM bla sts. but a low blast cell
count due to difficu lties aspira ting BM secon dary to fibrosis sho uld be excluded .
Fig. 6.12 AML WIth irlV(J)(Q21 q26.2). Bone marrowaspAte wrlhincreased blasts and atypica, rncnJIobaIed
marker CD42 (g lycoprotein Ib) is less frequently present. The myeloid~associated

markers CD 13 and CD33 may be positive.
CD34 , the pan-leukocyte marker C045,
and HLA-DA are often negative; CD36 is
Characteristically pos itive . Blasts are negative With MPO antibodies. lymphoid
markers and terminal deoxynucleotidyl
trans ferase (TdT) are not expressed, Cytop lasmic exp ression of CD4 1 or COBt is
more specific and sensitive than surface
staining ; the higher specificity is due to
possible adherence of p late lets to b last
cells in othe r types of AML, which may be
misin terpreted as positive staining by flow
cvtometrv
Genetics
Patients sho uld have karyotypic evidence
of t(1 ;22)(p1 3 ;q13) or molecul ar genetic
evidence of a RBMI5-MKL 1fusion, In most
cases, t( 1:22)(p 13;q 13) occurs as the sole
karyotyp ic ab normality, This trans locat ion
resu lts in a fusion of RNA-b inding motif
protem-rs (RBM1S) (also known as OTT)
and megakaryoc yte Ieukaemia- t (MKL 1)
(also known as MAL) (1352 ). RBMIS enco des RNA recognition motifs and aspen
par alog and ortholog C-terminal (SPOC)
domain , whi le MKL 1 encodes a DNAbin d ing motif involved in chromatin organization. The fusion gene may modul ate
chromatin orga nization . HD X-ind uced differenti ation and extrace llular sig naling
pathways 11461}.
Postu lated normal counterpart
Myeloid stem cell with predominant megakaryocytic d ifferentiation .
Defi1ition
,' cute myeloid leukaemia with t( 1;22)
(p13;q 13); RBM15-MKL 1 is an AMl genEJaJy showing maturation in the megakaryocyte lineage.
IrrmJnophenotype
The megakaryoblasts express one or more

of the platelet g lycoproteins: CD41 (glycoprotein lIb/l lla ), and/or COO1 (glycoprotein
ilia). The more matu re platelet-associated

Although early report s suggested a poor
prognosis for AM l with t( 1;22)(p13; q 13)
1205.34 11. more recent studies have found
the patients to respond well to intensive
Acute myelotd leukaemia WIth recurrent genetic abnormalities
117
AML chemothe rapy with long disease-free

survival 16201. Cases wi th the t(1;22)
(p13;Q 13) an d <20% blasts on aspirate
smears should be correlated withthe biopsy
to excjooe 8M fibrosis as a cause of a
falsely low b last cell count. 11 this is exc luded, these pat ients must be monitor ed
closely for d evelopment of more definite
evide nce of AML, such as the pres enc e
of extramec ouary di sea se or myeloid sarco ma,
AML with gene mutations

In add ition to translocations and inversions,
specific gene mutations also occur in AML.
They include frequent mu tations of fmsrelated tyros ine kinase 3 (FLT3), nucleophosmin (NPM 1) and . less corrmonly,
mutations of the CEBPA gene (encoding
the CCAAT/enhancer bi nding protein -c).
KIT, MLL. WT1 , NRAS and KRAS. Alone or
in com bination, mutations of FLT3, NPMI
and CEBPA have been reported in patients
with AML with a normal karyotype where
they have prognostic significance in the
co nte xt of most cu rrent therapies . althoug h they may be seen in pat ients with
ab normal karyotypes as well 115321,
FLT3, loc ated at 13Q1 2, encodes a tyrosine kinase rec ep tor that is involved in
haematopoietic stem cell differentiation
and proliferation. FLT3 is expressed on
these progenitor cells as w ell as on the
b last cells in most cases of AML. FLT3
mutations may occur with any AML type
(20-40% of all cases) and in MOS, but
a re mo st com mon in AML with 1(6 ;9)
(p23;q34 ), acute promy elocytic leukaemi a
and AML with a norm al karyotype 11184,
2035 1, The two primary typ es of FLT3 mutations a re intern al tandem duplications
(FLT3-ITO) within the lu xtamemb rane doma in (75 - 80%) and mutations affecting
codons 835 or 836 01 the second tyrosine
118
kinase domain (TKO) (20-35%). 'vVhile FLT3

mutations may occur in association with
recurrent cytogenetic abnormalities, such
as t(6;9XP23 ;Q34) and t( 15;17){Q22;Q12),
they may also occur with other so-called
cooperating mutations. FLT3-HOmul ations
are associated with an adve rse outcome,
b ut the sig nificance of the less common
FLT3- TKO mutations remains c ontroversial
1117, 1447,2396 1. Detection of FLT3-lTO
is important be cause th e prognosis of
most cytogeneti cally normal AML subtypes
correlates with the presence or ab sence
of this muta tio n KIT, loca ted at 4Q11-12,
is a mem be r of the type III tyrosine kinase
family and encodes a 145-kO transmembrane glycoprotein. Gain-of-function mutations of KIT occur in a variety of d iseases,
including g astrointestinal stromal tumours.
germ cel l tumours , mastocytosis and AML
Mutations of KI Thave been shown to have
prog nostic signifICance among AML with
t(8;2 1)(Q22 ;Q22) and inv( 16Xp13.1 Q22)1
t(16;16)( p 13.1;Q22), in which mey are associ ated with a poo r prognosis 11696 1.
These KITmutations most common ly occur
within exoo 8 and 17. To date, WT1 rrotat cos
have been shown to co nfer a poor prog nosis in AML patients with a rormat karyotype 11 696A I, but there is less compelling
evi de nce of p rognostic significance for
the less freq uent mutations of MLL, NRAS
and KRAS . Molecular studies have shown
tMtthe MLL gene is rea rrang ed more freQuently than is revea led by conventional
cytogenetic studies. A partial tand em dup lic ation of MLL has been reported in
5- 10% of ad ults Wi th a norma l kary otype
[313,6031 and in patients with isolated trisom y 11[3141. Its adv erse prog nostic significance in patients with a normal karyotype
is reported to be e liminated in pati ent s
rec eiv ing an auto logous stem ce ll tran sp lant in first rem ission 123951.
NPM1 mutations occur in about one third
01 adul t AML an d CEBPA mutations in
Acute myeloid leukaerTlla and related precursor neoplasms
6-15% of all AML. NPM 1 mu tations are

typically heterozygous and the leukaema
cells retain a wild-type allele [6671. They
usually oc cur at axon 12 01 the NPMr
gene 16661 but rarely involve exon 9 a t1
11 About 40 mutation variants ha...e
been described 16671. the most COf1Yl"O'l
being mutation A, a TCTG tenanucreotoa
dupl ica tio n at posi tions 956 to 959, which
accounts lor 70-80% of ad ult AML wltn
NPMI mut ation , Ind ep end ent of type,
NPM 1 mutat ions g enerate common ejeatrons at the C-terminus of NPM t
leukaemic mutants, i.e. re plac ement o!
tryp tophan (s) at position 288 and 290Mld
cre ation of a nuclear export signal (NESl
motif, which mediates aberrant localization of NPM to the cytoplasm 16671.
CEBPA (CCAAT/enhancer-bind ing pro.
teo-c) mutations occur only in AMl <W'C
are usually baneic mutations . The normal
ge ne encodes a transcription factor Illvolved in control 01 proli feration and dd
ferent iatio n of myeloi d p roge nitors. Whi'e
mutations may occ ur throughout the whole
gene sequen ce , tw o general c ategories
of mutat ion occur: out-of-frame insertions
and deletions in the Nterm inal regioo art
in-f rame insertio ns and de let ions in t'le
C-terminal reg ion. Mutations of NPM I ere
CEBPA are freq uently observed in At.l
with a normal karyotype an d , in the absence of FLT3-lTO, are associated wma
favourable prognosis 1216, 602 , 19711
2198 ,23311. In view of the freque ncy :;
Ihese mutations. the ir prognostic sigMcance. and their association with certan
morpho logic and clinical features , it has
bee n sug gested that they may ident~'
uniqu e subse ts of AML. Therefore, tIW
new provision al entities, AML with mutated
NPM 1 and AML with mutated CEBPA are
proposed. These have been giv en provisio nal status bec ause they have beer
on ly rec ently described and more sfudt
is requi red to confirm these categories as
"
E
re
p
Tillie &.01
Moleculaf geneticalteratioos allectlrtg dir1ical outcome of AML patients in specific qtogeoeUc groups.
Geoetics
Cytogenatiu
KiT mutabon$
t(8:21)(q22;q22)
Prognosticslgnillcance
Signlfocann~'~"""'
~~-:"'''',,~uenls
wiId-~
OFS andRFS
Wlth KITmutatons (especially ecse ill 8loo17) lXIIf4)8red 'Mtt1
KlTpalients
{233A., 2Q09A,
CIRandRI Slgoificantly higher fof peteots wilh KITmutaloons compared Wlth patients with wild.fype KIT{310A, 1696}
EfS signlf!canny shorter forpabents with KITmutatons (especialy eese n e.oo 17) ~red IIIilh pall8/1ts with w~ KIT(233A.
1969Aj
OS si!1liflCalltly shortef I'tlr patents WIth KITmuta!lorls (espec:iaIyIhOs8 ill elOfl 17)compared wrltJ pabents wr01 wiId-4ype KlT{233A..
31QA. 1969A. 2009A}
No Slgf1fflcanl dllJerence 111 0$ bereeen patients IIIilh -"' wilhOul KITmutatl(lllS {1696}
<IT_
FiJ><TD
ilw(16)(p131q22)1 RR'IIIOfSe lor patients wrltJ KlTmutatioos 111 el M 8 COIf4lilred WIlt1 patients \\'III'l wid-type KrTf33Ml
t(16.16)(p13,1;q22) CIR hIglMlI' and OS '/II'OIWfor pabents WIth KIT rrotations 11 elOfll1 c:unpared wr01 PI1ients with wid-typeKIT{1696}
No Sigr*ant dillereooe in EfS , RI, RFS and OS between pabentS withand 'Mlhoul KJTrnuIatols (2~ 31 0A)
Normar
......... .
CRa and DFS ~ shor1erfor pabenl$ WIth Fl.T3-lTD comparedwith palienls 'IIIClOlIl A.TJ.lTD {193A., 216. 736A 2394A)
EfS SiglWanty sI'o18r lor patents WIth fLT3-fTO comperedwotll palienl$ 'IlIltI'loIA A.TJ.lTD (2338)
OS~, sIlcrterlor patlents wotll A.T3-ITO c:unpared withpalients wrlholA FLTJ.lTD {193A. 216. 736Ai
No SIgI'ificart dIIetence in OS b8t'ween palietn WI!! a'ld witlCUfLT3-lTD(2338, ~
OfS .-.:I OS sqv6c:llIy shorter b patients Wlth FlT3-lTO and no 8~ rJno-l)1:Ie FlTJaIele ~ 'MiD'! ~ W!IhOut
FlTJ.lTD (m4A)
RJJ.m)MII t'1)
t,peRTJaWe
""00
w.-P1D
e_
::lflAli mutabCW'lS
.."".
OFS sagnficantty shorter for patienls wit! FLT3-TKD ll'I'IPB!t:Id Mlh petlenls WIth wild-type FlTJ*'es (23961
"""'"
"""'"
CRD (but not OS) SignlfIcal1Uy srorter for patletlts WIlt1 AILL-PTD compnd with peli8nlsWIVlout ULL-PTD (313. 603)
Noli&renoe in OFS cnl
between patlenIswiIhand ntW AoIl-PTD recero'rlg I'IS8nSre treamenllIW*1g a**lgous SCT {2395l
N,,,,,,,
kaizalion 01
NPM
os
CRD and OS ~ longer or patients WIll1 CEBPA mulabalsa:mpared wrlh patients with~ CEBFl4. genes {216, 731}
NoSigMIcant diIIereoce in OSbetweeI'l patienls 'lWilh and withOut CEBFl4. mulalions f233B}
EFSsignlflcanUy shorter forpatJeflts with CEBPA rnutaliolls compared Willi patients 'IIIIh wid-type CEBPA genes f2338}
CRrate of pabellts WIth cytopIaSlTic Iocaizaboll of NPM not 19'1ifical'lUy I)/Ieren! from CRrateof pabenls WJ\ll nudearIocaJiZatiOn of
NPM in l,I'Iivariable analysis. Cyloplasri; IocaIzabon 01 NPM wasan intIepen(lenllaYOUr3ble prognosbc Iador for CR achievement in
mulbvBl1a!e Iogislic-regres&Oll model inckIding WBC. age, NPM localizatIOn and FLTJ mutations {666}
N'''''''
CRrate Sigoificantly betterlor patents wrtI1 NPM1 mulatiOns lhal'llor palienls W1lh wi:l-type NPMl geoes {1970}
~ Sigl'lilical'll dillerel1C8 il'lCRrates between patiarllswith arid witt10ut NPMI mutations {139A. 233B}
DFSaodRFS sigl1lfical'l~y lorIQeffor peeems willi NPM1 mlllabor1$ compared wtlhpatients W1lh wild.fype NPMl genes {602, 219l1}
~ sigMicaol diflerel1C8 fnRFS between pabenls withandWithout NPM1 mutatiorls {139A. 2338. 1970}
EFSsigniflCilnlty ooget' 101' patients with NPM1 mlltatforls compared withpatients with wild-twa NPMl genes {1970}
~ Significam dillerel'lC8 in EFSbetween patents withandwitr.out NPMl mutatiOflS {139A, 233B}
Nosignificant dillerence in OSteween patients withandwithout NPM l rl'llItations {139A, 233B. 602, 1970, 2198}
Normal
CRrales, EfS, RFS, DfS andOSsignificantly better lot patients with NPMf mutations wholackFLT3-ITD compared withpatients wittl
NPMl mu tations andFLTJ-iTD or thosewith wildtype NPMI gelleS withor without FLTJ-ITD NPMl mutations do notseem to significantly alleet poorprognosis of patients with FLTJ-ITO {B02, 1970, 2198)
Nosignificant dillereoces in EFSand 05 between patents with NPMl mutations andnoFLTJ-ITD compared with patients with NPMf
mutations andFLTJ-ITD arid those with wild-type NPMl genes with or without FLTJ-ITD {139A/
IfTlmulations
Normal
Failureto achieve a CRwith standard induction chemotherapy lor patients With WTl mutations andFLTJ-ITD {2120Ai,
OFS andOSsignificantly shorter forpati$nts with WTl mutallons compared With pabents Wltt'l wiIdtype WTI alleles {1696A}
BAAle
i'bmaI
CRrateandrate01 primary resistant disease significantly WOfSelor patients withhigh e~pression oflhe BAALC gene in blood
compared willi patients withlow eJqlreSSiOn of the BAALC gene{1358}
No significant diflereooe in CRratesbe\Weel'I patieols withhigh aodpaLenls With lowe.pressiOn 01 the BAALCgeoe {l 35A, 216}
DFS, EFS. RR and OSsignificat1Uy WOfSeaooCIR significantly htgher for patients With high elpression of lhe BAALCgeoe 11 blood
compared 'Mth pabents withIoYt eqJre'SSlon oIth8 BAALCgeoe {1J5A.. 1356, 216}
Normal
CRrates, EFS, CIA, andOS SIgnificantly worse lor PlltJents widllligtl e~ioo oIlhe ERG gene in blood compared withpalieols wrlt1
lowe~oflt18 ERG gene{1J9OA, 139OB}
Normal
OS and RFS significantly shorter and RR higher for pallenl$ WIth high e~ of the MN f genecompared WIth pabents withIoYt
elp(8SSion altha ",NI gene (9J7A)
'ftIl mutations
""e...,
lblIiIcI by[) Mn\z8k from MrOzek and Bloomtiekl {1531A).-.d MrOzek et Ill, {1532} WIth pemlI$SiDn.
EFS ...... SUl\'lYII: RFS, ralapse-frM Sl.fVival: OS, ova-aI surYi'IaI; CIA, eurnulative inl:icIence of relapse, RI. relapse inQdence: OFS, d1seas&4ree SUI'YMl; RR.fisk of
. . .. FL1J.ITO .,.,. tandem duplalllOll of the FLngene, FLT.HKD,1IkJtlOOns 11 the tyrOSII18 kinase domiIIo offhll FLDgene, CRO. compIeIe remission dIntioo ; AIU.n ,pnal llwldemduplicabon of118 AIU gene: SCT. stem cellrWlsplanta1ior CR. ~ I'eITissIon; ". NMnal kar)'otype,
Acute myeloid leukaemia with reclKrent genetIC abnQIrnaliltes
11 9
disease. entities rather than prognostic

teeters . A small number of AML will show
both NPMl and CEBPA mu tations. which
would no t fit well into the proposed classification structure. In addition, the prognostic signi ficance 01 the chromosome
aberrations reported to occur in 5-15% of
AML with NPM 1 or CEBPA mutations is
not yet clear. There fore. the presence of

any of the recu rrent nanstoc ations or inversions should be identified in any AML
d iagnosis . In ad d ition , because of the adverse prognos tic impact of FLT3mutations
in AML with NPMI mutations. mutation
analysis 01 FLT3 should always be performed with NPM1 and CEBPA
These mutations are not de tectable by

cytogene tic an alysis and are usually
detected by PeR. Detec tion of cytoplasrri:
NPM by immunohistochemistry coretaes
well wi th the molecular m ethod [6641. btl
similar immunohistochemical surrogate
tests are not currently available lor aI
known mutations.

with mutated NPM,
Definition
Acute myeloid leukaemia with rnnaied
NPM 7 carries mutations that usually f'\o
valve exon 12 of the NPMf gene AbetraW
cytoplasmic expression of nucleophosrTrl
(NPM) is a surrogate marker of this gefIe
mutation 16661. This AML type IreqJef1l,
has myeIomonocytic or rrooocstc feall.Jes
and typically presents de novo in ~
adults with a normal karyotype.
The WHO Working Group ass igned !his
lesion 10 a group of provisional ennnee
ICDGeode
9861/3
Synonym
Fig. 6.101 Acute myeloid leukaemia with NPAlt mutations and myelomonocytic features. A Bone marrow biopsy
showing complete teplacemel'l1 by large blaSCs With abuooanl cytoplasm and IoIded nuclei. B l elillaemic cells are
CD34-negalive. C l eukaeJTllC eels show aberrant cyloplasrric expression of rkJdeopilosrr'Wfl (NPM). D EXpt"ession of
C231nodeolin is restricted to Itle nucleus.
CEB~ +5 _ ~
CEBPA+lo\C.L-PTD+ 1.2%
FLJ'3.TKD+/KL PTD+ 0 .8%

FlJ'3.TKD+ 2."%
R.T3-lTD+/CEBPA+1.6%
Fl T3-lTO+IMLlP"TO+ 2."%
FlT3-lTO+ 8 .1%
NPM'+lFLJ'3.TKD+/ } O "
CEBPA +/KL-PTD+
"
NPM'+tf:;Un;::;: }o.,,%
NPMl+IFLT.J-TKD+/ } , _
CEBAI'+
-" ,.
NPAI, +,Fl n.rTO+l } , ' "

CEllA"
NPtrI1+,f=LT.J-m)+/ } , ' "
FLJ'3.TKD+
NPM1+.<:ESPJIl,+ 3. ~
Fig. 6.15 Pie dlaf\ based on 2"6 pabent$ analyZed tor Itle Ilf99l!I'lC8 01 mutations in Itle NPUI and CEBPA genes.
FLT3-ITD. FLT3-TKD and AIU.-PTD. E.actI seclof nIc3les the peI'C8flIllge 01 pabenIs harbotmg one Of ITOOl 0I1he
ab'emenliOlllld muIabons. WT rocates pabef\tS WlIh only ~ alleles01 genes tes1ed. FromIkozek (If 11I.(1532)
lnlltdapled!ram 00IVlllf (If Ill. (602}.
120
Acute myelOid leukaemia and related precursor neoplasms
Acute myeloid leukaemia wilh cytooasrc

nucreopnosrsn (NPMc+ AML) .
Epidemiology
NPM1 mutation is one of the most COOlTOl

recur ring genetic lesions in AML [283,
602.666.667.2198.2331 1. Prevalence
increases wit h age, occurring in 2-8%ci
c hil dhood AM L an d 27% -35% of adLJII
AML. NPMI mutat ions occur in 45- 64%ci
adult AML w ith a nor mal kar yotype 1283
351, 439, 666.2 198, 2331). This disease
appears 10 show a fem ale pr ed ominance
Clinical featu res

Acute myeloid leukaemia with NPMl
mutation usually pre sents without a history of a MDS or MPN {6661. Patients otten
exhibit anaemia and thrombocytopenia.
b ut onen have high er whi te blood cell and
platelet coun ts tha n other AML types
16021. Patients may show extramedullary
involvement. the most frequently affected
sites be ing gingiva, lymph nodes and Skm.
There is a strong association betweee
acute myelomonocytic and acute rrceocytic leukaemia and NPMI mutation {666
6671: notably. 80-90% of acute rTIOf()o
cvtc leokaerntas show NPMl mctetce,
,,
However, N.PM1 mutations are also detected in AML with and without ma turation
and in acute erythroid leukaemia. A subset
01 cases shows multilineage dysplasia.
These cases usually have a norm al
~aryotype and the blast cells are CD34
negative. The 8 M biopsy is usually
markedly nvcerceuutar. Bone ma rrow
blast percentages are generally higher in
AML with muta ted NPM1 than in other
acute myeloid reukaermes with a normal
karjOlype
16021.
The diagnosis relies on the identific ation

~ the genet ic lesion by molecular tech!1IQUE!S and/or imm unohistoc he mic al
detection in paraffin sectoos of aberrant

cytoplasmic expression of NPM 16671.
mronostaining with antiNPM antibodies
reveals involvement of two or IT'K)(e 8M
lineages (myeloid . monocytic . erythroid.
megakaryoc ytic ) in the vast majority of
ML Wlltl NPMl mutation 116981. The vanab~ lty of 8M cell types showing NPM 1
rrutations accounts for the wide rrorprological spec trum of this leukaemia.
Immunopheno type
In addition to myel oid an tigen s (CD13,
Fig. 6.16 W*eage IMIlvement in AAlt. WItl'l NPM1 mutabons. A Bone m<mlW biopsy. Massive replac:eITetlt by
myeloid blasts wittl maturalJon; !here are also megakaryocyles and occasional irTIrn<I~ erylhnlid eels (iIfl'OIW).
8 The same case as (A). Myeloid blasts (double arrtIlltS). rnegakarrocyles and mnaIu'e er)1tWOiCI eels (iIfl'OIW) sI'lOW
abemml cytr;lpIasri: po$l ~vity lor NPt.I (blue ). Immature erythroid eels (arrow) Ill! doubIe--slained lor gIytophonn
(brown) andNPM(bkJe~ C Bone marrow biopsy. UinmaIydilIenlnbaled llaIte myeIold leukaemia wrlh NPM1 rllIlaborls,
occasional immature g~ erythroid cells are present 0 The same caseas (C). Myeloid bIasls and
imrnatIR erythroid eels (amlW) showcytoplasmic eKl)feSSion of NPM.
CD33. MPO), the blasts in AML with
NPM I mutalion frequently express markers

01 monocytic differen tiation , incl uding
C0 14, CD 11b and the macrophagerestricted CD68. The roost striking inYnunophenotypic featu re 01 AML wi th NPM 1
mutation, which is independent of the
degree of maturation of leukaemic cetls,
is the lack of expression of CD3 4 (666).
By immunohistoch emistry on p araffin
sections, antibod ies aga inst NPM show
f e characteristic abe rrant exp ression of
the protein in the c yto plas m of leuk aem ic
cells(6661. In co ntrast, positivity for C23/
nucleolin (another major nucleolar protein)
isrestricted to the nucleus of leukaemic
cells. Immunohistoc hemical detection of
caoorasrnic NPM is predictive of NPM I
euatoos 16641. since the mutations c ause
critical changes in the structu re of NPM
native protein (c haracteristically located
'" the nucleolus), leading to its inc rease d
export tram the nucleus and aberrant
accumulation in the cytoplasm.
-c
, 2
NPM1 gMfe ~
..!
11
89
.)]"12
.. -iF .. -..::::::JI
NPOI '
'u...,r"
.. . \ . _' '''.
. .cc ~ ' .' . u ~. r '. . . c '
N "
N "
"
NU H
N. . .,
c ' . t t
,
eu
.aoc U
'. eOT
............. . ....... c .C<. e ~
.............,
04
' c
co
'
u.u ,
E _ 8ognol (NEll)
.......
_ . . - - . s . - lNt-'i
protein
M ur.redNPM
.
04 .
..-----.-=- -....,
WI~ryp. NPM
tc'.'
" ." 04" .' .'
c '
_
' . .
co CTe'TT""ee ' . '
=_
04
'c
...,,
leul<aemle protein
COOH
, II I
. T. _
Genelies
Acute myeloid leukaemia with NPMl
ITkrtation is usually associated with a normal karyotype . however. 5- 15% of AML
W!ttl NPMt mutation show chromosomal
aberrations 1666, 667J, inc lud ing +8 and
de/(9q) 121961. NPMt m..rtabons are usually
Fig. 6.17 AclJte myebd leukaerria with NPM1 "'-IlaIions. Mutations usualy 0lXIS at exon 12 of tlle NPAlI gene. The
irs! i:lenlified NPU1rIlIlabons (A" F)Ill! shown (666}. MiDtIon A1$fie most hqI.Jenl acaulbng lcr 70-80'10 01 cases.
AI rn.Jtabllns feSUIt in a:mnon changes at fie e.tllmwu (COOH) 01 fie WlJd.type NPM protein. These dlanges (asl!lnst
in the NPM nwtated proIeIn) c:onsisl of replacement of ~s) aI posibon 288 and 290 and aeation d I ~
export sqJaI (NES) motil. whiCtllre boIh responsible lor the inc:reased nuclear eJPl and abemIrlt t')'lcIpliIsrrC
aca.oTUabon of !he NPM 1TlJIlwits.
Acute myelOId leukaemia With recurrent genetic abnormalities
121
~-
POCO 000 1
l-
.._..
1-
NPMt-IFl r:J.fI'D-I
I:
~_.
.-.
_
T_

P-O.71
l-
Donor
CESPA-
No-Donor
, r_ _

with mutated CEBPA
NPM r-tFl rJ.,lTO"'"
.-.
C NPM""'/FL T34TD-o
.\-
P<o.OO(U
l_
CE8I'A -
favou rab le prog nosis to AML with a chromosomal aberration or with multilineage
d ysp lasia.
,
T_
_,
0 _
",
P-O.OO3
!: -
ICD-Ocode
-i-j-
CEBPA rrc tanons occur in 6-15% 01 de
Postula ted normal counterpart
Haenatopoenc stern cell 113941
122
9861 /3
Epidemiology
Donor
No-Oonor
,
T_ _
Fig. 6.18 Prcq10sis ofAML paltents. A,B ThegenotypesNPM' -JFL1J-lTlY'" and CEBA<I'" arelaYCUable progllOSOC
markers. C.DUnivariate donor IWSUSno-donof analysis onreepse-rree survival 01 AML with normal karyolype in fi~
compleIe remission. acttII'ding III g&IlOtype. The donor group ....as defifled by !he availability01 a HLA-maIched larrily
donor comprising a maId'! in toe loci HlA-A, HLAB and HLA-DR C Results in AML with li!VOUfab~ genotype
NPMf"'lFlTJ-lTO""; (0) !he results in AMl wilt! adverse gerotypes FLT3-/1D"" and NPI,/1"ICEBPA"JFLTJ.lTO"";
OnIyAML withactYerse gel'lOtypes (0) benefit from allogeneic stem celIlransptanlalion. From Sd1lenk RF 1:/1aI. {1962AJ
mutuallyexclusive of the recurrent genetic

abnormalities tha t define the AML entities
desc ribed in the p rec eding sec tion 16651
and with par tial tandem duplicat ions of
MLL and CEBPA muta tions, although concurrence of these abnormalities with
mutated NPMI have been reported 1602,
2198 1. Ab out 40% of AML with NPM1
mut ations a lso ca rry FLT3-ITD (6661.
NPMl mutations ap pear to precede FLT3ITO and these Ieukaermas are mo re
genet ically stetne during disease evolution
1439, 21981. AML wilhcytoplasmic mutated
NPM1 shows a di sti nct ge ne expression
p rofile characterized by up- reg ula tion of
HOX genes 119. 233 11 that di ffers from
th at of other AML typ es. inc lud ing AML
with MLL rearrangement 11539).
Definition
Acute myeloid leuk aemi a with rnctaiec
CEBPA usually meets criteria for AML
maturat ion or AML without maturation, bul
some cases may sho w myel ornonocyliC
or monobtastic features. This leekaema
usually presents de novo.
The WHO Working Group ass igned ~
lesion 10 a group of provisional entities

Acute mye loid leukaemia with mutated
NPM1 typ ically shows a good response to
induction the rapy 1666 ) Acute myelo id
leukaemia with mutated NPMI and a normal
karyotype, in the abse nce of a FLT3-ITD
mutation. has a characteristica lly favourable
p rognosis {283 , 60 2, 1970 , 2198 , 2331 1.
The coexistenc e of FLT3ITD mutations is
associated with a poorer prog nosis. b ut
Ihese patients still appear to have an improved prognosis c ompa red to AML that
is NPM1 negative and FLT3-ITD positive
17461. Younger ind ivid uals with AML and a
norma l karyotype exhi biting the genotype
NPM 1 mutated!FLT3-lTD negat ive show a
prog nosis that is comparable to that of
AML with t(8 ;21)(q22;q22) or inv(16)
(p 13.1q22) and may possibly be exemp ted
from allog ene ic stem cell transplantation
in first complete remission 16021. It is not
known whether a NPM1 mutated;flT3-lTD
nega tive genotype also confers a
Acute myelotd leukaemIa and related precursor neoplasms
novo AML and in 15-18% of AML W1:tl

norma l karyotypes 1216, 737, 12801. rtee
are no apparent age or sex d ifferences
between CEBPA mutated and l"IOI"HTUIale:!
AML [20401
Clinical features
Acute myelo id leukaemia with metered
CEBPA tends to have higher haemogkbn
levels . lower p latelet counts. lower lactae
dehydrogenase leve ls and higher PB
bl ast cell co unts when c ompared to
CEBPA non-mutated AML. This leukaemia
type also has a lower frequency of 1ymphadenopathy and myeloid sarcoma 1216,
7371.
Morphology and cyt ochemistry
There are no distinctive morpholog ic leatures ot AML with normal karyotype an~
CEBPA mutations. but the vast majority d
cases have features of either AML withoJ
Of with maturation Less commonl y. cases
have monocytic o r mveromonocvtc leatures. Three percent or more of the blasts
are myelope roxid ase or Sud an black B
positive, and most cases are non-specific
este rase neg ative.
Immu nophenotype
Leukaemic blasts usually express one (J
more of the myeloid-associated antigens.
CD13. CD33, CD65, C01 1b , and COIS
There is usually ex pression of HLA[)A
and CD34 on the majority of blasts
Monoc ytic markers such as C014 anc
C064 are usu ally absent. C07 is preset
in 50-73% of cases, while expression It
CD56 or otner lymphoid antigens is

uncommon 1216. 13081.
Postu lated normal co unterpa rt

Genetics
Seventy percent of A ML with CEBPA
mutation have a normal karyotype .
Fl.T3-lTD mutations occur in 22-33% of
Prognosis
Acu te myeloid leukaem ia with a normal
karyotype and CEBPA mutation is associated with a favourab le prognosis. similar
to that of A ML with inv(16)(p13.1q22)
cases.
or t(8:2 1)(q22;q22). The significance of

FLT3-lTO on the prognosis of this group (s
currently unclear. with small studies suggesting either no impact or a negative impact on prognosis 1737, 17801. Although
uncommon , the prognostic significance of
A ML with CEBPA mutations and other
chromosomal aberrations remains unclear.
Acute myeloid leukaemia With recurrent genetic abncemanoes
123

myelodysplasia-related changes
DA ArOOr
R D . Brunning
A .Orazi
Definition
Acute myeloid leukaemia (AML) with
myelo dysplasia-rela ted changes is an
acute leukaemia with 20% or more periphe ral blood (PB) or bone marrow (8M)
blasts with morphological features of
myelodysplasia or a prior history 01 a
myelodysplastic synd rome (MDS) or
myelodysplastic/myeloproliferative neoplasm (MDSlMPN), or MOS-related cvtogenetic abnormalities, and absence of
the specific genetic abnormalities of AMl
with recurrent genetic abnormalities. Patients should not have a history of prior
cytotoxic or radiation ther apy tor an unrelated d isease . Therefore , there are three
possible reasons for assig ning cases to
this subtype: AML arising from previous
MDS or MO S/M PN ; A ML w ith an MOSrelated cytogenetic abnormality; and AMl
with multilineage dysplasia. A given case
may be assig ned to this subtype for one,
two or alt three reasons (Table 6.02).
morphology, dysplasia must be present in

at least 50% 01 the ce lls in at least two 8M
ce ll lines. Dysq raoulo poresis is characterized by neutrophils with hypograOlJa'
cytoplasm, hyposegmented nuclei (pseLti>
Petqer-Huet anomaly) or bizarrely segmented nuclei . In some cases, these
features may be more readily identiliedoo
PB tha n BM smears. ()yseryItlropoiesls IS
characterized by megaloblastosis, karprhexis and nuclear irregularity, lragTllll1ahan or multinucleation. Ring sideroblasts,
cytoplasmic vacuoles and periodic acidSchiff (PAS) positivity are addlt~
features of cvsevtnroooesrs. Dysmegakaryo poiesis is characterized by microme gaka ryocytes and normal sized r:J
larg e megakaryocytes with non-lobulated
or multiple nuclei. Dy sp lastic megakaryo.
cvtes may be more readily appreciated n
sections than smears 169, 7421.
cases wiU not have sufficient
cell 8 M elements 10 adequately assessb
multilineage dysplasia or have sufficietw;
non-blast cells but do not meel the crilera
described above for a morphologic
nosis of AML with multilineage dysplasia
These cases are diagnosed as AML
mveiodvsptasta-retated changes by ee
detection of MD&-related cytogenetic aDnormalities anellor by a prior history ofMDS.
ICD-O code
989513
Synonym
Acute myeloid leukaemia with multilineage
dysplasia.
Epi d emiology
This ca tegory of AML with mveiccysptasiarelated cha nges occurs mainly in elderly
pat ients an d is rare in chi ld ren 1913,
12691. Although the d efinition 01 rnultitineage dysplasia is variable in the literature ,
this category appears to represent
24-35% 01 all cases of AML 169, 869 ,
1493 , 2465).
Clinical leatures
Patients with AML with myeiooysprasiarelated changes often present with severe
pancytopenia. Some cases with 20-29%
blasts, especially those arising from MDS
or in ch ildhood , may be slowly progressive.
These cases, w ith relative ly sta b le PB
co unts for weeks or months, co nsidered
refrac to ry anaemia with exc ess b lasts in
transformation in the Frenc h-A mer icanBritish Cooperative Group ctassmcauon.
may behave clinically in a manner more
similar 10 MDS than 10 A Ml.
and cyt """,,",stry
Most, but not all cases in this category of

AML have morphological evidence 01
muniuneaoe dysplasia which must be
assessed on well -stained smears 01 PB
and BM. To classify an AM L as having
mve covsoasta-retateo changes based on
BJ. Barn
sore
A.P<xw<
JW VardllTal
MoM. LeBeau
P.L Greertlefg
rcoees
Fig. 6.19 Acute myeloid le~~ with myelodysptasia-felated changes (murtilillllage dysplasia). The marrow aspirate shows numefOlJS I9"8nulaf blasts as wei as actIuII:
hypogrardar neutrophiIs with dul1lled nucleardWomatin and erytt'ftid preanors \MttI irreQlAar nuclear am..n. AA small. l'lypoIobated rnegakaryotyIe is IQS80I al lhe txb.
BAIigher magOOicaIion 01 anoltl8fcase showing rl'ICIre irregIJar nuclearfeatures 01 eryIhroi:I l)"eanors and ~ wiIhcbnped IIUd&ar etwomatn
124
Acute myelOtd leukaemia and related precursor neoplasms
Immunophenotype
Immunophenotyping results are variable
dueto the heterogenei ty of the underlying
genetic changes, In cases with aberralions
01 chromosomes5 and 7. a high incidence
oICD34, terminal deoxynucleotidyl trans!erase (Td T), and CD7 expression has
been reported 123241. In cases with anieceoent MOS. CD34+ cells frequently
const itute only a suboopuraton of blasts
m may have a stem-cell related immunopheootype with low expression of CD38
M"dkx HLA-DA. Blasts often exp ress pan myeloid markers (CD13. CD33). The re is
'Tequently aberrant expression 01 CD56
and CD7 116231. The maturing myeloid
cells may show patterns of antigen excesson differing from thOSe seen in nQ{mal myeloid development, and there may
ee alterations in the light scatter properDeS of maturing cells, particularly neutrotfWs, There is an increased incidence of
'TUlKinJg resistanceglycoprOlein (MOO-1)
expressiOn in the blast cells 11206, 1268,
t(2;1 1)(p 21;q23 ), if not associated with

prior cytoto xic therapy, should be classified
in this group rath er than as a variant
translocation of 11q23 ,
Cases of AML with multilineag e dysplasia
may carry NPMI and/or FLT3 muta tions
[23561. Most NPMI mutated cases would
be expected 10 have a normal karyotype,
CD34-negative blasts and no history of
prior MDS 120151. However, the presence
of an MDS-associated karyotypic abrormality should take diagnostic precedence
over the detection of an NPMI or CEBPA
mutation for classification purposes until
the significance of such rare genet ic c0mbinations is clarified . In patients wIth AML
with multilineage dysplasia and a nQ{mal
karyotype. information regarding the mu
tational status of NPMI, CEBPA and FLT3
may provide important prognostic informauon. and the presence of these mutations should be noted along with the
diagnosis of AML with myelodysplasiarelated changes (multilineage dysplasia)
12691.
123561.
Genetics
Chromosome abnormalities are similar to
Differential d iag nosis

The principal differential d iagnoses are
refractory anaemia with excess blasts ,
acute erythroid leukaemia, acute megakaryo blaslic leukae mia and the other categories of AML. not otherwise specified
(NOS). Caref ul b last cell counts. adnerence to the diag nostic criteria for morphological dys pl asia and evaluation for
MDS re lated c ytogenetic abnormal ities
shou ld resolve most cases, with this ca tego ry having priority over the purety morpholog ic ca teg ories of AML , NOS, For
exam ple, a ca se with >20% 8 M myeio blasts, multilinea ge dy spla sia, ove r 50%
BM erythroid precursors and monosomy 7
should be c onsidered as AML with
myelod ysplasi a-reiated c hanges rathe r
than acu te e rythroid leukaemia, Simila rly,
a case with over 20% 8 M megakaryoblasts and multilineage d ysplasia would
be considered AML with myelod ysp lasiarelated changes (megakaryoblastic type),
bose found in MDS and often involve

gain or loss of major segments 01certain
chromosomes with complex karyotypes
and -7/del(7q) and -5/del(5q) being most
ccmmon 11 269 , 1530 , 1641J, Additional
abnormalities that are considered sufficient for inclusion in this ca tegory are
given in Table 6.03, While trisomy 8 and
del(20Q) are also common in MOS, these
ffJdingsare not co nside red to be d iseasespecific and are not, by themselves, sufficient to co nside r a case as AM L with
myelodysplasia-related c hanges, Similarly,
bss of the Y ch romosome is a nonspecific find ing in o lder men and should
oo! be consi dered sufficient for c yto[Ie!1etic evidence of this d isease ca tegory
Balarced translocations are less common
in tnis disorde r, but when they occur are
of:en franslocations involving 5q32-33,
Tile t(3;5)(q25 ;q 34 ) is associated with
rrOtilineage dysplasia and a younger age
al presentation than most other cases in
tis disease group 1661. In addition, AML
W1h inv(3)(q2 1q26.2), t(3;3)(q21 ;q26 .2) or
W#l t(6;9)(p23:q34) may show evidence of
rru/tilineage dysplasia, but these are now
:ecognized as distinct entities in the AML
'MIll recurrent genetic abnormalities
goup and should be classified as such .
'*'wever, cases with the specific 11q23
wrangements. t(11 ;16)(q23;p13,3) and

Multipotent haematcooreuc stem cell.
Prog nosis and pred ictive fact ors
Acute mye loid leukaemia with myelodysplastic features generally has a poor
prognosis with a lowe r rate of ach ieving
complete remission than other AML types
169. 742 , 1269 , 1493 , 24651. While the re
are no overall prognostic differences
Table 6.02 Criteria lor the diagnosis of AML with

myelodysplasia-relatedfealu!'&S.
~ 20%
blood Of mam;lW blasts
AND
Anyof !tie Ioi:lwing
PreW:lus hislDry of myeIodysplaslic syndrome
MyeIodysj::QsbC syndrome--relaled L)'IogenetIc
abnormalrty (seeTable6.03)
Mullilineaga dysplasia
AND
......."bdh
?nor cytlItWc therapy lor an I.MlIaIed disease

RlICllfTing ~ abIllllT1lahl)' as descnbed
in AMl-Mlh reamlOI genetic abroomIakbes.
CytlgenetJc abnorr!\alIbes suIIicienI m

<iII(p'105e AM.. will myelodyspIasia-leatLRs wnen
~ PB or8M blasts are presett.
Table 6.03
('.oorpe. ~ '
UnbtIIItdd aMoonaiilies
llde(7ql
.-5qJ
~ l1q)'l l1p)
131de1(13q)
del(t1q)
del(12pj/l(l2p)
"'l9q1
idic(X)(q13)
&tI1l11Ud abnoonaiities
t1:11 ;t 6)(q23;p13,3)"
t1:311 )(q26.2;q22.1)"'
t1:1:3)(p36.3:q2t ,1)
t{2:11)(p21:q23)"o
1(5;t2)(q33:p12)
t(5;1)(q33:qtl .2)
t(5;11)(q33;p13)
t(5;10){q33;q21)
t(3;5){q25:q34)
' >3 unrelated abnomlalities, none of which are

includedin theAML withrecurrent genetic abnormalities subgroup: such casesshould be dassjfied
in the aPPfClPriate cytoger.etic group.
0' These abl'lormalities most commonly occur in
tnerapy-ffllated diseaseand lherapy-relatedAML
should be excluded before u~ng these abnormalilin asevidence lor a diagnosjs of AML with
myeiodysplaSlB-related features.
between cases with and without prior

MDS 1691. recognition of cases with prior
MDS and relatively low blast counts may
identify cases with less clinically aggres sive disease. Some cases with prior MDS
and 20-29% 8M blasts, considered
refractory anaemia with excess blasts in
transformation in the French-AmericanBritish Cooperative Group ctess'ucatcn.
Acute myeloid leukaemia WIth myelodysplaSIa-related changes
125
may behave in a manner rrore similar to

MOO than ome AML. These cases . as well
as cases with myelodysplasia and just
under 20% blasts, require regular monitoring of PB counts and 8M morpholOgy
lor changes suggesting disease progression to overt AML.
Although AMl with mu ltilineage dysplasia
is generally associated with a poor prog
nests. several studies have not found
morphology to be a significant parameter
when using multi-variant analysis thaI also
incorporates the results of cytogenetic
analysis, high risk cytogenetic abnormalities being more significantly associated
with prognosis {869, 2356, 24651. Therefore, mUltilineage dy splasia should b e
conside red as a po ssible indicator of high
risk cy togenetic abnormalities, bu t in the
abse nce of such abnorma lities. may not
be important. In such c ases, fluorescence
in situ hybrid ization (FISH) stu dies for
MO$-related abnormalities may be useful.
It is cu rren tly unclear whe ther a NPM1
posl livefFLT3-negative genotype in AMl
with multilineage dysplasia confers the
same good prognosis as in other AMl
with NPM, mutations. Cases of AML with
multilineage dysplasia and NPM1 metanone usually do not have adverse cytogenetic findings or a history of prior MOS
120151. However. the clinical impact of
mutation status versus the presence of
multumeaqe dysplasia requi res more
investiga tion. Therefore, it is not yet clear
how cases of AML with multilineag e dysp lasia without prior MOS or MOSrelated
cytogenetic abno rmalities and with an
NPM1 mu tation or a CEBPA m utation
should be c lassified . How ever, as noted
126
,!
--t_
4...
,
v.... ,,""' .......
Fig. 6.20 Survival curve lor cases of acu te myeloidleukae mia with adverse cytogenetic find ings in the "tRC-AMl IO
trial Reproduced from Grimwade Det al. {MB}.
above, at this time cases of AMl with

MOS-related cytogenetic findings and
one of these mutations should be diaqnosed as AMl wi th myelodysplasiarelated changes as well as noting the
mutation detected.
Diagnostic term inology
Because there are different pathways to a
diagnosis of AML with myelodysplasiarelated changes, which upon further
study may have clinical differences, it is
recommended that the reason(s) for
dia gnosing a case as such be included in
the di agnosis. For example , a c ase di agnosed solel y on mo rphology would be
considered "AMl with myelodyspla siarelated changes (rnultitineage dysplasia)":
a case arising from p reviou sly diag nosed
Acu te myeloid leukaemia and related p recursor neoplasms
MOS without assoc iated dysplasia idl!f$the lime 01 AMl diagnosis woUd
be considered ~ AMl with myelodysplasaarelated changes (following prevos
MOSt; and a case with prior MOS. dysplastic features and monosomy 7 WCllil
be considered "AMl with rnyeIoctyspIase
related Changes (fotleJ'oNing previous Ml.li
MDS-associated cytogenetic a~
and muttilineage dysplasia). Cases
NPM1, CEPBA and/or FLT3 mutatll)'lS
should also indicate the mutation hndrYJ
(r.e. "AMl with mverocvsotasta-reraiec
changes (multilineage dysplasia) aM
NPM1 mutation"). Finally, because ollhe
possible cli nical heterogeneity of cases
with low blast cell cou nts (20-29%), tt:E
b last count should be cl early stated in t~
repo rt.
ueo at
I""
Therapy -related myeloid neoplasms
Definition
Inis category include s therapy -rela ted
acute mye loid le ukaemia (IAML). rnyelodysplastic synd rome (I -M DS ) and m yelodysplastic/myelop ro life rative neoplasm s
(t-MDS/MPN) occurring as late compliea'ons 01 cytotoxic chemotherapy an d/or
-adtatlOn therapy adminis tered lor a pr ior
'lPIastic or non-neoplastic disorder. AIh:lu'Jh some patients may be d iagnosed
nnpt'dogicatty as 1-"'-105, t-MDS/MPN ()(
~AML according to the number 01b lasts
present. all of these therap y-related neoplasms are bes t considered together as a
IIlJque clinical syn d rome . Exc luded fro m
mig categor y is tran sfor mati on of MPN
srce it is etten no t possible to determine
if !his is disease evolution or therap yrelated.
992013
&,nlnym
Therapy-related acute myeloid
ielJ:.aemia. NOS.
-k>Iogy
Therapy-related t-AMl.../t-MDS and t-AMLJ
l.MDS!MPN ac count fo r 10 - 20% of a ll
cases of AML, MDS and MDS/M PN 11278,
1433, 1536 1. The incidence among paieras treated w ith c ytotoxic agents varie s
ElC cording to the underlying di sease and
fe treatment strategy. Any ag e group
rray be affected b ut the risk associated
lIllh alkylating agent or rad iation therapy
jjerlefally increases with age whereas the
rsillor those treated with topoisornerase II
II'hbIlors is similar ac ross all ages 1651,
12781,
E"*'lJy
Therapy-related neoplasms are thou ght to
bethe conseq uence of mutational eve nts
mceo by cytotoxic ther apy, Som e indiOOualsmay have a heritable predis position
due topolymorphism s in genes that affect
drug metabolism or DNA -repair rnecha ~sms. but for most cases the und erlying
08thOgenesis rema ins uncertain 11899 1.
Cy1oIoxic agents commonly imp licated
ire istec in the Table 6.04 . Although other
JW. Vardiman
DA Arber
RD. Bruming
RA Larson
E. Malutes
I. Baumann
J Thiele
the rap ies such as hydroxycarbamid e

(hyd roxyu rea), rad ioisotop es, L-aeo araqinase and naematcootetrc growth teeters
have been sugg ested to be reukae mogenic, their pr imary role in thera py-related
haema tologic neoplasms. if any. is not
clear. Characteristic clinical, morphologic
and genetic features often relate to the
previous ther apy received .
Peripheral b lood (PB) and bone ma rrow
(BM) are the princip le sites of involvement .
Clinical features
Near ly an equal number of patient s give a
history of treatment fo r a p revious baematologi cal ma lignancy as for a non -haematolog ical solid tumo ur. How ever. 5 - 20 % of
patients are reported to have rece ived cytotoxic therapy lor a rco-oecoasrc disease.
A smlar num ber develop a therapy-related
myeloid neoplasm afte r high dose
chemotherapy and autologous haematoporenc stem cell transplant for a prev i.
ously treated malignancy 11 433. 20411 .
Two subsets of t-AMlIt-MDS and t-A MU
t-MDS/MPN are generally recognized ,
The most common occurs 5- 10 years
afte r exposure to alkylating agents an d/or
ioniz ing rad iation. Patien ts often pr esent
with t-MDS and ev idence of 8 M failure
with one or mul tiple cyto penias, although
a minority will present with tMDS/MPN or
with overt t-AML This c ate go ry is com mon ly associated with unbalanced loss of
genetic material . often in volv ing chromosomes 5 and/or 7 . The second category
of t-A ML/t-MDS and t-A ML/t-MDSIMPN
encompasses 20-30% of patients. has a
latency period of about 1- 5 years, and
follows neannent with agents thai inte ract
With DNA tcoosorerase II (topoisornerase
II inhibitors). Most patient s in this subset
do not have a mveioovsotasnc p hase bu t
pre sen t initia lly with ove rt acute leukaem ia
tha t is ofte n assoc iated with a bal anced
cororoscrat translocation 1651, 1716, 20411,
A lthough it may b e useful to c onsid er
t-A MlIt- MDS and t-A MU t-MDSIMPN
as being alkylating agent and/or rad iationrelated or as top:lisctnerase II irtlibitor-related.
Fig. 6.21 Therapy.retaled AML with t(9;11)(p22;q23).

This pabenl deYeloped 1-AMl. 1essltlanone yearfoIow.
ing instilulion oIlherapy lor osteosartoma. The therapy
included both alkylabl'lQ agentS and ~ II inhibilorn.
in practice many p atients have rec eived

polychemotherapy that includes both
classes of drug s an d the boundary between the two categories is not always
sharp 120411.
t.1o<pIloIogy
The majority of patients present WIth
t-AMlIt-MDS associated with multllineage
dysplasia . Commonly, but not invariably
in such c ases, a history of p rior therapy
with alkylat ing agents and /or rad iation
therapy is elic ited and cytog enetic studies rev eal abno rmal ities of c hromosomes
5 and/or 7, o r a comp lex karyotype , Nevert heless, dysplasia may be seen in some
c ases wit h balanced tran siocauons as
well. The P8 shows one or more cvtopemas . Anaemia is almost always present
and red cell morphology is cha racterized
in most cases by macrocytosis and poikik::x:ytosis, Dysplastic changes in the neutn>
p hils include abnormal nuclear lobation,
particularly hypolobatoo, and cytoplasmic
hypogranulation . Baso philia is freq uently
present 11 4721. The 8M may be hyper.
ce llul ar, no rmcceuurar or twpoc euuiar.
and slight to mark ed 8M fibrosis occurs
in approximately 15% of c ases. Dysgranulcpoiesis and dy serythropo iesis are pre sent in mos t patients , Ring siderobla sts are
rep orted in up to 60% of cases and in
some c ases exceed 15% of the erythroid
precu rsors. Meg akaryoc ytes ....ary in nurnTherapy-related myeloid neoplasms
127
00
000
00 O __
000 0 00 00.p~ . _
o 0000000 &0 , _
000 00 0
10.Q 0 0 000
~ 00 0
00
00
00 .
00
0
0 00
0
00 0 1
A O OO. O O O_O..~O!?C .
Fig.6.22 Thefapy-relaled MDSlAML This 42-year-old man was lrealed withABVD therapy lor dassical Hodglin IymJ:tloma but retapsed 161T1OflthS laterandwas!Jven 9vage
chemolt1erapy and radiolt1erapy, Two years later he presented W11t1 pancytopenia in l!le PB(A), a BM asprate (8) and BM tMopsy (C) st'lowtld ilCteased bass and mullili1eaile
dysplaSia. A complex karyotype Jnduded lossof d1romosomes 5 and7.
ber but dysp lastic fo rms of variable size

with rnooo- or hypolobated or widely separated nuclei are seen in the ma;orlty of
ca ses 11472, 164 71- The percenteae 01
b lasts also varies but in patients presenting with a rnyelodysplastic pha se a lmost
50% will have less than 5 % 8 M b lasts
11472, 2026J About 5% of pat ients have
features of MDS/M PN, suc h as c hronic
mveromooocvnc leukaemia 120261. Althou gh patient s presentmq With rnyeiodyspl asia and cvtoperaas may be
desi gnated as l-Moo or t-AMl depending
on their mo rphology an d b la st counts.
suc h subclassification may lack clinical
sig nifica nce 120261.
In 20-30% of c ases, the first man ifestation
of therapy-re late d mye loi d neoplasm is
ov ert acut e leu kaemia without a preceding myelodysplastic phase , Often , but not
invariably , these cases follow toposomerase II inhibitor tnerapy. The majority of
the cases are associated with balanc ed
rec urren t c hromosomal transtocanons
that frequently involve 11q 23 (MLL) or
21q 22 (RUNX1) , and hav e morphology
that resembles de novo ac ute leukaemi a
associated wi th these chromosomal

abnormalities 136. 1886 . 2034 1although a
lew cases may pr esen t as MDS or have
dysplastic teatures as well . Many cases
fall in the categories of acute monoblaslic
leukaemi a or mverononocvtc leukaemia.
but ca ses with granuloc ytic d ifferentiation
al so occur Case s mo rph ologi ca lly (and
cytogenet ica lly) identical to those observed in all of the subtypes of AMl
With rec urring cytogenetic abnormalities
have been descri be d , inc luding acute
pronverocvnc leuk aem ia , Such cases
should be designated as t-AMl with the
ap propriate cytogenetic abnormality indi c ated. e.q. t-AML with t(9; 11)(p2 1;q23 ).
Cases of lymphoblastic leukaemia (All )
also occur in this group , usually associ ated
with a t(4 ; t 1)(q2 1;q 23) c hromosomal
abnormality 11022,19841.
Immuoophenotype
There are no specific immunophenotypic
findings in tAMUMDS ()( in t-AMljt-MDS/
MPN. lmmunophenotypi ng stud ies reflect
the heter og eneity of the und erly ing morph olog y and often show c hanges similar
....kylating agents
Melphalan. cydophosphamide , nitrogen mustard, cI*lrafnbldl. MuIIM, carboplalin. eisplabn ,
dacarbazirle, procarbazine.carmustine. mitomycin C .lh~epa,lomus ~ne. etc.

Ionizingradiationtherapy
large fields IfIcIuding active bone marrow

Topoi_
aMIl inhibiton
EIOpOSide. 1eoipO!iiOe. dolOf\ban, d8ulorIbcin.lIWJ.dnlrorle, arnsacrnt. acIIrom';an

"TCJP(lI5OlTIeIaS IIirlhbIr:Jts may abo be associated WIltIIherapy-related ~ leukaemia
""""
Anilmetaboilles: thiopurines, ITl)'tOI)Ilenolate, fludarabine

An titublJlin agents(usuallyin comblnenco withother agents):vincristine, vinblastine, virdesine, paditaxet,
docetaxel
128
Acute myeloid leukaerrua and rela ted precursor neoplasms
to their de novo counterpa rts 1681. Blasts

are generally CD34+ and express panmye loid markers (CD 13, CD33), There 1$
freq uent aberrant expression of CD56
and lor the lym phoi d- associated marker
CD7 . The ma turing myeloid cells may
show patterns of antigen expr ession that
diff er from that see n in norm al myeloid
development. and there may be alterations
in the light sc alier properties of maturing
cells. particularly reutropnus .
Genetics
The leukaemic cells of ove r 90% eX
patients with t-AMUt-MDS show an
abn ormal kary ot yp e , The cy tog enetic
abn or ma lities often co rre late with the
laten t pe riod be tween the initial l herapy
and the onset 01 the leukaemic disorder
and With the pre vious cytotoxic therapy
11254.1433,1716, 1886,20411. Approximately 70% of patients harbour ureaanced chromosomal aberrations. mainly
whole o r oaruat loss of ch romosomes 5
and /or 7, that are often assoc iated wit!l
one o r more ad d itional ch romosomal
abnormalities [e .g . d el(13q ), del(2OQl,
d el( 11q ), del(3p), -17, -18 , -2 1, +8} in a
complex karyotype. These changes are
usually associated with a long latent period . a preceding myelodysplashc phase
or t-A Ml with dysplastic features, and
alkylating agen t and/or rad iation therapy
The remaining 20 -30% of patients have
balanc ed c hromosomal transloc aticns
that invo lve rearrang ements of 11Q23
[including us,11)(p22:q23l and t( 11 :19)
t(8;2t)
(q23 ;p13l] . 2 1q22 [inc lud ing
(q22;q22) and 1(3;21)(q26.2:q22.1)] and
other abnormalities such as 1(15;17)
(q22;q12) and inv (16)( p 13q22) , The balanc ed transtocano ns are generally associ ated with a short latenc y period, most
often present as ove rt AMl without a
pr ec ed ing mverocvsptasnc phase. and
are associated with prior toootsomerase

II inhibitor therapy.
Haematopoietic stem c ell.
The prognosis 01t-AML./l-MOS and t-AMU
\-MDS/MPN is generally poor. although it
is strongly influenced by the associated
karyotypic abnormality as well as the
comorbidity of the underlying malignancy
or disease for which cytotoxic therapy
wasl'itialyrequired. CNeratl, 5-year SlJVivaI
of less than 10% is commonly reported .

Cases assoc iated with abno rmalities of
chromo some 5 and/or 7 and a com ple x
karyotype ha ve a particularly poo r outcome. with a median survival time ot less
than one year regard less 0 1 whether they
pre sent as overt acute leukaemia or as
t-MOS 11472, 20261. In contrast to de novo
MOS, some report s have suggested that
neither the blast percentage nor subclassification have a significant impact on
clinical outcome, and the designation of
t-AMUt-MOS or t-AMUt-MDS/MPN may
be more appropriate 11472. 20261. Patients
with balanced translocations genera lly

have a be tter prognosis, but. except for
those with t(15;17)(q22;q 12) and inv(16)
(p 13.1q22) or t( 16;16)(p 13.1;q22). median survival times are shorter than for
their de novo count erparts 136. 227 , 1886.
2034 .20411 .
It shou ld be noted that occ asional patients assigned to the category of therapyrelated myeloid neoplasms represent
coincidental disease and would be expected to behave like other de novo
disease.
Therapy-related myeloid neoplasms
129
Acute myeloid leukaemia,

The c ategory of ac ute myeloid leukaemia,

not otherwise spec ified (AML. NOS) enco mpasses those cas es that do not fulfil
criteria lor inclusion in one of the p revi ously desc ribed groups with rec urrent
genetic abnormalities, myelodysplasia-relate d c hanges or tha i are therapy-related .
These tumours are fell 10 be derived from
haematopoietic stem cells . The clinical
relevanc e of some subgroups 01 AML.
NOS is of q uestionable significance 169.
21531 bu t they are reta ined in the cl assi fication because they define criteria for the
d iagnosis 01 A ML ac ross a diverse morpholog ic spectrum and include the unique
d iagnostic criteria for ervmroreukaemra.
Mutation ana lysis and cytoge netic studies are rec ommend ed for c ases in this
ca tegory and may offer more prognostic
sig nificanc e than the morphologic subtypes. The pr imar y basis for subclassification within this category is the
morphological and cylochemical/immunophenotypic features of the leukaemic cells
that indicale !he major lineages involved
and the degree of maturation. The de fining cntenon for AML is 20% or mo re
mveioorasts in the peripheral b lood (PBl
or bo ne marrow (BM): the promonocytes
in AML wiltl monocytic di fferentiation are
consi dered blast equiva lents, The cl assification of acute eryt hroid leukaem ia is
uniqu e and is based on the percent ag e
of abnorma l eryth roblasts for pu re ery throid leukaemia and the percen tage of
myeloblasts among non-erythroid cells for
the eryt hroid/myeloid type. It is rec ommended that the blast percentage in the
BM be determined from a 500 cell
differentia! count using an acceptable
Roma nowsky stain . In the PB, tne differential shoul d include 200 leukoc ytes: If
Ihere is a marked leukopeni a, b ufty coa t
smears can be used , Should an aspi rate
smear not be obtainable due to BM fibrosis
and if the b lasts exp ress CD34, immun ohistochemical detection of CD34 on b iopsy
sec tions may p rovide valuab le information and may allow the diagn osis of AML
if the 20% b last threshold is me l. The
major crite ria required for this c ategory
are based on examination of BM aspirates,
130
D.A. Arber
R D. Brunning
A.Orazi
L. Peterson
J. Thiele
M.M. Le Beau
A. Porwil
PB smears , and 8 M trep hine b iopsies,

The recommendation s for cl as sif ic ation
are applicable only to specimens obtained
prior to chemoth erapy. It should be noted
tha t most of the epidemiolo gic data cited
for each AMl, NOS entity has been
lar gely g athered from studies using the
p rior FAB classi fication scheme, and may
not directly apply to series of patients
classi fied by the WHO sys tem, in which
most patients will be classified into other,
more specific entities , and fOf which sufficient epid emiologic d ata is not yet available.
Acute myeloId leukaemia with

minimal differentiation
Definition
Ac ute myeloid leukaemia with minimal
differentiatioo is an AML with no evidence
0 1 myeloi d differentiation by morphology
and light mic roscopy cytochemistry. The
myeloid nature 0 1 the bl asts is demonstrated by immunological markers and/Of
ult ras tructural studies including ultrastructural cytochemistry. Imm unop henotypi ng studies are essential in all cases to
distingui sh this disease from acute lym phoblastic leukaemia (ALL) ,
ICD -O code
9872/3
Epidemiology
These cases comprise <5% of cases of
AML. The disease may occur at any age,
bu t most patients are ei ther intants or
older adul ts.
Clinical features
Patients wiltl AML, minimally differentiated
usually present with evidence of BM failure
With anaemia, ltl rombocytopenia and neutropenia. There may be leukoc ytosis with
a mark edly inc reased number of b lasts,
Morphology and cytoc hemistry
The blasts are usually of medium size with
dispersed nucl ear chromatin, round or
slightly ind ented nuc lei with one or two
nucl eoli . The cytoplasm is agranular with
Acute myelold leukaemia and related precursor neoplasms
..
f ig. 6.23 AcuIe myeloblastiC leukaemia. minirnaI"

enlJated. A&nI 1I8TOW sme. The blasts wary II Silt.
ilITICV1t d ~ and prorrWlen(;e d ru:id. ThM
ate no QfferenlIabng lealU'8$. B Bone man'OW sedioIl
TIis lxlne marrow is COl,lpIetely replaced by tusts..,.
Olf 11l1lerenbalJng I8alures.
a varying degree of basophilia Less frequently, the blasts are small with more
cond ensed chroma tin, inconspicuous
nucleoli and sca nty cytoplasm resemb ling lymp hoblasts. The c ytochemical
reactions for myeloperoxid ase (MPO),
Sudan Black B (SBB) and naphthol-ASDctnoroacetete esterase (CAE) are neqetive 3% positive blasts): a naphthyl
acetate and butyrate es terases are negative or may sbow a noo-specmc weak C1
local reaction distinct from that 01 rT"IOOl>
cvtrc cells 1186, 1084, 1880 1. In some
unusual cases of AML with minimal ditter
ennanon there may be a residual norma
population of maturing neutroo nue. These
c ases ma y resemb le AML with maturenon. but are distingui shed by the absence
of MPO or SBB positivity in the b lasts and
the abse nce of Auer rods, The BM sections are usually markedly hvoerceuuie
with poorly differentiated blasts. With sensitive ultrastructural studies, MPO, CAE
ac tivity may be demonstrated in sma
granules. endoplasmic reticulum, Goigi

area and/or nuclear membranes.
1",,,,,,,OP" 011Otype
Most cases express earty, heernetoooetcassociated antigens (such as CD34,
CD38 and HLA-DR) and lack antigens
associated with myeloid and monocyti c
maturation. such as CD 11b. C01S , CD14,
CD64 and CD65 Biasi ce lls usually express CD13 and/or CO l 17 while expression of CD33 is found in approximately
60% of cases, Blasts are negative tor Band T-assoc iated cytoplasmic lymphoid
markers cCD3, cCD79a and cCD22 .
MPO is neg ative by cytochemistry. but
may be positive in a fraction 01 blasts by
flow cytometry Of immunohistochemistry.
Nuclear terminal oeoxvnocieonoyttransterase (Td T) is positive in approximately
50% of cases. Expression of CO? has

been reported in approximately 40% of
cases, while expression of o ther membfane,lympood-associated markers is rare.
Genetic s
No unique chromosomal abnormality has
been identi fied in AM L with minimal differentiation. The most co mmon abnormalities previously reported are complex
karyotypes and unbalanced abnormalities, such as -5/del(Sq), -7/del(7q), +8
and del( 11ql , but the presence of some
01 these abnormalities would now pl ace
the case in the category of AML with
myelodysplasia-related changes. Mutations of RUNX 7 (AML 7) occur in 27% of
cases and 16-22% of cases have FLT3
mutations.
The differential diagnosis incl udes ALL,
acute megakaryoblas!ic leukaemia, mixed
phenotype acute leukaemi a and more
rarely. the leukaemic phase of large cell
lymphoma. Immunophenotyping studi es
are essential to dis tinguish these condi-
oons
without maturation
Definition
Acute myeloid leukaem ia without maturation is characterized by a high percentage o! 8M b la.''-.ts l~I,~\1 $~":li~ic.5\'71
evidence of maturation to more matur e
neutrophils. Blasts constitute ~% of the
roo-erythroi d cells. The myeloid nature of
Fill.6.2" Acute myeloid leukaem ia without maturation. Bone marrow smear. AThecellsarepredominanlty myelobIasts:
OCC3S;onal myeloblasts contain azllrophilic grarlules or Aller rods. There is rIO e'o'i Oenc41 01 maturation beyornllhe
myeloblast stage. B Myeloperoxidase reaction showing OOmertlUSmyeIoblasls with strong peroxidase reactivity. There
areseYeraI peroxidase negative tfYlhroid precursors ifl the centre.
the blasts is demonstrated by MPO or

S8B (3% or more of blasts) posi tivity
and/or Auer rod s.
ICD-O oode
9873/3
Epidem iology
Acu te myeloid leukaemia without maturation comprises 5- 10% of cases of AML. It
may occu r at any age but the majority of
patients are ad ults; the median age is approximately 46 years.
Clinical features
The patients usually present with evidence of 8M failure with anaemia, thrombocytopenia and neutropenia, There may be
a leukocytosis with marke dly increased
blasts.
Some cases of AML without maturation
are characterized by obv cos mveicorasts.
some of which have azurophilic granulation
and/or unequivocal Auer rods. In other
cases, the blasts resemble Iymphob lasts
and lack azurophilic granules: MPO and
SBB positi vity are present in a varia ble
number of bl asts , but always in at least
3% . The 8M biopsy sections are usually
markedly nvperceuutar although rormocellular or nvooceuuiar cases may occur.
Immunophenotype
Acute myeloid leukaemia without maturation usually presents with a popu lation of
blasts expressing MPO and one Of more
of myel oid -associated antigens suc h as
C0 13, C033 and C0 117. C0 34 and HLAOR are positive in approximately 70% of
cases.
r,~q'6' , ~ ~%'l '~\~' ,';\7 ex~<%'S\iJ'l'i'
of markers assoc iated with granu locytic

matu ration such as C0 15 and C065 or
rrcnocync mark ers such as C0 14 and
C064. C0 11b is expressed in a fraction

of cases. Blasts are negative for B- and Tassociated cytoplasmic lymphoid markers: cC03. cC079a and cCD22 . CD7 is
foond in -30% of cases , while expression
of other membrane , lymphoid-associated
markers such as C02, C0 4, CD 19 and
C056 has been described in 10- 20% of
cases
Genetics
There is no demonstrated association between AML without maturation and specific recurrent chromosomal abnormalities.
The immunoglObulin heavy chain gene
and T-eel! receptor chain genes. in most
cases , are in a germline configuration.
The differential diagnosis includes ALL in
cases with blast cells lack ing granules or
having a low percentage at MPO-positive
blasts, and AML with maturation in cases
with a higher percentag e of MPD-positive
blasts.

with maturation
Defin ition
Acu te myeloid leukaemia with maturation

is cha racterized by the presence of ~
blasts in the BM or PB and evidence of
maturation (~10% matUringcells of neutrophil lineage); cells of monocyte lineage
com prise <20% of BM cells.
ICO-D cod e
9874/3
~~iilblbm'
Acute myeloid leukaemia with maturation

com prises approximately 10% of cases 01
AML (691. It occurs in all age groups;
Acute myeloid leukaemia. not otherwise specified
131
expression of HLA-OR, CD34 and/or

CDl 17, which may be present only in a
fract ion of blasts. Monoc ytic ma rkers
such as CD 14 and CD64 are usually ab sent. CD7 is present in 20-30% of cases.
while exp ression of CD56, C02, CD19
and CD4 is uncommon (- 10% of cases) .
Nts l'I'Iylllod leulo:BMilI Wllh mlll.ralD'" Booe

marrow &ITlNf. kl ~ tJ !he myeIobIa$l$. lhere 8111
sewraI more malure nevtrophIs; one neutrophI has a
psetJdo Pelger-HIJill Ikldeus.
F"
1g.6.25
20% of patients are <25 years of age and

40% are ~ years of age 120781.
O inical features
Patients often present with symp toms r
elated to anaemia, thrombocytopenia and
neutropeni a. The white blood cell coun t is
variable as is the number of blasts.
_ o g y and cytochemisOy
Blasts with and without azurophilic granu
larion are present. Auer rods are frequently
present. Promyelocytes , mveiocvtes and
mature neutroph ils com prise at least 10%
of the BM cells; variable degre es of d ysplasia are frequently present. Eosinophil
precur sors are frequ ently increased but
do not exhibit the c ytolo gical or cytochemic al abnormalities ch aracteristic of
the eosinophils in acute myelomonocyti c
leukaemia. associated with inv(16)(p13,l q22).
Basophils and/or mast ce lls are some times increased . The BM biopsy is usually
hyoe rceuular.
Immunophenotyp e
l eukaemic blasts in AML with maturation
usually express one or more of the
myeloid-associated antigens, C0 13,C033,
C065, C0 11b and C01 S. There is often
132
Genetics
There is no demonstrated association between AM L with maturation and specific
recurrent chromosomal abnormalities.
The differential diagnosis includes retractOf'y anaemia with excess blasts in cases
with a low bl ast percentage, AML withOut
maturation when the percentage of blasts
is high, and acute myelomonocytiC
leukaemia in cases with increased monocvtes.
Acute myelomonocytic
leukaemia
Definition
Acute myelomonocytic leukaemia is an
acu te leukaemia characterized by the
proliferation of both neutrophil and monocyte precu rsors, The PB or BM has ~20%
blasts (including prorronocvtes): neutrophils and their precu rsors and monocytes
and their precur sors eac h comprise at
least 20% of BM cells, This arbitrary minimal limit of 20% monocyt es and their
precu rsors disting uishes acute myelomonoc ytic leukaemia from cases of AML
with or without maturation in which some
monocyte s may be present. A high number (usually ~5x 1 09/L) of monocytic cells
may be present in the PB,
ICD-O code
Acute myeloid IeukaEtnlla and related precursor neoplasms
9867/3
Ep id em iology
Acute myelomonocytic leukaemia c0mprises 5- 10% of cases of AML. uoccca n
all age groups but is more corrrnoo in ddEJ
individuals; the median age is 50 years,
There is a maleJemaIe ratio of 1.4:1 120781.
Clinical features
Patients typically present with anaerre
and thrombocytopenia, fever and fatigue
The white blood cell coun t may be high
with numerous blasts and promonocytes
Morphology and cytoct>erT;sOy

The monoblasts are large cells, wm
abundant cytoplasm which can be m0derately to intensely basophilic and may
show pseudopod formation. Scaneeo
fine ezurconmc granules and vacuoles
may be present. The monoblasts usuaJy
have round nuclei with delicate lacy ceemann and one or more large prominert
nucleoli. Promonocytes have a more irregular and delicately convoluted nucIe<r
con figura tion : the cytoplasm is usua~
less basophilic and sometimes more oIr
viously granulated , with occasional large
azurophilic granules and vacuoles. Monocvtes and promooocvtes ma y not always
be readi ly distingui shab le in routinely
staine d BM smears. The PB typically
shows an incre ase in monocytes. whlch
are often more mature than those in the
BM. The monocytic component may be
more evident in the PB than in the 8M, N.
least 3% of the blasts should show MPO
positivity. The monoblasts, promonocytes,
and monocytes are typically non-soecnc
esterase (NSE) positive, although in some
cases reactivity may be weak or absent. I
the cells meet morphologic criteria IO'
monocytes. absence of NSE does not exclude the diag nosis. Double staining IO'
NSE and CAE or MPO may show dual
pos itive cells ,
--~7"
f'll. 6..27 Acute myeIomonocytIe 1eI*aen'ia.
A BIoocI smear. myeloblast monoblast al'ld prormnocytes. B Bone marrow smeaf. MyelobIas1s.1ld smnIlOOre mallJ'e mooocyte5
rdudir9 prornonocytes, C Nm-specific esterase reactionon bone marrow smear. 5eYetaI NSE positi'Ie eels819 presert. The l'ICIl'Hll8dII1 eels 8111 ~ myeIcitlIasls
m~ preaJ ~.
!rrmunophenotype
These ieusaemras generally show several
populations of blasts variably expressing
myeloid antigens C013. CD33, COO5 and
CD15, One of the b last populatio ns is
usually also positive for some markers
find ing s and perc ent of mo nocyt ic cells.

The differential d iagn osis with c hron ic
myelo monoc ytic leukaemia is c ritical and
rel ies on the p ro per id entific ation of
p romo noc ytes.
characteristic of monocytic d iffer entiation
such as CD 14, CD4, C0 11b, COl le,
CD54.CD36, macrophage-restricted CD68

(PGM1), CD l63 and lysozyme. In pa rticular. co-exp ressio n of CD15 and strong
C064 is characteristic of monocytiC di lferentiatoo. There is often also a popctam ol irrmature blasts tha i express CD34
<rdIor COll]. Most cases are positive for
~-DR. approximately 30% for CD7 ,
illtlile expression 01 othe r fvmpnoc-assoCiated markers is rare.
Genetics
Myeloid-assoc iated , non-s oecrnc cytogenetic abnormalities, e.g. +8, are present in the majority of the cases.
Differential diagn osis
The major d iffe renti al d iagnoses inc lude
AML with matu ration , acut e mo noc ytic
leukaemia and c hronic mvelomonocync
leukaemia. The distinction from the other
Mi L types is based on the cytochemical
n;. 6.21
Acute monoblastic and

monocytic leukaemia
Def inition
Acute monoblastic leukaemia and acute
monocytic leukaemia are myeloid
leukaemias in which 80% or rrcre of the
leukaemic cells are of monocytic linea ge
incl udi ng monoblasts, prorooocvtes and
monocytes : a minor neutrophil component,
<20%, may be present. Acute monobIastic
leukaem ia
an d
ac ute
mo nocyti c
leukaemia are d istingu ished by the
relative proportion s of mono blasts and
p romo noc ytes. In ac ute monobreettc
leukaem ia, the major ity of the monocytic
c ells are monob lasts (typ ica lly ~80 % ) , In
acu te monocytic leukaem ia, the majority
of the mo nocyti c c ells are crornonocvtes.
ICD-O cod e
9891/3
A Acute monoblaslic leukaemia, Bone marrow biopsy showing complete replacement by a ~lation of
llrge blasts wilh abundant cytoplasm. The nuclei aregeneraly rOI.Ild to oval: occasional nuclei are di&lol1ed
<TIO'lOCytiC leukaemia Bone marrow sedion . The nudea!'IoIds in the promonocyles arepfOmineol.
8 Acute
Ep idem io log y
Acut e monob lastic leukaemia com prises
<5% of cases of AML. 11 may oc cur at any
age bu t is most co mmon in young individuals, Extramed uliary lesions may occur.
Acute mo noc ytic leu kaemi a comprises
<5% of cases 01 AML : the mare.ternare
ratio is 1.8:1. It is more common in ad ults
(median. 49 years) 120781.
Clinical features
Bleed ing d isorders are common presenting featu res . Extramedullary masses .
cutaneous and gingival inlit1ration. and
c entral nervous system (eNS) involvement are common.
Monoblasts are large cells , with abundant
cytop lasm which c an be moderately 10
intensely baso philic an d may show
pseudop od formation. Scattered fine
az urop hilic g ranules and va cuo les may
be present. The monob lasts usually have
round nuc lei with delicate lacy c hromatin,
and one o r more large prom inent nucl eoli , Promonocytes have a more irregular
and delicately con voluted nuc lear con fig uration; the cytoplas m is usually less ba sophilic and sometimes more obv iously
g ranulated , with occasional large azurep hilic g ranules an d vacuoles. Auer rod s
are rare in acute mono blastic leukaemia
and. when present, are usu ally in ce lls
ident ifiable as myeloblasts. Haemophagocytosis (eryttrophagocytosis) may be 0bserved and suggests an associated
t(8;16)(p11 .2:P13.3) chromosomal abnormali ty 120 791. Haemoph agocytosis wilh
an associated t(8 :16)(pll.2:p 13.3) may
also be observed in AML with maturation .
The monobtasts and p rornonoc ytes usually show intense non-sp eci fic este rase
activity in mos t cas es, In up to 10-20% of
ca ses of acute monooasnc leukaemia, the
Acute myeloid leukaemia, not otherwise spec ified
133
can be dis tinguished with well-stained

smears . The differential diagnosis with
chronic myetomonccytc leukaemia is critical and relies on the proper identification
of promonocytes and their inclusion as
blast equivalents. The abnormal promyebcvtes in APL are intensely MPO and CAE
pos itive whereas the monocy tes are
weakly reactive or negative.
Fig. 6.29 Acute monocytic leukaemia, testcclar infiltralion Al ow magnification of a biopsy ot a testis from a patienl
with acute monocytic leukaemia. There is extensive expansion and infiltrationof tile space between the seminiferous
tubu les. 8 ThemonocyIic cells nave relati ~e ly abundant cytoplasm and ~ery dispersed chroma tin.
non-specific esterase reaction is negative

or very weakly positive. In some of these ,
immunophenotyping may be necessary
to estab lish monocytic diffe rentiation ,
Monoblasts are typically MPO negative;
promonocvtes may show some scattered
MPO positivity. The BM biopsy in acute
monobtastrc leukaemia is usually hypercellular with a predominant population of
large, poorly d ifferentiated blasts with
abundant cytop lasm, Nucleoli may be
prominent. The prornonccytes in acute
monocytic leukaemia show nuclea r lobulation. The extramedul lary lesion may be
predominantly of monoblasts or prornonocvtes or an admixture of two cell types.
Immunop henotype
By flow cytomet ry these leukaemias variably express myeloid antigens C013,
C033 (often very bright), C015 and
C065. There is gene rally exp ression of at
least two markers characteristic of monocytic differentiation such as C014 , C04,
C011 b, C011c , C064, C068, C036 and
lysozyme, C034 is pos itive only in 30% of
cases, while C0117 is more often expressed, Almost all cases are positive for
HLA-OR. MPO may be exp ressed in
acute monocytic leukaemia and less often
in monoblastic leukaemia. Abe rrant expression 01 C07 and/or C056 is found in
25-40% of cases. By immunohistochemistry
in paraffin-embedded 8 M biopsy specimens and in extramed ullary myeloid
(monobtast'c) sarcomas , MPO, CAE are
typica lly negative but may be weakly positive. Lysozyme is often positive, but is relatively non-specific. Macrophage-specific
CD68 and C0163are oftenpositiveand appear to be morespecific for monocyticdifferentiation.
134
Genetics
Myeloid-assoc iated, non-specif ic cytoge netic abno rmalities are present in the majority of the cases. The t(8;16)(p 11.2;p13.3)
may be associated with acute monocyt ic
leukaemia or acute myelomonocytic
leukaemia and , in the majority of cases, is
associated with haemophagocytosis by
leukaemic cells, particularly erythrophagocytos is and coagulopathy 12079).
The major differential diagnosis of acute
moncorastrc leukaemia incl udes AML
without maturation , AML minimally differentiated and acute megakaryoblastic
leukaemia. Extramedullary myeloid (monablastic) sarcomas may be confused with
malignant lymphoma or soft tissue sarcomas. Occasi onal cases resemble prolvmphocytic leukaemia; they are readi ly
distinguished by immunophenotypic analysis and cytoch emistry. The major differential diagnosis of acute monocytic
leukaemia inc ludes ch ronic mvelomonocytic leukaemia, acu te myelomonocytic
leukaemia and microgranu lar acute
promyelocyt ic leukaemia (APL). These

Definition
Acute erythroid leukaemias are acute
leukaemias that are charac terized by a
predominant erythro id popu lation. Twa
subtypes are recognized based on the
presence or absence of a significant
myeloid (granu locytic) component:
Erytnroleukaernia (eryth roid/myeloid) is
def ined by the presen ce in the 8M of
~ 50% erythroid precursors in the entire
nucleated cel l popula tion and <::20%
myeloblasts in the non-erythroid cell population, i.e. the myeloblasts are calculated
as a percen t of the non-erythroid cells.
Pure erythroid leukaemia represents a
neoplastic proliferation of immature cells
(undifferentiated or proerythroblastic in
appearance) committed exclusivelytothe
erythroid lineage (2:80% of BM cells) with
no evidence 01 a significant myeloblastic
componen t 1753).
ICD-O code
9840/3
Epidemiology
Erytnroleukaernia (erythroid/mye loid) is
predominantly a disease of adults (20781.
It compr ises <5% of cases of AML. Pure
erythroid leukaemia is extremely rare and
can occ ur at any age, including childhood
.'
Fig. 6.30 Acute erythrcleukaemia. erythroid/myeloid. BOlle marrow smear. A Myeloblasls and erythroid precursors
with dyserythropoietic changes are present. B Bone marrow smear Perocc acid-Schiff reaction. There are se~eraI
erythroid precu rsors atvaryingstagesof maturation wilh PAS-positi~ cytoplasm. The more immature precursors Mile
a coarsely granu laril10bular reaction; thelater stage precursors havea diffuse cytoplasmic positi~Fty.
"
,... .
Fig. 6.31 Acute erythroid leukaemia, erythroid/myeloid.

Bone marrow biopsy, There is a population of erythrokl
precursors and myeloblasts refi ecting the duallineage
proliferation. A binucleate megakaryocyte is present.
Clinical features
The clinica l features of the eryth roid
leukaemias are not unique but profound
anaemia and circulating erythrob lasts
are common, Erythroreukaernia (erythroid!
myeloid) may present de novo or evolve
from MDS or, less common ly, from chronic
myeloproliferative neop lasms (MPN),
Morphology and c ytoc hemistry
Erythroleukaemia (erythroid/myeloid)
All maturation stages of the erythroid precursors may be present, frequently with a
shift to immatu rity. The erythroid precursors are dy splastic with meparobras torc
nuclei and/or bi- or multinucleated forms ;
the cytoplasm in the more immature ce lls
frequently contains poo rly dema rcated
vacuoles, which may coa lesce , Large
multinucleated erythroid cells may be
present. The rnveioorasta are of med ium
size, often con taining a few cytoplasmic
granules and occasionally Auer rods and
aresimilar to the mveiobrasts in AML with
and without maturation. Dysplastic changes
of maturing neutrophils and megakaryocytes are common, The iron stain may
show ring siderob lasts and the perio dic
acid-8ch iff (PAS) stain may be positive in
re erythroid precursors either in a globular or diffuse p attern. The MPO, CAE and
SBS stains may be positive in the myeloblasts. The 8 M biop sy in erythroid!
myeloid leukaemia is usually hypercelluar. There may be prominent mega karyocytic dysplasia.
Pure erythroid leukaemia
The undifferentiated form of pure erythroid leukaemia is usually ch aracterized
by the presence 01 medium to large size
erythroblasts usua lly with round nucl ei,
fine chromatin and one or more nuc leoli
Fig.6.32 Pure erythroid leukaemia. Bone marrow smear

with numeroos very immafure erythroid precursors; these
cells have cytoplasmic vacuoles which occa sionally
Immunoph enotype
Erythrole ukaemia (erythroid/myeloid)
The erythroblas ts in ervtbroieokaemia
generally lack myeloid-assoc iated markers and are negativ e with anti-MPO; they
react with antibodies to haemog lobin A
and glycophorin, but the more immature
ce lls may be negative. An aberrantly low
expression of CD71 may be present. The
immunophenotype of the myeloid population usually co rresponds to that 01 AML
without differentiation or AML with minimal
differentiation.
coalesce,
(proerythroblast): the cytoplasm is deeply

basoph ilic, often agranular and frequently
con tains poor ly demarcated vac uoles
which are often PAS-posi tive, Occasionally the blasts are smaller and resemb le
the Iymphob lasts of ALL. The ce lls are
nega tive for MPO and SBB; they show reacti vity with a -naphthyl acetate esterase,
ac id phosphatase and PAS, the latter usually in a block-like staining pattern, In the
BM biops ies of pure acute erythroid
leukaemia the ce lls appea r undifferentiated.
Pure erythroid leukaemia

The more differentiated forms can be detected by the expressio n of glycophorin
and haemoglobin A and absence of MPQ
and other myeloid markers; the blasts are
often negat ive for HLA-DR and CD34, but
may be pos itive for CD117. The more immature forms are usually negative for glycophor in or this is only weakly expressed
in a minority of blasts. Other markers such
as ca rbon ic anhydrase 1, Gero antibody
against the Gerbich blood group or CD36
are usually pos itive as they detect
erythroid progeni tors at earlier stages of
differentiation. However, CD36 is not specific for ervtbrobrasts and may be
Fig.6.33 Pure erythroid leukaemia,Bone marrow section, A Apredominant population of veryimmature erythroid precursors , some of which aremuRilobated (arrow). B The immature erythroid precursors and mrtotic figures showpositivity fof glycophorin A.
Fig.6.34 Pure erythroid leukaemia. A Bone marrow smear shows fourabnormal ptcerythrcblasts. The erythroblasts
are large withfinely dispersed chromatin. prominent nucleoliand cytoplasmic vacuoles, some ofwhfch are coalescent.
B The cytoplasm of the proerythroblasts shows intenseglobular PAS staining.
Acute myeloid leukaemia, not otherwise specified
135
expressed ..by mo-ocvtes and mega karyocvtes. Antigens associated with me gakaryocytes (CD41 and CD6 1) are typically
negative, b ut may be partially expresse d
in some cases . Immunohistoc hemistry to
haemoglobin A or glycophorin may be
helpf ul in establishing cell origin in biopsy
specimens.
Genetics
There is no specific chromosome abnormality described in this type of AML.
Complex karyotypes with multiple structural abnormalities are com mo n, with
-5/del(Sq), -7/del(7q) and +8 the most
corrvnon 112821. However, cases with
-5/del(Sq), -7/del(7q) and/()( complex
chromosomal aonomaunes should be
classified as AML with myelodysplasiarelated changes if the other requirements
f()( that category are satisfied.
Differential d iag nosi s

~(~)shouId
be distinguished from refractory anaemia

with excess blasts (RAEB) , AML with
mye lodysplasia-related changes, AML
wi th ma turation with increased erythroid
precu rsors and reactive eryth roid hyperplasia follow ing therapy sx administration
of eryt hropoietin. A BM differential coun t
of all nuc lea ted cells should be pe rforme d. If the ove rall percentage of b last
cells is ~20% and muJlilineage dysplasia
is prese nt in ~50 % of the cells of two or
mo re lineages, a di agnosis of AMl with
myelodysplas ia- relate d c hanges should
be made . When there are <20% total
blasts an d the erythroid p rec ursors are
~ 50% of all cells, the di fferential co unt of
non-erythroid ce lls shou ld be ca lcu lated .
If blasts are ~20% of non-eryth roid ce lls ,
the di agn osis is erythro leukaemia (erythroid/myeloid ); if <20%, the d iagnosis is
usually MOS. The d ifferential diagnosis of
pure erythroid leukaemia inc lud es megaloblas tic anaemia due to vitamin B 12 or
folate de ficienc y. In eq uivoc al cases, a
trial of 81 2 o r folate thera py should be
considered.
Pure erythroid leukaemia without mo rphologic evidence of erythroid maturation
may be diffic ult to distinguish from othe r
type s of AML . particularly megakaryob lastic leukaemia, and also from ALL or
lymphoma lack of expression of lymphoid antigens will exclude the latter diagnoses. Distinction from megakaryoblastic
leukaemia is the most difficult: If the
immunophenotype is characteristic of
136
er ythroid pr ec ursors, a diagnosis can be

e stab lished , howeve r some cases are
am big uous and there may be cases with
concurrent erythroid-megakaryocytic involvemen t.
Erythroi d/myeloid leukaemia is generally
associated with an aggressive clinical
course. The morphologic find ing s may
evolve to a mo re predominant myeloblast
picture. Pure erythroid leukaemia is usually
associated with a rap id clinical course.
Acute megakaryoblastic
leukaemia
Definition
Acute megakaryoblastic leukaemia is an
acute leukaemia with 20% ()( more blasts
of which at least 50% are of megakaryocyte line age; however, this category
excludes cases of AML with myelodysplasia-related changes, AML with
t(1;22)(p13;q 13), inv(3)(q21q26.2), t(3;3)
(q21 ;q26.2) and Down syndrome-related
cases.
ICD-O code
99 10/3
Ep idemiology
Ac ute meg akaryo bl astic leukaemia occ urs in bo th adults an d children. This is
an unc ommon d isease compris ing <5%
of ca ses of AML .
Clinica l features
Patients present with cyto pe nias. often
thromb ocytop enia, although some may
have thrombocytosis. Dysplastic features
in th e neutroph ils, er ythroid precu rsors,
p late lets and me ga karyocytes may be
pres en t. Hep atosplenomeg aly is intre-
Acute myeloid leukaemi a and related precursor neoplasms
quent. An association between acute
meqekarvonrasnc leukaemia and mediastinal germ cell tumours has been ocserved in young adul t males 115941.
Morphology end cytochemistry

The megakaryobl asts are usually of
medium to large size (12-18 jJm) with a
round , slightly irregular or indented l'MJcieus with fine reticular chromatin andce
to three nucleoli . The cytoplasm is baseprune. often agranular, and may showdistinct blebs or pseudopod formation. In
some cases the blasts are predominaf1ty
small with a high nuclear-cytoplasmic
rato resembling Iymphoblasts; large and
small blasts may be present in the sere
patient. Occasionally, the blasts occur I'l
small clusters. Circulating micromegakaryocytes. megakaryoblastic fragments,
dysplastic large platelets and hypogralurar neutrophils may be present. Micromegakaryocytes are small cells with 1rx
2 round nuclei with condensed chromalfl
and matu re cytoplasm: these should rwx
be counted as blasts. In some patients,
because of extensive 8 M fib rosis restJ!.ing in a "dry tap ", the percent of 8M
blasts is estimated from the 8 M biopsy.
Imprints of the biopsy may also be uselul.
Although acu te megakaryoblastic leukaemia may be associate d with extensive
fibrosis, this is not an inva riant finding.
The histopathology of the b io psy vanes
from cases with a uniform population of
poor ly d ifferentiated blasts to a mixtureof
poorly differentiated blasts and maturing
dysplastic megakaryoc ytes; varying deg rees of reticulin fibrosis may be present.
Cytoc hemical stains for SBB, CAE and
MPQ are co nsistently negative in the
megaka ryob lasts ; the blasts may show
reac tivity with PAS and for ac id phosphatase and punctate or foc al nonspecific esterase reactivity.
_ B
:.til
fig.6.36 ACVle mega~ 1eI.*aenia. A Bone marrow smear. The two megaka-yoblasts are large ceHs with
GytlpIasmic pseudopod lonnatiOn: portIOnS of the cytqllasm are "zoned" with granular basoplliliC areas and dear
~_ Nucleoli cwelAl$lJ3ly ptCIII1nerL B Bone marrow smear reac:t8d wrth alllilOOy to CD61 (pIal9lel: gIycopro.., II). The eyklpIasm of the ITlI!9lkalyoblasls is in&enSeIy reactJYe
0rm.n0phen0Iype
The meqakarvobtests express one or
'!'(Jfa of the platelet glycoproteins: CD41
19yooprotein 1Ib/llla). and/Of COOl (glycoprotein ilia). The more mature plateletassociated marker CD42 (glycoprotein Ib)
s less frequently present The myeloidassociated markers, CD13 and CD33.
'fay be positive. C034. lhe pan-Ieukocyte
marker CD45. and HLA-OR are often negalIVe. especially in children; CD36 is characteristically positive. Blasts are negative
with !he anti- MPO antibody and with other
markers 01 g ranulocytic differentia tion.
Lymphoid markers and TdT are not

expressed. but there may be aberrant
eqxesson of CD? Cytoplasmic expression of CD4 1 or C06 1 is more specific
and sensitive than surface staining, due
tl possible adherence of pl atelets to bl ast
,:ells, whic h ma y be m isi nte rp re ted as
positive sta ining by f low c ytometry In
cases with fibrosis, immuno phe no ty ping
011 BM trephine biopsies is particularly
mportant for di agn osis. M eg akary ocytes
and in some cas es rr eq ak arvo brast s can
te recognized by a positive reac tion w ith
antibod ies to von wmeorand's factor, the
platelet glycopro teins (CD6 1, CD 42b)
irld LAT (linker of activation of r -cenej the
eetecton of platelet glycop roteins is the
rest lineage specific but detection is
Ilighly dependent on procedures used for
ixation and decalcification.
Genetics
There is no unique chromosomal aonorTe'rty associated with acute meqakarvoblastic leukaemia in adults . Complex
r.aryofypes typical of MD S, inv(3)
!:321(126.2) and t(3;3Xq21q26.2) can all
be associated with megakaryoblasticl
n!gak.aryOcytic differentiation 1507, 16371
but these cases are all assigned to other

categories of AML (See AML with recurrent
genetic abnormalities) ,
In young males with mediastinal germ cell
tumours and acute meqakarvobtasuc
leukaemia. several cytogenetic acoomauties have been observed of which i( 12p) is
characteristic.
The differential diagnosis inc ludes minimally d ifferenti ated AML, AML with
myelodyspl asia-rela ted changes, acute
panmyelosis with myelofibrosis, ALL , pure
erythroid leukae mia and blastic transforma tion of chronic myelogenous leukaem ia
or rneqakarvobrasnc crisis of any MPN. In
the latter tw o conditions, there is usu all y
a history of a chronic phase an d splenom eg aly is an alm o st consta nt find ing.
Some metastatic tumours in the 8M, particularly in c hild ren , e.q alveo lar rhabdomy osarcoma , m ay resem ble acute
m eqak aryobla stic leukaemi a. In g en eral.
acute meqakarvoblastic leukaemia repr ese nts a p rol ifer at ion pr ed omi nan tly of
rne q ak arycbta sts. whe reas acut e p anm yelosis is c har acterized b y a trilineage
proliferation, i.e. granulocytes, megakaryocvtes and erythro id precursors. The distinction between acute megaka ryoblastic
leukaemia, ac ute pan myelosis with fibrosis
and AML with m yelodyspla sia-re lated
Changes is not always clear.
Prognosis and predictive fact ors
The prognosis 01 this category 01 acute
mecakarvobtasnc leukaemia is usually
poor when compared to other AML types
as well as in comparison to AML with
t( 1;22XP13;q 13) 1620 , 16371 and acute
megakaryoblastic leukaemia in Down
syn d rome,
Fill, 6,37 Acu1e megakaryoblastic 1e\Jkaen'ia. Bone

Il'\I'OW biopsy shows vi1uaRy ~ repIacemenl by
a popuIaIion 0/ blasts CI'ld weW1IerenhaIed megakaryo.

cya There is a n'WlOl" popJabon 0/8I)'IIVOid preanors,
Acute basophilic leukaemia

Defin ition
Acute basophilic leukaemia is an AML in
which the primary differentiation is to ba-
sopnns.
ICD-O cod e
987013
Epidem iology
This is a very rare disease with a relatively
small number of reported c ases, comprising < 1% 01 all cases of AML.
Clinical fea tures
As in other acute reokaemras. patients
present with featu res related to 8 M failure
and mayor may not have c irculating
bl asts, In addition, cutaneous involvement, organomegaly, lytic les ions and
symptoms related to hy perhistam inemia
ma y be present.
The circulating PB and 8 M bla sts are of
medi um size with a high nuclear-eytoplasmic
ra tio, an oval, round or b ilobed nucleus
c harac terize d by disperse d chromatin
an d one to three p rom inent nucleo li. The
cytoplasm is moderately basophilic and
contains a varia ble numbe r of coarse basophilic granules wh ic h ar e positive in
me tachromatic stains; vacuolation of the
cytoplasm may be present. M ature basephi ls are usually sparse. Dysplastic tealures in the erythroid precursors may be
present. Electron microscopy shows that
the granules contain structures characteristic of basophil precursors; they contain
an electron-dense particulate substance,
are internally-bisected, e .g. have a theta
character, or contain crystalline ma terial
arranged in a pattern of scrolls or lamellae , the latter finding is more typical of
Acute myeloid !eukaerma, not orrerwse specified

1
137
ma st cells. ,Coe xistenc e of basop hil and

mast ce ll granules may be iden tified in the
same immature cells {17321. The mo st
charac teristic c ytochemi cal react ion is
metac hroma tic positivity with toluidi ne
blue. In addition. the blasts usually show
a diffuse pa ttern of staining wit h acid
p hosp hatase and . in some cases. PAS
posi tivity in b locks or lakes; the blasts are
often neg ative by light mic roscopy for
SBB, MPO. CAE and non-specmc esterase. The BM trephine biopsy shows diffuse replac ement by blast ce lls.
' rrm.Jnophenolype
Leukaemic blasts expre ss myeloid markers such as C0 13 arldJor C033, and are
usually positive for CD 123. C0 203c and
CD 11b. but negative for other monocytic
markers. Blasts may express CD34 and
in contras t to normal basophils may be
positive lor HLA-DR but are negative for
CD 117. Immunopheno typic detec tion of
abnormal mast cells expressing CD1 17.
mast cell tryptase and C0 25 will distinguish
mast cell leukaemia tram acute basophilic
leukaemi a. Usually blasts show exp res sion of COO. Some cases may be positive
for memb rane CD22 and /or Td T. Other
mem brane and cytop lasmic. Iymp hoidassoc iated markers are usually negative
11295.207 41.
F"Ii- 6.38 Acute ~ 1eINema . Bone marrow smear. A Blasts and irrmature basophiIs. The bascJpIj pUIs
vary from large roarsegraUes III smaI8rpUBs. B Bone marrow trepl1n8 biopsy. The bIa:sls /we pco1y~
Clinica l features
Patients pre sent acutel y with severe constitutional sympt oms including weakne ss
and fatigue ; fever and bone pain are also
frequently ob served. Pancytopenia is
alwa ys p resent. There is no or minimal
sp lenomeg aly. The clinical evolution is
usually rapidly progressive 122251.
Occasional neutrophil precusors inc::kJl:ilv

bla sts may be id entified . Dvsotastc
Changes in myeloid cells are frequent
Abnormal platelets may be noted . aoe
marrow aspiration is frequently uosocce ssful: either no 8M is obtained or ee
specimen is suboptimal. Bone marroe
biopsy supplemented with immunohis:o.
logy is required for diagnosis /2124.
2225 1. The 8 M b iopsy is hypercelljjw
and shows , within a diffusely fibrotIC
stroma . an increased p ronteratco of erythroid precu rsors. granulocyte precursors
and megakaryocytes (panmyelosis). wt'ich
is variable in terms of the relative prooction of each given component. Characteristic findings include foci of immature
baematcpolettc cells including blasts
associated with cons picuously dvsplastc
megak aryocyt es p redominately of smat
size with eosinophilic cytoplasm showing
variable d egrees of cytological atypia il'leluding the presence of hypolobulated cr
non-lobulated nuclei with dispersed crso
matin. Mic romegakaryoc ytes may be
present but should not be cou nted as
bla sts. The visib ility of the small meqakaryoc ytes may be ac centuated with the
PAS stain and immunohistochemistry
l 22251. The overall frequency of blasts ir
APMF marrows is uncertain. Based onBIll
biopsy, a median value of 22.5% was
found in a recent study /165 11. Mosl cases
have a range of 20-25%. The degreed
myelofib rosis is variable. In most patients
there is a marked increase in reticulir
fibres with coarse fibres; frank collageroo;
fibrosis is. however, uncommon.
_logy and cylochem;stty

The PB shows panc ytopenia whic h IS
usually marked . The red blood cells
show no or minimal aniso poiknoc v tosrs
and variab le macrocytosis; rare erythroblasts c an be seen b ut teardrop-shaped
c ells (d acryocytes) are not observed.
Immunophenotype
If sufficient 8 M specimen is obtained!o'
immunologic markers or circulating bIas:s
are p resent in the P8 . the c ells sh:)w
phenot yp ic heterogen eity, with va~
d egrees of expression of myeloid-aSSOCIated antigens . The blasts usually express
Prognosis and p redictive factors

Since this is a rare type of acute leu kaemia. there is little information on survival. The cases observed have genera lly
been associated with a poor prognosi s.
Acute panmyelosis with

myelofibrosis
Definition
Acute panmyelosis with myelofibrosis
(APMF) is an acute panmyeloid proliferation with inc reased bla sts and accompanying fibrosis of the 8 M {168, 2 1201 that
does not meet criteria for AML with
myelodysp lasia-related changes.
ICD-O code
Genetic s
There is no consistent chromosomal
abnormality identified in these cases.
AML with t(6:9)(p23;q 34) is speci fic ally
excluded as are cases associ ated with a
BCR-ABL 1 fusion gene.
The d ifferential d iagnosis inc lud es bl ast
ph ase of MPN, other AML subtypes with
ba sophilia suc h as AML with t(6;9)
(p23:q 34), mast c ell leukaemia and , more
rare ly, a subtype of ALL with prominent
coarse granules. The clinical features and
cytogenetic pattern will distinguish cases
p resenting de novo from those resulting
'rom transformation of chronic my elogenous leukaemia and from other AML subtypes With basophilia. Immunologica l
markers will distinguish between granulated AlL and acute basophilic leukaemia
and light microsc op ic c ytochemist ry lo r
myelope roxidase and elect ron mlcroscopy will distinguish acute basophilic
leukaem ia from other leukaemias.
138
993 1/3
Synonyms
Acute (malignant) myelofibros is, acute
(malignant) myelosclerosis.
Epidem iology
Acute panmyelosrs with myelofib rosis is a
very rare form of AML APMF oc curs de
novo. It is primar ily a disease of adu lts but
has also been reported in children.
the progenilotlearly precur sor-associated

market CD34 and one or more myeloid associated antigens: C013, C033 and
CD117 11651, 2 124, 2225 1. Myeloperoxidase is usually negative in the bla sts. In
some cases a proportion of immature
cells express erythroid antigens. Immunohistochemistry can facilitate the identi fication of the relative proport ions of the
various myeloid components on the
biopsy specimen and is g enerally used to
confirm the multiline age nature of the
proeteranon. This is usually d one by
employing a panel of antibodies which inclodes myeloperoxid ase, lysozyme , antimegakaryocytic markers (C06 1. C0 42b ,
C041 or anti-von Wil1ebrand 's fac tor) and
erytIYOid markers such as g tycophofin and
haemoglobin A. These confi rm the preseoce 01 parvnyelosis and allow exclusion
ci specific unilineage" -predominant proilerations.such as acute rnegakaryObtastic
~emia .
GeneIics
If sufficient specimen for cytogenetic
analysis is obt ained , me results are usually abnormal. The d etec tion of a com plex
karyotype, frequ ently Involving ch romosomes 5 and/or 7 [-51del(5q), -7/d el{7q)]
122251, means that the case is assigned
to AML with my elodysp lasia-related
changes, not to ac ute panmyelosis.
The major di fferential diagnosis of APMF
includes other type s of AML with associated BM fibrosis including acute megakaryoblastic leukaem ia 116511. Usual ly
ess problematic is the di stinction from
primary myelofib rosis (PMF), po st-p olycythaemia vera myelofibrosis, post-essen~ a l lh rom boc yt h ae m i a myelofibrosis, and
eon other neopla sms that c an be encountered in a myelofib rotic BM such as
metastatic malig nancies with a de srnoplastlc stromal reaction . The distinction between AML. particularly c ases of AML with
myekxiysplasia-related changes with multi~neage dysplasia and myelofibrosis and
acute megakaryoblastic leukaemia with
myelofibrosis, and APMF may be difficu lt,
particularly if no specimen suitable for cytogeneti c analysis can be obtained.

If the proliferative process is predominantly
one cell type. i.e. myeloblasts, and there is
assoc iated myelofibrosis, the case should
be classified as AML with a specific subtype, e.g. AML-myelodysplasia-related .
and then desig nated with the qua lifying
phrase w ith mveronbrosrs". Acute megakaryoblastic leukaemia is assoc iated with
the presence of 2': 20% b lasts, of which at
least 50% are mega karyobla sts. In contrast, the b lasts of APMF are more heterogenous, poorly differentiated and express
CD34. The majority of blasts do not display
megakaryocytic reactivity, and the proliferative proces s involves all of the major BM
c ell lines.
Particul arly difficu lt is the di stinction between APMF and cases of MOS associated
with both an excess of blas ts and myelofibrosis (AAEB-F), since the latter cases c an
share roost of the morphological finding s
seen in APMF. Clin ica lly, APMF can be
separated from MOS by its more abrupt
onset with fever and bone pain. In APMF.
histology of the BM shows more numerous megakaryocytes and , on average, a

higher numb er of blas ts than what are
found in AAEB. Cases of AAEB-2-F. except for their usually less acute clinical
presentation , may be indisti nguishable
from APMF 116511. APMF is distinguished
from PMF by the more numerous blas t
ce lls in the former and the distinct cytological characteristics of the megakaryocy tes in the latter (See Chapter 2). The
presence of a metastatic malignancy or,
rarely a lymph oid disorder c an be excluded by studies with appropriate antibodies.
Haematcpoie tlc stem cell. The fibroblastic
proli feration is secondary.
Prognosis and predictive fac tors
The disease is usually associated with poor
response to chemotherapy and usually
only a few months survival 1165 1, 21241 .
Acute myeloid leukaemia,
Il(){
otherwise spec ified
139
Myeloid sarcoma
SA Pileri
A. Orazi
B. Falini
Definition
A myeloid sarcoma is a tumour mass consisting of myeloid blasts with or without
maturation occurring at an anatomical site
other than the bone marrow (BM) . Infiltrates of any site of the body by myeloid
blasts in leukaem ic patient s are rot cl as-
sified as myeloid sarcoma unless they
Almost every site of the body c an be involved , the skin, lymph node, ga strointestinal tract, bone, soft tissue and testis
be ing more frequently attectec 1663.
1742 1. In less than 10% of ca ses . myeloid
sarcoma presents at multiple anatomical
sites 1663, 17421.
proportion of c ases, it d isp lays rnyelomonocytic or pure monoblastic morphology 1663. 17421. Tumours with trilineage
haematopoies is Of predom inantly erythroid precursors or megakaryoblasts are
rare and may occu r in c onj unction W1tt1
transformation of MPN 117421.
Clinical featu res

Myeloid sarcoma ma y occur de novo: its
detection should be conside red as the
equivalent of a d iag nosi s of AM L. It may
precede or coinci de w ith AML or represent acute b lastic tran sfor ma tion of
myelodysplasti c syndromes (MDS), MPN
or MDS/MPN 1663, 17421.
Finally, myeloid sarcoma may also be the
initial manifes tation of relapse in a pa tient
with prev iously diagnosed AML, regard less
of blood or 8M findi ngs 1t7421.
On imp rints, cytochemical stains for

myelo pe roxid ase (MPO), naphthol-AS().
c hloroacetate esterase (CAE) and l'"Il;no
specific estera se (NSE) ma y assist in
d ifferentiating granukx::ytic lineage (Mfl()+,
CAE+) from rroooblasnc forms (NSf+~ In
addition , CAE reaction can be applied to
rout ine sec tions , although the results may
depend o n fixation and d eca lcifying
agents.
present with tumour ma sses in which the
tissue arch itecture is effaced
ICD-Ocode
Synonyms
Extramedullary myeloid tumour; granulo-
cytic sarcoma : cmorona

Epidemiology
There is a predilect ion for ma les and last
de cades ctute. The mare.t emaie ratio is
12 :1. The median ag e is 56 years (rang e.
1 month-89 yea rs) 1663 . 17421.
Etiology
The same as for acute myeloid leukaemia
(AMl) and myelop roliferative neop lasm s
(MPN).
140
Cytochemistry
Morphology
A myeloid sarcoma most c ommonly consists of myelobl asts with or w ithout features of promyeloc ytic or neut rophilic
maturation that pa rtially o r totally efface
the tissue arch itecture. In a sig nific ant
Acute myelotd leukaemia and related precursor neoplasms
Immunophenotype
On immunohistoc hemistry in paraffin sections, C D68 /KP1 is the most c ommonly
expressed marker, followed in decreasing
frequency by MPO , CD t 17, CD99 . CD6&'
PG-M t , lysozyme , CD34 , termin al deoxvnucreoncvt trans ferase (TdT ), CD56,
CD6t/lAT/von Willeb rand antigen, CD30,
glycophorin, .and C D4 117421 . Foc i of

plasmacytoid dendritic c ell differentiation
(C0 123 +) are occasionally observed in
cases carrying inv(16) 117421 . The combination at the above mentioned markers
allows the recognition of tumo urs with a
more immature mye loid pheno type, as
well as of c ases with mveromonccvtrc.
monoblastic, erythro id or megakaryocytic
differentiation. Exceptionally, aberran t antigenic expres sions are obs erved (cytokeratins. B- or T-cell marker s). Ca ses that
meet cntena for mixed phenotype AML
are not c lassified as my eloid sarcoma
(See Chapter 7). Flow cvtorenlc ana lysis
on cell suspensions revea ls posmvmes for
C0 13. C033. C0 117 and MPO in tumour s
with myeloid d ifferentiation. and for CD 14.
COl 63 and COll e in the monob las tic
ones.
Geneti cs
By FISH andlor c ytog enetics, c hromosomal aberrations are detec ted in ab out
55% of cases. They incl ud e rnonosomy 7,
trisomy 8, MLL-rear rangement. inv( 16).
trisomy 4, monosomy 16, 16q-,
2Oqand trisomy 11 {17421. About 16% of
cases carry evidence of NPM 1 mutations
as shown by aberrant cytopl asmic NPM
expre ssion 1663. 666/. The t(8;2 1Xq22;q22)
observed in paed iatric series seem s to be
less frequent in adu lthood 1' 742 , 19 781.
sc-.
Differential d iag nosi s

The major d ifferential d iag nosis is with
mali gn ant lymphoma , The d iag nosis of
my elo id sar coma is valid ated by the
results of c ytochemical and /or immu nophenotypic analyses. These allow the
d istinction of myeloid sarcoma. from: 1ymphoblastic lymphoma, Burkitt lymphoma .
diffuse large B-cell lymphoma. small round
c ell tumours, part icu larly in child ren, and

blastic pl asmacyt oid dendritic cell neopla sm 11742/. These tumours must be
di stinguished from non-effa ci ng tissue
infiltrates by AML or MPN
Haernatopoietic stem c ell.
Prog nosis and predictive factors
The cli nic al be haviou r and respon se to
therapy seem not to be influenc ed by any
of the following factors: age , sex, anatomical site(s) involved . de novo presentation,
clinical history related to AMl. MDS or
MPN , histological fea tures. immunophenotype and cytogenetic find ing s
117421. Pat ients 'Nho undergo allogeneic
or aUIOOgous BM transp lantation seem to
have a hig her pr ob ab ility of prolonged
surviv al or cu re 1268. 17421.
MyelOId sarcoma
141
Myeloid proliferations related

to Down syndrome
Individuals with Down syndrome (OS)

have an inc reased risk of leukaemia compar ed to non-OS individ uals 1716. 23651.
The inc reased risk is variously estimated
at 10 to 100 Iold . The inc reased risk ex-
tend s into the adult years. In addition to

the increased Incidence, the ratio of acute
lymphoblastic leukaemia (A LL) to acute
myeloid leukaemia (AMl) in OS chil dren
less than 4 years of age is ap proximately
equal, 1.0 :1.2, compared 10 nonDS children in the same age group in which the
ratio is 4 :1 . There is an approximately 150
fold increase in AML in OS children less
than 5 years of age; 70% of the cases of
AM l in OS children less than 4 years of
age areacute megakaryoblaslic leukaemia
in con trast 10 the 3-6% incidence otttns
to m of leu kaemia in r"lOfl-DS child ren . The
acut e megakaryob lasl ic leukaemia whic h
occurs in OS children has somewhat
uniqu e morpho logic, imm unophenotypic,
mol ec ular and clinical characteristics
wh ich d ist ing uish it from other forms of
ac ute megakaryob lasli c leukaemia, inelud ing GATA 1 mutations 1635. 1362 J
These va riou s featu res serve as the rationale for the recog nition of this form of
leukaemia as a d istinct type in the WHO
c lassification, In add ition to the uniq ue
characteristics of the pred ominan t form of
AM L in OS ch ild ren less than 4 yea rs of
age , ap p roximately 10% of OS neonates
manifest a haema tolog ic di sorder refe rred
to as transient abnormal my elop o iesis or
trans ient myelop roliferative otsoroer wh ic h
may be morphologi ca lly ind isting uishab le
from the predominant form of AML in OS
child ren 127 1, 1409 1, This disorder resolves
sponta neously over a peri od of seve ral
weeks to 3 mo nths , In 20-30% of the affected cases. non-remi tting ac ute megakaryoblastic leu kaemi a su bs eq uently
develop s in t to 3 yea rs. It is important to
rec og nize that altho ugh the atore mennooeo d isorders have rec eived the most
attention in OS p atient s , they occur in a
specific age g rou p and other fo rms of
ac ute leukaemia, bo th ALL and AML. affec t OS individuals. The ove rall inc reased
risk for OS individuals includes all types.
The same approach lor characterizing the
142
I. Baum ann
C M, Niemeyer
AD. Brunning
O.A. Arber
A, Porwit
specific type of teukaemia in OS patients

m ust incl ude the same ca reful morpholoqic, lmmunoonenotvoic. cytogenetic
and mol ecular eval uation as in non-OS
individu als to ensure that appropriate
the rapy is administered 124891.
Transient abnormal
myelopoiesis
Definition
Transient abnormal myelopoiesis (TAM) is
a unique d isord er of Down syndrome (OS)
newborns that presents with clinical and
mo rphologic find ing s indistinguishable
from AML. The blasts have morphologic
and irrrnunologic features of megakaryocytic lineage.
ICD-Ocode
The provisiona l code proposed for the
fourth edition ofICO-O is 9898/1.
Synonym
Transient mye lopro liferative d isord er.
Epide miolog y
Trans ient abnormal myelopoi es is occurs
in approximately 10% of OS newborn s: it
uncommonly occ urs in phenotyp ica lly
normal neonates with trisomy 21 mosaic ism,
Clinical fe atures
At presen tation , thrombocytopenia is most
commo n; other c ytopeni as are less freq uently encoun tered, There may be a
ma rked leukoc ytosis and the pe rcentag e
of blasts in the per ipher al blood (PB ) may
exceed the blast pe rce ntage in the bon e
ma rrow (BM ). Hepatospl enomeg aly may
be present. Rarely, cl inical complications
incl ude ca rd iopulmonary failure. hyper.
viscosity. spl enic necrosis and p rogressive hepa tic fibrosis 15921. The proc ess in
the major ity of patients undergoes spontaneous remission Within the first three
months of life; a few chil dren experience
life th reaten ing or even fatal clinical complications.
Acute myeloid leukaenlla and related precursor neoplasms
.-
Fig. 6.41 Blood 5me from a ore day-old Ilfanl ...

00rM'l synOrome and lransieot abnofmal ~
The PB contailed 55% f*Ists. C)1Jgenek studystx.:l
horny 21 as hi soleabnormality. The process ~
~1MIl" a period ofbJ" weeks.
Morphology and immunophenotype

The morphologic and immunophenotyplC
features of TAM are simila r to those of the
blasts in most cases of OS AML. Peripheral blood an d 8 M blasts ouen have
basophilic c yto plasm w ith coa rse besop hilic gra nules and cytoplasmic blebbing suggestive of meqakervobiasts.
Some patients have PB bas op hilia; eryth roid and meg akaryoc ytic dysplasia is
often present in the BM 127 11. Blasts in
TAM d isp lay a cha rac teristic immunoph enotype 11 25 11 . In most cases the
bl asts are positive fo r C034, CD56.
C0 117, CO t3, C D33, CD7 , CD4 dim,
C041, C0 42, TPO-R, lL-3R, C036, COOt,
C071, and a re negative for myeio pe rc
case. C0 15, C0 14 and g lyc oph orin A
The bl asts in approximately 30% of cases
are posi tive for HLA-DR.
Antibod ies to C04 1 and CD61 may be
p artic ularly useful in id entifying cells of
megakaryocytic lineage in immunohistologic prepa rations .
Genetics
In ad dition to trisomy 2 1, ac quired GATAI
mutations are present in blast cells of TAM
1635,942,2347/. While gene eneysnoes
have suggested differences in expression
between AM L of OS an d TAM. these
findings have not yet been cootsrreo
1258, 1298, 1439/.
..:....."!;;.4 . ....," -'
FIg. 6.42 UyeIoid 1eukaerr'U associaled wilh Down syrdome in a two year-dd d*l. A Bone marrow smear. ThePB and8M smearsc:ontarled ITIJIbpIe blasts as ~_ loWry
ollie bIasls contained runetOUS coarse basoIlI*CI:lIcAnd gJarUes . wtidl were myeloperoxidase ~_ Cy!OgenetJC sludy et 1M bme showed trisomy 8 in ali:lIbDn kllrJsomy
21. B Bone marrow trephrle biopsy !rom !he same pabenl There aft! I'II.I'flef'OI. blasts and occasional megakaryocyles induding one with a IIOIHobated IllJl::llM. C An irTmJnl>
IJst*9C readJon WIth CD-61 antibody. There are r...metOUS readJng eels indtdng otMous megakatyocyles and sevetaI smaIer eels .
Prognostic and predictive factors
individuals beyond the neonatal period .
Although the d Isorder is characterized by

a high rate of spontaneous remission,
rco-nansent AML develops 1 103 years
There are no biok>gical differences in OS

individuals between myelodysplaSbC ~
later in 20-30% ot mese children 125031.

Indic ations lor chemotherapy in TAM are
not firmly established ,
Myeloid leukaemia associated

with Downsyndrome
Definition
Individuals with OS have a 50 fold increase in incidence of acute leukaemia
during the first 5 years of life compared to
non-OS individuals. Acute myeloid

leukaemia in OS is usually an acu te
megakaryoblaslic leukaemia, accounting
for 50% of cases of acute leukaemia in OS
drome (MOS) and overt AMl; therefore, a

comparable diagnost ic differentiation algorithm is not relevant and would have no
prognostic or therapeutic consequences.
Since this type of disease is unique to
ch ildren with OS the term myeloid
leukaemia of OS encompasses bOthMOS
and AML.
ICD-Ocode
fourth edition of ICo-O is 9898/3.
Epidemiology
The great majority of children with OS with
myeloid leukaemia are under 5 years of
life. Abou t 1- 2% of ch ildren with OS will
develop AML dur ing the first 5 years of
Fig. 1.'3 SedicI'I d iWI atldl:ri'III ~ node In:lm eNd wrltl Ck:Jr,yrJ syncmne lnl ac:uIe megakar'yobl9sbc Ieo..*aerTia
The I'lXIe is ~ ~ by b8sls wifl occasicI'laI ~. sane d.n::n ae dyscllasIc.
Iile. Children with OS account lor - 20% of

all paediatric pat ients with AMUMOS
1271 .592.9081 _Myeloid leukaemia of OS
occ urs in 20-30% 01 children with a pr ior
history of TAM and the leukaemia usually
occ urs 1-3 years after TAM.
Blood and BM are the princip le sites of involvement . Extramedul lary involvement,
mainly of sp leen and liver, is almost always present.
Clinical features
The disorder manifests predominantly in
the first 3 years of life, The clinic al course
in children with tess than 20% blast cells
in the 8M appears to be relatively indolent and presents initially with a period of
thrombocytopenia. A preteokaemc phase
comparable to refractory cytopenia of
ch ildhood (RCG)generally preceeds MOS
with excess blasts or overt leukaemia.
Morphology
In the pre-leukaemic phase. which can
last for several months, the disease has
the features of RCC (See Chapter 5) lacking a significant increase of blasts. Erythroid cells are macrocytic. Dysplastic
features may be more pronounced than in
primary refractory cytopen ia.
In cases of AML, blasts and occasionally
erythroid precursors are usually present
in the PB. Erythrocytes often show
con siderable anrscooikllocytoele. sometimes dacryocytes. The platelet count is
usually decreased and giant platelets
may be observed,
In the 8M aspirate, the morphology of the
leukaemic blasts shows particu lar features with round to slightly irregular nuclei
and a moderate amount of basophilic
MyefOid proliferatIOnsrelated to Down syndrome
143
c ytoplasm; cy topl asmic b lebs may be

present. The cytoplasm of a variable number of blasts co ntains coarse granules resembling b asoph ilic gra nules. The
granules are generally myeloperoxid ase
negalive. Erythroid p recursors often show
megaloblastic changes as well as dysp lastic forms, including bi- Of trinuc leated
cells and nuclear fragments. Dysgranuloporesrs may be present .
The 8M core may show a dense network
of reticulin fib res, making adequate 8M
aspi ration difficult or impossib le. Erythropoiesis may be increased in cases with a
low blast percentage and decreases with
disease progression. Maturing cells of
neutrophil lineage are usually decreased.
In cases WIth a dense blast cell infiltration
rare dysplastic megakaryocytes may be
seen. In other cases of acute megakaryootasnc leukaemia. megakaryocytes may
be markedly increased with clusters of
dysplastic small forms , micromegakaryocvtes and occasionally an increase in
promegakaryocytes.
144
Immunophenotype
Leukaemic blasts in acute megakaryocytic
leukaemia of OS display a similar immunoph enotype to blasts in TAM /125 11. In
mos t cases, the blasts are posi tive for
CD 11?, CD 13, CD33 , CD? , CD4 , CD42 .
TPO-R, IL-3R. CD36, CD4 1, CD61, CD7 1.
and are negative for myeloperoxidase,
C0 15. CD1 4 and glycophorin A. However, in con trast 10 TAM, CD34 is
neg ative in 50% of cases and approximately 30% of cases are negative for
CD56 and CD4 1. Leukaemic blasts in
other types of AML in OS display phenotypes corresponding to the particular
AML category
Antibodies to C041 and C061 may be
particularly useful in identIfying c ells of
megakaryocytic lineage in irrvnunohistologic preparations.
Genetics
In addition to trisomy 21, senate rmtatcos
01 the ge ne encoding the transc npnon
factor GATA1 are considered pathognomonic of transient ab normal mveicooeeis
of Down syndrome (TAM) or Mo S/AMl oi

OS 1835 . 942, 13621. Children above the
age of 5 with myeloid leukaemia may not
have GATA 1 mutations and such cases
should be consi de red as 'conventional"
MDS or AML. Trisomy 8 is a comrTlO'l
cytogenetic abnormality in myeloid
leukaemia of OS occurring in 13-44% at
patients 1908, 9181. Monosomy 7 is very
rare in Ds-associateo myeloid leukaemia
Postulated nonnal cou nterpart
Prognostic and predictive factors

Clinical outcome for young children WlI!l
OS and myeloid leukaemia with GATAI
mutations is unique and is associated
with a better response to chemotherapy
and very favourable prognosis
to non-OS children with AML 112501. rte
children should be treated on DS-specrllc
protocols. Myeloid leukaemia in older OS
children with GATA' mutation has a
poorer prognosis comparable to AMl i'l
patients without OS {75 11.
corceec
Blastic plas macyto id dendritic cell

neoplasm
Definition
Blastic plasmacytoid dend ritic cell (BPDC)
recoesm is a clinically agg ressive tumour
defived from the precursors of otasrnacvklid dendritic cells (also known as pro tesSlOnaI type 1 interferon producing cells or
plasmacytoid morocvtes). with a high trecuencv of cut aneous and bo ne marrow
(8M) involvement and leukaemic d issemination.
ro<l code
9727/3
Sjoonyms
Blasbc NK-celilymphoma 11039/. aqraniJaf CD4. natural kille r cell leukaemia
12771. blastic natural killer leukaemia/lympt'(ma \576 J, aaranurar CD4 +CD56+
reematooerrmc neoplasm 117361ltumour
19201
Epidemiology
This is a rare form of haem atologic neoplasm. without any known racial or ethnic
predilection. It has a male/fema le rano of
33:1; most patients are elderly, w ith a
eererecnan age at diagnosis of 61-67
years. but it can occ ur at any age , inCkldlngchildhood 1702. 920 ,1031 1.
Ebology
There are c urrently no cl ues to the etrobgy 01 BPDC , bu t its association w ith
myelodysplasia in some cases may suqgeS! a related pathogenesis. There is no
association with Epstein-Ba rr virus (EBV) .
F. Pacchem
D.M. Jone s
T. Petrella
The d isease tends to involve mul tiple
sites . w ith a p redi lection for skin (almost
100% of cases). followed by 8 M and peripheral blood (PB) (60-90%). and lymph
nodes (40 -50%) 1920, 17351 .
Clinica l features
The pat ients usua lly present with asymptomatic solitary or multip le skin les ions
that c an be nod ules, pl aque s. o r b ruiselike areas, Reg ional lympha denopathy at
presentation is c ommon (20%); PB and
BM involvement can be minimal at pre sentation . but invaria bly develops w ith
progression of d isease . Cytopenias (especia lly thrombocytopenia) can occur at d iag nosis, and in a minority of cases can be
seve re, indic ating BM failure 1702, 920 1.
Follo wing initial respo nse to chemotherapy , re lapses invariab ly oc c ur, involv ing
skin alone. or skin associated with othe r
sites . includ ing soft tiss ues and the centrat nervous system. In most cases a fulminant leukaemic phase ult imately
develop s 1702 1.
About 10-20% of cases of BPOC are associated with or develop into a mveromonocytic leukaemia or acu te myeloid
leukaemia 1702, 920, 924 , 1142 . 1735 ,
18301 . Thes e second teukaermas can
evo lve from underl ying mye lodysplasia,
or appea r sud de nly upon prog ression or
relapse 1702, 924 ,1 1421
BPDC must be d istinguished from the
occasional association of a myeloid neoplasia (especially chronic myeIornonOCylic
leukaemia) with massive nod al or extranodal localization of plasmacytoid dendritic cells, in which the plasmacytoid
cells are rrnphoIogica/ly mature
and C056 negative 123351.
oeoouc
Morpho<ogy
BPDC is usually characterize d by a dif fuse, monomorphous infiltrate of mediumsized blast ce lls with irreg ular nuclei, fine
c hromatin an d one to seve ral small nucleoli . The cytoplasm is usually scant and
appears grey-blue and ag ranu lar on
Giemsa stain . Mitoses are variable in
number. but rarely prominent; angiOlnvasion and coagulative necrosis are absent.
In cutaneous inlihrates, tumour c ells predominantly occupy the dermis, sparing
the ep ide rmis , but eventually extending to
subcutaneous lat. l ymp h nodes are diffusely involved in the interfollic ular areas
and medulla, with a leukaemic pa ttern of
infiltratio n .
Bo ne marrow b iop sy may show either a
mild interstitial infihrate only delectable by
immunophenotyping , or massive infiltration ; residual haeroatcooetc tissue may
exh ib it dysplast ic features, especially in
megakaryocytes 11735}. On PB and BM
smears tumour cells may show cytoplasmic
rmcrovacuoles localized along the cell
memb rane and p seudop od ia.
Cytochem istry
BPDC tumour cells are non-reactive lor
naphthol-butyrate esterase and perox idase cytochemic al react ions .
r.. .-" 8IastJC pIasmacyIoid llendnOC eel neoplasm.
"' '\;I''~CIoJii.
A Ski'I tI.I'I'lWfand plaques. B The inIiIlrate diftu$ety imoIYes !he demis andedends tl subc:Wnews fat. but spares lIle
1Pde!fM, CThe neoplasbc eels are mediI.m-sized. wiIh lineetwomatin and scanly cytoplasm. reminiscentof undlf!erentiated blasts,
Blastic p lasmacytoid den d rrtic ce ll neop lasm
145
Immunophenotype
Tumour cells express CD4, CD43, CD45RA
and CD56, as we ll as the plas mac ytoid
dendritic cell-assoc iated antigens CD123
(interleukin-3 a-chain receptor), BDCA-2/
CD303, TCU , CLA (cutaneous lymphocyte-associated antigen) and the interferon-a dependent molecu le MxA (92,
920,924 , 1735-1737, 1739, 1747, 1830,
22791. Rarely, the C056 antigen can be
negat ive, which does not rule out the diagnos is if CD4, CD123 and TCl 1 are
present. Tumours that share some but not
all immunophenotypic features of BPDC
may be better class ified as "acute
leukaemia of ambig uous lineage".
C068 (an antigen typical ly found on normal plasmacytoid dend ritic ce lls) is expressed in 50% of cases , in the form of
small cytoplasmic dots (1735 , 1739J.
Among lymphoid and myeloid-associa ted
antigens, CD7 and C033 are relatively
common ; and some cases have shown
expression of C02, CD36 and CD38 ,
while CD3 , CDS, CD13, CD16, CD19 ,
CD20, CD79a, LAT (linker for act ivation of
T cells) , lysozyme and myeloperoxioase
are regularly negative , Granzyme B,
which is reg ularly found in norma l plasmacytoid de ndritic cells , has bee n
demonstrated on flow immunophenotyping and mRNA analysis in BPDC [395 ,
820\. but it is most ly negative on tissue
sec tions, similarly to other cytoto xic
molecules such as oertonn and TIA 1,
Terminal deoxynucleotidyl transferase (TdT)
is expressed in about one third of cases ,
with pos itivity rang ing between 10% and
80% of cells; CD34 and CD117 are negative. EBV antigens or EBV-encoded small
nuclea r RNA (EBER) are not found.
Except for CD56 and TdT, the immunophenotype of BPOC largely overlaps with
that of plasmac yto id dendritic cells occu rring in reactive lymph nodes and tonsils [654}. Because other heematotoqic
neop lasms (such as acute myeloid
leukaemia, extranodal NK/T-eeil lymphoma,
nasal type and mature T-cell lymphomas),
with or without skin involvement, may express CD56 with or without CD4, an
extensive immunohistochemical and/or
genetic analysis is manda tory before a
definitive diagnosis of BPDC is made (92,
173,386,920, 1386).
gamma rearrangement 1920, 1735}. Two

thirds of patients with BPDC have an abnormal karyotype: specific chromosoma l
aberrations are lacking, but complex karyotypes are co mmon; six major recurrent
ch romosomal abno rma lities have been
recognized, including 5q21 or 5q34 (72%),
12p 13 (64%), 13q 13-21 (64%), sqza-qter
(50%), 15q (43%)and lossofchrornosome9
(28%) 11279, 1737, 18301. Gene expression
profiling and array-based comparativegenomic hybridization have shown recurrent

de letions of regions on chromosome 4
(4q3 4), 9 (9p 13-p11 and 9q12-q34) and
13 (13q 12-q31) that conta in several tumour suppressor genes with diminished
exp ression (RB 1, LATS2), while elevated
exp ression of the products of the OrtCGgenes HES6, RUNX2 and FLT3 is notassociated with genomic amplification (5781.
Genetics
J-ceu and a-cen receptor ge nes are usually ge rmline {92, 1735, 1830}, except for
a few cases that showed T-cell receptor
146

The normal co unterpart is the p recursor
of the plasmacytoid den dritic cells .
Data on anligen 139 5. 396 . 820 , 920. 924.
1031 , 1051,1736, 1739.2279landchen"ll>
kine rec ep tor expression {18Sf, in vitro
functional assays {18S, 3961. gene e xpression profiling 15781. as well as on the
tumour-derived cell line CAL-l 11361 1all
point toward a derivation from the precursors of a special subset of dendritic cells,
!he plasma cytoid dendrit ic cells 1356,
857,20591 . These c ells are distinguished
by their p rod uction of high amounts of u Interferon in humans 1357l; in the pas t.
!hey have been defined with many different terms. such as lymphoblast, t-essocrated plasma cell , plasmacyt oid T-ce U
and plasmacytoid monocyte {6541 . The
i'nmunophenotypic heterogeneity with regards 10 TdT and the assoc iation with
myeloid disorders suqqests a multihneage po tential lor some cases 01 BPOC.

The c linical co urse is aggressive . with a
median survi val of 12-1 4 months . irrespective of the initial pa ttern of disease .
Most cases (80 - 90%) show an initial response 10 mulliagent chemotherapy, but
relapses with subsequent resistanc e to
drugs are regularly observed . Long-lasting remissions have been documented in
spor adic c ases, usua lly occurring In
young p atients who have been treated
with acute leukaemia-type induction therapy, followed by allogeneic stem cell
transplantation in first complete remission
192.920, 17351
Blastic plasmacytoid cencntc cell neoplasm
147
CHAPTER 7
Acute Leukaemias of Ambiguous Lineage
Acute leukaemias of ambiguous lineage
Ac ute leukaemias of ambigUOlls line age

encompass those leukaemias that show
no clear evidenc e of differentiation a long
a singl e lineage. They include Ieukaemias
with no lineage-specific antigens (acute
und ifferentiated leukaemia. AUL) and
those w ith b lasts that express antigens of
more tha n one line age to such a degree
that it is not possi ble to assign the
\eukaefT'Wa to any o-e lineage with certainty
(mi xed phenotype acute ieukaermas .
MPAL). The latter can eithe r contain d isIinc t b last populations. each of a different
line ag e. or one population with multi ple
an tigen s 01di fferen t line ages on the same
cell s. or a com bin ation.
Historically, there has been confusion
both in the term ino log y and d efinitio n of
MPAL. The term ac ute b ilinea l (o r b ilineag e) leukaem ia ha s been ap plied to
leukaemias con taining separate po p cta.nons of b lasts of mo re than one lineage,
and the ter m b iphenotyp ic leukaemi a to
thos e co nta ining a sing le populat io n of
b lasts c oexpressing antigens of mo re
thanone lineage I885, l267, 1427 , 21 19},
although some times the ratter term also
encom passed blnneaueu kaemta. Here the
term mixed p henot yp e acute leukaem ia
applies to this g roup of lesions in general,
and , as d efined b elow, the mo re spec ific
terms B/my e lo id (B/MY) and T/mye lo id
(T/MY) leukaemia to refer to reu keemra s
c onta ining the two linea ges specified,
irres pec tive of whether one or mo re than
one po pulation of bl asts is seen .
Some well-d ef ined mye lo id leukaem ic
en tities may have irnrnunoonenorvplc
features that might suggest that they be
classified as Bimye loid (BlMY ) Of Tlmyeloid
(T/MY) leukaemras. However, MPAL, as
de fined here, exc ludes c ases that c an be
cl assified in another category, eithe r b y
genetic or clinical features. These speci fic ally inc lud e c ases with the rec urrent
acu te myeloi d leukaemia (AML)associetec uansiocenons 1(8;2 1), t( 15;17 ) or
inv( 16); the first of these especiall y freq uently exp resses muniple Bceu markers
/22361. In addition, cas es of leu kaemi a
with FGFR I mutations are not con side red
TIMY leuk aemias Cas es of c hronic
150
mye logenous leukaemi a (C ML) in b last

c risis, MDS-re lated AMl and therapyrelated AMl shou ld be cl assified pnma rily as suc h , even if they have a mixed
phe notype, with a secon dary notation that
they have a mixed phenoty pe .
The d iag nos is of amb ig uou s lineage
leukaem ias rests on irnmunophenotyping .
Flow cytometry is the preferr ed method
for establishing the d iagnosis, especially
when a d iagnosis of MPAl is de pen dent
upon demonstrating coexo ressoo of 1ymphoid and myeloid d ifferentiation antigens
on the same cell. Cases in which the d iag nosis rests on demonstration of two distinct leukaemic populations with a d ifferent
p henotype may also be established by
immunohistochemistry in tissue sections,
or with cytochemic al stains for myeloperoxid ase on smears c oupled with flow cvtomet ry to detec t a leukaemic B or T
lymphoid population.
The myel oid component of an MPAL c an
be rec ogn ized in one of three ways:
1) When ther e are two or more d istinct
pop ulations of leukaemic c ells, one of
whic h wo uld meet immu no pheno typic
c riteria for ac ute mye loid leukaem ia {with
the exception that this po p ulation need
not c omprise 20% of all nuc leated cel ls}
2} When there is a sing le population of
b lasts that by itself wou ld meet c riteria for
B acute lymphoblastic leukaemia (B-ALL)
or T acute lymphob lastic leukaemia (T-ALl)
and the blasts also expressmyeloperoxidase,
M ,J Borowitz
M ,-e , Bene
Nt.. Harris
A. Porwit
E. Mat ures
most freq uently show n by flow cvtomeuc

positivi ty, on b last c ells coexp ressing 1ymp hoid mar kers. The myeloid lineage anngens CD 13, CD33 and CD l 17 are no!
specific enough to allow identification cA
a mixed phenotype leukaemia.
3) When there is a single population ot
cells that by itself would meet criteria forB
Of T-All in which the blasts also show tXIequivocal evidence of monoblastic differen tiation: either d iffuse positivity !t;)
non-specific esterase or expression cA
more than one monocytic marker such as
CD 11c, CD 14, CD36, CD64 Of lysozyme
The first of these three ins tances wooId
previously have be en consid ered -bilineage leukaemia" while alternatives 2 and
3 represent wha t wou ld have been
termed "bi phenotypic leukaemia".
The t-een component of an MPAl is recognized by strong express ion of cvtop lasmic CD3, either on the ent ire blast
population, or on a sepa rate suo oc ouanon of leukaemic c ells. Surface CD3,
thOugh rare, also ind icat es T-cell lineage,
Expres sio n of cC D3 is bes t determined
by flow c ytometry using relatively brighl
fluo roph ores such as phyc oerythrin or er
lophyc oc yanin , and should be as bright
o r nea rly as br ight as that of norma l residual T ce lls p resent in the samp le. T-cell
linea ge can also be demonstrated by
CD3 expression on b lasts by immunohistoc hem istry on bone marrow biop sies,
thou gh it should be noted that polyvalent
Table 7.01 RllQuiremefils for assigrlingmore than onelineage toa Single ~asl populaton.
Myeloid lineage
~xidas.e (fbw cylomeIfy,
immunohislOChemistry or cytoChemistry)
"
Mi:Inocy1icdifterentiaticl'l (al least2 of lhe kllIowrng: NSE. CDlle , C014, CD64 ,~)
Tlineage
Cytoplasmic COO (!kM' cytomeIry wi1l'l antibodies 10COO epsilon etIatn: irnn~nolliStoehemistry USIIIg polydonaI
<W1b-C03 <W1tbody maydeled CD3zeta chain, wt\id'I is not T<:eII spec::ific)
"
SOOace COO (rare W1 mixed pIlenoIype lClJIe leUkaen'liasj

8 lineage (multiple antigens requnct )
Strong C019 wiltl a1ieas11 oftnefclowing strr.Tf/'I e~ . CD79a. C)1OpIasrrMc C022. COlO
"
Weak CD19withill least 2 oIlhe IoIowilg 5IfOn!lIY exp!&S:Sed: C079a, cyqMsmic C022.CD10
Acute ieckaenes of ambiguous lineage
T-cell antibodies used in immunohistochemistry also reac t with the zeta (~)
Chain of the
receptor present in the
cytoplasm of NK-c ells , an d are thus not
absolutely
specific .
In contrast to w hat is d esc rib ed above
with mye loid and t -een lineages, no single marker is sufficie ntly specific to indicate B-cell differentiation with ce rtainty, so
that a constellation of find ing s is needed.
Been diffe rentiation can be recognized
v.tIen there is a distinct subpopulation of
cells that by itself meets criteria for B-ALL
When only one population of cells is present. then B-lineage assignment requi res
either 1) strong Co 19 exp ression coupled
with strong exp ression of at least one of
the follow ing antige ns : C01O, Co79a or
cCD22; or 2) weak CO 19 exp ression co upled with strong ex pression of at least two
of the following : C01O, Co79a and
cCD22. Rarely, a case may be ass igned
as B lineage even If C0 19 is negative,
though care must be taken when doing
this because of the relative lack of speci!iclty of C010 and Co79a.
Cases of MPAL based on one cri terion at
diagnosis (e.g. 'biph enotypi c leukaemia ")
may c hange ove r tim e or at relap se to the
other (" bilineage leuk aem ia"), o r vic e
versa. Also, following therapy, per sistent
disease or relap se may occur as eithe r
pure ALL o r AML. Some cases of wh at
'as been termed "lineage switch" 11684,
18251may reflect this phenomenon
Ambiguou s lineage leukaemias are rare
and account for less than 4% of atl cases
ol acute leukaemia. Many cases of w hat
have been rep o rted as undiffe rentiated
'eukaemia ca n b e d emon str ated to be
eokaemtas of un usua l lineag es, and
'TIany ca ses of what have been reported
as biphenotypic acu te leukaemias may in
tact represent acute lymphoid or myeloid
letJkaemias With cross-lineage ant igen
expression , so that the actual frequency
may even be lower, The se leukaerruas
occur both in children and adults but
-rore frequent ly in the latter, although
some su btypes of MPAL may be more
common in c hild ren 11145, 16711 .
Avariety of genetic lesions hav e been reported in am bigu ous lineage leukaemi as,
especially MPAL. Two of these , the t(9 :22 )
(Q34;q 1l ) BCR-ABL 7 translocation, and
sansrocanons associated with the MLL
gene occur frequently enough and are
associated with distinctive features that
lhey are considered as sep arate entities.
t-een
t-een
Acute undifferentiated
leukaemia
Genetics
There are too few case s des cnbed to
know whether any consistent ge netic
lesions occur.
Definition
Ac ute undifferentiated leukaemia expresses no markers co nsidered specific
for e ithe r lym pho id or myeloid line ag e .
Before categorizing a leukaemia as undif ferentiated, it is necessary to perform irnmunophenotyp ing w ith a comprehensive
panel of monoclonal antibodies in order
to exclude leukaemias of unusual lineage s, such as those derived from myeloi d
Of p lasmac ytoid dendritic cell p rec ursors,
NK-c ell precursors, basophils or even
non-baernatocoietrc tumo urs

While anecdotal experience generally
considers these leukaemias to be of poor
prognosis , information is too scanty to
make any defin itive statements.
ICD-O c od e
(q34;q11.2); BCR-ABL1
980 1/3
Synonyms
Acute leukaemia, NOS; stem c ell acute
leu kaemia.
Epidemiology
These leukaemfas are very rare , and
nothing subs tantial is known about the ir
frequency.
Bon e ma rrow and b loo d . There a re too
few cases to know wh ether the re is a
predilect ion for othe r sites.
Clinical featu res
There are no features that distinguish this
from other ac ute ieukaemias.
Morphology
The b lasts have no morp holog ic feature s
of myeloid d ifferentiation .
Cytochemistry
The blasts are negative for nweicoe ro xlcase and esterase.
Immunophenotype
These reukaemas typ ically express no
more than one membrane ma rker of any
given lineage. By definition , they lack the
T or my eloid lineag e specif ic ma rkers
cC 03 and MPO and do not expr ess Bce ll specific ma rkers such as cCD22,
cC079a or strong C0 19. They also lac k
specific features 01other lineages such
as megakaryocytes or p lasmacytoid denontrc ce lls. Blasts otten express HLA-oR.
CD34 , and/or C038 and may be posi tive
for terminal d eoxynuc leoti dyltransferase .

Haematopo ietic stem cell.
Mixed phenotype acute

leukaemia with t(9;22)
Definition
This is a leukaemia meeting the criteria for
MPAL in which the blasts also have the
t(9 :22) tra nslocation or BCR-ABL 1 rearrangement. Some pat ients with chronic
myeloid leukaemia may develop or even
presen t with a mixed blast phase that
would meet criteria for MPAL, however
this d iagn osis should not be made in patients know n to have had CML.
ICD-O code
fourth edition of ICo-o is 980613.
Epidem iology
Althoug h this is the most common recurrent genetic abnormality seen in mixed
p henotyp e ac ute leukae mia. it is a rare
leukaemia , prob ably accountin g for less
than 1% of ac ute leukaemias. It occurs in
bot h children an d ad ults , b ut is more
common in ad ults 1338 ,11 451.
Clinica l featu res
Patients present with features similar to
those of other patients with ac ute
leukaemia. Though there are not enough
da ta to be ce rtain , it is likely that they
present with high white b lood cell counts ,
similar to patients with Ph-s ALL.
Mof'phology
Many cases show a dimorphi c blast
population , one resembling Iymphoblasts
and the OIher nwecotasrs. although some
cases have no d ist inguishing features
Cases generally do not show significant
myeloid maturation ; care shoold be taken
abou t making this diagnosis in a case of
Acute leokaernias of ambiguous lineage
151

leukaemia with t(V;11q23);
MLL rearranged
Immunop henotype
In the majority of cases it is possib le 10
rec og nize a lymp hoblast popula tion With
a CD 19-positive , CDlO-negative B prec ursor (p ro-B) irnmuncphenotype , frequently positive for CD15. Expression 01
other B markers such as CD22 and
CD79a is often we ak. In addition to this,
cases also fulfi l criteria lor myel oid lineage as defined above, most comrnonly
via demonstration of a separate papUa.
tion of myeloid. and usually monobIaSIJC
leukaemic ce lls 1167 1. 237 11. Coexpessian of myeloperoxi d ase on Iymphold
blasts is rare. MLL translocations can also
produce T.ALL, so that it is thOOfeticaly
possible that T/myeloid Ieukaemias
oc cur, although these have not been
reported .
Definition
Genetics
Fig.1 .01 ElJrnyeIoid I8ulalInN with 1(9.22Nq34;q11 2). Theblasts vary from smaI ~ iIppeWVlg bIasIs kl ~
blasts WIlh dispersed c:lVl:lmaIin, prorninefJl nudeoIi and a Il'llXlefllte ann.n of pale ~.
myeloid leukaemia with maturation that

also expresses lymphoid markers, because such a pattern may be seen in patients with blast phase 01CML.
Irrvnunopheootyp
The grea t majority 01 cases have bl asts
meeting c riteria tor 8 and myeloid line age,
as descr ibed above , though some cases
have T and myeloid b lasts . Triphenotypic
leukaemi a has also rarely been reported .
Genetic s
All cases have either the 1(9;22) detect ed
by classical karyotyp ing . or the BCR-ABL1
transloc ation d etect ed by FISH or PCR.
Many c ases have addit ional c ytogenetic
abno rmalities, and of ten have comp lex
kary olypes.

Murnootent haematopoietic stern cell.
Ther e is no evidenc e thai this leukaem ia
derives from a di fferent cell from other
cas es of Ph+ acute leukaemia .
Progn osis and pred ict ive factors
This type of leukaemia has a poor orogno sis ; it a ppe ars to be worse than that
of other patients with MPAL {1 145 1, It is
not c lear whether the p rog nosis is wo rse
than that of patient s with Ph+ ALL, or if d iffere nt therapy can improve ou tcome.
There a re no known fact ors among pa tients with this leukaemia that c an p red ict
who w ill do better or worse. It wou ld be
expected that imatinib and related tyrosine kinase inhibitor s mig ht be useful in
the treat ment of this type 01 leukaemia;
how eve r. there are no data availa ble to
state this with ce rtainty.
152
Acute
This is a leukaemia meeting req uiremen ts

for mixed phenotype acute leukaemia in
which the b lasts also have a translocation
invo lv ing the MLL gene . Many cases of
A LL wi th MLL transiocauons express
myeloid-associated an tigens , bu t these
should not be considered MPA L unless
they meet the specilic c riteria noted above.
ICD-O code
The prov isiona l code p ropo sed for the
fourth ed ition of ICo-O is 980713.
Epidemiology
This is a rare leu kaemia that is more common in child ren th an in adults . As with
AL L or A ML with MLL rearran gem ent s,
th is leukaemia is relatively more co mmon
in infancy 11 145 , 16711.
Clinical featu res
Patients present similarly to other patients
with acu te leukaemia. As with other ac ute
ieukaemras w ith MLL transtcceuons. hig h
wh ite blood cell counts are common .
ewa
All c ases have rearrangements of se

MLL gene, with the most corrmon partner
gene being AF4 an chromosome 4 bafld
q2 1 1338. 16 71 1. r ranstocanons t(9:111
and t(1 1;19 ) have also been reported
The rearrang ement may be detected
either by standard karyotyping or by FISH
with an MLL breakapan probe or, less
com monly, by Pe R. Cases w ith deletions
01 ch romosome 11Q23 detected by
karyo typing shoul d not be considered in
this ca tego ry. The MLL tra nsloc ation may
be the only lesion present or there may be
other seconda ry cytog enetic or rrolecular ab nomaunes althoug h no additiooal
g enetic lesions common to multiple cases
have been d escr ibed
Progn osis and p redi ct ive factors
This is a poor prognosis leukaemia 111 45,
237 11. Patients with B/myelo id leukaemia
with MLL translocations are often treated
di ffere ntly from patients d iagnosed witn
ALL with MLL transtocatlons . but there is
no evidence that this is nec essary or
helpful.
Morphology
Most commonl y these leukaemias display
a d imorph ic blast population , with one
population clearly resembling monoblasts
and the ot her resembling Iymphob lasts .
However. in other cases they may have no
d istinguishing features and appear only
as undiffe rentiated b last cells. Cases in
whi ch the e ntire blast po pulation is
monobtasnc are more likely to be A ML
with an MLL translocation.
'eokaenes of ambiguous lineage

leukaemia, B/myeloid, NOS
Definition
This leukaemia mee ts c riteria for assign.
ment to both B an d myeloi d lineage as
described above. but in which the btass
lack the above-mentioned g enetic abrc-
mantes.
ICD-O cod e _
The provisiona l code propo sed for the
ftxmh edition of ICD-O is 9808/3
Epidemiology
This is a rare leukae mia , p rob abl y ac counting for ab out 1% 01 leukaemi as
overall. It can be seen bo th in ch ildre n
and adul ts bu t it is mo re common in
adults.
Clinical features
Immu noph enotype

Blas ts meet the criteria for both Bclymproto and myeloid lineage assignment
listed ab ove. Mveiooeroxioase-po sluve
rnyeloblasts or mon ob lasts commo nly
also express other mye loid -assoc iated
marker s includ ing CD 13, CD33 or CD 117.
Exp ression of more mature markers of Bcell lineage such as CD20 is rare but may
occur, particu larly when a sepa rate
population of B-cell lineag e is id entified
{23 71 I,
There are no uniq ue c linical features,
""""""'"
Most
cases have blasts with no d istin-
(p.ishing features, morph060gicaJIy resembk'lg ALL, Of hav e dImorphic ocoutetcns

with one rese mbling Iymphobl asts and
ee other resembli ng myeloblasts.
--.f""""C"
5: .~"( -..
,
Genetics
Most cases of B!myeloi d leukaemia have
c lonal c ytogenetic abnormalities. Ma ny
d ifferent lesions have been demonstrated. thou g h none is of such frequency
to sug g est specifici ty for this g roup of
leukaemias. lesions that have been seen
in more than a single case include de l(6p) ,

Multipotentia l naematopoeuc stem cel l.
There is g rowing evidence of a poss ib le
relation ship be tween a-.cell and mye loid
d evelop ment suggesting either involvement 01a corrrnon precursor, or of a precu rsor of one lineage that has reactivated
a d.tte renueton program of the other
11 127, 12401
B/myeloid leukaemia is generally cons ide red a poor prog nosis leukaemia. Many
pat ients mee ting c riteria lor B/myeloid
leukaemia have the unfavourable ge netic
lesio ns and it has bee n sugg ested that
this ac cou nts for the ir poor prog nosis
11145 1. Whether ad verse cytog enet ic features entirely exp lains the poor outcome is
not definitively established 11267, 23711.
-- _ .
Sf"
.'-,j"-""
;: ..~ -.
'
12p 11.2 abnormalities, del (5q) , structural

ab normaliti es of 7, and numerical abnorma lities inc ludi ng near tetraploidy [338,
16711, Com ple x karyotyp es may be seen
There are insufficien t da ta in the literature
to sugg est that B/mye loid and T/myeloid
leukaemias have differ ent freque nc ies of
oeterent genetic lesions, once the t(9:22)
and MLL rearra ngements have been accounted for.
..::<:-'...
;. '
' I' :"'.: .
..
. ,
Mixedphenotype acute
leukaemia, T/myeloid, NOS
Def inition
This leukaemia meets c riteria for assign ment to both T and mye loid lineage as desc ribed above , but in which the blasts
lack the above men tioned genetic abnormalitie s.
COlO m e
ICD-O code
The provi siona l code proposed for the
fourth ed ition of ICD-O is 9809/3.
,, ;.
.
...'
I"
.:,~.;
. :.~..
: C
of.,'" ''':-1 '' , Ii.,

eN
. ~ )
FITe
Fig. 1.D2 FkIw L)'IOmetty in EIJmyeIoid 1euUemia. A C045 'IS Side scatter display ShoWlIlQa ma,a popuIaIlon of din
COt5+ !:*lsts. B ~ 1111 bloe. residual normal B cells red and rnyeIoperoxidas posIbYe c:eIls (ndudong boIh
tesls and I1ISiduaI nonnaI ceh)~ . aeTheIk:et ~ CD19 and C022 areslrOI9Y expressed on !he B Iym~ blasts. II"" CXlll1lIlable b!hal seen WIII'I residual nonnaI Ek:eIs (in red). 0 t.b;t of !he B-ceI blasts IaciMPO
..., many hJu!1l nol aI of !he ~ blasts are MPO posiIi'Ie. There is a smaIpopUabonof blasts eoexpmsing
1I1l9 rei MPO.
Epidemiolog y
This is a rare leukaem ia, probab ly ac co unting for less than 1% of leukaemias
overall. It can be seen both in c hildren
and ad ults . It may be relatively more Irequent in c hildren than is 8/myeloid acute
leuka emia .
C linical features
There are no unique clinica l features.
Acute leukaemias of ambiguous lineage
153
the t(9:22) and MLL rearrangements teve

been accounted lor.
Pos tulated normal counterpart
Mctnpot entrar haematopoietic stem cell.

There is growing evidence 01 a possible
relatio nship between T-c ell and myeloiO
development suggesting either irM:llverne1:
01 a common precursor, or of a Iymphoicl
precursor that has reactivated a myeloid
differentiation program 11 127, 12401.
PrognosiS and predic tive factors
Tfm ye loi d leukaemia is generally CQl'lSI'
dered a poor prognosis IeU<aema a/Ito..I;1l
data are limi ted on the outcome of trese
patients distinct from other MPAl pawns.
Patients with TtmyeIoid leukaemia teve I'l'A
been treated un iformly. although carrOnations of myeIoid-directed and IymptloiOdtrected therapy have been tried . and scm!
patients may respond to one or the OCher,

leukaemia, NOS rare types
""""""Most cases have blasts with no cnstmguishing features. morphologically resembling ALL, or have dimorphic
populations. with one resembling lympboblasts and the other resembling myeio-
addition to cCD3, the
t-een com ponent

t-een
fre quently expresses othe r

ma rkers
including C07,CD5, and C02. Expression
of surface G03 may occur when a separate population of
line age is ioenu-
t-een
fied 123711.
b lasts.
lmmunophenotype
Blasts meet the criteria for both T-lymphoid
and myeloid lineage assig nment listed
above. My eloper oxid ase-p ositiv e mvero-
blasts or monoblasl s com monly also ex

pr ess othe r m yeloid-associated ma rkers
including CD 13. CD33 or CD 117. In
Genetics
Most cases have clonal chromosomal abnor ma lities , although no ne is of such frequency to sug gest specific ity fo r this
g roup ofleukaemias. There are insufficient
data in the literature to sug gest tha t B/MY
and T/ MY le uka emi as hav e d ifferent freque nc ies of d ifferent ge netic lesions, once
Fig. 7.001 ThnyeIoid 1euIlaenU. ThIn ill . dimlrphicpop.MtionaI blasts wilh many smaI~ ; larger blasts
alsoMoe high ~sm 1'lIlio. h manatin arid inalnspicuous rndeoL
154
Acute leukaemlas 01 ambigUOUS lineage
Some cases of leukaemia have been seen

in which leukaemic blasts show clear-cut
evidence of both T and B lineage commitment as defined above. This is a very
fare phenomenon, with a frequency that is
likely lower than what has been reported
in the literature. As strictly applied, the most
recent EGIL c rite ria for biphenotypic
leukaemia (scores hig he r tha n 2 in more
than one lineage), whic h assigned 2 points
to CD79a expression 153, 187) would
likely overest imate the inc idence of BIT
leukaemia bec au se CD79a can be detected in T-ALL 11 750). In assig ning B lineage to a case of T-cell leukaemia, CD79a
and CD 10 should not be considered as
evidence of B-celt d ifferentiation. There
have also been a few c ases with e~i
dence of trilineage (8, T and myeloid lineage) assignment. Overall ther e are too
few cases of either of the se to make any
specific statements about cl inical features, genetic lesions or prognosis.
To date, there have been no reports of B
or T/meg akary ocyt ic or B or Tferythro1eukaerJias. Because it has been suggested
that erythroid and megakaryocytic lineages
are the earliest to branch off from the
plur ipotent haematopoietic stem cell , lea...
ing progenitor cells w ith T, 8 and myeloid
potential 1111 , neoplasms of these corenations of lineages may not occur. If It'ey
do occur, it is possible that the definitions

used here might not detect all cases, as
these leukaem ias would not be expected
to express MPO .
_.-
, '.
-.. .. -
."
Other ambiguous lineage

feukaemias
Under some circumstances leukaemias
may express combinations of markers
that do not allow classification as either
AUL or MPAL as defined above. yet de Iinitive c lassific ation along a singl e lineage may be difficult. Examples of suc h
cases mig ht includ e cas es that express
J-ceu-assoctated but nol
markers suc h as C D7 and C OS without
cytoplasmic C03. along with myeloid-associated antigens such as C0 33 and
CD13 without mvetoperoeoase. Such
cases are best considered ac ute uncle ssiliable teukaemes. With more extended
panels containing newer, less commonly
used markers, such leukaemi as might be
able to be c lassified.
B
-'j'-'<':;;;,;,......:
. .~.. _, , ...., . .. ,. ,
CVTOPlo\SMlC f1"O
coe """"
rrrc
r-cen-soecmc
Natural killer cel l tymphobIastic leukaemia!
.,',',- C
.;:
., ,....,
. . ..,.,
"Ii, ,..,.,
SS L..
~phom.
This neoplasm has been very difficu lt to

define, and there is con siderable con fusion
inthe literature, Con tributing to the confusion is that many cases rep orted as NK
leukaemia because of the expression of
N-CAM (COS6) are now recognized to
represent cases of plasmacytoid dendritic
cell leukaemia 11735, 1736J. Similarly, the
entity at mye loid/NK-cell acu te leukaemia
11980, 2129J, whic h has been suggested
to be of prec ursor NK origin 11660) has a
primitive immunophenotype that cannot
be d istinguished from acu te myeloid
leukaemia w ith minimal different iation,
and until further evidence emerges these
should be considered as cases of AML.
Early in development, Nrc-celt progenitors
express no spe cifi c markers 17331 or ex pressmarkers that overlap with those seen
inT-cell All.., including C07. C02 and even
CDS and cytoplasmic C03 120701. so that
distinguishing between TALl..and NK -ce ll
tumours may be d ill icult. More mature but
rrore specific markers suc h as C016 are
rarely expressed in any acute leukaemia.
while some markers that m ight be c on sidered relatively more scecmc . but st ill
expressed on NK progenitor s. suc h as
CD94 or C0161 17331 are not commonly
tested. Some we ll c ha rac terized cases of
NK precursor tumours WIthlymphomatous
..
'
cf'FOFlTC
...
.'
,
.. .'
~.
. ,.~
. ..' .-
,.
presentations that expressed NK -specilic

CD94 lA transcripts have been de scr ibed
113061. It is hoped that wider availability of
more specific NK markers includ ing panels
01 antiboclies against killer inrnunog lObuhnlike receptors (KIRs) will he lp c lanfy this
d isease. but until then th is is best coosrcereo a provisional ent ity. The diagnosis of
precursor NK lymphoblastic leukaemia}
lymp homa may be considered in a case

thai expresses C056 along with immature
T-associated markers such as COl and
C0 2 and eve n incl udi ng cCD3, provided
that it lacks B-eell and mye loid markers,
and IG receptor genes are in the
germline configuration\1128, 1174, t6601
and blast ic plasmacytoid oenonuc c ell
leukaemia has been excluded
t-een
Acute leukaemias 01 ambiguous lineage
155
CHAPTER 8
Introduction and Overview

of the Classification
of the Lymphoid Neoplasms
Introduction and overview of

the classification of
the lymphoid neoplasms
Defini tio n
B c ell and liNK c ell neopl asm s are clonal
tum our s of matu re and immature B cel ls ,
T ce lls o r natural Killer (NK) c ells at various stages of differentiation , Because NK
ce lls are closely related . and share some
immunopheno typic and functional properties with T cells , these two classes of
neoplasms are considered together.
B-cell and T-cell neopla sms in many re-
spects appear to recapitulate stages 01

normal B-cell or t -een differentiation, so
tha t they c an be to some extent c lass ified
accord ing to the correspon d ing no rma l
staqe . However, some common B-cell

neo pl asms. e.q . hai ry celt leukaemi a, do
not c lea rly correspond to a no rmal B-cell
differentiation stage. Some neoplasms

may exhibit lineage heterogeneity. or
j lnnate immune system
E.S. Jaffe
N.L. Ha rris
H. Stein
E. Campo
SA Piler i
S.H. Swerdlow
even more rarely. lineage plasticity 11037 ,

13571, Thus, the normal co unterpa rt of the
neop lastic ce ll c anno t at this time be the
sal e basis for the c las sification.
Pathob iology of lymphoid neoplasms
and the normal immune system

The re are two major arms of the immune
system tha t d iffer, both in the nature of the
target and the type of the immune response, known as the innate and adaptive
immune responses , Ce lls of the innate
immune system represent a first line of
defense, a primitive response. Cells of the
inna te immune system inc lud e NK cells,
CD3+ CD5 6 + t-eens or NK -like t-eens.
and y6 T ce lls. These ce lls playa ro le in
b arrier defenses inv o lv ing mu cosal and
c utaneous immu nity. They d o no t need to
IAdaptive immune system I
yl T - . _ _
T_._--.
Toll like receptors

Not MHC Class II
restriCted
Cytokines
Chemokines
Complement
Agopeafic
-'''''
on B + T cells
First line of defense with a

maJor role in banief immunity
Ag presentation to
T cells in
context of MHC
Immunological defense
cha racterized by specificity and memory
Fill, 1.01 There are I\lIO mainarms of tile immur.e system. the innate immur.e system, and the adaptive immuroe
system, Diagram shows respective roles 01 lymphocyte sutlpopulations in the innate and adaptive immuneresponses
NKcells, N K~ike Tcells, and yfo Tcellsfunction with othercell types including granulocytesand macropha ges asa first
Hna of defense. These cells havecytotoxicgran ules (shown in red) oontainingperIorin andgranzymes The inna teimmuoe system lacks specilidty and memory. In the adaptive invnuoe system, B 00115 andToeIIs r&COgnize anligeos (Ag)
lhrough specific rec:e~ , immunoglobulin (Ig) and !he T-eeII recepD" rompIex (TCR) respediwly, Antigen presenta,
tion to T eels must take pIac:e via anligen-presenling cells (APe) in lhe conlell of Ihe appropnale majorhlstoa::lmpatibihly c:omplex (MHC) ClassIIantigens. FiglIe R'I()Ijfied from {1035}.
158
Introduction and overview 01 the cassmcatoo 01 the lymphoid neoplasms
encounter an tigen in the context of the

major histoc ompatib ility co mplex (MHC),
and thus do no t require antig en presenting ce lls to ini tiate an immune response,
The adaptive immune sys tem is a more
sophisticated type of imm une response.
It is specific for a particular pathogen; two
key feature s of the adaptive immune response are specifici ty and memory This
con trasts with innate immune responses
whi ch are non- specific lor the target. and
do not req uire o r lead to immunological
memory.
B-eeli lymphomas: lymphocyte differenti

ation and function
Bccell neo plasms tend to mimic stages 01
normal B-cell d iffe rent iation , and the reo
semblance to normal c ell stages is a
ma jor basis for their classification and
nomenclature.
Normal B-eeU d ifferentiation begins WIth
precursor B c ell s known as progenitor
B c eli sIB Iymphoblasts (b last ce lls thaI
are the precursors of the ent ire B-eell
line) , wh ich undergo irTYnunoglobuhn IDI
gene rearrangement and differentiate into
man se surface immunoglobulin (slg) pesitive (lgM+ IgO+) naive B cel ls via pre-8
cells with cytoplasmic ~ heavy chains and
imma tu re IgM+ B cells Naive B cells . that
are often CD5 + , are sma ll rest ing lymphocytes that c irculate in the peripheral blood
(PB) and also occupy pr ima ry lymphoid
foll icl es and follicle mantle zones (socalled recircula ting B cells) 11004A,
1152AI. Most cases 01 man tle c elilymphoma are thought to correspond to CDS
positive naive B cells 1994A I.
On encountering antigen that fits their 51.1'
face Ig rec eptors, naive B cells undergo
transformation, prolifera te, and ultimately
ma ture into an tibody-secreling plasma
cells and memory B cells. Translormed
cells formed from nerve B c ells that have
encountered antig en may ma ture d irectly
into plasma ce lls mat produce the early
IgM antibody respon se to antigen. T-cell
ind epend en t ma turation can take place
ou tside of the germinal centre 14241, It is
debated whether somatic hypermutatiOl"l
of the IGH@ genes occurs du ring this
Central lymphoid tissue

Precursor s-cene
Bone
marrow
Peripheral lymphoid tissue

Peripheral (mature) B-cells
Interfollicular
area
Na...
Follicular
area
Perifollicular
area
B<e<1.
Progenitor
.... AG
B<e<1
.......
Memory B-cells
Marginal zone
ExtrafotJiCular
Pre-Ekell
(@f~
4
Immature
B-<ell
c:
--
I
/
/
/
-------
8-<011
Precursor B-cell neoplasms

B lymphoblastic
Ieukaemlallymphoma
Pre-GC neoplasm
GC neoplasms
Follicular lymphoma
Burkill lymphoma
OLBGC. (some)
Hodgkin lymphoma
Post-GC neoplasms
Marginal zone & MAlT lymphomas

lymphoplasmacytic lymphoma
DlBCl(some)
Plasma cell myeloma
Fig, auz Diagrammatic represenlatiooof ~II diflerentiatioo and relationship to major ~II neooasms. ~II neocasme correspond to stages of B-cell maturation, even ItIoogh
the precise cell counterparts are not known in all Instances. Precursor s-ceu nat mature in the bone marrow may undergo apcotose or develop intomature naive B-cells that, fol..
'(lw'ng e~sure to antigen and blast transformation, may deveiop into shOl1lived plasma cells or ent8l'thegerminal centre (GC) where somatichyp&mlulatiOn and heavy chain class
switchingoccur. Centroblasts, the transf()(ll16(j cells of the GC, either undergo apcotcsis or develop into centrocytes. Post-GC cells include both klng-lived plasm a cells and mem-
cursu:
ory/marginal zone B-cells. Most B-cells areactivatedwithin the GC, butT-cell independent activation can take place ootsideof thegerminal centreandalsoprobably leads to memory type B-cells. Monocytoid B-cells, many of which lack somatic hyperm utatioo, are not illustrated.
Dl.BCl, diffuse large Bcell 'Ymphoma; CLUSll, chronic lymphocytic leukaemia/sma ll 'Ymphocytic lymphoma; MAlT, meccsa-essccated lymphoid tissue; AG. antigen; FDC, fojlic
u1W Oeooriticceli. Red bar. irmnurKlglobulinheavy cha in gene (IGH@) rearrangement;bluebar,immunoglobulinlightchaingene(IGl)rearrarJgem&nt; b1ad1 insertions in thered and
blue tersindK:ite !WI'Iatic hypermutation.
extratollicular maturation . Other antigenexposed B cells rniqrate into the ce ntre of

a primary follicle, proliferate, and fiJi the
follicular d endr itic cell (FOG) mesh work,
forming a germinal cenlre (l 325A, 1355AI.
Germinal centre centrobtasts express low
levels of slg. and also switch oH exp ression of BGL2 p rotein; thus . they and their
progeny are susceptible to death through
acootose ( 1828A1. Centrobtasrs express
COlO and BGlS protein. a nuclear tran scription factor that is expre ssed by bo th
centroblasts and centrocytes. BCL6 is not
expressed in naive B cells and is switched
off in memory B cells and plasma cells

11346 . 1760 1.
In the germinal centre, somatic hypermutation occu rs in the imm unoglobulin
heavy and ligh t chain variable (IGV)
region genes; these mutations may result
in a non-funct ional gene. or a gene tha t
produces antibody with lower or higher
affinity for antigen than the native IG
gene. Also in the germinal cen tre some
cells switch from IgM to rgG or Ig A production. Through these mechanisms, the
germinal centre reac tion gives rise to the
higher aHinity IgG or 19A antibodies 01the
late primary or secondary immune response 11 356 A I. The BCL6 gene also undergoes somatic mutation in the g erminal
cen tre, however, at a lower freq uency
than is seen in the IG genes l 1698A 1. Ongoing IGVregion gene mutation with intraclona l diversity is a hallmark of germinal
cent re cells. and bo th IGV reg ion gene
mutation and BCL6 mutation serve as
markers of cells that have been through
the germinal c entre. Most dilfuse large
B-cell neoplasms (DLBCL) are composed
01cells that at least in part resemble cantrobtasts and that have mutated IGV
Introduction and overview 01the classification of the lymphoid neoplasms
159
Table 8.01 Immuoophenotypic featuresof CO!M'!OIl mature B-<::el reooasme.
Neoplasm
slg;
C05
C0 10
C023
CQ.t3
C0103
BCL6
c~
CWSL l
IRF.....
CyeUn
MUMI
D1
ANXA1
(+PCI
LPl
+/.,+
HCl
."
;.
.,.
','
MALT lymphoma
Iym_.
f ollicubr
. t,
.,
. ;.
MCl
' ,'
IIrge
8-cIll lymphoma
. /.;.
/.
811ttitl
. ;-
--
."
01-
....
NA
,.
NA
.,
NA
.'~
. /-"
, >90% 01 cases -: . /., >50% 01 cases -: 01., <50% 01 cases e:-, <l<ni. 01 cases IRF4IMUM1, inletfeton regu3a
and 311; - , DLBCl oIgerTTlInaI centre 8<eI type (GCB) elqlAlSS COlOand BCl6; " . DlBQ. 01 aclro'aIed 8<eI
type (ABC) aretypically posllMt lor IRF41MUM1; "'. some Dl8Cl are C05. ; NA. not applc:able; lPl,1yrnptooo
Iabng Iacb' 4:ANXA1 , AnneXll"lAl; PC, praIileratIon celllreS: " plasma eel c:ornponent po$IllYe;', some grades
p1asmacylic lymphoma; MIL, ITIlIrgmI zone I)mphoma; MeL nlall1le eeI~ .
P~B
Pre-8
Immature
Mature
Gemlinal
naive 8
eeoee B
Antigen Independent
Memory B
(Marginal zooe)
Plasma cell
Antigen Dependent
I,-,--~==~=
I CD79A
[PAX5
[ CD20
n nnours.
Centrobrasts ma ture to centrocstes. and
these cene are seen predomina ntly in the
light zone of the ge rminal cen tre. Centrocvtes express slg that has an altered antibody combini ng site as compared WIth
that 01 their oroqenrtors. based both on
somatic mutations and hea vy chain class
Swit ching Cen trocytes with mutations thai
result in increased affini ty are rescued
from eocotose and they re-express Bel2
protein 11355A1. Throug h inleraction"";tn
surface molecules on FDC 's and t-cees.
such as CD23 and CD40 ligancL centrocytes swilch off BCL6 p rotein expression
1346, 17601. and oitterennate into either
memory B-eetts Of p lasma
1t 355AJ.
BCL6 and IAF4/M UM 1 are rec iprocally
exp ress ed , w ith IAF4/MU M l being positive in late cer nrocytes and plasma cells
166 1. t 9t4AI. IRF4/MUM 1 plays a critical
role in down-regulating BCL6 expresser
11914AI, Follicu lar lymphomas are 1lJTlCU'S
of g er minal c entre B-c etts (centrocytes
and centrobiasts) in wh ich the germinal
c entre celts fail 10 undergo apcorosts. in
most cases du e to a chromosomal rearran gement. t{14 :18), that prevent s the
normal switc hing off 01 BCL2 proten
expression, Centrccvtes usua lly preooninate ove r cen t roblas ts , and these neoplasms tend to be ind olent.
Post-germinal ce ntre memory Bccells cir
cu lat e in the PB and comprise at least
in the follic ular marginal
some of the
zone s of lymph nodes, spleen and mucos a-assoc iated lymphoid tissue (MALT).
Marginal zone e-cens of this co-roanmen t typ ica lly express pan-B antigens,
surfac e Ig M w ith only low level IgO and
lac k both COS and COlO 12064 A. 2293Bl.
produced in the ge rminal
Plasma
c entre enter the PB and home 10 the bone
marrow (BM). They conran predom inantlY
IgG or IgA ; they lac k slg and CD20, bI.C
exp ress IRF4/ MUM 1, C D79a , C03B and
CD 138. Both memory B-eetl s and long.
lived p lasma cens have mutated IGV
reg ion genes , bu t d o not continue 10
undergo mutation . Posl-germinal centre
Beene reta in the ab ility to home to tissues
in wh ic h they have undergone antigen
cens
cens
ceus
fig.I.O] SChematic diagram showing pherlotype 0/8 ~ at ~ stages of mah.ra1ion. TOT is II feature of
earty Iyn1)hOid preanors, irdIclIng boIh Band T IyrrfJhobIasts. as wei as!he blasts in some cases of acu1ll myeloid
leukaemia. C079A and PAX5 appNI' allhe bme of heavy etlan ger-.e rearral'lQelTlelll. COlO is I'IOt e~ IA'ltIIIhe
stage of inIrrI.JllOgIobuIirlliljll chain gene (/GLJ I'8aITllflQE!I' TOT, Iermml ~ IransJerase; SHM, soma1lc~ ; Red t .,/GH@ ~ll blue bar./GL rearrarJgelTleflt; Pre-8CR. pre-8<eI receplor ~
sisIi1g 01 a IG heavy thaI'l and !he IIWfOgale io,tJl chail (YItIch is ~ d two lri;ed smaI pepIides VpreB llf'Id
45, represenled in ~J; BCR. B celIl'llOfII*;Irol rnetln 8 eels : Redbar and blue bar wiItl bladti'lser1DJs, fNIfIIIglId
IGH@ and IGl. QeIleS WIth somabc h~.
160
ge nes , consis tent with a derivation from

c ells that have been exposed to the qe minal centre. Burkitt lymphoma cells are
BCL6+ and have mu tated IGH genes,
and are Ihus also though l to correspond
to a g erminal cen tre b last celt. Both
Burk itt and DLBCL co rrespon d 10 prolferating c ells. and are cli nically aggressr.oe
Introduction and overv-ew 01 the ctess.tcauoo of the lymphoid neoplasms
stimulation, probably through su rface integrin exp ression, so that B-cells that
arise in MA LT tend to return the re, while
those that arise in lymph nodes will home
to nodal sues and BM p03AI . Marg inal
zone lymphomas of MALT. splenic . and
nodal types correspond to post germinal
centre, merTIOfY B cells of marginal zone
type thaI derive from and proliferate
specifically in extranoctal, splen ic or nodal
nssoes. Plasma cell myekma corespooos

to a 8M homi ng p lasma cell.
T-cell lymphomas : lymphocyte differen tia
tion and function

Tlymphoc ytes arise from a 8M prec ursor
that undergoes maturation and acqui sition
of function in the thymus g land . Antig en
specific T cells mature in the thymic co rtex,
Tcells recognizing selt-peptides are eliminated via eccotosrs. in a process med iated
Peripheral lymphoid tissue
Central lymphoid tissue

Precursor T-cene
Bone
ryi.i;;~:"
.. ... .....
,
t-een
receptor. The 0.1\ and

structu re of the
"}'IS chains are each composed 01a variable (V) and const ant (C) po rtion. They
both are associated with the CD3 complex. which con tains 't- 0 and t chains.
NK-cells dO not have a complete 'r-cen
receptor com plex, ac tivated NK cells
exp ress the t and l; c hains of COO in the
cytoplasm. They express C02. COl , and
sometimes C DS. but not surfa ce COO.
They also typi cally express CD16 , CD56,
and variably COSl and contain cytoplasmic cytotoxic granule p roteins . NK-cells
kill th eir targets. through antibody depend ent cytotoxicity (ADCC) or a second
mechanism involving killer activating
rec ept ors and killer inhibi tory recept ors
, (KIRs). As NK-cells do not rearrange the
T-cell rec eptor genes, analysis of clonali ty
in NK -c ell prol ifera tions c an utilise antibod ies to the various KIR receptors ,
b y cortical e pithelial cells an d thymic

nurse cells. Co rtical thymocytes have an
imma lu re j-ceu phenotype . and express
termina l deoxynucleolidyl transferase
(TOTl. CO la . COO. CDS, and COl. CD3
is lirst expressed in !he cytoplasm, prior
10 complete t-een receptor gene rearrangement and export to the ce ll membrane. Cor tical thymoc ytes are initially
dou ble-negative lor bo th CD4 and CDS.
These ant igens are co-expressed in rnaluring mvmocytes. and later more mature
T-c ells express only CD 4 or CDS. These
varying sta ges 01 j-ceu matur ation are
ref lected in T lymphoblastic leu kaemia!
lymp homa (T-ALULBL).
Med ullary thymo cyt es have a ph enotype
similar to that of mature t-eens of the periph era l lymphoid o rga ns, There are two
classes of t-eens: o.~ t-eens and ~ T-c ells
12841. This d istin ct ion is b ase d on the
Peri heral mature T- and NK-cells
.
Skin
""W
T
T-binI , . . "
c;ell
~ ~f ~, -,------+-------?~ffl'
AG
L~ ZT~'
Thymus
T tvmphoblastic
Iymphomaneukaemia
FDC
Follicle
Peripheral (mature) T-cell and NK-cell tymphomaslleukaemlas
Fig. ' .0<& Diagrammatic representation d T-cel drflerenbabal. T-<.:eI neopIastnscorrespond lCI dJflerent stages 01 mabntion. Lymphoid progenilClfs enteree thymus wherePfflCU'sorT-cees deYeIop intovaried typeS 01 naive T-ceis. The~ rnauationaI palhd natural kiIer cells andy6 T<.efls is not filly ~tood. Thea~ T<:eIsleave1he1l'Iyrrus where
\.p)n expl)Sl.Q 10 anligen they mayUI'ld9rgo b1asllranslormabon and developfurther intoC04+andCD8+ elledor andmemory T<ets, T regulalory eels en 1hemajortype 01 COol
eIIector T<ells. AnoIhllf speciIic type 01 eIJedor T<eIls is the IoIliculaf helperT-eel that is found in gernjnal centres. Upon anligetjc stimulabal, T-cel teSj)(Ilses may OCW" irJd&.
pendenl ollhe gemWoal ceoue. or in 1hecontext 01 a germinal centre reaction. FDC. Follicular dendritic cells: AG. antiQen.
Introduction and overview of the classifica tion of the lymp hoid neoplasms
161
Toll-like receptors playa role in ce ll-cel l

interac t ions and sig nal ing. They p laya
critical role in the rec og nition of infectious
agents, init iating signaling through NFKB.
While they func tion most prominently in innate immune respo nses, t hey also have a
role in the adaptive immune system
[ 1282AI
The lym phomas of the innate immune
sys tem are pr ed ominant ly extra nocal in
p rese ntation, mi rroring the d istrib ut ion of
the fun ction al componen ts of this system.
It is interesti ng that ma ny t-een and
NK-ce il lymp homas o bse rved commonly
in the paed iatr ic and youn g ad ult age
group are de rived from cells of the innate
immun e system {10351. These inc lude aggressive NK -c ell leu kaemia, systemic
EBV-positive t-een lymphoproliferat ive
disease (LPD) of ch ild hood. most heo atosp lenic t-een lymp homas, and y8 Teen
lymphomas affectin g cutaneous and
mucosal sites. Anaplastic larg e cel l lymphom a (ALC L) is the most comm on paedi atri c T-cell lymphom a , and also is of
cytotoxic origi n. However its normal cellular
co unte rpa rt, if o ne exists, is unkno wn.
y8 t-eens exp ress nei ther CD 4 nor COB,
and also usually lack CDS. A subpop ulation
expresses COB. They comprise less than
r-ceus.
5% of all nor mal

and show a restricte d d istrib ution, being found mai nly in
the sp lenic red p ulp , intestinal ep ithelium,
and other epi the lial sites. It is notable that
these sites are mo re com monly affected
by yo T-cell lymphomas, w hich otherwise
are relatively rare 147, 241, 1303j. yO T-cells
hav e a restricte d range of antigen recognition, and repr esent a first line of de fense
against bacterial oeotroes, such as heat
shock proteins l2841. They are often involved
in respo nses to mycobac terial infec tions,
and in mucosal immunity
More rece ntly, the pattern of c ytolytic molecules has been investigated and co rrelated with both c ellular origin and
funct ion . For exa mp le, to da te five
g ranzymes have been demon strated in
human cel ls j 1984Aj. These enzymes are
simi lar in struct ure, but differ in their substrate speci fic ity and chromosomallocanons. G ranzyme M, a nove l me mber of
this family, has unus ual e nzyme specificity, preferring clea vage after meth ionine,
leuci ne or no rleuc ine. It has been sugg ested that this enzyme may p laya role
in the effector phase of innate immune responses . Its expre ssio n is rest ric ted to
NK-cells, CD3+ CD56 + t-eens. and yo
J-ceus, bu t it is absent in other cytotoxic
Ml:tdullary
(3
88~~e~"
a-cens.
CD1a
CD2ICDS
C0 3
Cytoplasmic
Surface
CD4 +
CD4/CD8
Double +
CD8+
I
I~T~-ce=':Iym=P:h:"':":':bc=lou:k:.:om=_
===m:':(:T-Al
=:lIl:B:l~)IIPeripheral T-eell lymphomas
I
I
TOT
Fig.8.05 Schematic diagram of T-<:ell maturation illustrating changes inantigenic expression. Tccell receptor (TCR)
genes (TRA@, TRB@, TRG@,TRD@) are shown schematicallywith solid red bars indicating absence ofrearrangement, and rearrangement ofrelevant TCR genes as additional black segments.The TRG@generearranges first, followed by TRB@ and TRD@ . up T cells delete the TRD@ gene during TRA@ gene rearrangement, as TRD@is
contained within the TRA@ locuson14q11.2. HOIVevef, yO Tcells may haverearranged TRB@genes,withoutassembly
ofa complete up TCR Productive rearrangement gives rise to two mainT-<:ell populations. ul3and yO. wiltlexpression ofltle relevantTCR complex on the cell membrane (shown as double red bars).
162
t-een subsets , Granzvme M is expressed

in bepatosorenrc T-cell lymp homas, cutaneous .,8 t-een lymphomas, and most
intestinal t-een lymphomas tested, linking
these neoplasms to the innate immune
system 11 1911.
T-cells of the adaptive immune system are
heterogeneous and functionally comp lex,
and inc lud e naive. effector (regulatory
and cy toto xic) , and memory t-eens. Interesting ly, t-een lymphomas of the adapt ive
immune system p resent pr imarily in
adu lts, and are mainly nodal in origin,
contrasting w ith the extranodal r -cenfym.
phomas of the innate immune system
/10351. CD4-positive T-cells are primarily
regulatory, acting via cytokine production
CD4-positive ce lls a re divided into two
maj or types, based on their cytokine
sec retion profiles, known as Th1, and Th2.
Th1 cells secrete inter leuk in {IL)-2 and
interferon t , bu t not IL4 . 5, or 6. In contraer , Th2 ce lls secrete IL4, 5, 6 , and 10
12841, Th 1 cel ls provide help mainly to
other t -eens and macropbaoes. whereas
Th2 ce lls provide help ma inly to Bcens.
in the prod uction of antibodies /2851.
CD4-positive T-cells can act to both help
and suppress immune responses, and
cons ist of mu ltiple sub po pu lations only
rece ntly recog nized .
Recen tly much has been learned about a
unique CD 4+ t-een subset found in the
normal germinal centre. These cells,
termed fo llicular T-helper ce lls (TFH), provide help to B-cells in the co ntext of the
ge rm inal centre reaction j63 1, 852.
1656A l . They have a unique p henotype.
exp ressing the germinal centre-associated
ma rkers BCL6 and COlO, norma lly found
on
TFH exp ress CD 4, CDS? PD
1, and p roduce the chernckine CXCL13
and its rece ptor CXCR5, CXCL 13 causes
ind uction and prolife ration of FOe;
CXCL 13 also facili tates the migr ation of 8
and T cel ls exp ressing CXCR5 into the
germina l cen tre. Recen t stud ies have
identified inc reased expression of CXCL13
in angioimmuno blastic T-cell lymphoma
{A ITL}, a finding that he lps to link tog ether
many of its c linica l and pathological teatures 163 1, 852. 1656A l . Notably AITL is
associ ated with polyclonal hype rpamma.
glo b ulinaem ia and expansion and prolif
eration of bot h B-ce lls and CD2 1+ FDC's
within the lymph node.
A CD 4+ T ce ll with very d ifferent properties
is the regulatory T cel l (Trag), w hich fuoctrons to shut off and sup press immune
responses 12043Aj . This cell is thoug ht to
Introduction and overview of the c lassification of the lymphoid neoplasms
Table a.o2
Imm~typic
Neoplasm.
features 01 common manse T-cell arid NKoCeII reooasrns.
CD)
CD4
CDS
CD7
COS
C02
TlA1
GrB
CDJO
CD2S
C056
C016
COS7
BCl6
COlO
EaV
EMA
PM
teu
T.lGl
Ani.
Ao'l"
ENKIT, Maul typt
EATL
.,
.,
"ISS
Pmry cutMllOU .,6

T"", _
AITl
AlCl,ALK+
AlCl,AlK
.,
.,.,.,-
.,-
-.
<
"
HSTL
SPTCl
.,-
.,-
<.,
,'- .,- ,
.,- .,- .,- .,-
.,-
-,.
.. ..
.. ..
.,-
.,
-'
-'
-'
--
..
c, cytopla~ C03(01)'. restricled to C03&: " T<eII receptor 'l'6: 'IIi, a rJIfIOriIy of cases expresses the o;fI T-ceHreceptor. " cose is exprMSed in Iha moIlO1'lOI"phic t)1Itt of
EAR 0( Type II: " , EBVis Ibsenl in neoplastic cess. but is nearly always present in a subpopuIabon of backgrourld 8-ceIs; . , PTCl. OOS is 001 a Slrg\e disease, buI a hettrOgenttOUS group, andItlefelore, a vanety of imml.flOPhenotypic proftles canbe seen. A, a subset of PTC,l. NOS Ire 0&riVed !rom loIicuIar helper T-eels FH), and often express CDS7, COlO and BCl6: TPLl , T~ proIymphocytic leukaemia; T-LGl, T<eIIlarge gra1u!af lymphocyllC leukaemla; ATLl, adiJft T-<;8" leukaemia/lymphoma: AggNK,
aggressive NK-cel leukaemia, ENKIT-nasaltype. Mranodal NKfr-telllymphoma, nasa~lype; EATL, enteropathy-associated T-eelIlymphoma; HSTl. hepatosplenic T-ceH
lyrrloma: SPTCL, subcutanlC!JS panl'licu~tis-li ke T-een Iymptloma; MFISS, mycosis tungoides and sezary syndrome: primary cutaneous COJO+ lPD, primary cutaneous
CD30+ T-<;elI lymphoproll!erative disease, including primary cutaneousanaplasticT-cell lymphoma: AlLY. ang'oimmunoblestic T-ce~ lymphoma: PTLC, NOS, periphlfa! T-cell
lymphomas, nototherwise specified: ALCL, anaplastic large cel lymphoma. 00, granzyme B; Per, perforin,
rr
play an imp ortant role in preven ting autoimmunity. Tregs exp ress high den sity
CD25, and the tran scription fact or
FOXP3, in com binatio n w ith C04, Adul t
T-cell leukaem ia/lymphoma (ATLL), ha s
been linked to Treg ce lls b ased on expression of both C025 and FoxP3 , and
this finding helps to explain the marked
m munosuppression associated with ATLL
11862A1
Recent studi es have tried to relate the
pathological or c linical manifestati ons of
t -een lym phom as to c vtokme or onemokine expre ssion by the neoplastic cells, or
accompanying ac cessory cells w ithin the
lymph nod e . For exa mple. the hypercalcemia assoc iated with ATLL has be en
linked to sec retion of fact ors with osteoClast-activating ac tivity 1664, 13581. The
haemophagocytic synd rome seen in scme
T-cell and NK-celt ma ligna nc ies has bee n
associated wit h sec retion of both cy tokines and c herno kmes . in the selt ing
d efect ive cytolytic function (737 , 12761.
Geneti cs
Seve ral ma ture B-cell neopla sms have
characteristic genetic abn ormalities tha t
are impo rtant in determining their biologi c
features and can be useful in d ifferential
d iagnos is . These includ e the t( 11:14) in
mantle c etl lymphoma, t(14 :18) in follicu lar
lymphoma, 1(8 :14) and var iant s in Burkttt
Iymphana, and 1(11:18) in MALT lymphoma
1515 ,1 104, 12851. The 1(11;14) is seen in
both mantle c ell lymphoma and a fraction
of c ases of pla sma cell myeloma, but
mino r differences in the tra nslocation
exist , invol ving d ifferent portions of the
irnrronoglobu lin heavy chain gene (IGHO)
(1991. The most common paradig m tor
trans locations involving the IGHtlon 14q ,
is tha t a c ellula r proto-oncogene come s

under the influence of the IGH @p romo ter
For example, in follic ular lymphoma. the
overexpreeeton of BCL2 blocks apoptosrs
in germinal c entre Bccells. The t(11;1 8),
c ommon in MALT lymphoma, results in a
fusion ge ne , AP/2/MALTI 1574, 1837,
2 109AI. The expression of API2 inhibits
the act ivity of several caspases. The partner g ene , MALTI, act ivate s the NF",B
pathway, as do other nensrocatons found
in MALT lymp homa, suc h as t(1; 14) and
t(14 :18).
Only a few T-cell neoplasms have thus far
been associated With speci fic genetic
abnormali ties . Anap lastic larg e cell lymphoma, AU< +, is def ined by trensocercos
involving the ALK (anaplastic lymphoma
kinase) gene on ch romosome 5, (t(2;5)
and variants 1582 .12291). Hepat osoieoc
lym phoma is assoc iated with
r-cea
Introduction and overview of the classification of the lymphoid neoplasms
163
Diffuse large B-cell 37%

Follicular 29%
WII... T l)rnp homa 9%
ManUe celll)rnphoma 7%
.CLLlSLL 12%
Primarymed large B-cell 3"A:
High Grade B. NOS 2.5%
Burkitt 0.8%
Splenic marginal zone 0.9%

Nodal marg inal zone 2%
l)rnphoplasmacylic 1.4%
Fig. 8.06 Relative frequencies of B-celilymphoma subtypes in adults. Significant differences exist in different geographicregions. However, dilluse large B-eelilymphoma(OlBCl) and~ I icular lymphoma are the most common subtypes irrespective of geographicor ethnic group. Note that these figures unoerasmate theincidence of CLUSLl, as
only patients presenting clinically with lymphoma were included, MCl , mantle 0011 lymphoma; ClUSlL, chronic lymphocytic Ieukaemialsmali lymphocytic lymphoma; PMLBCl , primary mediaslinal large B-celi lymphoma; SMZl, splenic
marginal zone lymphoma; NMZL, nodal marginal zooe lymphoma. Oala based on {51}.
isochromosome 7q . However, the molecular pathogenesis of most other T-cell and

NK-cell neoplasms remains to be defined,
Multiple othe r genetic tools have been
broug ht to bea r on the study of mature
lymphoid neoplasms, These include com parative genomic hybrid isation (CGH) ,
and the newer and more sens itive tech nique of array CG H, both of which can
identify areas of deletion or amp lification
within the genome \165-167}. Gene
exp ression microarrays can interro gate
the exp ression of thousands of genes at
the RNA level, helping to elucid ate pathways of activation and transformation 1509,
510,513,701, 1507, 1867, 1944}. Most
recently, studies have begun to explo re
changes at the epigenetic level that control
the expression of multiple genes {13141.
Principles of classification
The class ification of lymp hoid neoplasms
is based on utilisation of all available information to define disease entities 1898l.
Morphology and immunophenotype are
sufficient for the diagnosis of most lymphoid
neopl asms. However, no one antigenic
marker is specific for any neoplasm, and
a combination of morpholog ic features
and a pane l of antigen ic markers are
necessary for co rrect d iagnosis, Most
B-cell lymphomas have c haracteristic
164
immu nophenotypic profiles that are very

helpful in dia gnosis. However, immu ne
profiling is somewhat less helpful in the
subclassification of T-cell lymphomas.
In add ition, wh ile certain antigens are
commonly associated with specific disease entities, these assoc iations are not
entirely disease-specific. For example,
CD30 is a universal feature of ALCL, but
can be expressed in other T-cell and B-cell
lymphomas and classical Hodgkin lymphoma (CHL), Similarly, while CD56 is a
ch aracteristic feature of nasal NKff-cell
lymphom a, it can be seen in other T-cell
lymphomas, and in plasma cell neoplasms
1208,701,13251. Within a given disease
entity, variation in immunoph enotypic features can be seen For example, most
hepatosplenic 'teen lymphomas are of yi5
't-een phenotype, but some cases are of
aj3 derivat ion. Likewise, some follicular
lymphomas are CD1Q-negative. Additionally, the presence of an aberrant immunophenotype may suggest or help to confirm
a diagnosis of malignancy (10341 ,
While lineage is a defining feature of most
lymp hoid malignancies , in recent years
there has been a greater appreciation of
lineage plasticity within the haematopoietic
system, Lineage switch, or demonstration of
mUltiple lineages is most often encountered
in immature haematolymphoid neop lasms,
lntroduction and overview of the class ification of the lymphoid neoplasms
but also can be seen rarely in mature lymphomas l451A, 675A, 88DAI.
Genetic features are playing an increasing ly impo rtant role in the classification of
lymphoid malignancies, and for manyofth:l
small 8-celllymphomas and leukaemias,
recurren t genetic alterations have been
identi fied. However, the molecular pathogenes is of most T-cell and NK-ceillymphomas remains unknown,Genetic studies,
in pa rticu lar PCR stud ies of IGH@and
Teen recep tor (TCR) gene rearrangements and fluorescence insituhybridization
(FISH), are valuable diagnostic tools,both
for determinat ion of clonantv in 8-ce ll and
T-cell proliferations (aiding in the ditteren.
tial diagnosis with reactive hype rplasia),
and in identifying translocations associated with some disease entities,
The WHO class ification emphas izes the
impor tance of knowledge of clinical leateres, both for accu rate diagnosis, as well
as for the definition of some diseases,
such as margina l zone lymphoma of
MALT type versus noda l or splenic marginal zone lymp homa, mediastinal large
B-celilymphoma versus DLBCL, and roost
mature T-cell and NK-ce ll neoplasms.
Diagnosis of lymphoid neoplasms should
not take place in a vacuum , but in the
context of a complete cl inical btstorv
Lymphoid malignancies range in their
cl inical behaviour from low grade to high
grade, Howeve r, within anyone entity a
range in clin ical behaviour can be seen
Moreover, histological or clin ical proqressian is often encountered during a patient's clin ical co urse. For these reasons,
the WHO class ification does not attempt
to stratify lymphoid malignancies in terms
of grade . Both morphology and immunephenotype often change over time, asthe
lymphoid neoplasm unde rgoes clonal
evolution with the ecqutstion of additional
genetic changes , In addition, evolution
over time does not necessar ily lead tothe
develop ment of a more aggress ive lymphoma, For example, patients with DLBCL
can relapse with a more indo lent clonaity
related follicular lymphoma, Some of these
clonal evolutions can be unexpected and
not obv iously connected, such as the development of a plasmacytoma in a patient
with CHl [1042B).
Traditionally,classical Hodgkin lymphomas
(CHL) have been considered separately
from so-called "non-Hodgkin lymphomas'
However, with the recognition that CHL is
of B-cell lineage, grea ter overlap has
been app reciated between CHL and
many form s Qf Been ma lignancy. The 4th

edition of the WHO classifica tion reco gnizes these gr ey zones, and provides fo r
the recog nitio n of c ases tha t bridg e the
gap between the se various forms of lymphoma 12265).
Epidemiology
Precursor lymp hoid neopl asms incl ud ing
B lymphob lastic leukaemia/ lympho ma
(B-ALL.JLBL) and T fyrnphoblastic leukaemia!
lymphoma (TA LLJLBL) are p rimarily d iseases of c hild ren. 75% of cas es occur in
children unde r six years of age Ap oroxrmately 85% of cases presenting as ALL
areof precur sor B-ce ll type. whereas lymphoblastic ma lig na nci es of precursor
T-cell type more often present as lymphoma, with med iastinal ma sses. A mal e
predominance is seen in lym ph ob lastic
malignanc ies of bot h B-c e ll and T-cel l
lineages.
Mature s-een neoplasms comprise over
90% of lymph oid neoplasms worldwide
151, 791. They repr esent approximately
4% of new cancers each year. They are
more common in d evelop ed coun tries ,
particularly th e United States. Australia,
New Zealand and Weste rn Europe. The
most recent surve y from the Survei llance,
Epidemio log y and End Resu lts (SEER)
program in the United States indic ated an
incidence rate per 100 000 per sons per
yearof 33.65 for al l lymp ho id neop lasms,
26.13 for a-ce.r neoprasms. 1.79 for all Tcell neoplas ms, a nd 2.67 for Hodgkin
lymphoma 11525A). The most co mmon
types are foll ic ular lymp homa and
DLBCL, which tog ether mak e up more
than 60% 01 al l lymphomas excl usive of
Hodgkin lymp homa and plasma c ell
myeloma 137, 511. The inc idenc e of lymphomas. in pa rtic ular Been lymph omas,
is increasing worldwid e, with mo re than
280000 cases occurring ann ually each
year 121 12A) . The ind ivid ual a-cen neoplasms vary in their relative freq uenc y in
different parts of the world . Follic ular lymphoma is more common in th e United
Slates (35% of non-Hodgkin lymp homas)
and Western Europe, and is uncommon
in South America, Eastern Europe , Africa
and Asia. Burkitt lymp homa is ende mic in
equatorial Africa, where it is the most
common c hildhood mal ig nanc y. b ut it
comprises on ly 1-2% of lymphomas in
the United States and Wes tern Europe.
The med ian age for all types of mat ure Bcell neoplas ms is in the 6th and 7th
decades, b ut med ias tina l large B-c ell
c AduI T..::eI leukemlatlylT1jlhomll 9 no
. Al'IalUs lic I8fge cell lymphoma. Al K. e n.

. Anaplas tic '-lie cel
lym~ AlK .
55",
C P fim ary Cu!arlIIOUll Ala. 1.7%
c l.lnctall s<table PTCl 2.,5%
fig. 8.07 Relative frequenciesofmature T<elllymphoma subtypesinanadultpatient population. Significant differences

exist indifferent geographic regions. However. peripheralT<elllymphorna. not otherwise specified (NOS)and AITL are
two ofthemost common subtypes intemationally.' Notethatlhe category of enteropathy-type T<elilymhpoma (Erel )'
used inthisstudy was not eqllivalent toenteropathy-associatoo T<eII ~ (EATL)as deflood in this monograph. ErCL
was utilized largely asageneric category lor most T<ell lymphomas ifl'/Ol'ving theintestine. inclusive of EATL and )'0T-<:elI
lymphomas. Data courtesyofJ. Vase and The International PeripheralT-CellLymphoma Project (57A).
lym p homa has a med ian age of -35

year s. Of the mature B-cel l lymphomas ,
only Bu rkitll ymphoma an d DLBCL occur
with any sig nifica nt frequen cy in chi ldren .
Mo st type s have a mal e p redo minance
(52 -55%), but ma ntle cel l lymp homa has
a str iking ma le p redo minance (74%) ,
wh ile fema les pre dom inate in follic ular
lymp homa (58 %) and most partic ularly in
pr imar y me diastinal large B-ce ll lymphoma (66 %). Primary med iastinal large
B-c e ll lymphoma a nd cl assical Hodgkin
lymphoma of the nodular sclerosis subtype
have simi lar cl inica l p rofiles at presen tation , most commonly affecti ng ado lescent
an d young ad ult females. These common
clinical featu res first prompte d co nsrce ratton that these lymphomas might be related 11870, 1944, 2265)
O ne majo r known risk factor for mature
B-ce ll neop lasia appea rs to be an abnormal ity of the imm une sys tem, e ithe r immunod efic iency or autoimm une d isease.
Although evide nc e of immune system ab no rma lities a re lac king in most patients
with mature B-c ell neop lasms, immunodeficie nt p atients have a ma rkedl y inc rease d inc idence of a-cen neoplasia ,
partic ularly DLBCL and Burkitt lymphoma
(193,33 1. 1569 }. Major forms of immunod efic iency c urrently incl ud e infec tion with
the human immunode ficiency virus (HIV),
iatrog enic immunosuppression to preven t
allog raft rejection or graft versus host d isease (GVHD) and primary immun e defic ienc ies. Some autoimmune diseases are
also assoc iated with an inc reased risk of
lymphoma, pa rticu larly B-ce illymp homas
in patients with lympboepithelial sraraoentis or Hashimoto thyroiditis 11114, 11161.
Mutations in genes con trolling lymphoc yte epo ptosfs have been linked to a risk
for both autoimmu ne d isease and lymphoma (ma inly B-cell types). Patients with
the autoimmu ne Iymp hop roliferative syndrome. wh ich usua lly is ca used by
ge rmline muta tions in FAS, have an inc reased risk for a-cer lymp homas and
Hod gk in lymp homas 12108). Somatica lly
acquired FAS gene mutations also have
bee n reported in some spo rad ic B-cell
lymp homas, most co mmo nly marg inal
zone lymphomas 1855). Recen t stud ies
employing mo lecula r epidemiology have
identified pol ymorp hisms in a number of
immun ore g ulator y genes that appear to
impa ct both risk of lymphoma and prognosis within a patient cohort l359A.
1248A , 2358C) . Molec ular ep idemiology
is a relatively rec ent area of investigation
and more data will be accumulated in the
com ing yea rs. For example , a recent
stu dy foun d incre ased risk associated
with polymorph isms in certain drug
metabol izing enzymes 116A}.
Mature T-c ell and NK-c eil neoplasms are
Introd uction and overv iew of the c lassificat ion of the lymp hoid neoplasms
165
relatively uccorrmon. In a large international study that evaluated lymphoma

cases from the United States, Europe,
Asia and South Africa, T-cell and NK-cell
neoplasms acco unted for only 12% of all
non-Hodg kin lymphomas [51}, The most
com mon subtypes of mature t -een lymphomas are peripheral r-eef lymphoma,
not otherwise specified (NOS) (25.9%)
and angioimmunoblastic T-cell lymphoma
(AITL) (18.5%), respectively (57A}.
T-cell and NK-cell lymphomas show significant variations in incidenc e in different
geog raphical regions and racial populations In gene ral, "l-cell lymphomas are
more common in Asia [6161 . These differences result from both a true increased incidence , as well as a relative decrease in
the frequency of many B-cell lymphomas,
such as follicular lymphoma. One of the
main risk factors for T-ce ll lymphoma in
Japan is the virus, HTLV-1. In endem ic
regions of southwestern Japan, the seroprevalence of HTLV-1 is 8-10%. The cumulative life-time risk for the development
of adult r-cenieokaemlaavrrctoma (ATLL)
is 69%"for a seropos itive male and 2.9%
fora seropositive female [6831. Other regions
with a relatively high seropreveience for
HTLV-1 include the Caribbean basin. where
Blacks are primarily affected over other
racial groups {760f. Differences in viral
strain also may affect the incidence of the
disease [523,13451.
Another major factor influencing the inc idence of r-cea and NK-ceil lymphomas is
racial predisposi tion. EBV-associated NK
and T-cell neoplasms. including extranodal NKfT-cell lymphoma, nasal type, aggressive NK leukaem ia, and paediatric
EBV+ T-cell and NK-cell lymphomas are
much more common in Asians than they
are in other races {2n In Hong Kong,
nasal NKfT-cell lymphoma is one of the
more common subtypes, accou nting for
8% of cases By contrast, in Europe and
North America , it acco unts for less than
1% of all lymphomas. Other popu lations
at increased risk for this disease are individuals of Native American descent in
Central and South America , and Mexico
{40,3411. who are geneticall y related to
Asians [8921. Finally, enteropathy-associated J-ce!l lymphoma is most co mmon in
individuals of Welsh and Irish descent, who
share HLA haptotvpee that confer an
increased risk of gliadin allergy and suscep tibility to gluten-sensitive enteropathy
154S}.
10 PTCL occu r with increased frequency
166
in the setting of immune supp ression,

especially following organ transp lantation, a finding that is not well understood
{758A, 1582Al The comb ination of two
factors, both immunosuppression and
ch ronic antigenic stimulation. appear to
increase risk. Hepatosptenic T-cell lymphomas are most com mon, but primary
cuta neous and mucosa-assoc iated T-cell
lymp homas have been rep orted as well
{3311. Recent data from the SEER prog ram indicate a modest inc rease in the
inci dence of t-ceu neop lasms in the
United States to 2.6 cases per 100000
persons pe r year, with the greatest
increase occu ring in the category of
cutaneous T-eeillym phoma (492A, 1525A).
Etiology
Infectious agents have been shown to
contribute to the development of several
types of mature B-cell, T-cell and NK-cell
lymphomas. Epstein-Barr virus (EBV) is
present in nearly 100% of endemic Burkitt
lymphoma and in 15- 35% of sporad ic
and Hrv-assocrateo cases {877, 1780Al.
and it is involved in the pathogenesis of
many B-eelilymphomas arising in immunosuppressed or elde rly patients, including
many post-transp lant Iymphoproliferative
disorders, plasmablastic lymphoma and
EBV+ large B-ceillymphoma of the elderly. EBV is also associated with extranodal NKfT-cell lympho ma and two
paediatric t -een lymphomas. systemic
EBV+ t-een LPD of childhood and hydroavaccin iforme-like t-een lymp homa. The
exac t ca use of these EBV+ T-cell lymphomas of childhoo d is not clear. Risk
factors may be either high viral load at
presentation, or a defective immune response to the infect ion {179n Chronic
active EBV infect ion may precede the
deve lopment of some EBV+ t-een lymphomas {1094, 1797f.In cases associated
with chronic EBV infection, a polyclonal
process may be seen early in the course,
with progression to monoclonal EBV+ T-cell
lymphoma 11 094}.
Human herpesvirus-8 (HHV8) is found in
primary effusion lymphoma and the lymphomas associated with multicentric
Castleman d isease, mainly seen in HIVinfected patients {372). It is of interest that
the same virus ca uses a number of B-cell
Iymphoproliferative disorders whic h differ
in their cl inical manifestations {617A) .
Human T-ceil lymphoma/leukaemia virus
type 1 (HTLV1) is the causative agent of
adult T-cell lymphoma/leukaemia, and is
Introduction and overview of the classification of the lymphoid neop lasms
clona lly integrated into the genome of

transformed T-cells !2148). In this condition as in HHV8-associated disorders, a
spec trum of clinical behaviours are seen,
although most cases of ATLLare aggressive.
Hepatitis C virus has been implicated in
some cases of Iymphoplasmacytic lymphoma associated with type II cryoglobulinaemia. splenic marginal zone lymphoma,
noda l margina l zone lymphoma and
DLBCL 112A, 88A, 527A, 534A, 1073A,
1434, 1775A, 2506), The role of the virus
in tumour initiation is not clear. However, it
does not directly infect neoplastic
and appears to influence lymphoma
development through activa tion of a
B-cell immune response.
Bacteria, or at least immune responses to
bacter ial antigens, have also been implicated in the pathogenesis of MALT lymphoma. These include H. pylori in gastric
MALT lymphoma (998, 1587,2444,2445),
B. Burgdorferi in cutaneous MALT lymphoma in Europe {192), Chlamydia
psittaci. C. pneumoniae and C. trachomatis
in ocula r adne xal MALT lymphomas in
some geogra phic areas {394, 18981and
Campy lobac ter jejuni in intestinal MALT
lymphoma associated with alpha heavy
chain disease {1781, 1812f
Environmental exposures also have been
linked to a risk of developing B-ceil lymphoma. Epidemiolog ical studies have
implicated herbicide and pesticide usein
the development of follicular lymphoma
and DLBCL !460A, 903A) . Exposure to
hair dyes had been ident ified as a risk
factor in some olde r studies, but newer
dye formations have removed potential
carc inogens {2496AI.
a-cens.
Conclusion
The multipa rameter app roach to classification adopted by the WHO classification
has been validated in international studies as being high ly reproducible, and enhancing the interpretation of clinical and
translational studies. In addition, accurate
and precise class ification of diseaseentities facilitates the discovery of the molecular basis of lymphoid neoplasms in the
basic science laboratory151, 1034, 1525A1.
I
I
i
I
I
l
B lymphoblastic leukaemia/lymphoma,
Definiti on
B lymphoblastic leukaemia/lymphoblastic
lymphoma is a neoplasm of precursor
cells (lymphoblasts) corrmined to the Bcea
lineage. typically composed of small to
medium-sized blast cells with scant cytoplasm. moderately condensed to dispersed
chromatin and inconspicuous nucleoli,
involVing bone marrow (BM) and blood
(8 acute lymphoblastic leukaemia/ALL)
and occasionally presenting with primary
involvement 01 nodal or extranodal sites
(B lymphoblastIC IymphomallBl), By cooventon. the term tymphcma is used when

the process is confined 10 a mass lesion
with no or minimal ev idence of peripheral
blood (PB) and 8M invo lveme nt. With extensive 8M and PB involvement, lym phoblastic leukaemia is the appropriate term .
If the patient presents with a mass lesion
and Iymp hob lasts in the 8 M. the d istinc tion between leukaemia and lymphoma is
arbitrary 11 550 1. For many treatment protocols, a fig ure of 25% BM blasts is used
as the thresho ld for defi ning leukaemia .
In contrast to mye loid Ieokaemtas. there
is no ag reed-upon lower limi t for the
perc entag e of b lasts required to establish
a d iagn osis of lymphoblastic leukaemtas
In g eneral, the d iagn osis sho uld be
avo ide d when the re are few er than 20%
blasts, Presentations with low blast co unts
c an occur b ut are unc omm on; c urrently
there is no co m pe lling evidenc e that
failure to treat a pat ient whe n there are
fewer than 20% 8M Iymph ob lasts has an
ad verse effect on ou tcome,
The term B-ALL shoul d not be used to
indicate Burk itlleukaemia/lymphoma, in
spi te of its historica l assoc iation with tha t
lesion, Cases of BALU LBL with recu rrent
genetic abnormalities are considered
separately below
ICD-O code
The p rovisional code proposed for the
four th edition of ICO-O is 981 113
Epidemiolog y
Acute lymphoblastic leukaemia (AL L) is
primarily a d isease of children; 75% of
cases occur in c hild ren under six years of
168
Precursor lymphoid neoplasms
M .J, Borowi tz
J ,K ,C. Chan
age . The worldwi de incidence is estimated

at 1- 4.75/ 100 000 pe rsons pe r year
{18271. The estimated number of new
cases in the United States in 2000 is
approx imate ly 3200, with approximately
80-85% bein g of precursor B-cell phenotype {1845 , 20391.
B-lBL constitutes -10% 01 lymphoblastic
lymphomas. and the rema inder are of
"T lineage 12421 Ap proximately 64% 0198
cases reported in a literature review were
less than 18 years of age 113671. One report
indi cated a ma le predominance {13101.
Etiology
Some transiccenons associated with
B-ALL have been detected in neonatal
specimens long befo re the onset of
leukaemia. and monozygotic twins with
concordant leukaemia frequently share
genetic abnormalities {832, 15t41 , suggesting a genetic cornponen tto at least
some c ases. Many of these trans locations
appear to be p rimary initiating events.
By definition, BM is involved in all cases
c lassi fied as B-AL L, and PB is usually
invol ved. Extramed ullary invo lvement is
frequent. with parti c ular pred ilect ion for
the c entral nervous system , lymph nod es,
spleen. liver and testis in males. The most
frequent sites of involvement in BL BL are
th e skin, soft tissue, bo ne and lymph
nodes 1202, 1310, 13671- Med iastinal
mass es are infreq uent {202, 1367, 19281.
Clinical features
Most patie nts with B-ALL presen t with
evidence and consequences of BM failure: throm bocytopenia and/or anaemia
and/or neutropenia, The leukocyte count
may be decr eased , norma l or markedly
elevated, Lymphadenopathy, hepatcmegaly
and splenomegaly a re frequent. Bone
pain and arIt1ralgias may be prominent. Patients with B-LB L without leukaemia are
usually asymptomatic , and most have limited stage disease. Head and neck presentations are particularly common,
especially in children. Marrow and PB involvement may be present . but the
Fig. 9.01 B lymphoblastic leukaemia, Bone rnarJOll

smear. A 5everal ~asls with a highIIlIdearIc't
lopiasmic ratiO and variably conoensed nudear dWl).
mallO, B B Iymphoblasls containing numerous eo<ne
azurophihc granules,
percentage ollymphoblasts in the 8M is

<25% 11310,13671 .
Mor phology
The Iymphoblasts in B-ALlA.BL in smear
and imp rint preparations vary from sma"
blasts with scant cytoplasm, condensed
nuclear ch romatin and indistinct nucleoli
to larger cells with moderate amounts
of light blue to blue-grey cytoplasm
occasionally v ac uolated . d ispersed nuclear chromatin and mult ip le variab ly

oronrent nucleoli. The nucl ei are round ,
tregUar or corwoIuted. Coarse azurophilic
granules are prese nt in some fvmoroblasts in approximately 10% of cases. In
some cases. the Iymphoblasts have a cytoPlasmic pseudopod (hand mirror cells)
In most cases the morphology of the Iympeootasts differs from that of no rmal
Be en precu rsors (haematog on es) with
which they may be confused . The latter
typically have even highe r oucieu s/cytoplasm (N/C) ratio s, mo re homogeneou s
chromatin and no discernible nucleoli,
In BM biopsies. the Iymp hoblasts in
B-ALL are relatively uniform in app earanc e
with round to oval, indented or co nvoluted
nuclei. Nuc leoli range from inco nsp icuous
to prominent. The c hromatin is fine ly
dispersed The number of mitotic figures
varies Lymphob lastic lym phoma is
generally charac terized by a di ffuse , o r
less comrT'lOflly, paracomca r pattern 01
involvement of lymph node or other
1JSSUe. A single-file pattern of infiltration of
sot! tissues is common. Mitotic figure s are
usually numerous and in some cases
\hefe may be a foca l "starry sky " pattern.
The morphologiC features of Band T lymphoblastIC proliferations a re inoisnngliShable.
Cytochem~try
Cy10chemistry seldom con trib utes to the

diagnosis of ALL lymphoblasts are
negative 'or nweiope roxio ase. Gran ule s,
Ifpresent, may stain light g rey with Sudan
Black-B staining bu t are less intense than
myeloblasts. lymphob lasts may show PAS
positivity, usua lly in the form of coarse

granules . Lymphob lasts may reac t with
non -specific esterase with a mutntocat
punctate or Galg i zone pattern that shows
variable inhibition with sodium fluoride .
Immunopheoo<ype
The Iymphoblasts in B-AlLllBl a re almost always positive for the Been markers
CD 19, cytoplasmic CD79a and cytopla sm ic C022; wh ile none of these by
itself is spec ific , po sitivity in c om bination
or at high intensity strongly sup ports the
B lineag e. The Iymphoblasts are pos itive
for C01O, surface C022, C024, PAX5 and
TdT in most cases. while C020 and C034
expression is var iabl e: CD45 may be abse nt. The myelo id-associated antigens
C0 13 and CD33 may be expressed. and
the presence of these myeloid mar kers
doe s not exclude the diagnosis of B-ALL
In tissue sections, C 0 79a and PAX5 are
most frequ ent ly used to demon strate
B-cen different iation, but the former reac ts
with some cases of T-ALL and is not spec ific 19061. PAX5 is generally considered
the most sen sitive and speci fic ma rker for
B lineage in sections 122511but it is also
posi tive in cases 01 AML with t(8 :21) and
rarely in other AML 122851. Myeloperoxicase express ion in leukaemic cell s detected with anti-MPO antibodies excludes
this d iagnosis and wou ld ind icate either
acute mye loid leukaemia or B/mye loid
leukaemia.
The degree of differentiation of a-uneace
Iymp hobl asts ha s cl inic al and g ene tic
co rrelates. In the earliest stage, so called
ea rly precursor B-ALl or p ro-B-ALl. the
blasts express CD19, cytop lasm ic C079a,
cytoplasmic C022 and nuc lear Td l ln the

inte rmedi ate stag e. so called common
ALL. the b lasts expre ss C01O. In the most
matur e precursor B d ifferentiation stag e,
so c alled pre-B-ALL. the blast s exp ress
c ytoplasmic ~ c hai ns (c -u ). Surface immunoglobulin is c harac teristica lly ab sent
alt hough its pre senc e does not exc lude
the pos sibil ity of B-AlLllBL (15841. provided that other immuno p henotypic teatures, morphology and c ytog enetics are
co nsistent With B-AlL. Although CO l O.
positivrty is seen both in B-ALl and in normal haematogones. the immunophenotype
of prec urso r B-AL l differs in alm ost all
cases from that seen in no rmal Been precu rsors, The tatter sho w a continuum of
expression of ma rkers of 8-cell maturation. includ ing surface Ig light c hain. and
d isp lay a reprod uc ible pattern of acqui sition and loss of normal antigens {14421.ln
con trast. c ases of B-A LL show patterns
that d iffer from normal with either overexpres sion o r uno erexpres sion of many
markers incl udi ng CO l O, CD45, CD38,
C058 or Td T, among others 1326. 401.
134 2. 23721. These crttererces c an be
very use ful in evalua tion of followup BM
specimens for minimal resid ual d isease,
Genetics
Antigen recep tor genes
Near ly all cases of B-ALL have clonal OJ
rearrang eme nts of the IGH@gene. In ad d itio n, t-een recepto r gene rearr angeme nts may be see n in a sig nifican t
proportion of c ases (up to 70%) 122941so
that these rear rangements are not helpful
for lineag e assignmen t.
Ft;. 9.03 B~sbc lymphoma, A Skin, The ~Iic cells diffusely infiltrate the dermis -Mlh sparing of theepidermis. B Samecase aI h p magnification shows ~
SI.mU'ldW'9 a blood vessel.
8 lyrnp hobtastic leukaemiaJlymph orna. not otherwise speci fied
169
:
B
..
Fig. 9.04 IrIcnIased haemalcJlp'le$ A Bone marrow sedJon . B Bone marrow smear In::m an et;;rt year.Qd male.
showing tympnoid eels with I high nucIeaIlcyqJlasmicratio and hcm:lgeneou$ nudear dlromaW1; nucleoli . . not
observed or areindl$1lllCl These cells resemble!he ~ in All 01 dtilood.
Cytogenetic abnormalities and onrogenes

Cytogenetic abnormalities are seen in the
majority 01 cases of B-AlLABl; in many
cases they define specific entities with
unique phenotypic and prognostic features. These cases are considered separately Additional genetic lesions that are
not associated with these entities include
del(6Q), del(9p). del( 12p). though mese
do not have an impact on prognosis.
Some genetic lesions that may be
assoc iated with poo r prognosis include
the very rare 1(17;19); E2AHLF ALL and
the lonachromosonat amplification 01the
AML 1gene on chromosome 21 (iAMP21),
whic h ac cou nts for about 5% of cases of
All 11510]. The latter is being recognized
with increasing frequency with the increased
170
use 01 FISH studies to detect TEL AML 1

translocations, because it can be detected with the same AML 1 probe.
Depending upon the specific leukaemia ,
B-ALL arises in e ither a naematopoienc
stem cell or a B-ceU progenitor.
Prognosis and p red ictive factors
BALL has a good prognosis in ch ildren,
but it is less favourable in adults . In c hild ren, the ove rall complete remission rate
is >95% and in adults 60-85%. Approximately 80% of children with BALL appear
to be cured, while this fig ure is less than
50% for adults Mo re intensive therapy
makes a d ifference in c ure rates , and
r~
9.05 B IympIw)I:lIask leukaerria. L~ rnje. The
neoplastiC eels infiIlrate cMlusely sparW1g IUmallaides
there is some evidence tor youngeradlAls

at least , that therapy with more intensive
"paediatric-type" regimens is associated
with better outcome 1233, 8721. Inlancy.
increasing age (> 10 years), higher white
blood cell count, slow response to initial
therapy as assessed by morphologic ex
emmanon 01P8 and/or 8M , and the presence 01 minimal residual disease after
the rapy are all associated with adverse
prognosis 1488, 679, 19 76 , 2023 , 2093.
22951. The presence of eNS disease at
diagnosis is associated with adverse out
come, and requi res specific therapy 14461.
The prognosis of B-LBL is also considered relatively favourable. and as with BALL appears better in ch ildren than accns
113671.
with recurrent genetic abnormalities
This group of d iseases is c harac terized

by recurrent genetic ab normalities, in-
clud ing balanced translocations and

abnormalities involving ch romosomes,
Many ch romosomal abnormalities that are
non-rand omly associated w ith B acu te
tymphoblastic leukaemia (BALL) are not
inCluded as separate ent ities in this sectal. While inclusion or exclusion 01 a genetic -entity- is somewhat arbitrary, those
lesions that are specifically mentioned are
chosen because they are associated with
distinctive clin ical or phenotypic p ropertes. have important proqnosnc implie arcos.demonstrate omerevidence that they
ale biologicall y di stinct an d are generally
mutually exc lusive w ith other ent ities.
BLymphoblastic
leukaemiallymphoma with
~9;22)(q34;q 11 2); BCRABLt
Oefrlition
Aneoplasm of Iyrnphoblasts corrmitted to
lhe e -cen lineage in whic h the blasts
harbour a trans location be tween the BCR
gene on ch romosome 22 and the ABL 1
oncogene on ch romosome 9
ICD-O code
The provis ional co de prop osed for the
fourth ed ition of ICO-O is 98 12/3.
Epidemiology and cl inical features
Presenting features are generally similar
to those of other pat ient s w ith B-All.
BCR-ABL 1 associated ("Ph . -) All is
relatively more common in adults than
Children, accounting for about 25% of
adult All but only 2-4% of childhood
All. Most chil dren with Ph. B-All woul d
be consid ered "hig h risk " b y sta nd ard
age and white b lood ce ll (WBC) feat ures,
but there are otherwise no cha racteristic
docalf indings Though patients with t(9;22)
BAl l may have organ invo lvement. lymphomatous presentations are rare
and cytochemistry
There are no un ique mor phologic or
MoJ. Borowitz
J.K.C. Chan
cytochemic al feat ures that d istingui sh this

from other type s of ALl.
Immunophenotype
B-Al l wit h t(9;22 ) is typicall y C 01O .
C0 19. and TdT . There is more frequ ent
expression of myeloid -assoc iated anngens C0 13 and C033 19851: COl17 is
typically not expressed . C025 is highly
associated with t(9.22) B-All, at least in
adu lts 116791. Rare ca ses of t(9 :22) All
have a T precursor phenotype.
Genetic s
The t(9 :22) results from fusion of BCR at
22q l 1.2 and the cy to plas mic tyrosine
kinase gene ABL 1 at 9q3 4. w ith produ c tion ot a BCR-AB lfusion protein, In most
chi ld hood cases of Al l w ith the t(9 ;22), a
p1 90 kd BCR-ABU fusion p rotein is
produced. In ad ults, ab out o ne half of
cases of ALL w ith the t(9 .22) prod uc e the
p2 10 kd fus ion protein that is present in
chronic myelogenous leukaemia (C ML) .
and the rema inder prcouce the p190. No
de finite cl inical differences have been attribu ted to these two different gene produc ts. The t(9 ;22) may be associated with
other ge netic abnorm alities, inc lud ing
rare cas es that mig ht othe rwise c ause a
cas e to be plac ed in one 01 the other categories below, It is ge nerally conside red
that cl inica l features in suc h c ases are
governed by the p resenc e of the t(9:22) .
Fig. 9.06 Ttis bone marrow from ., iICkJIl WIth 119"22)

posIbve &-ALl is ~leIy replaced by tyrnp1ctlIasb.
Mitolic figl.l'eS areI'lUI'IlefOUS.
ad d ition to hig h-dose c hemotherapy has

been reported to imp rove early event-free
survival {19751.
B Lymphoblastic
t(v;11q23); MLL reafT8t1ged
Definition
A neoplasm ol lymphoblasts ccmm ined to
the B lineage that harbours a transl oca tion between the MLL g ene at band
t 1q23 and anyone 01 a large number of
differe nt fus ion pa rtne rs. Patien ts with
leukaemias that have dele tions of 11q23
w ithout MLL rear rangemen ts are not incl ud ed in trns group ,

There is some suggestion that the c elt 01
origin of t(9 :22) ALL is more immature
than that of othe r B-All cases 14521.
ICD-O code
The p rovis iona l code proposed for the
fourt h ed ition
is 981313

In both c hild ren and adults , t(9 ;22 ) All
has the worst prognosis among pat ients
with All. Its hig her frequency in adu lt
All expl ains in pa rt but not completely
the relativ ely poorer outcome of ad ults
w ith All. In ch ild ren . the prese nce of
favourab le c linical features inc lud ing age.
white count and response to thera py, is
associated with somewhat better outcome
1771. althoug h prognosis is still cons idered
relatively poor . Treatment with imatinib in
Etiology
Wh ile the specific et iology of leukaemia
with MLL transJocations is unknown . this
translocation may occur in utero. with a
sho rt latency between the transloca tion
and dev elopment of d isease , Evidence
for this inc lud es the fact that these
leu kaemias are frequ ent in very young
infants, as well as the fact that this translocation has been identified in neonatal
b lood spots of patients who subsequently
develop leukaemia {7451.
oucn-o
B lymphoblastic leukaemia/lymphoma With recu rrent genetic abnormalities
171
proteo-qryca n neural-glial antigen 2

(NG2) is also characteristically expressed
and is relatively, thoug h not absolutely,
spec ific.
Genetics
Fig, 9.07 B tymphoblasbc le ukaemia~ym phom a with MLL reerrarqement FISHstudy usingan MLL breekapa rt probe.
The normal MU gene"MLL(11q23)"appears as ajuxtaposed red and green, Of sometirnas yellow signal, The trensJocatioo is demonstrated by separation of theredandgreen probes r MLLsp") (Cocrtesy of Or AJ carroll)
The MLL gene on chromosome 11Q23

has many fusion partners. The most cammon partner gene is AF4 on cnrorosore
4q 21. Othe r commo n partner genes
incl ude ENL on chromosome 19p13and
AF9 on chromosome 9p22. MLLENL
fusions are also co mmon in TALL and
fusions between MLL and AF9 are
more typ ica lly associated with myel()d
leukaemia. Leukaemias with MLL nanslocations are frequently associated with
overexpresston of FLT-3 l 801. Cases with
deletions of 11q23 are not included in this
group of leukaemias as they appear not
to share the same clinical, phenotypic or
prognostic features.

Leokaerreas with the MLLAF4 translocation have a poor prognosis. There is some
cont roversy as to whether reukeenee
with translocations other than the MLL-AF4
rearrangement have as poor a prcqross
as trcse that do , Infants with ML1. translocations, particularly those <6 monfhs ~
age, have a particularly poor prognosis
B Lymphoblastic
laukaemlaJlymphoma with
1(12;21)(p13;q22);TEL-AML 1
(ETV6-RUNX1)
Flg.9 .08 B tymphoblastic leukaemialtymphoma with1(12;21) (p13:q22); TEUAML 1 (ETV&-RUNX1) FISH study using
a red probe against RUNX1 and a green probe against ETV6. The normal genes appear as isolated red or green
signals, wMe evcerce of the fusion gene (arrows) appears asa yelklwsignal, (Coortesy of Or. AJ carroll).
Epidemiology and clinical features

ALL with MLL rearrangements is the most
common leukaemia in infants < 1 year of
age . It is less common in older child ren
and inc reases with age into adulthood .
Typica lly pa tients with this leukaemia
present with very high white blood cell
counts, frequently> 100 OClO/J-J-L. There is
also a high freq uency of eNS involvement
at diagnosis. While organ involvement
may be seen , pure lymphomatous presentations are not typical.
There are no uniq ue morpholo gic or
172
cytochemical features that distinguish this

from other types of ALL. In some cases of
leukaemtas with MLL rearrangements it
may be poss ible to recog nize distinc t
lymphoblastic and monoblastic popul ations , which can be confirmed by
immunoph enotyping; such cases should
be consid ered Blmyeloid leukaemias .
Irrrnu nophenotype
ALL with ML L transiocanons. and most
especially t(4;1 1) ALL typically have a
CD 19+, Cu tn-neqenve. CD24-neg ative
pro-B immunophenotype, also positive for
CD15l985, 169 11. The Chondroitin sulfate
Definition
A neoplasm of Iymphoblasts committed to
the B lineage with a translocation between
the TEL (ETV6) gene on chromosome 12
with the A ML 1 (RUNX 1)gene on ctecrcsome 12.
ICD-O code
fourth edition ol lCD-O is 98 14/3.
This leukaemia is common in chiklren
accounting lor abou t 25% of cases ~
B-ALL It is not seen in infants and
decreases in frequency in older children
to the point that it is rare in adulthood.
to those of other patients with ALL
Morphology-and cytochemi stry
There are no unique morphologic or

cytochemica l features that diSlinguish
this from ot her types of ALL.
.'
..
Imrru1ophenoIyp
Basts have a C019+ , C010+ phenotype
and are most often CD34+; other phenotypic features. includ ing near or complete
absence of COO, C020 and CD66c 1245,
533,9851. are relatively but not absolutely
specific. Myeloid-associated an tigens.
especially CD13, are frequently expressed,
but this does not indicate mixed phenotype acute leukaemia 11551.
Genetics
The t(12;21)(p13;q22): ETV6-RUNX1 translocation results in the p rodu c tio n of a
fusion prote in that likely ac ts in a dominant negative fashion to interfere with
normal func tion of the transcri ption
factor RUNX1. This leukaemia appears to
possess a unique gene expression
signature 12469 1. The E1Y6-RUNX1 translOCahon is co nsid ered to be an ea rly
lesion in leukaemog enesis, as evidenced
by studies of neonatal blood spots that
have shown the presence of the translocation Il'l child ren who develop leukaemia
many years later 124001. There is evioeoce that the translocation is necessary
but not suHicient for the development of
leukaemia 12400 1.
This leukaemia appears to d erive from a
Been progeni tor rather than from a
naematoooetrc stem cell 13441
B-Al l with the TELAML 1 transloc ation
hasa V8fY favourab le prog nosis with c ures
seen in >90% of c hildren, espec ially if they
have other favo ura ble risk factors. Relapses often occur muc h late r than those
at other types of ALL. Beca use this
translocation appears to occur as an early
event, it has been sug gested that some
laterelapses in fact de rive from pe rsistent
"preleukaemic clones that ha rbour the
lI'ansIocalion and unde rgo ad ditional
genetic events afte r the first leukaemic
cICIIe has been eliminated 17191 Ch ildren
"MIh this leukaem ia who also harbour adverse prognostic factors . such as ag e
ewer 10 years or high white count d o not
have as good a prognosis, b ut may still
lare better as a g roup than other
patients with these same adverse fac tors .
"
"
"
... ..
"
..
..
. .~
"
,>4
"
!!'
r'
f,
"
Fig. U9 Hyperdiploid ALL. G banded karyotwe stlowlng 55d'll'omosomes. indudlng trisomies of 4. 10 and 17and
kltrasomy 2t. Thefe are nostruc:llnl abnor'malitJes. (Courtesy of Dr. AJ carrol).
B Lymphoblastic leukaemia!
lymphoma with hyperdiploidy
Defi nition
A neoplasm of Iymphoblasts comm itted to
the B lineage whose b last s c ontain >50
and usually <66 c hromosomes, typically
withou t uansiocanons or other struc tural
a lterations . There is controversy as to
whet her specific c hromos omal ad ditions.
rather than the specific numbe r of c hromosom es. should be part of the def inition
1894. 1806,21231.
ICO-D code
The p rovisional co de pr op osed for the
fourth edit ion ofICDD is 981513.
Synonyms
Hype rdi ploi d ALL; high hyp erd iploid ALL :
ALL with favo urable trisom ies.
Epkl_
This le ukaemia is common in children ,

accounting for about 25% of c ases of
B-ALL It is not seen in infa nts, and
decreases in freq uenc y in older c hild ren
to the point that it is rare in adulthood.
Cli nical featur es
to those of other pa tients with ALL.
cvtocremcet teatores that distinguish this

from other types of ALL.
Irrm.mophenotype
Blasts are C0 19 +, C01O+ . and expre ss
other markers typi cal of B-ALL Most
c ases are C 0 34 + and C045 is often
ab sent 19851. Patients with T-ALL with
hyperdiploidy should not be considered
part of this group, though most such
patients have near tetrap loid karyotypes.
Genet ics
Hyperd iploid B-Al L contains a numerical
increase in chromosomes. usually without
struc tural abnormal ities . Extra co p ies of
c hromosomes a re non random. with
ch romosomes 21, X, 14 and 4 being the
most co mmo n and ch romosomes 1. 2
and 3 being the least of ten seen 19151.
Hyperd iploid B-AlL may be detec ted by
standard karyotyp ing , FISH or flow cvtomet ric DNA ind ex 11 40 11. Some ca ses
that appear as hyperdiploid ALL by standard karyotyping may in fact represent
hypodiploid ALL that has undergone
enooreouoncetco. doubling the number
of chromosomes. Specific chromosomes
that appear as trisomies may be more impo rtant to prognosis than the actual
number of chromosomes, with simultaneous trisomies 014. 10 and 17 carrying the
best prognosis 121231.
Morphology and c ytochemistry

There are no un iq ue morph o log ic or
B lym phob lastic leukaemia/lymphoma with recu rrent genetic abnorma lities
173

Hyperdiploid B-ALl has a very favourable
prognosis with cu res seen in >90% of
children. especially if their risk p rofi le is
favourab le Presence of adverse tee te rs.
such as ad vanced age or high white
count may ad versely affect the prognosis,
but patients may not fare as badly as otbers without this favourable abnormality.
B Lymphoblastic
hypodiploidy (HypodiploidALL)
Definition
A neop lasm of Iymp hob lasts committed to
the B lineag e whose blasts co ntain <46
chromosomes. A stricter definition of <45
chromosomes , and possib ly even <44
chromosomes , more accurately reflects
the clinic al pa thologic entity 115541.
ICD-O code
The provisional code p roposed for the
fourth edi tion ofICD-O is 981613.
Epidemiolog y and clinic al features
Hyp odiplo id ALL accounts for about 5%
of ALL overall, but if the d efinition is
restric ted to those with <45 chromosom es
the figure is close r to 1%. It is seen in both
chil dren and ad ults. although near haploid ALL (23-29 chromosomes) appe ars
limited to ch ildhood . Presenting teamre s
are gene rally similar to those of other pa tents with ALL
stand ard karyotyping because the

hypodip loid clone may undergo endoredo oucanon . doubl ing the number of
ch romosomes. reSUlting in a near dip loid
or hyperdiploid karyotype. Flow cytomeny
c an gene rally detect a clone with a ONA
index <10 , though this may be a minor
popul ation . FISH may also de tect c ells
hyp odi ploid for certain ch romosomes,
and this diag nosis should be suspected
when there is a discrepanc y between
karyo type and FISH results with respec t
to the number of ch romosomes present.
Prognosis and predictive features.
Hypodiploid B-ALL has a poor prog nosis.
The prognosis depends on the number of
chromosomes: those with 44- 45 chromosomes have the b est p rognosis! 1554).
and tho se with near hap loid B-AL L fare
worst in some b ut not all studies [900,
15541. There is some evid enc e that. in
con trast to other type s of B-ALl. patien ts
may fare poorly even if they do not have
minimal residual disease follc::Nving therapy.
B Lymphoblastic
t(5;14)(q31;q32); 1l.3-IGH
Definition
A neoplasm of IymphOblasts comnitted 10
the B line age in which the blasts harbour
a translocation between the IL3gene and

the JG H@ gene. resulting in a variable
eosinophilia. This diagnosis may be made
ba sed on immuno phenotypic and qenetc
finding s even if the bone marrow (8M)
blast count is low.
ICD-O code
The p rovision al co de proposed for the
fourth edition of ICO-O is 981 713.
This is a rare d isease. accounting for < 1%
of cases of ALL. It has been reported 1'1
bo th children and ad ults. Presenting
clin ic al ch aractensncs may be similar 10
other pa tients with ALL , Of patients may
present with an asymptomatic eosinophilia, and blasts may not even be presen n
the PB 10 raise the suspicion of Ieu~.
MorpOOlogy and cytochemistry

Blasts in this neop lasm have Ihe typical
morphology of Iymphoblasts. but the
striking finding is the presence ot an
incr ease in circulating eosmcotes. This 1$
a reactive population and not part of the
leukaemic clone.
Immunophenotype
Blasts have a CD 19+C0 10+ phenotype
Finding even small numbers of blasts with
this p henotype In a patient with eosirop hiha should strongly suggest this diagnosis .
Morp holog y and cytochemist ry

There are no unique morphologi c or
cytochemic al features that distinguish this
from other types of ALL
Immunophenotype
Blasts have a Bcprecursor phenotype,
typically C01 9+. C01O+ b ut there are no
other d istinc tive ph enotypic features.
Geneti cs
All patients b y d efinition show loss of one
or more chromosomes, having from 45
chromosome s to near haploid . Structural
ab normalities may be seen in the remaining chromosomes though there are no
spec ific abnormali ties that are characteristically associated Structural abnorma lities
are uncommon in near-haploid B-ALL
The diag nosis of near haploid or low
hypodip loid B-ALL may be missed by
174
Fig. I .10 B IymphoblastJc ~ with l(5;14MQ31:Q32j. Bone manow smear sl'kMng a jXlIl\AbCrId
typicaIlymphobIasls along Wlth I'U'l'l9fOO$ mature eosinophil$. Thegrar.J1e Iislnbubon in some 01 the ~ illJIusual, bullhisis not a consisIenl lactor.
Genetics
The unique characte ristics of this
neoplasm de rive from a functional rearrangement between the fL3 gene on
chromosome 5 and the IGH@ gene on
chromosome 14, resulting in constitu tive
overexoresson of the IL3 gene 18461.
Functional consequences of this rearrangement other than eosinophilia . if
any. are not well understood. The abnormality is typically detected by standard
karyotypi ng ; it can also be detected by
FISH. though app ropriate probes are not
widelyavailable.
Prognosis and predictive features
The prognosis is no! considered to be ditlerent from other cases of ALL. though
there are too few cases 10 be ce rtain .
Blast percentage at diagnosis is not
known to be a pred ictive tacror.
B Lymphoblastic leukaemia!
lymphoma with 1(1;19)
(q23;p I3.3); E2APBXl
(feF3-PBX1)
Definition
This is a neoplasm of lympho blasts committed to the B lineage with a t( 1;19)
uaosrocatron between the E2A(TCF3)
gene on chr omosome 19 and the PBX 1
gene on chromo some 1.
ICD.Q code
The provisiona l co de proposed for the
fourth edition of ICD-O is 981813.
Epidemiology and clinica l features
This leukaemia is relatively common in
chil dren, accounting for abo ut 6% of
cases of B-ALL. It is also seen in adults .
but not at as high a frequency. Presenting
features are genera lly similar to those of
other patients with ALL.
logy
and cylochem;stry
There are no unique morphologic or cytochemical features that d isting uish this
from other types of ALL.
Immunophenotype
Blasts typically have a CD19 +.CD10+
cytoplasmic u (ctJ) heavy chain-positive
ore- e-ceu phenotype. although not all
cas es of preB-ALl have the t( 1:19). This
leukaemia can be suspected even when
cu is not determined as these teukaemias
typ ically show strong exp ression of COO
and lack CD34 , or show very limited
CD34 expression on only a minor subset
of leukaemic cells 12441 .
Genetics
The E2A-PBX1 translocation results in the
production of a fusion protein that has an
onco ge nic role as a transcri ptional activator, and also likely interferes with the
normal function of the transcription factors
coded by E2A and PBX t 112621. The

functional fusion gen e resides on chromosome 19, and there may be loss of the
derivative chromosome 1 in some but not
all cases , resulting in an unbalanced
translocation. Gene expression profiling
studies have shown a unique signature to
this lesion 124691 . An alternative E2A
translocation t(17:19) occurs in rare cases
of ALL involving the HLF gene on chromosome 17 and is assoc iated with a dismal prognosis. Thus demonstration 01an
E2A rearrangement by itself is not a
diagnostic criterion for this leukaemia.
A subset 01 B-AlL, usually hyperd iploid
B-ALL has a karyotypicaIIy idenlicall( 1;19)
translocation that involves neither E2A nor
PBX1 and sholAdnot be confused with this
entity. Cases of B-All with t(1;19) that
lack the expected phenotype probably do
not represent E2A-PBXl B-Al L.
PrognosiS and predictive features

In early studies , E2A-PBX1 was associated with a poor prognosis, but fhis is now
read ily overcome with modern intensive
therapy. Many treatment protocols no
longer require identification of this genetic
lesion, but the findings of unique immunephenotypic and genetic features supports
its inclusio n as a distinct entity.
B lymphoblastic leukaemla/lymphoma WIth recurrent genetic eboomautes
175
T lymphoblastic leukaemia/lymphoma
Definition
T lymphoblastic leukaemia/ lym pho b lastic
lymphoma is a neoplasm of Iymphoblasts
committed 10 the t-een lineage . typ ically
composed of sma ll 10medium-sized blast
cells with scant c ytopl asm . moderately
con de nse d to d isper sed c hrom atin an d
inco nspicuous nucleoli, involving bone
marrow (8M) and b lood (T-acu te lymp hob lastic leukaemia, T-AL L) or p resenting
w ith primary involvement of thym us, nod al
or exlranodal sites (T-ac ute lympho blastic lymphoma, T-LBL). By co nvention. the
term lymphoma is used when the process
is confined to a mass lesion with no or
minimal evidence of peripheral blood
(PBl and 8 M invo lvement. With extens ive
8M and PB invo lvement, lym phobl asti c
leu kaemi a is the appropriate term . It the
patient p resen ts w ith a mass lesion and
Iymphoblasts in the 8M. the d istinction between leuk aemia an d lym phoma is arbitrary. Fo r many treatment p rotocols . a
figu re 01 >25% 8 M blasts is used as lhe
threshold lor defining leukaem ia, In contrast to myeloid leukaemi as. mere is no
agr eed -upon lowe r limit lo r the pe rcentag e 01 blasts req uired to estab lish a d iag nosis 01 ALL In genera l, the d iag nosis
should be avoided wh en there a re <20%
bla sts,
ICD -D cod e
The p rovisional co d e p ropo sed l or the
fourth ed ition of ICD -Q is 983713.
Epidemiology
T-ALl comprises abou t 15% 01 c hild hood
ALL; it is mo re common in adolescents
than in younger c hild ren and mo re
common in ma les than in females . T-ALl
comprises ap prox imat ely 25% of cases
of ad ult ALL T-l Bl comp rises approximat ely 85-90% of all lymphoblastic
lymphOmas; similar to its leukaemic counterpart , it is mos t freq uent in ad olesc ent
males but may be seen in any ag e group.
Etiolog y
One study repo rted T-ALL in monozygotic
twins that share the same
rece ptor
ge ne rearra ngement 17201. sug gesting
t-een
176
on
M .J. Borcwttz
J.K.C. Chan
_~",1
Fig. 9.11 T-lymphoblasticleukaemia, A Blood smear. The Iymphobla sts varyinsize from large cells tosmall cells with
a very highnuclear/cytoplasmic ratio, B Bone marrow section.
an in utero origin at the earliest ge netic

lesions .
Sites of involv eme nt
The 8 M is involved in all cases 01
T-All, and in contrast 10 B-All, aIet.Jkaenjc
presentations in the face of 8M replacement
are UI'"ICO'MlOfl . T-L8l frequently shows
mediastinal (thymic ) invotvement, though
it may involve any lymp h nod e or extr anod al site. Skin, ton sil, liver, splee n, central nervous system and testis in males
may be involved, although presentation at
these sites withou t nodal or mediastinal
involvemen t is uncom mon.
Cli nical features
T-ALL typ ica lly presents with a high leukoc yte c ount, and often a larg e med iastinal
mass or other tissue ma ss. l ymp hadenopathy and hepatosplenomeg aly are cammon. For a given leukoc yte c ount and
tumour b urden, TAl L pa tients often show
relative sparing of no rmal 8 M hae rnetopoie sis c ompared with 8 -ALL
T-lBL frequently p resents with a mass
in the ant erior medi aslinum , often exh ib iting rap id gr owt h , and some time s p resen tin g as a respiratory eme rgency.
Pleural effusions are corrmon.
Mar_
The Iymphoblasts in T-AlL..A..8 L are morp hologi cally ind isting uishab le from those
of 8 -AlLJL8 L. In sme ars, the c ells are
of med ium size with a high nuclearl
cytopl asmic ratio; there may be a co nsid erable size range from small !ymphoblasts
with very conde nsed nuc lear chromat in

and no evident nuc leol i 10 large r blasts
with finely d ispersed c hromatin and relatively prominent nucleoli . Nuc lei range
!rom round to irreglJar to con'lOluted , Cytl>'
plasmic vacuoles may be present.
sionally blasts of T-Al l may resemble
more ma ture lymphocytes ; in such cases
immuno phenotypi c stud ies may be requ ired to d istingu ish this d isease Irom a
mature (peri pheral) t-een leukaemia.
In 8M secti ons the Iymphoblasts have a
high nuclear/cytoplasmic ratio, thin nuclear
memb rane. finely-s tipple d c hromatin and
inconspicuous nucleoli. The numbe r of
mitotic fig ures is report ed to be hig her in
T-ALL than B-ALl. In T-LBL, the lymph
node ge nerally shows com ple te ettaceme nt of arch itec ture and invo lvemen t of
the ca psule . Partial involvement in a paraco rnea! loc ation with sparing of germinal
ce ntres may occur- Sometimes, a mu ltinod ular pattern is p roduced du e to stretching 01 the fib rous framework, mimic king
follic ular lym phoma. A starry-s ky effect
may be present, thus sometimes resembling Burkln lymp homa , althoug h typically
the nucleoli arld cytoplasm are less
prom inent. The blasts can have round or
convolu ted nuc lei, Mitol ic figures are
often numerou s. In the thymus, there is
ext ensive replacement 01 the Ihymic
pa rench yma and pe rmeative infiltration .
Cases with histological finding s 01 T-LBL
with a sig nific ant infiltrate of eosinophils
among the lymphoma cells may be
assoc iated with eosino philia and mye loid
hyperplasia and a Bp 11.2 cytogenetic
occa-
abnormality inyolving the FGFR1 gene 13,

10061 (See Chapter 3).
Cytochemistry
TIymphoblasts frequently show focal acid
phosphatase activity in smear and imprint
preparations. though this is not spec ific .
Irrmunophenotype
The Iymphoblastsin T-ALlABL are usually
TdT positive and variably express COla,
C02, COO, C04 , CDS, C07 and COB. Of
these, C07 and cytop lasmic C03 (cC 03)
are most often positive , but 01 these only
C03 is considered lineage specific. C04
and COB are frequently co-expressed on
the blasts, and C010 may be posit ive.
These latter phenotypes are not speci fic
for T-AU as C04 and COB double positivity may be seen in T-PLl and C010 in
peripheral t-een lymphomas, most commonly angioimmunobiastic r-ceu lymphoma. In addihon to TdT, the most
specuc markers to indicate the precursor
nature of T Iymphoblasts are CD99, CD34
and COla: the first of these is most useful
118521. In 29-48% of cases. there is nuclear staining for TAl l , but this does not
necessarily correlate with presence 01
TAL-1 gene alteration 1407. 543J ,
CD79a positivity has been obse rved in
approximately 10% of cases 117501. One
or both of the myeloid associa ted
antigens C0 13 and CD33 are expressed
in 19- 32% 01cases 11 139, 22771 . COl17
(c-kil) is occasionally positive; such cases
havebeen associated with activating mutations of FLT31 1677 1. The presence of
myeloid markers does not exclude the diagnosis of T-ALLjLBL, nor does it indicate
mixed phenotype T/myeloid leukaemia.

Many markers characteristic of immature
t-eens such as C07 and C02, and even
CD5 and cCD3 may also be seen in
natural killer cell precursors [20701. Thus
it may be very difficult to distinguish the
rare true NK precur sor All from T- AlL
that expresses only immature markers.
C056 expression. while characteristic of
NK-cells, does not excl ude t-een
leukaemia. T-ALUlBL can be stratified
into different stages of intrathymic differentiation according to the antigens
expressed: pro-T (cC03 +, C07 +. C02-.
COl ao. C034+/-); pre-T (cC03+ , C07+.
C02+. COlao. C034+f-) ; co-nee! T
(cC03 e-, C07+. C02+ , cora-. C034-)
and medullary T (cC03+. C07 +. C02+,
COla-, CD34-. surface COO+). The pro-T
and pre-I stages are double-neg ative toC04 and C08. and the co-neat T stage
shows a double-positive (C04+ COB+)
phenoty pe. The medullary T stage expresses only either C0 4 or C08 1187,
8791. Some studies have shown a correlation between the stages of T-cell differentiation and survival 15001 T-ALltends
to show a more immature immunophenotype compa red with TlBL but the
groups overlap 123761
Genetics
Antigen receptor genes
T-AlULBL almost always shows clonal
rearrangements of the T-cell rece ptor
genes ( TCR), but there is simultaneous
presence of IGH@gen e rearrangements
in approximately 20% of cases 11749,
2138).
Fli- ' .13 T IyrnphobIasllc 1eIJkaerRa. 1I'I this example.

the IyrnphobIasts Iaci nudear convoIution$ The dVomatil is lilely $~.
Cytogenetic abnormalities and oncogenes
An abnormal karyotype is found in
50-70% of cases 01 T-AlUlBl /830.
8791. The most common recurrent cytogenetic abnormality involves the alpha
and delta TCR loci at 14Q11.2. the beta
locus at 7Q35, and the gamma locus at
7p14- 15. with a variety 01 partner genes
{830. 8791. In most cases. these translocations lead to a dysregulation of transcrip tion 01 the partner gene by
juxtaposition With the regulatory region of
one of the TCR loci. The most commonly
involved genes include the transcription
factors HOX 11 ( TLX1) ( lOq24) occurring
in 7% of childhood and 30% of adult
T-Al L, and HOX1 IL2 (TLX3) (5q35), occurring in 20% of childhood cases and
10-15% of adu lt 18301. Other transcr iption factors that may be involved in
translocat ions incl ude MYC (8Q24.1),
TAU (l p32), RBTN1 (LM 01) (11p 15),
RBTN2 (LM02) (11p13) and LYL 1(19p1 3)
1519, 830) The cytoplasmic tyrosine kinase LCK (1p34.3-35) can also be
FlO- ' .12 T/ynllI'lObIaStic 1'fnllhOma. A low ~tion 01 a tyn'4lh rode ~ ~ repIac:ement by ~ 1ympI'loma. Nwerous IrIgibIe 00dy rnacropnages ll(ll
scauered fYoul1IOul the rode. B H9'I rnagM:atlorl ol lhe specimen lin (A) s/'JcJwWlg ~ WIltI I'llUI"d tooval to ~-s/'Iaped nudei withdisperse(l etvorna!Jn a"d lisra bul nollllUSUaly PfOIl'W*'Il ru:W. 5eYeraI nvloIic ligIns en preset'(
T lymphoblastic leukaelTllaJlymphoma
177
Gene expression profiling studies have

identified several gene expression signatures. some of which correspond to specific
stages of normal thymocyte development:
LYl1+ sig nature corresponds to pro-T
stage. HOX 11+ to early cortical stage,
and TAL1+ to late co rtical thymocyte
stage /6891. The HQX11+ group appears
to have a relatively favourable prognosis.
t-een progenitor (T-ALL) or thymic lymphOCyte (T-LBL).
Fig. 9.14 T ~!ynllhoma.
lowmagriflcabon
stowi"lg a ~a~pattem ltlalcan
sometimes ITWlIC IoIil::l8" lymphoma.
involved in a translocation. In many cases

transiocanons are not detected by karyotyping but only by molecular genetic studies. For example, the TAL 1locus is altered
by translocation in about 20-30% of
cases of T-ALL. In only about 3% of cases
c an a t(1, 14)(p32;q1 1) transloca tion be
detected , but much more often it is fused
to the SIL gene as a result of a cry ptic interstiti al deletion at ch romosome 1p32
1281,914 , 1046 1, Aberrant TAL1 expression interferes with differentiation and proliferation by inhibiting the transcri ptional
act ivity of E47jH EB {16151. Other important transloc ations in T-ALL include
PICALM-MLLT10 [CALM-AF 10, t( 10:11)
(p13:Q14)), occ urring in 10% of c ases,
and transloc ations involvin g MLL (8%),
most often with the partner ENL at 19p 13
{B301. Neither of these is T-ALL sp ecific,
as the first occurs in AML and the seco nd
in B-ALL. Abe rrant expr ession of TAL1,
LYL1, HQX11 and HOX11L2 appea r to be
mutually excl usive from eac h other and
also from PICALM and MLL transioc ations, sugges ting non-overlapping, patho-
178
gen etically distinct subgroups (5191.

Deletions also occur in T-ALL. The most
important is del(9p), resul ting in loss of
the tumour suppressor gene CDKN2A (an
inhibi tor of the cvcun -oepenoent kinase
CDK4). which occurs at a frequency of
about 30% by cytogenetics, and a highe r
percentage by molecular testing. This
leads to loss of G1 control of cell cycle.
About 50% of cases show ac tivating
mutations involvi ng the extracellular
heterodim ertzation domain and/or C
terminal PEST domain of the NOTCH 1
gene , which encodes a protein critical for
early t-een dev elopm ent {2385}, The
d irect downst ream target of NOTCH1
appears to be C-M YC, which contributes
to the grow th of the neop lastic ce lls
[23861. Acc ord ing to one study , NOTCH1
mutation is asso ciated with shorter survival in adult but not paed iatric pa tients
{24gB}. In abou t 30% of cases, there are
mutations in hCDC4 gene. a negative regulator of NOTCH " These missense mutations result in increased half-lite ot the
Notch1 protein {13751.
4

TALL in childhood is generalty considered
a higher risk disease than B-AlL though
this is in part due to the frequent presence
of high-risk clinical features (older age,
higher while blood cell count). HO'Nevet",
T-ALL patients without high-risk features
dO not fare as well as B-ALL standard risk
patients unless intensive therapy is given.
Compared to B-ALL patients, T-All
patients have increased risk for induction
failure, early relapse and isolated eNS relapse 18091 _In cont rast to B-ALL. while
count does not appear to be a prognostic
factor. The presence of minimal residual
disease following therapy is a strong
adverse prognostic factor 124061. In adult
protocols, T-ALL is treated similarly to
other types of ALL. The prog nosis of
T-ALL may be better than B-ALL in adults.
though this may reflect the lower incidence
of adverse cytogenetic abnormalities. The
prognosis of T-LBL. as with other lymphomas, dep end s on the age of the
patient, stage and LDH levels /15121.
Rare c ases of indolent T lympho b lastic
proliferation involving the upper aerodigestive tract, charact erized by multiple
loca l recurrences but no systemic dissemination, have been desc ribed 12106.
23231. These cases are morphologically
and immunophenotypica lly indistinguishable from T-l BL. bu t lack clon al rearrange ments of the TCR genes.
__________________________----'1
-. - &
'
~.
C HAPTER 10
Mature Bcell Neoplasms
Chronic lymphocytic leukaemia Ismail lymphocytic lymphoma

Splenic marginal zone lymphoma
Splenic tyrnphomaIIeukaemia, unclassifiable
ExtranodaI marginal zone lymphoma 01 mucosa-associated
lymphoid tissue (MALT lymphoma)
Nodal marginal zone lymphoma
FoUicular lymphoma

Diffuse lerge B-ceillymphoma (DLBCL), NOS
T-ceUhli stiocyte-rich large s-.celllymphoma
Primary DLBCL 01 the CNS

Primary cutaneous DlBCL, leg type
EBV positive DLBCL of the elderly
DLBCL associated with chronic Inflammation
Primary mediastinal (thymic) large B-eelllymphoma

Intravascular large 8-celilymphoma
,"
.....
ALK positive large B-ceillymphoma

Large B-ceillymphoma arising in HHV8-associated multicentric
castleman disease
Bur1<itt Iymphome
B-ceillymphoma. unclassifiable, with features intermediate between
DLBCL and Bur1<itt lymphoma
B-celllymphoma. unclassifiable. with features Intermed iate between
DLBCL end classical Hodgkin lymphoma
Chronic lymphocytic leukaemia/small

lymphocytic lymphoma
H.K. Muller-Hermelink
E. Montserrat
D. Catovsky
E.Campo
NL Harr is
H. Stein
Defi nition
Chronic lym phocytic leukaemia/s mall lymphocytic lymphoma (C Ll/SLL) is a neop lasm com posed of monomorphic small,
round to slightly irregular B lym phocytes
in (he peripheral blood (PS) , bone marrow
(8 M), spleen and lymph nodes. admixed
with pro lymphocytes and parammunoblasts forming proliferation centres in
tissue infiltrates.The CLUSlL ceus usually
coexpress COS and CD23. In lhe absence of extramedullary tissue involvement. there must be ~5x l ()91l monoclonal
lymphocytes with a ell phenotype in the
PB. The intemanoret Workshop on Chronic
Lymphocytic Leukemia (IWell) report
requ ires that the lymphocytosis be p resent for at least 3 months and also allows
for the d iagnosis of eLL to be made with
lower lymphoc yte counts in patien ts with
cytopenias or disease-related symptoms
1873AI. Whethe r patients who would have
fulfilled the Criteria In the past for Cll but
who luHili the criteria only for monoclonal
B lymphocytosis (MBl) are better considered 10 have low stage Cll or MBl
remains to be determined. Some may
prefe r to sun consider many of these
cases more like Cll.
The term Sll is used for nonleukaemic
cases with the tissue mor phology and
immunophenotype of Cll. The IWCl l definition of Sll requi res lym phad enopathy,
no cytopen ias due to BM infiltration by
Cll./Sll and <5x 1CP/l PB e-ceus [873AI .
ICD-O code
9823/3
Epklemiology
Cll is the most common leukaemia of
adults in Western countries . The incidence
rate is abon 2-6 cases per 100,OCO person
per year, increasing with age reaching
12.81 100,000 at age 65 , the mean age at
diagnosis 11888]. It is now diagnosed more
often in younger ind ividuals 15251. e l l has
a male:fema le ratio of 1,5- 2: 1. CLUSll
accounts for 6.7% of non-Hodg kin lymphomas in biopsies (5 11. It is very rare in
far Eastern countries. This low incidence is
maintained in migrant populations speaking in favou r of a genetic predisposition.
180
Mature 8 '< e1l neoplasms
Etiology
B-ce ll recep tor s (BCR) of Cll ce lls
demonstrate high ly selected immun og lobulin heavy c hain variab le (lGH V) gene
usag e or even very simila r entire antigenb ind ing sites, coded by both heavy and
lig ht chain genes, and thus d iffer from the
much b roa d er diversity found in normal
B lymphocytes. These findings argue in
favour of a limited set of (auto-)antigens
promoting div ision of precursor cells and
clonal evolution 1423, 1153,22431 .
Peripheral blood and BM are usually
involved, lymph nodes, liver and spleen
are also typ ically infiltrated, and other exiranoda l sites may occasionally be involved.
Rarely, patients with ClllSLl present with
aleu kaemic tissue involvement, but usually develop BM and PB involvement during the evolution 01 the disease.
Clinical feature s
Clinical features are very variable including
presentation, co urse and outcome. Most
p atients a re asym ptoma tic, bu t some
presen t with fatigue, autoimmune haemolytic anaemia , infections, sple nomegaly,
hepatomegaly, lymphadenopathy or extranodal infilt rates 1221 , 18051. A small
M-eomponent may be found in some patients .
Monoclonal B-cell lymphocytosis

Healthy indiv iduals may show monoclonal
or oligoclonal Been expansions with the
characteristic phenotype of e l l in about
3.5% of tested subjects >40 years old
]1395, 1823). Monoc lonal Bceil lymphocvtosis with a non-cu. phenotype (CD5-)
may correspond to similar phenomena in
other B-cell neoplasms [301. Whether
MBl is a predisposing condition or even a
precursor of overt CLL has to be elucidated.
~.
"""'" .
". C'
'\30''''''
~......
s l
..
~.'"
Fig. 10.01 AALymph node in'o'Olved bydllooic ~ leukaemja, showing regulartyspacedproliferation centres
in a dar1l background (Giemsa stain). B High mllQflilicatiorl ilIustrabng a mixture of small lymphocytes with sen
C'r'JPIasrn <r'ld clrrl>ed dYomattn. SOOlasIig1Iy larger ~ wiIIllTO'e disper$ed cMmabn and small ~
and single paralnwnunoblasts (arrows), lIIrtlidl are larger cells WIth I'OIJnd to oval nudei, dispersed chromalJn and a
""""-
-logy
Lymph nodes and spleen
Enlarged lymph nodes in patien ts with

CLLlSl L show effacement of the architecture , with a pseuootomcurar pattern of
regularly-distributed pale areas corresponding to proliferation centres contain-
ing larger cells in a d ark bac kground of

small cells 11 84, 12731 . Involvement may
be limited 10 inle rfo llic ular areas. The p redominant ce ll is a small lymphoc yte,
which may be slig htly larger than a normal lymphocyte, w ith c lumped c hroma tin,
usually a round nucleus, and occas ionally

a small nucleol us. Mitotic ac tivity is usually very low. Prol iferation centres conta in
a continuum of small, med ium and large

cells. ProIymphocytesare smallto mediumsized cells with rela tively c lumped chromatin and smallnucleoli; parairrmunoblasts
are larger cells with round to oval nuc lei,
dispersed chroma tin, cen tral eosinophilic
nucleoli and slightly basophilic cytoplasm. The size of pro liferation centres
and number of pa raimmunoblasts vary
from case to case, but there is no correlation between tymph node histology and
clinic al course 11841. In the spleen , white
pulp illV'Cllvement is usually prominent. but
the red pulp is also involved; proliferation
centres may be seen bu t are less con spicuous than in lymph nodes. In some
cases, the small lym phoi d cells show

moderate nuc lear irregularity, which c an
lead to a differential diagnosis of man tle
cell lymp homa {2351 Some case s show
plasmacytoid differentiation.
Bone marrow and blood
On BM and PB smears, CLL cells are
small lymphocytes with clum ped ch romatin and scanty cy top lasm 11 9 11.
Smudge or ba sket ce lls are typi cally seen
in PB smears, The p rop ortion of prolym ph oc ytes (larg er cells with p rominent
nuc leoli) in PB films is usua lly <2%. Increasing number s co rrelate with a more
aggressive d iseas e co urse. More tha n
55% prolympho c yles, however, would
favour the diagnosis of B-cell prolymphocytic leukaem ia ( B-PLL ). Atypical CLL
shows less condensed nuclear chromatin
an d nuc lear irregularities in PB lymp hocytes. These findings are more frequent
in cases with trisomy 12 and other chromosomal abnormalities {19 11. Bone marrow involvement as seen in treph ine
b iop sies may be interstitial, nodular
and /or diffuse {1509, 18881: proliferation
centres are less common in the 8M than
in lym ph nodes; pa ratrabecurar aggregates are not typical. The definition 01
m inimal 8 M involvement required to diagnose CLlISLL in the absence of other
de fining features is not established ,

although the IWCLl describes >30% lymphoid cells as "charac tenstcanv" present
18l 3AI
lmmunophenotype
Using flow cytometry, the tumou r cells exp ress dim surface IgM/ lgD, C020, C022,
COS, C019, C079a, C023, C043 and
Co 11c (wea k). COlO is negative and
FMC7 and CD79b are usually neg ative or
weakly expresse d in typical CLL. The immunop henolype of PB lymphoc ytes has
been integ rated into a scoring system that
helps in the differential diagnosis between
CLL and other B-c ell leukaemias 1t 430,
151 11 , In tissue sections. cy toplasmic Ig
may be detectable, and cvcun 01 is negative 12508 1; howeve r cvcnn 0 1 has been
detected in cells of the proliferation centres 116141. Some cases may have an
atyp ical immunep henotype (e.g COS- or
C023-, FMC7+ or C01 1c+, strong slg , or
C079b+) 1492 ,14291 .
Genetic susceptibility
CLL has the highest genet ic pred isposition of all haernatologic recotases. A family predisposition can be documented in
5- 10% of patents with CLL based on finding 2 or more cases in the same family.
The overall risk is 2-7 times increased in
Chronic lymPhocytIC leukaemialsmalllymphocytic lymphoma
181
firsl degree tetanves of Cll patients 18 10,

19901. Family members of patients with
Cll show an increased incidence of ellphenotyp e monoclonal Been lymphocytosis at all ages, but espec ially in thase
<40 years old 15301.
Genetics
Antigen receptor g enes
IG genes are rearranged with 40- 50% of
cases unmutated (> 98% homOlogy with

ge rmline) and 50-60% showing somatic
hypermutation 1505, 8761. These two subtypes differ in many other biologica l and
clinical parameters. IGHV gene usage in
Cl l is highly selective, and etten associated with autoantibody reactivity 11658) ,
BCR signaling is most important in unmutated ell 1403, 538, 1252).
Gene expression profiling
Mutated and unmutated Cl l show a single distinctive signature, although there is

a group of genes that distinguishes these
two genetic subtypes 11160. 18671 The
tyrosine kinase ZAP-70 is among the
genes whose expression is associated
with an IG H V unmutated Cll genotype
124021. Ftow cytometry assays for ZAP-70
have been developed as a surrogate for
Cl l mutational status; however, in up to
20% of the cases the mutationa l status
and ZAP-70 expression are d iscordant
1490, 1653, 18221
About 80% of the cases have cytoge netic
abnormalities de tected by FISH 160 11.
About 50% of Cll show del 13q14.3,
about 20% trisomy 12 and, less commonly. deletions of 11q22-23, 17p 13 and
6q21 1601 ,1196. 1197,1 4291 . Thed istri
button of these abno rmalities varies
based on mutational status. The possible
Tab1l 10.01 Retation of VHmutaliOn slalusand genorNc
abefrationl ll CLl(1197)
Mutated VH
11"'132 (44%)
Unmutated VH
80'10
65"4
84'4
50"4
26'Il.
iTriSOmy 12
11qdeleIIon'
15"4
4%
19"4
271i.
17p~'
3%
7"4
10"4
35'4
Abemtion
cmaI aberTMon&
~ 3q ~.
Isolaled 13qdeleIO'l'
17por 11qdelebon'
n:168 (56'1l.)
(8'Il.
Signi~cant dll!$!tlfICe belWeen cases 'Mlh and WIth

out VH mutations.
182
Mature B-c ell neoplasms
Fig. 10.05 Aow t)'1omeIJy detection of ZANO in ClL. The left pIol shows \tie selecbon of the ~
subpopWbons ac:etlIding to the ~ (T-<:eIs in dar1l blue. NK<eIII iI'llight blue. CI..L cells iI'lllf'llllge and resdJaI
normal B-cells n grey). The CLl cellsate C05+ (see n left plot) arw:l CD19+ (seen II otherpIols). The plotin !he centrll shows a CLl wilh noIN'70 expression (2".4 positive CI..L cells) and the plot on the right a CI..L with t9 ZAP70
e.pression (65% positive CLlcelli). CLl cases with mote than 20% ZAp70 e~ are usuallyconsidered as
positi ve.
targets in the 13q14.3 region are two

micro-RNA genes, miR-16- 1 and miR-15a,
ATM in the l1q22-23 region and TP53 in
the 17p13 region 1475, 601, 19571. A specific micro-RNA expression signature that
includ es miR- 16-1 and miR-15a has been
reported to distinguish between mutated
and unmutated Cll and ZAP-70 negative
versus positive Cll13151.
Antigen expe rienced B-<:eIl14241 .
The Rai and Binet clinical staging systems
are used to define disease extent and
prog nosis 1221, 18051. New biolog ical
prognostic factors have become increasingly impor tant especially in early stage
CLL 1222, 1129, 1986J. Patients withmutated
Cl l have a bette r progno sis than those
with unmutated Cll, at least for those
with a low stage (median survival 293
months versus 95 months for patients with
Binet stage A) 18761. Expression of ZAP-70
and CD38 are both associa ted with an
adverse prognosis 17901 . Dell1 q22 23,
del17p and del6q are associated with a
worse outcome and isolated del 13q14.3
is associated with a more favourab le clinica l course 1475, 6011 . Usage of VH3-2 1
independen t of VH mutation status is an
adverse prognostic marker 122441. Additional adverse pred ictive factors inctude
a rapi d lymphocyte doubhog time in the
PB 12 months) and serum markers of
rap id celt turnove r. includin g elevated
thymidine kinase, sCD23 and ~ 2 microglob ulin 12221.
Progression and transformation of Cl l

to hig h grade lymphoma
Over time, Cl l may show an increase in
cell size and proliferative activity as well
as confluence 01 proliferation centres in
lymph nodes and BM. Often, this may
correlate With an increase in prolymphOcvtes in the PB. Progression of ell to
B-PLl is extremely rare.
2-8% of pat ients with Cll develop dif
fuse large B-<:elllymphoma (OlBClj and
< 1% develop classical Hodgkin Iyr1'lpt"ona
(Hl) 12691. The median survival for patients with DlBCl (Richter's syndrome) is
less than one year. The majority Of the
DlBCl have been reported to be clonally
related 10 the previous Cl l and are unmutated. whereas the cioneuv unrelated
cases 01 DlBCl usually occurred in rnutated Cll 11385, 22401. The vast majority
of Hl cases occ ur in mutated ClL.
Epstein-Barr virus (EBV)-associated Hodgkin
Of Reed-Sternberg (RS) cel ls frequently
are unrelated to the Cll clone 11 3851.
Some Cll cases show scattered EBV
positive or sometimes negat ive ReedSternberg cells in the backg round of Ctt.
These cases should not be diag nosed as
Hod gkin lymphoma. The diagnosis of
Hodgk in lymphoma in the setting 01 CU
requires classical RS cells in an aoorconate background . EBV-associated Iymphoproliferative disorders includ ing Hodgkin
lymphomas may occur after fluda rabine
therapy 14. 22341 .

Definition
B-cell prolymphocytic leukaemia (B-PLl)
is a neoplasm of B prolymphocytes affecting the pe ripheral b lood (PS ), bone
marrow (8 M) and spleen, Prolymphocytes
must exceed 55% of lymphoid cells in the
PB, Cases 01 tran sformed ch ron ic lymphocytic leukaemia (ell). ell with in
creased p rolymphocytes and lymphoid
prQifefationS with rela~ smlar m0rphology bu t carrying the t( 11;14)(q13:Q32)
translocation are ex cluded.
IC().() code
983313
Epidemiology
B-PLl is an extremely rare disease, com prising approximately 1% 01 lym p hocytic
leukaemias. Mos t pa tients are over 60year-old . with a median age of 65-69 and
similar male.temale distribution 11456 1.
The leukaemic cells are found in the PB,
8M and sple en .
Clinical features
Most pat ients present with B symptoms,
massive sp lenomeg aly wi th abs ent or
minimal per ipher al lymp had eno pathy,
and a rapid ly rising lymphoc yte count,
usually over 1(X)x1()llA... Anaemia and

thrombocytopenia are seen in 50%
{11941.
Mo<phology
Peripheraf biood and bone marrow
The majority ( >55% and usually >90%) of
the circulating cells are prolymphocytes
-medium-sized cells (twice the size of a
lymphocyte) with a round nucleus, moderately condensed nuclear chromatin. a
prominent central nucleolus and a rela tively small amount of faintly basophilic
cytoplasm 1750 . 1456 1. Although the nucleus is typically round . there may be
some ind entation in some cases. The 8 M
shows an interstitial or nodu lar infiltrate of
nocieotateo cells with an intertrabe c ula r
d istribution.
Tissues other than bone marrow
The morpho logy of B-Pl l in tissues is not
we ll know n since pr evious histolog ic al
studies have inc lude d cases with the
t(11; 14) transloc ation that co rrespon d to
leu kaemic variants of mantle cell lymphoma (MC l ) 11892.1963). The sp leen
shows expanded white pulp nodul es and
red pu lp infiltrat ion by intermediate to
large ce lls with abu ndan t c ytoplasm and
irregu lar or round nuclei with the presence
E. Campo
0 , Catovsky
E. Montserrat
H ,K , Muller-Hermelink
N.L. Harris
H . Stein
of a central eosino phil ic nuc leolus 118921.

l ym ph nodes show d iffuse or vaguely
nodular infiltrates of similar cells . Proliferation centres (pseudofollicles) are not seen.
Oistinctioo from bl astoid variants of MCl .
splenic ma rginal zone lymphoma . and
Cll with an inc reased number 01 prolymphocytes may be diff icult 00 morphological grounds. The differential diag nosis
req uires immunophenotypic and genetic
studies. in part to rule out the presence 01
the t{1 1. 14) translocation or c yctm 01
overexpresson.
Immunophenotype
The cells of B-PLL strongly express surface

IgM +/ - IgO as well as B-c ell antigens
(C019, C02O . C022. C079a and b.
FMC7) : COS and C023 are ooly positive
in 20 -30% an d 10-20% of cases, respectively 1542. 1194. 18921. ZAP-70 and
C038 are expressed in 57% and 46% 01 the
cases but they are not related to the mutational status 01 the immunoglob ulin genes
15421
Ge netic s
Immuno g lo bulin genes are c lonally rearranged with an unm utated heavy chain
ge ne in ab out half of the c ases. All B--PLL
--
'
.~
183
have been reoorteo to use mem bers 01

the VH3 (68%) and VH4 (32%) gene families 15421.
the progressive course and relative treatment resistance of B-PLL. FISH analysis
detects deletions at 13q14 in 27% of the
cases 15421. Trisomy 12 is unconvnon

Initial studies had demonstrated the
t(11 ;14)(q13;q32) translocation in up to
20% 01 B-PLL 12741 Howe ver, these
cases are now c onsidered leukaemic
variants of MCL {1892, 1963, 2439J Cornplex karytotypes are c ommon 11963J
Del(17p) is dete cted in 50% 01 the cas es
15421 and is associated with TP53 gene
mutations 11 2771. This probab ly underlies
15421.
164
Mature B-cell neoplasms
Postulated normal cou nterpa rt

Unknown mature B-cell.
BPLL respond s poor ly to therapies for
eL L and median survival is 30- 50 months
1542. 18921 Neither ZAP-70 expression.
CD38 positivity. 17p dele tions nor the
mutational status 01 the immunoglobu lin

genes seem to correlate with survival
15421. Splenectomy may improve the
patient's symptoms. Responses have
been recorded with the ccnomatco
CHOP (cytcxan. adriamycin. vincr istine
and prednisone), and the nucleoside
analogs fludarabine and cladribine. A
co mbination of chemotherapy and ntuximab may b e a reasonable approach to
treat these patients 11194J
Splenic B-cell marginal zone lymphoma
Definition
Splenic marginal zone lymphOma (SMZl)
is a Been neoplasm composed of small
lymphocytes which surrCM.Jnd and replace
the splenic white pulp germinal cen tres ,
efface the follicle mantle and merge with
a peripheral (marginal) zone of larger
ceus includ ing scattered transformed
blasts: both small and larger celts infiltrate
the red pulp . Splenic tater lymph nodes
and bone marrow (8M) are often invotved :
lymp homa cells may be found in the peripheral blood (PSI as villous lymphocytes
ICD-Ocode
9689/3
Synonym
Splenic lymphoma with circulating villous
lymphoCyte s (SLVL).
Epidemiology
SMll is a rare disor der, comprising less
than2% of lymphoid neoplasms 179}. but
it may accoun ttor most cases of otherwise unclassifiable ch ronic lympho id
ieckaemies that are CD5-, Most patients

are over 50 and there is an equa l se x
incidence 11951.
J'-
P. G. Isaacson
M .A Piris
F. Berger
S,H. Swerdlow
C, Thieblemont
S, Pillaluga
NL Harris

The tumo ur involves the spleen and
splenic hilar lymph nodes, BM and often
the PB. The liver may be involved. Peripheral lymph nodes are not typ ically
involved 1195, 14971.
Clinical features
Patients present with splenomegaly,
sometimes accompanied by autoimmune
thrombocytopenia or anaemia and a variable presence of PB villous lymphocytes.
The BM is regularly invol ved, but pe ripher al lymphadenopathy and extrarooar
infiltration are extremely uncommon.
About one third of the patients may have
a small monoclonal serum protein, bu t
marked hyperviscosity and hypergammaglobulinaemia are uncorrrnon 1195, 1497 1.
An association with hepa titis C virus has
been described in southern Europe 172,
9261
Morphology
In the splenic white p ulp, a central zone of
small round lymphocytes surroun ds . or
more commonly replac es reactive germinal centres with effacem ent of the norma l
follicl e man tle 11 0 14, 149n This zone
merges with a peripheral zone of small to
med ium-sized c ells with more di sp ersed
Fig. 10.08 Splenic rnatgIl'IaI zone ~. Gtoss

~ 01 spleen shoIfIling m;rled e~ dh
wtWI pUp. as.el as Plllralion dille red pUp,
chroma tin and abundant pale cytoplasm.

which resemb le marginal zone cells and
interspe rsed trans formed blasts. The ted
pulp is always infiltrated. with both small
nodules at the large r cells and sheets of
the small lym phocytes, which often invade sinuses. Epithelioid histiocytes may
be present in the lymphoid aggregates,
Some c ases may have a markedly pred ominant population of the larger marginal zone-li ke cells 18781. Plasmacytic
differentiation may occur and in rare
c ases, clus ters of p lasma cells may be
present in the ce ntres of the white p ulp
nodules, In sp lenic hila r lymp h nodes
the sinuses are dil ated an d lymphoma
........._
~~~_
Splenic B-eell marginal zone lymphoma
185
in the PB, they are usually, but not always ,

characterized by the presence of short
polar villi. Some may appear p lasmacytoid 114571. The differential diagnosis
includes other small Bccell lymphomasJ
leukaemias. including ch ronic lymphocytic
leukaemia. hairy cell leukaemia, mantle
cell lymphoma. follicular lymphoma and
Iymphoplasmacytic lymphoma. The nodular
pattern on BM biop sy exclu des hairy cell
leukaemia. bu t the morphologic featu res
o n BM examination may not be sufficient
to disting uish between the other subtypes.
This requires integration with the morphology and immunophenotype of the cells in
the PB and BM.
Irrrounophenotyp
Fig. 10.09 SpIel'IiClTI<WgI'Ial zone lymphoma. Peripheral

blood containing tumour cells with ~ar villi (villous
IymptlocylesJ.
surrounds and replac es ge rminal centres,

but the two cell types (small lymphoc ytes
and marginal zone cells) are etten more
intimately admixed without the forma tion
01 a distinct "marg inal" zone. This has
given rise to doubts about suggestions
that the tumour arises from sp lenic marginal zone cells. In Ihe BM there is a
nodular interstitial infi ltrate cytologically
similar 10that in the lymph nodes. Occasionally, neopl astic ce lls surround reactive
follic les. Intrasinusoid allymphom a cells,
better revealed after C020 immunostaining , are a helpful feature although they are
sometimes observed in othe r lymphom as
[7271. When lymphoma cells are p resent
Tumour cells express surface IgM and

usually, but not always, Ig O, are C020+ ,
C 0 79a +, C05-, C01O-, C023-, C043and ann exin A1 - P014, 14281. C0 103 is
usually. but not always, negative and
cyclin 0 1 is absent 119451. Staining for
Ki67 shows a d istinctive targeto id patte rn
based on the presenc e of an inc reased
g rowth fraction in both the germinal centre (if p resent) and the marginal zone. The
absence 01 cycnn 0 1 and the infrequent
exp ression of C05 are usefu l in excluding
mantle cell lymphOma and chronic lymphocytic leukaemia respectively. Absence of
ars-exm A1 excjuoes hairy ceueckaeraa.
and absence 01 COlO and BCl6 helps to
exclude follicular lymphoma 119451.
Ge netics
Immunogl ob ulin heavy and lig ht chain
genes are rearr anged and approximately
ha lf 01 th e c ases hav e somatic hypermutation . Bias in VH1-2 usage has been
found in both mutated and unmutated
cases suggesting that this tumour derives

from a highly selected Been populat ion
1231. Other
biased VH gene usage has

also been reported 11251. In addition , intraclonal variation has been rarely detected.
suggesting ongoing mutations 1624. 249n
Cytogenetic abnormalities
Allelic loss 01 ch romoso me 7q3132 has
been de sc ribed in up to 40 % of SMZL
11 416 1. Oysregulalion of the CDK6 gene
located at 7q21 has been report ed in several cases of SlVL wilh translocations involving this region 14741. Trisomy 3q and
a number 01 other cytogenetic abnorma lities have been described 1319, 766, 859,
929 , 1669llNhile BCl2rearrangement and
t(14 ;18) are absent. CCNDl rearrangement , t(11 ;14) and cyclin 01 express ion
have been reported in a small propoton
01 the cases; however, the possibility that
these cases represent examples of mantle
cell lymphoma has not been excluded,
since c ycnn 0 1 exp ression is absent Irom
weu-cbaractere ec cases of SMZl119451 .
Transloc ation t(1 1; 18), common in extranodal marg inal zone lymphoma of mucosaassociated lymphoid tissue (MALT) type.
is not a leature of SMZL 1575, 18371.
Splenic marginal zone lymphoma has a
specific transcnptooat profile compared
with other B-eell , especially small B-eell
lymphomas. This specific molecular signature includes genes involved in the
signaling cascade of the AKT1 pathway
and B-eell receptor signaling {374. 21971.
Postulated norma l counterp art
B-ce ll of unknown di fferentiation stage,
The prese nce 01 IG gene somatic hypermutations in 50% of ca ses suggests
B Infillnlbon 01 red pulp sinuses.

186
Mature 8-eell neoplasms
fig. 10.11 Splenic margI'IaI ZOfIll~ . .. SpIeric!*lr Iymj:tII"IJde s/'loIWIg a nodlNr infillra1e
C High ~ shows a rrU1ured smaI ~ and larger cells.
exposure to antigen in the germinal centre microenvironment.

The clinical course is indolent , even with
8M involvement 172. 195, 1538, 2196,
219n Response to chemotherapy of the
type that is typically effective in other
chronic lymphoid leukaemias is often
poor, but patients typically have naematoloqrc responses to splenectomy. with

long-term survival. Transformationto large
B-cell lympho ma may occur , as in other
indolent Bccetl neoplasms 115381. HeVpositive cases have been reported to respond to antiviral treatment using
interferon r with or without ribovarine 1926.
21951. Adverse clinical prognostic factors
include a large tumour mass or poor general health status 13741. A clinical scoring
system has been proposed 1721 and
cases with mutated TP53 may show an
aggressive course 18581. The presence of
7q dele tion and unmutated IGHV genes
may be associated with an unfavourable
outcome 123, 22631.
(
Splenic B-eefl marginal zone lymphoma
187
Definition
Hairy ce ll leukaemia (HCL) is an indolent
neoplasm of small mature B lymphoid
ce lls with oval nuclei and abundant c ytoplasm with "hairy" projections invo lving
per ipheral blood (PBl and diffu sely infiltrating the bone marrow (8 M) and splenic
red pulp.
ICD-O code
994013
EpidemOOgy
Hairy ce ll leukaemia is a rare disease.
comprising 2% of lymphoid leukaemias .
Patients are predominantly midd le-aged
to elderly adults with a median age of 50
years ; HCl has been di agn osed rarely in
patients in their 20's, but is exceptionally
unc ommo n in children , The male.ternare
rali o is 5:11642/ .
Etiology
Although the natu re of the underlyin g

oncogenic events in HC L is not known,
severersiudies provide an explanation for
many of the unique features of this entity
1157. 348 ,22351 (Table 10.02 ).
Sitesof involvement
Tumour c ells are found predom inantly in
the 8M and spleen . Typically a small number of c irc ulating c ells are noted. Tumour
infiltrate s may occu r in the liver and lymph
nodes, and oc c asionally also in the skin .
Rare pat ients demonstrate prom inent abdom inal lymphadenopathy, whi ch is associ ated w ith large ha iry cells; this may
rep resent a form of transformation 119991.
.-smears.
Fill. 10.13 Hairy cel leukaemia.
K. Foucar
8 . Falini
D. Calovsky
H. Stein
Cli nical featur es

The most common pr esenting symptoms
include weakness and fatigue, left upper
quadrant pa in, fever and bleeding . Most
patients present with sple nom egaly and
pa ncytopenia with few circulating neoplastic cells. Monocyto penia is ch arac teristic.
Other common distinctive manifestafions
include he patomegaly and recurrent ooportunistic infections. while less corrroon
unique findings includevasculitis , bleeding
d isorders. neurologic disorders , skeletal
involvement and othe r immune dysfunc tion /95 1}.
Fig. 10.14 Hairy oeI leukaemia. The spleenis ~

enlarged wittI ddIuse eqllllSion of the red pulp ....,.
pulp is nol. discema ble. Numerous blood ceII lBkes of
vaf}'ing size are visible.
Mor phology
Peripheral blood and bone marrow
Ha iry ce lls a re sma ll to med ium-sized
lympho id cells w ith an oval or indent ed
(b ean -shaped ) nucl eus w ith hom og eneou s, spon gy. g rou nd- gl ass c hromatin
that is slig htly less c lumpe d than that of a
normallyrnphoCyte . Nuc leol i are typicall y
absent or inconspicuous. The c ytoplasm
is abundant and pa le blue , with circumferent ia l "h airy" p rojections on smears
1212, 19991. Occasionally the cytoplasm
contains d iscrete vacuoles or rod-s haped
inclusions that rep resent the ribosom e
lamellar complexes that have be en identified by electron micr oscopy 11999J.
The d iagnosis is be st made on 8M
biopsy. The exte nt of 8 M effacement in
HCl is variab le . The pr imary pattern is interstitialor pa tc hy with some preservation
of fat and naematoporetrc elements . The
infiltrate is c haract erized by wideIy...gpaced
lymphoid ce lls with oval or indented nuclei.
in contrast to the c lose ly packed nuclei of

most other ind olent lymphoid neoplasms
invo lv ing the 8 M. The abundant cytopla sm and pr om inent cell borders may
p rod uc e a "frie d-egg " ap pearance 1212,
19991. Mitotic figures are virtually absent.
When inf iltration is minimal, the subtle
c lusters of hairy cells can be overlooked.
In patients with advanced d isease. a dr!fuse solid infiltrate may be evident. The
obvious d iscr ete aggregates that typ ify
8 M infiltrates 01 many other chronic JyrTVioprol iferative d isord ers are not a feature of
HCL. An inc rease in reticu lin fibres is associ ated with all hairy c ell infiltrates in 8 M
and othe r sites, and often results in a "drytap ". In a proport ion of patients, the 8M is
hypocellular with a loss of haematopo ietic
eleme nts , espec ially the gra nulocyt ic noeage, which can lead to an erroneous diagnosis01 aplastic enaeraa. In such cases,
invnunostain ing lor a B-eell antigen such
A,B Note 1helyf:icaI ~ fealuresoiciroJlatWlg hairycels ~ the range in nuclear morphology. C There isstrong~
tesistanl acid p/'lOSpI'IaIaSe posiMy c:IIar'aderisbc oIl1aily oeI lNaemia
188
Mature B-eeU neoplasms
as C020 is esse ntial tor the identification

of an abnormal B-ce ll infiltra te , prompting
the cedomance of more specific immunohistochemical stains lor HCl. The pr oduction of cytokines by the hairy c ells is
presumed to be the cause of mrs
haematopoietic sup pression 13481.
Other leukaemiaS/1ymphomas suc h as
splenic marginal zone lymphomas and
some urclassihable splenic Iymphoma sl
leukaemias show mor phologic and immunopheootypic ove rlap with hairy cell
Table 10.02 Palhogenesjs ofhairy ~Ilel;ka&mia

Property
Proposed pathogeneticmechanism(s)
Derived fmm I'Nlture memory B-cell. Leukaemic llairy eels diller from
fIOITIIal memory B.oeIls because of altenldeJqll"ession of c:hemolOO8
and adhesiOn I"8ClIJlkn
Inlluenced byo'<'enlllpreSSiDn and consbtuIive ~ of members
of Rho lamit)' of smaI GTPases and ~ oflhe ~ eresspetlfJcmolecule Gas7.
Hairy cell morpI1oIogy
May relate toconstlbJtrve 8ClMIbDn of adhesiDMootiIit rec;eplor$,

tIItryoeIsI11Brad sponIaneously WIllextraeeIIAar maW; c:ornponera;
MIry cells lIlJIere and bI'llI frMy onto ftbronecbn in bone nwrow
miODeI'wrcnment
W<aema
HCl eels synIheslzeand bI'llI to fibrooedin in bone ma-mw ~
eovworwnent. Proc1Jctictl me oflbonedin I5INer 00fltrtlI cJawR

baSIC rtJroblast ~ IKU (bfGF) seoeled by hlwycels. Translon'ring ~ tactJr lit (TGF131) also ~ a IOIe in reliwiInfbtlsis
Spleen and other tissues

In the spleen . HCL infiltrates are found in
the red pulp. The wh ite pul p is typically
atrophic. The cells characteristicall y fill
the red pulp cor ds. Red blood cell lakes,
collections 01 pooled erythrocytes su rrCllMlded by elongated hairy cells, are the
presored consequence of d isruption of
normal blood flow in the red p ulp 1212.
19991. The liver may show infiltrates of
hairy cells , predominantly in the sinusoid s lymph node infiltration may occur
especially with ad vanced d isease , and is
variably mtertouicurarzparacoruc ar, with
sparing of follic les and intact sinuses.
~tobMemamlW . ~~
liair'fcels home to ~ Q)Ii"',enls ia ~
actovaIed integrin ~ and over expres:siDn cJ matIJ-mecaIDpr'oIeinasfI mitIikn.. Down ~ 01 dWll,()Q18 rec:epkn Sl..Id1 as
CCR7 iIl'ldCXCR5e~ absence 01 ~ node ~
ill'lCl hepatic sftIsDidS
"",.""""
Pseudosinus bmalion
CMl!expressiM 01 Amen'l1 and adI'I pos:stlIe rnediakn.

f1 spleen
Related toconstitutrve eel aetiYllflDn.

Cons1itubve prOl:b:bon ollJ.mi:U necrosis Iador (TNF), intetIeum ~
(IL-6) and 0YeI'e~ d apopt06is irhbib. BCL2_
lnhibiIion 01 noonaI haemalopoiesis
Cytochem;SUy
The only cytoc hemical stain utilize d in the
diagnosis is tartrate-resistant ac id phosphatase(TRAP), and this techn ica lly chal lenging cytoc hemic al stain has be en
largely supplanted by immunophenotypic/
immunohistoc hemica l tech niques. If appropriate air-dried unf ixed slide p reparations are ava ilable , vi rtually all cases of
HCL will contain at least some ce lls w ith
strong , granu lar cytoplasm ic TRAP positivity, while wea k staining is not of d iagnostic utility (212, 1999 1.
InleraetIa1 d hairycelI5l11'iltJ 8fIdoltlIUI cells rMl.Cing in repIacemenl

of MdDlheIiaI c:elIl by Ieiukaemic hairycells.
(hypocelllW Hell
References {157, 348,2235}.
ConstiMive PI'(lllJcliDn 01 tr.InslomW1g growth fada~
""'-
(TGF~ )
by
Immunophenotype
The assessmen t of an anti gen profi le that

takes into account inte nsity of antig en
expression and assessment 01 multi ple
antigens is very useful in the d iag nosis of
HCl. The classic immunophenotypic profile of HCL consis ts of bri ght monoty pic
surface immunoglobulin, bri ght coexpression 01 C020, CD22 and CO lle, and
expression of C0 103, C025. C0123,
t-eet. Annexin A l (A NXA1), OBA.44,
FMC-7 and cycun 0 1 (usually weak) 1348.
541 ,670, 1062, 1423 , 1999 . 23921 .
Most cases 01 HCllack both COlO and
CDS. although irrmunopheootyp variants
are welt known 1404, 1050 1 Anne xin A 1 is
Hairy cea leukaemia
189
the most specific marke r since it is not

exp ressed in any B-cell lymphoma other
than HCL 16 701 Expression of Annexin A 1
can be used to distinguish HCL Irom
splen ic marginal zone lymphoma and
HCL variant which are bo th Annexin A 1
neg ative 16701. Immunostaining for Annexin A 1 must always be com pa red wi th
that lor a B-cell antigen (e.g . C020), since
Annexin A 1 is also expressed by myeloid
cells and a p roportion of t-ceus 16701. For
this rea son, Annexin A 1 is not a suitable
marker for mon itoring minimal residual
disease . More suitable approaches for
assessment lor residual d isease after
therapy include either mutticolor llow
cytometry targ eting the d istinctive HCl
profile or ITml..nohistochemical techniques
including C020, TRAP, DBA 44 and 'l-bet.
However, low numbers of TRAP positive
Of OBA.44 posi tive cells may be seen in
normal BM 114231. Similarly, some t-eens
may be I-bet posmve. and weak staining
for T-be t may be seen in other B-ce ll neoplasms 110621, The clinical value 01monitoring for residual disease is not yet
estab lished .
~"
F-'g, 10.16 Huy cellel.taenN. A.S Bone marrow biopsy. Hypoc:eljar ha-y cel leuk.aerlia lIIilhsublIe netsbtIaI ....
lillrcIles(A). lrmuIoperoxidas lor C020 ~ sublIe Ieukaenic: in6Itrates in hypocelUar HCl (B). C Spleen.Red
pulp i1iIlraticI'I lIIilhrunerous red bkxxlcel lal<es, 0 LiwM". Bo8l portal iI1d SinJ5CidaI irI6Ilr.3lion by ~ eelsis presert
Gene tics
Although exceptions have been reported .
the majority (>85%) of cases of HCl
demonstrate VHgenes with somatic hypermutation indic ative of a post germinal centre stage of maturation 183. 348, 22351. A
unique feature of HCl is the comm on c oexpression of multiple cronauv related 19isotypes. sug gesting arrest at some point
during lsotype switching (22351.
No c ytogenetic abnormal ity is specific for
HCl: numerical abnormalities of chromosomes 5 and 7 hav e been de scribed, but
transl ocations are distinctly uncommon
13481
Fig.10.17 Hairy cel leukae!l"ia, iml'T'l.J~ features. A,B,C Bone malfOWbiopsy. AD8A44 positivityothai'y

late, activat ed memo ry B-cell .
eels accef1luat nghairy projedlons. B com ~tYity ot hairy cells C Hairy cees express Annexin 11'ttli1e eryttwoid
prew-scn arenegaUve. 0 Uver. Sinusoidal inFiltration byAn!lexinA1-pClSjbve leukaemichairycells.

HCl is uniquely sensitive to either a -interferon or nucreosices (purine analog s)
such as pentostatin and ctaonbme. Patients receiving pu rine an alogs often
achieve com plete and durabl e remissions
{2235 1. Prolonged remission may also result Irom splenectomy, but this is uncommon 17981. The overall t n-year surviv al
rate exceeds 90% {642, 7981. Rituximab
offers therapeu tic effica cy in combination

with pu rine analogs in patients with renact orwreiaosed HCL: experimental therapeutic ag ent s incl ude anli-C022
ant ibody therapy or anti-C0 25 immunotoxin therapy 118501. l ong term HCL survivors have an inc rease d risk of second
cancers com pared to the general population with a cumulative probab ility of 30%
for secon d neoplasms by 25 years after
190
HCl diagnosis 1940 1- Hodgkin and nonHod gkin lymphomas as well as thyroid
cancer pr edominate in these long term
survivors 19401.
Splenic B-cell lymphoma/leukaemia,

unclassifiable
M . Piris
K. Fouca r
M . Mollejo
E. Campo
B . Falini
There are a number 01 variably well-
Synonyms
Splenic ma rginal zone lymphoma (SMZL)diffuse variant {1496 1, lym phocytiC lymphoma simulatin g hairy cell leukaemia
116811, splenic B-c eil lymphoma with villous lymphocytes (also used for SMZl
and HCl-vatiant), splenic red pulp lymphoma With numerous basophilic villous
lymphocytes 122621-
defined entities that represent small Be en

Clonal lymphoprolil erations involving the
spleen, but which do not fall into any of

the other type s of B-cell lymphoid neoplasms recognized in the WHO classifteaton. This chapter reviews the two best
oeteeo of these relatively rare provisional
entities. splenic diffuse red pulp small
B-cel lymphama and hairy cell leukaemia
variant. The relationship of splenic diffuse
red pulp small Been lymphoma to hairy
cell leukaemia variant and omer p rimary
splenic B-celllymphomas remains uncertain, the ir precise diagnostic criteria are
not fully established and the most appropnale terrTWdogy is wserned. Other splenic
small B-cell lymp homas not fUlfilli ng Ihe
criteria lor either otmese provisional enti ties or for other tetter established B-eall
lymphomas should be diagnosed as
splenic Been Iymp homall eu kaemia. uoclassifiable until more is known .
Splenic diffuse red pulp small
B-<elllymphoma
Definition
Splenic diffuse red p ulp sma ll B-c eillymphoma is an uncommon lymphoma w ith a
diftuse pattern of invo lve ment ot the
splenic red pu lp by small monomorphous
B lymphocytes. The neopl asm also involves bone marrow (8 M) sinu solo s and
peripheral blood (P8 ), co mmonly w ith a
villous cytology, This is a provisional entity that needs add itional molecu lar studies tor defining its main features and
d iag nostic markers. This diagnosis should

be restricted to ch arac teristic cases, fulfillin g the majo r fea tures d escr ibe d here
and not applied to any lymphoma grow
ing diffusely in the spleen. Chronic 1ymphocytic leukaemia (CU). hairy cell leukaemia
(HeL), _ " " " " Y l C IynVooma (Lf'L)
and prolympI-ocybC ieLl<aema (PU) should
be excl uded through appropriate studies,
A c ertain d iag nosis may require the examination of the spleen. bu t may be suggested to- cases showing purely
intrasinusoidaJ BM involvement and villous
lymphocytes in the PB. In case of doubt,
the use of the term splenic Been Iymphoma/leukaemia, unclassiliable is warranted .
Some deg ree of overlap exists with cases
that fulfil the criteria for hai ry cell
leukaem ia variant {1913A, 14311. The
neoplastic cells in bo th entities are
0 8 A.44 +, frequently IgG +, IgO and have
freq uent chromosomal alterations, Addi
tiona ! stud ies are req uired to confirm
these find ings and to furthe r evaluate the
extent of overlap betw een these entities,
par ticu larly as not all stud ies rep or t the
same phenotypic or cytogenetic findin gs ,
A rare subtype of large B-cel l lymphoma
involving the sinusoid s , both in the sp leen
and the 8M, has been d esc ribed by two
d ifferent g roups 11 495A, 1523) , Although
these cases may be related to those d escr ibed above , the diagnosis of sp lenic
d iffuse red pulp smal l B-ceil lymphoma is
restricted to an indolent lymphoma composed of small lymphocyt es ,
fCD-OCOde
959113
Epide miology
Splenic d iffuse red pulp small B-cell
lymphoma is a rare disorder, accounting
lor < 1% of non -Hodgkin lymphomas. It
rep resents about 10% of the B-c eil lymphomas diagnosed in splenectomy spec imens. Most patients are over 40 and
there is no gender bias .
All c ases are diagnosed at clinical stage
IV, with spleen, 8M and PB involvement.
Periphe ral lymph node involvemen t is
only rarely repo rted.
Clinical features
Sp lenic diff use red p ulp smal l B-ce Ulymphoma is a leukaemic neoplasm , usually
w ith a relativ e ly low lymphoc ytos is. Almos t all patients have, frequently massive,
sp lenomeg aly. Altho ugh not consistent
among all stud ies, thromboc ytopenia and
leukop enia a re frequently pres ent. while
anaemia has been reported more rarely,
B symptoms are infreq uent. A sma ll group
of these patients show cutaneous infiltration
.". .
_ .. ao
flll.10,18 Sj:IIehc do1luse red pulp smaI fk:elI~. A Peripheral blood cyloIogy wrItl YiIous eel. B Reticulin stairIIog oullinn!he mixed lllfillTation 01 bolh red Pl4I
CllI\'Wl8I'IlS: cordsarwj SinIsOidS. C BentITWTtIW innsilusoidal ldillratlon hiQt6lt4edby C020 Ulrlg
SplenIC B-celllymphomalleukaen"Na. uoctassmatae
191
translocation t(9;14)(p13:q32) inIJo!ving
PAX5 and IGH@genes have been fOlind

in thes e cases 11411 bUI they lack del 7Q
and t( 11:14). Frequent TP53 alterations
have been des cr ibed , with inc reased p53
expressio n 114961. Othe rs have reported
a frequent absence 01 any cytogenetic
abnormalities and occasio nal cases of
det 7q /2262 1.
Unknown pe ripheral b lood Be en.
Prognos is and predictive factors
This is an indol ent but incurable disease.
with good responses after sp lenectomy.
Hairy cell leukaemia-variant (HCl.v)
in the form 01 erythema tous and pruritic

papules at the lime of the initial d iag nosis. Presence 01 a pa raprotein has not
been reported.
Morphology
Peripheral b lood: Villous lymp hoc ytes
similar to those reported in SMlL are
p resent.
Bone marrow: lntreslnusolc at infiltration is
the rule, occasionally as a sale find ing
This can be accompanied by inte rstitia l
and nodular infiltration, l ymphoid follicles,
as in SMZl. have not been repo rted,
Sp leen. A diffuse pattern of involvement
of the red pulp, with both co rd and sinu soid infiltration is present. Characteristic
intrasinusoidal aggregates with occasional
p seud osinuses lined by tumoural cells
may be seen. In contrast 10 SMlL, the
tumou r shows an ab sence of follicular rep lacement, bipnasc cytology or marginal
zone infiltration. The neoplastic infiltrate is
corcceec 01 a monomorphous population
of small to me di um-sized lymphocytes.
with round and regu lar nuclei. vesicular
c hroma tin and occasional d istinc t small
192
Merure B-ceu neoplasms
nucleoli, with scattered nucreorateo blas t

ce lls. Tumoural cells have a pale or lightly
eosinophilic cytoplasm. with plasmacytoid
features but lac king other featu res of
plasmacytoid differentiation, such c ytoplasmic Ig o r CD38 exp ression.
Definition
The de sig nat ion HCL v encompasses
c ases 01 B c hronic lym phop roliferallYe
d isord ers that resemble cl assic HCl but
exhibit variant "cvroneematotoqc" features (i.e. leukocytosis. pre sence 01
morocytes. cells with prominent nucl~,
c elts with bla stic or convoluted nuclei
andJor absence of ci rcumlerential shaggy
co ntou rs). var iant immunophenotype (i.e.
ab sence of C025, anne xin-A 1, or TRAP)
and resistance 10 conventional HCl ther
apy (r.e . lac k of dramatic respo nse to
claonbme). These cases are no longer
considered to be biologically related 10
HCL
ICD-Q code
959 1/3
Cytochemistry
Tartrate-resistant acid prosoatase (TRAP)
staining is not p resent.
Synony m
Prolymphoc ytic variant of HCL.
Immunophenotyp e
The ch arac teris tic profile is CD20+,
DBA44+, IgG+, Ig D-, Annexin A1-, C025- ,
COS-, C0103-, CD123-, C0 11c-, C01O- ,
C023- P 429 A, 1496, 19221. Ig O+ c ases
can be seen with similar featu res. Others
have rep o rted c ases with IgM+ lgG,
CD103+ an d COt t c- with infreq uent
CDS and C0123 exp ression 122621.
Ep idemiology
Cases of HCL-v account for about 10% of
HCL with an inc idence of approxrrnately
0.03 per l 00 ,CXXl persons per year 118501.
Middle-aged to elderly patients are attecteo and there is a slight male predominance 11431 1. Cases of HCL-v have been
des cr ibed in Asian patients where HCl -v
may be more comroon than HCL 114311.
Genetics
Most c ases seem to harbour a relatively
low load of somatic hypermutation in the
JGHV genes. No bias lor VH1.2 gene has
been seen , as in SMZl. Overrep resentstton of VH3-23 and VH4-34 . as in HCl,
has been reported 122621.
Complex cytogenetic alterations, including
Sp lee n. 8M and PB are involved but
hepatomegaly and lym phadenopathyare
relatively uncommon / 143 11. Involvemert
01other solid tissues is rare.
Clinical features
Patient s with HCL-v typically mamfesl
..
signs and symptoms related to either

splenomegaly or cytopenias. Leukocytosis
is a consistent feature with an average

white blood cell count of about 35xl()9/L.
while thrombocytopenia is present in
about half of the patients and anaemia in
one quarter 114311. The absolute mono-
cyte coun t is typically within normal

range.
""-y
Circulaling HCL-v cells are read ily appar-
ent on the PB smear ; commonly these

cells exhibit the hybrid features of prolymphoc ytic leukaem ia and classic HCl .
although several o ther morp hologic sub-
may be subtle and very inc on spicuous,

otten requ iring irrmunohistochemical
stains to high ligh t the pattern and extent
of infiltration 13731. Recent publicati on s
note a distinct p redilec tion lor nearly exclusive sinusoidal infiUration 1373, 1431,
24601
Similar to HCL and splenic diHuse red
pul p small Been lymphoma. the red pulp
of the spleen is dittuselv involved and expan de d in HCL-v, resulting in atretic or
abs ent white pulp follicl es. The leukaemic
c ells fill dilated slnusoios and red b lood
cell lakes ma y be noted 1143 1] Liver
involvemen t is characterized by both
portal tract and sinuso idal infiltrates.
types (blastic, convolu ted) have also

been described 11 850 1, Nucl ear fe atu res
range from condensed c hromatin with

prominent ce ntral nucl eol i o f a prolym pho-
cync cell to dispersed chroma tin with

highly irregular nuclear co ntours. Cytoplasmic features are similarly variabl e, although some degree of hairy project ion s
is typically noted 13731 Transformation to
large cells with co nvoluted nucl ei has
been describe d an d c ases of so-called
convoluted HCL may be explained by this
phenomenon 114311. Unlike Classic HCL ,
the 8M is aspirab le without significant reliculin fibrosis 13731_The infiltrates of HCL-v
Cytochemistry
Unlike classic HCL, cytoc hemica l staining
for tartrate-resistant acid pnospetase
(TRAP) is weak to negat ive in HCl -v (541.
1431, 18501.
Immunophenotype
Cas es of HClv sha re man y immunop henot yp ic and immunohistochemical
(IHe) features with HCl , although HClv
cells characteristica lly lac k several key
HCl antigens usually includ ing C025.
Anne xin A 1, TRAP-IHC. C0123 and HC2
1670, 1431, 18501. Positive "markers" in
HCLv includ e DBA .44. pan-B-cell antigens. COlle. br ight monotypic surface
imm unoglob ulin (more frequently Ig G ),
CD 103 and FMC711423. 14311.
Genetics
There are no known specific genetic
changes. Some cases demonstrate complex cytogenetic abnormalities involving
t 4q32 or 8Q24 and TP53 deletions
114311.
Postulated norma l counterpart
Activated Been at late stage of maturation.
These patients have an indolent cou rse
with a long survival l ime, even though
patien ts with HCl -v do not typ ic ally
respond to either IFN-a or pu rine nucleoside analogs (oeoxvcotormvcln and
cladrib ine ) !l 850 ). Recent p reliminary
studies sug gest that monoclonal antibody
therapy (rituximab and anti-C022 immunoto xin ) is highly ellective 11850 1 In add ition. good clinical responses have been
achieved with resolution of cytopenias
after sple nec tomy 118501.
Splenic B-ceillymphoma/leukaemia, unclasslhable
193
SH. Swerdlow
F. Berger
SA Pilen
N.L Harr is
E.S. Jaffe
H. Stein
..
Definition
lymphopl asmac yt ic lymp homa (LPL) is a
neoplasm of small 8 lymphocytes, plasmacy toid lymp hocytes, and plasma cells.
usually involving bone marrow (8 M) and
sometimes lymph nodes and spleen ,
which does not fulfill the c riter ia for any of
the other small Bccell lymphoid neoplasms that may also have ptasmacytlc
differentiatiOn. Because the distinction be-
tween lPL and one of mese other lymphomas. especially some marginal zone
lymphomas (MZL), is not always clear-cut.
some cases may need 10 be diagnosed
as a small Bceujvmoboma with plasmacvtrc di fferentia tion and a d ifferential diagnosisprovided. Although often associated
with a paraprotein usually of IgM type, it is
not required for the diagnosis, Waldenstr6m
macroglobulinemia (WM) is found in a
significant subset of patients with LPL and
is defined as LPL with 8M involvement
and an IgM monoclonal gammopalhy 01
any concentration (16731.
ICD-{) code
967113
Epldem k>logy
LPL occurs in adults with a median age in
the 60s and a slight male predominance
1581,23371.
Etiology
A familial predispo sition may exist in up to
20% of pa tients with WM {29, 2267f.
These pa tients are diagnosed at a
younger age and with greater 8M involvement .
194
_..
-.
fl9- 10.22 lym~ ~ A Bone marrow biopsy shows a ~ infiltrate """ a PASpo5Itrve Ouk::her body (8fTOW). B The ~smaq1ic I1fi1lrale is alsoseen in ee asptalesme.
Hepatitis C virus (HCY) is associated with
type II c ryoglobulinemia and with LPL in
some but not all series, perhaps related
to geog rap hic d ifferenc es 1534 . 1271,
1450A, 1597 , 1680 , 1791 . 1932,21661 .
Some of the HCV-associated Iymphoplasmacytic proliferations even if monotypic, are non-progressive and others may
be more like chronic lymphocytic leukaemia (Cll) 11506. 23261. Treatment 01
these patients with anti -viral agents may
lead to regression 01 the Iymphoplasmacync proliferations {1434 . 2 1661. Apart
from the role 01 HCY, mast cells may help
drive the proliferation in LPL 122591.
Sites of invol vemen t
Most c ases involv e the BM and so me,
lymph nod es and other extranodal sites.
About 15- 30% of patien ts with WM also
have splenomegaly, hepa tomegaly and/or
adenopathy {5811 Per ipheral blood (PB)
may also be involved.
Cli nica l features

Most patients present with weakness and
fatig ue , usua lly related to anaemia. The
majority of pa tients have an IgM serum
parap rotein although othe rs may have a
different paraprotein or no paraprotein at
all. A minority have both 19M and IgG or
other paraororens. Hyperviscosity occurs
in up to 30% 0 1 patients, The paraprote in
may also have autoantibody or cryog lobulin activity, resu lting in autoimmune
phenomena or cryoglobulinemia (seen 10
up to -20% 01 patients with WM). Neuropathies occur in a minority 01 patients and
may result from reactivity of the IgM parap rotein with myelin sheath antigens, cryoglo b ulinemia or pa raprotein deposition,
Depos its of Ig M may occur in the skin or
the ga strointestinal trac t, where they may
cause diarrhoea Coagulopathies may be
caused by Ig M binding to clotting factors.
platelets and fibrin . Ig M paraproteins are
not diagnostic 01 either LPL or WM as they
can occur in patients with other lymphoid
neoplasms or without an oven neoplasm.

A minority of pa tients inJ\ially present with
an IgM -related disorder such as cryo-
globulinemiaor IgM-monoclona1gamrT"l()o
pathy of undetermined significance and
only later develop an overt lPl 1370.
1230. 15241.
Bone manowand peripheral blood

Bone marrow involveme nt is c ha rac terized by a nodular. dlftuse and/or interstitial
infiltrate usually composed predominantly
of small lymphocytes admixed with variable
rwroes of plasma cells and plasmacytoid
tymphocytes 11672.16731 Paratrabecular
aggregates may also be p resent. Increased mast cells are often present. Similar cells may be present in the PB . but the
white blood count is typ ica lly low er than
in ClL.
Lymph nodesand other tissues

In the most class ic cases that are usually
associated with WM , lymph nod es show
retention of normal architec tural fea tures
with dilated sinuses with PAS+ material and
sometimes small port ion s of residual germinal centres. There is a relatively mo nolonoos proliferation of sma ll lymphocytes.
plasma cells an d plasmacyto id lymp hocytes with relatively few transformed cells.
Dutcher bod ies (PAS+ intranuclear pseudoinclusions), increased mast cells and
haemosiderin are othe r typical features .
Other cases show greater arch itectural destruction, may have a vaguely follicular
grcmlh pattern . more prom inent residual
germinal centres, epithelioid histiocyte
clusters and sometimes a much g reater
proportIOn of plasma cells or a more poIynn-phic appearance with more numerous
transformed cell slimmu no b lasts 11934AI.
Protilerahon centres. as seen in CWsmal1
~ic lymphoma (Sl l ) must be abo
seN: and the presence of paler-appearing
margina l zone type cntterennatoo shou td

suggest the diagnosis of one of the MZL
There may be associated amyloid. other
immunoglobulin deposition or crystal
storing histiocytes. Spleens demonstrate a
IymphopIasmacytc infiltrate tha t may form
small nodules in the red pulp or grcrw more
d iffusely.
invotving the CCND1, MALTt , BeL 10 or

BCL2genes with the possible rare exception of the tarter. WM is reported to have a
homogeneous gene expression profile. independent of 6q deletion, that is more sendar to CLl and normal Bcens than to
myeloma 14291. This study also suggested
the importance of upregulated Il6 and its
downstream MAPK signaling pathway
",.",unophenoIype
Most cells express surface Ig and the
ptasmacvnc cells express cytoplasmic Ig .
usually IgM. sometimes IgG and rarely IgA .
They are typ ically IgD- , express a-conassociated an tigens (CD 19. CD2O, C022 ,
CD79a) and are COS-. CD1o-. CD 1Q3-and
CD23- with frequent but not invariable
CD25 and CD38 expression. Some studies
report more varia tion especially in CD22
and CD23 expression . The p lasm a cells
are CD 138 positive . lack of CD5 in most
bu t not all cases an d the presenc e of
strong cytop lasm ic Ig are useful in the d istinct ion from ClU SLl.
Genetics
IG genes are rear ranged usually with V
regions that show somatic hyp ermutation
but lac k ongoing mutations (2349). The re
ma y be biased VHusag e 11026 , 1193 ).

No speci fic c hromosomal or oncogene
abnormalities are recognized in lPl. The
previou sly reported IGH@!PAX5t(9;14)is
rarely. if ever, found in lPlI463, 774, 13791.
Deletion 6q is reported in up to somewhat
over haN of BM-based cases but it is not a
specific finding and appears at best to be
infrequent in tissue based LPlI464 . 1379,
16 17, 19721. Trisom y 3 and 18 are infrequent . Trisany 4 has been reported in about
20% of WM 121831. lPl do not demonstrate any of the other B-eell Iymphomaassociated transocetoos such as those
Postulated normal COlSlIe rpart

Probable post-follicular B-eel1lhat d ifterentiates to plasma cells.

The clinical course is typically indolent , WIth
median survivals 015- 10 years 1581. 23371Advanced age. PB cvtcoemas especially
anaemia. oertomance status and high f}-2
microglobulin levels have been repor ted to
be associated with a worse prognosis 158 1.
2337f. Cases w ith incr eased transformed
ce lls/imm uno blasts may als o be associated with an adverse prognosis; however, a
va lida ted g rad ing system doe s not exist
143, 1941. Cases with del(6q) have been
associated with feature s 01 adver se prognosis 116171 . Transformation to d iffuse targe
B-eeillymphoma occurs in a small propo rtion of the cases an d is assoc iated with
poor survival 113111. Patients who have
developed Hodgkin lym phoma are also
reported 118631.
Variant: gamma heavy chain disease
Gamma hea vy chain dis ease results trom
secretion of a trunca ted gamma chain,
whic h lac ks uqnt-cnam bin ding sites. It is
usually associated with a lymphoma that
fulfills the cri teria lor LPl involving lymph
nodes. 8M. liver. spleen and PB but some
cases resemble plasma cell myeloma. The
clinical course is vari able , but probably
more aggressive than that of typical IgMproducing lPl.
l ymphOplasmacytic lymphoma
195
Definition
The hea vy chain d isea ses (HCD) comprise
3 rare Be en neoplasms that produce

monoclonal heavy chains and typically no
light chai ns. The monoclonal immunoglobulin component is composed of
either IgG (gamma HeD ). Ig A (alpha
HCD) or 19M (mu HCD ), The heavy chain
is usual ly inc om plete and thu s incap able
of lull assembly. Variab ly sized p rotein s
are produced , thai may not pr odu c e a
c ha rac teristic se rum prot ein elec trophore-
sis peak. and require immunoelectrophoresis or immunofixation to detect.
Nt.. Harris
P G . Isaacson
1 M. Grogan
E.S. Jaffe
tight chain binding sites and does not

bind to light chains to form a complete
immunoglob ulin molecule.
Synonym
Franklin d isease .
Epidemiology
Thi s is a rare d isea se of adults wi th a med ian age of 60 ; approximately 130 cases
hav e been described 1687 , 23521. There
is no partic ular geo graphic d istribution ,

and a slight male predominance in most
but not all series 123521.
Alpha HCD is conside red to be a varian t
of extranccar marginal zone lymphoma of

rrccose-essoceteo tyrrVOO tissue(MAln.
Ga'mla HeO is characterized by a ~
plasmacytiC population resembling Iymprcctasmacync lymphoma and Mu HeO
typically resem bles eLL: however bolh
are sufficiently distinctive to be considered separate enti ties .
ICD-O code
976213
,
Definition
Gamma heavy chain disease (gamma

HCDj is a neoplasm of lymphocytes,
plasmacytoid lymphocytes and plasma
ce lls that p rod uce s a trun ca ted gamma
immunog lobulin heavy ch ain, whi ch lacks
The tumour may involve the lymph nodes,
Waldeyer ring . gastrointestinal tract and
other extranodal sites, bone marrow (8M),
liver, spleen and peripheral blood (PB).
Clinical features
Most patients have systemic symptoms
such as anorexia. wea kness. lever. weight
loss or recurrent bacterial infec tio ns.
Au toimm une manifes tations are found in
about 25% 01 the cases. mostlreq uently
rheumatoid arthritis, but also autoimmune
haemolytic anae mia or thrombocytopenia
or both, va sc ul itis, SjOgren synd rome,
systemic or cu taneous lupu s erythem atosus, myasthenia g ravis or thyroidit is 168 7,
997 . 235 2 ) Autoimmu ne d isease ma y
pre ce d e t he di agn osis of lymphoma
by seve ral yea rs Most pat ients have
~ .
..J!.
...,
Fig. 10.24 Gamma heavy lilain disease. A. This polymorptIous tymphoplasmacytic proIifefabon is coovised 01
admixed plasma cells, plasmacytoid ~es and IympIloid cells. B Immunollistochemistry shows monotypic
staining lor gammaheavy chain,
196
Mature B-eell neoplasms
generalized disease, including lymphadenopathy, sp lenomegaly and hepatomegaly; involvement of Waldeyer

ring, skin and subcutaneous tissues . thy.
raid . salivary glands or gaslrointestinal
trac t may occur, and PB eos inophilia may
be present 16871. Circulating p lasma cells
or lym phocytes may occasionally be
p resent. The pa tients generally do not
have lytic bone lesions or amy loid deposit ion, The 8M is invo lved in 30-60% of
the cases 168 7, 997, 23521, Cl inica l and
laboratory dis tinction from an infection or
inflammatory process may be difficult in
view of this co nstellation of symptoms and
the some times broad band or near-nome
serum protein electrophoresis.
The diagnosis is made by demonstration
01 IgG without light chains by immunofixation in the PB, urine Of both.
L ymph nodes typically show a poIymor.

phous proliferation with admixed lymphocytes. plasmacytoid lymphocytes, plasma
cells. Wrm.JnobIasts. histiocytes and
phi ls I 1540AI The presence 01 eosinephils , beuocvtee and immunoblasts may
ca use a resemblance to ang ioimmunoblastic T-eeill ymphoma (A ITl) Of Hodgkin
lym phoma (HL); it is not cl ea r whether
rare repo rted cases of gamma HCD assoc iated with AITl or HL rep resent a true
association or a resem b lance of the infil
trate 01 ga mma HCD to HL 1565, 992J, In
some cases plasma ce lls p redominate
and may resemble plasmacytoma The
PB may show lymphocytosis with or Wlthout plasmacytoid lymphocytes. reserrtJling
chronic lymphocytic leukaemia (CLL) a
Iymphoplasmacytic lymphoma. Transfor
mation to diffuse large B-eell lymphoma
(DLBCl) is rare 16871 The 8M may stlOt
Iyrnphoplasmacytic aggregates or only a
subtle increase in plasma cells with
monotypic garrrna heavy chains WltholA
light chains.
eosoc-
," ""'-
The cells contain monoclonal cytootasnc

ga mma chain w itho ut lig ht chains, exp ress CD79a, CD20 on the lymp hocytic
Fig. 10.25 Gamma heavychain oseese. Bone marruw biopsy. ASmall ~les cx:mposed of plasma cells Md tympnoid eels arepreserK. C(ll'I'Ipl'iSing awroxma!ety 5%oflhe
overaI marrow cellularity Some plasma cells appear malin. wtIile others are atypical WJ\h open etwomatin (B). C Immunohislochemital stain shows cytoplasmic IgG
Images COU'leSy of Dr. AJiyah Rallemtula h {1~l
component, CDl38 on the plasma cell

component. and are CDS and CD to negative (1S40Al.
Genetics
Immunoglob ulin genes are cronauv
rearrang ed and conta in high levels of
somatic hypermutation 16861. Deletions in
the gamma heavy chain gene are present
that result in expression of a defective
heavychain protein that cannot b ind light
cnem to form a complete irrvnunog lobulin
molecule 121 . 658. 686 , 728 , 732. 1989,
235 11. These deletions involv e the VHregion and variab le amounts of the CHI region. and there may be insertions 01 large
amounts of DNA of unknown origin 16861.
Abnormal karyotypes have been present
in about half of the reported cases. but no
specific or recurring genetic abnormality
hasbeen reported 123521.
Post-germinal cen tre 8 cell with the ability
to diHerentiate to a p lasma ce ll, with a
defective gamma heavy cha in gene.
The clinical outcome is variable, ranging
trom indolent to rapidly progressive; the
median survival has been reported to be

12 months (6861; but a recent study of 23
cas es rep orted a med ian of 7.4 yea rs,
with over hall the deaths not related to the
Iympnoprotiferative disorder 123521 Most
patients with low-grade appearing Iymphoprasmacvtc infiltrates appear to respond
to non-anthracycline-containing che motherapy, and respo nses 10 rituximab have
been reported 123521.
Mu heavy chain disease

Definition
Mu heavy chain disease (mu HCD ) is a
EkeII neoplasm resembling chronic I'ympt1ocvnc leukaemia (Cll). in which a defeclive mu heavy chain lacking a variable
region is produced . The 8M contains an
infiltra te of characteristic vacuolated
plasma cells, admixed with small, round
lymphocytes
Epidemiology
This is an ex treme ly ra re disease of
adu lts. with between 30 and 40 c ases
reported; a med ian age of 60 and an
approximately equal frequency in males
and females {6861.
Spleen. liver, 8M and PB are involved; peripheral lymphadenopathy is usually not
present
Fig. 10.2! Mu heavy chain disease. Bone marrow

asprIIe shows predomlnanlly plasma cells with prominenl C)t:ifJIasmic vacuolation.
Clinical features
Most patients present with a slowly progressive disease resemb ling chronic 1ymonccvtlc leukaemia Mu HCD differs from
most c ases of Cl l in the high frequency
of hepatosplenomegaly and the absence
of peripheral lymp had enop athy. Routine
serum protein electrophoresis is frequently
normal. Immunoelectrophoresis reveals

reactivity to ann-rno in polymers of diverse
sizes. Although mu cha in is not found in
the urine, Bence Jones light chains are
commonly found (50%) in the urine, particularly kappa chains . The tatter. while stilt
produced in mu HCD, are not assembled
into a complete immunoglobulin protein
because of heavy chain gene aberrancies
leading to truncated forms 1136, 23501.
Mo<phology
The BM c ontains vacuolated plasma
cells. which are typically admixed with
small . round lymphocytes similar to
chronic lymphOCytiC leukaemia cell s.
Immunophenotype
The cells contain monoclonal cytoplasmic
mu heavy chain , with or without monotypic light chain , express a-cen antigens ,
and are CD5 and COlO negative.
Geneti cs
Immun oglobul in genes are clonally rearrang ed and contain high levels of
somatic hype rmutation (6861. Deletions in
the mu heavy chain gene are presen t that
result in expression of a defective heavy
chain protein that cannot b ind light Chain
to form a complete immunoglobulin molecule 1686, 7291 . These oeienons involve
the VH region and variable amounts of the
CH 1 region , and there may be insertions
of large amounts of DNA of unknown
origin {686)
Postulated normaJ coun terpart
Post-germinal centre B cell which is able
to differentiate to a plasma cell , With an
abnormal mu heavy chain gene .
Prognosis
The clinical course is slowly progressive
in most cases (136. 686, 729. 23501.
197
-.
A ....
...
...
Fig. 10.27 Serum protem aleclrophoreSlI (SPE) and unne protein eleclrophoreSlS (UPE) in gamma heavy chain
eeeese. It dis1Inc:! bInd .... 1dent1fJed by SPE in Ih8irTIrluIogIotUn region1IIlOdal1o!he panof ongIl (A. IIITOW) The
1ok:oi.4IOi iIMllyped as IgG(t\llnoIed by the bind seen in lhelgG lane). but WIlhout a IXlrT9$pOI'ldin igIt d'\8Wl (0t'Iy
lain: pctyck:Jnal pa1lemS . . . seen in !he kappa and Iam/xIa tales) (A). UPE periormed rewaIedsirrU results , WIth a
broad ITIOIlOdonaI band correspondlllg 10 IgG withoul a rorrespooding lighl chain (B). Repmted from 11540A).
(1ma!;Ies allRlsy of Or. M. .......)
Variab le size
deletio n in HCO
Ant igenbinding
site
light-ehainbinding site:
deleted
in HCD
Complement-
(H ,
(Hl
binding site
Fe-receptorbind ing sit e
eOOH
eOOH
Fig. 10.28Structure ol1heimmunoglobtJIIn rnoilIaMin heavychain disease. Animmunoglobl*1 mollIaM is ~
of two heavy chains (H) and two I9rt chains ll}. which are JOined by d,sulflcle bonds (5-S). The nmnallleavy ellalll
constant region has 3 ronstanl domaill5: CHI is responsible for binding 10 !he li!;.f11chain. CH2 10r binding to
~ and CH3 b' bindI'Ig 10 Fe recepttn. kllhe absence of an associaled (gill d1ain. lhe CH1 domain biIds
to heat-shock J:fCI\8in 78 and U"ldergo&$ ~ degadation; 1l1us. normaI lreeheavychains ae not secreted. In
I1eavy chain dtseases (HCD). ~ deIebons in lhe CHl domail preventboIh bi1dJng a11he heavychain 10
the light diann de\1'adation IIIh proteasane, and free heavy chalns are secreIed VanablHized delebons also
OCXU' inIhe heavy dIain lliversiIy I8giOn (OH). !he heavychain joining region(JH) and the I1eavy chainv.wiabIe rtlgiOn
(VH), COR denoIes COi ' .'ilh'llarily-.deteillil_tg region. a. light dIain const.Tlregion. COOH cartloxyt \emWIal.l
igIt chainjoiWIg region. NIi2 llITW'O lerrrN M:I VLIg1l chainv<wiclbIe region. ReprI1Md WIltI pemis:sicrllrom {154MJ.
(FJP8 QlU1esy cI OrN, M!nhi)
198
Definition
The ter m a lpha heavy chain d isease
(alp ha HCD) has been extensively used
in the liter ature , sinc e many case s are
initially recognized by the p resence of an
abn ormal alpha chain in the serum. However, the term nnmunoorouteranve small
intestinal d isease (IPSID) was adopted by
the WHO in 1978 and will be used here.
IPSID is a variant of extranodal marginal
zone lym phoma of mucosa assoc iated
lym phoi d tissue (MALT), in whic h defective alpha heavy c hains are secr eted ; It is
also d iscussed in the ch a pter on MALT
lymphoma. It occurs in young adu lts and
involves the g astrointestinal tract , resulting in malabsorption and d iarrhoea. tPSID
beg ins as a process somet imes reversible
by antibio tics but may progress to diffuse
large B-ce tl lymp homa (DLBCL ).
EpKlemKllogy
This is the mos t common of the heavy
chain d isea ses. Unlike the ot her HCD,
IPSID involves a young age group with a
peak inc id ence in the second and third
decades: it is rare in young ch ildre n and
older adults, and there is an equa l incidence in ma les and females. It is most
common in areas bordering the Mediterranean inc lud ing Israel, Egypt. Saudi
Arabia and North Africa . It is assoc iated
with low socioeconomic status including
poor hygiene, malnutrition and frequent intestinal infec tions {178 1, 18 12, 1988).
Etiology
Chronic intestinal infec tio n, with Campylobacter jejuni in some ca ses, is believed
to result in c hronic inflammation, a setting
in which neoplastic transformation of a
clone of abnormal 8 cells develops (12641.
This disorder involves the gastrointestinal
tract, mainly the small intestine and
mesenteric lymph nodes; gastric and
co lonic mucosa may be involved 1686J.
The 8 M and othe r organs are usually not
invo lved . although rare respiratory tract
involvement is described I1988 J.
Clinical featu res at presentation
Patients typica lly present with ma labsorption, d iarrhoea , hypocalcem ia, abdominal
pain . wasting . fever and steatorrhoea . Because of defective heavy cha in assembly
and con seq uent d iversaty oIlgA molecular
forms, the serum protem elect rophoresis

(SPE) is usually normal or shows hypogalTVTlaglobulinemia. Typically. specific
antilgA antibody is requ ired to de tect
aberrant lgA by immunofixalion 119881.
Mo<phology
The lamina propria of the bowel is heavily
infiltrated with plasma cells and admixed
small lymphocytes; marginal zone Bvcells
may be present with formation of lymphcepithelial lesions. The Iymphoplasmac ytic
infiltrate separates the crypts, and villous
atrophy may be present 110 12, 178 1,
18121. Sheets of large plasmacytoid cells
and immunoblasts that form solid , destructive aggregates WIth ulceration characterize progression to DLBCL 16861.
Immunop henotype
The plasma cells and marg inal zone cells
exp ress monoc lonal cytopl asmic alpha
c hain without light chain. Marg inal zone
cells express CD20 and are CDS and
COlO negative; plasma cells are typica lly
CD20 negative and CD138 positive 110 121.
DNA of unknown origin 16861.

Cytoge netic abnormalities have been
reported in rare sing~ cases. The t(1' ,18)
associated with gastric and pulmonary
MALT lymphomas has not been de scribed 117211. One reported case had
t(9 ;14)(p11;q32) 11 7211.
Genetics
Immunog lobulin heavy and light cha in
genes are cioreuv rearranged and contain
high levels of somatic hyp ermutation
16861. Deletions in the alph a heavy chain
gene are present that result in expression
of a defective heavy c hain prote in that
cannot bind lig ht chain to form a complete lmmurcqiobuun mole cu le. These
deletions involve the VH region and CH I
reg ion, and there may be insertions of

In the early phase, IPSID may completely
remit with antibiotic therapy. Many patients, however, expe rience transformation to diffuse large B-ceil lymphoma, and
a latal outcome is frequent 1182,1 9881.
Treatment With anthrac vcnne-contammq
regimens has been repor ted to result in
remission and long-te rm survival in some
pat ients 1161.
199
The p lasma cell neo plas ms resul t trom me

expa nsion of a c lone of immu nog lob ulin
(Ig )-sec reting , heavy-chain c lass-switc hed ,
terminally d ifferenti ated B ce lls thaI typ i-
A.w McKenna
RAKyle
WM Kuehl
T.M. Grogan
N.L. Harris
RW. Coupland
Monoclonal gammopathy of
undetermined significance
(MGUS)
cally secrete a single homogeneous

(monoclonal) immunoglobulin ca lled a
pa raprotein or M-protein; the presence of
such a protein is known as monoclonal
gammopathy. The true plasma cell neoplasms, discussed in this chapter. include
plasma cen myeloma. plasmactyomaand
the syndromes ueuneo by the consequence of tissue immunoglobulin deposilion, p rimary amyloidosis (Al) and light
and heavy chain deposition diseases.
The presence in the pe ripheral b lood (PB)
ot a tow leve l of pa raprotein that is be low
the us ual thr eshold for th e diagnosis of
plasma ce ll myeloma may prece de the
development of overt myeloma for a varying time: this phenomenon , kno wn as
monoclonal gammopathy of undetermined significance (MGUS), is also included in this chapter as a precursor
lesion. Other immunoglobulin-secreting
neoplasms that comprise both lymphocytes and plasma cells, including lymphOpiasmacytic lym phoma. Walden strom
macroglobulinemia and the heavy chain
diseases. are d isc ussed in other chapters,
---
Defin ition
MGUS is defined as the p resenc e in the
serum of an M-protein <30 gJ1..., bone marrow (BM) clonal plasma celts <10%, no
end organ damage (CRAB: hypercalcemia, renal insuffic ienc y. anaemia. bone
lesions) and no evidence of B-eell lym phoma or other disease known to produce an M-protein. Although it reflects the
presence or an ex panded clone of immunoglobulin-secreting cells. this process
is not co nside red neop lastic since it does
not alw ays progress to overt malig nancy.
The presence 01 a sma ll IgM paraprotein
(lg M MG US) is associated with a clone of
Iymphoplasmacytic cells that may progress
to a Iymphop lasmacytic lymphoma. and/
or Walden strom macroglobulinemia (WM).
Non- lg M MGUS (lgG, IgA l is associated
with tbe presence of clonal plasma cells,
and may progress to a malignant plasma
cell neoplasm . Although the two forms of
MG US may be id entica l in their clinical
presentation. they have a different genetic
b asis and different outcomes in terms of
malig nant prog ression ,
ICo-O code
9765/1
Tabl, 10.03 Plasma cellneoplasms
-""-
~g~y~uooe~
SI\1IIficanc.e (MGUS)
"""'""'"
" '"
_1"-""' Plasma celleukaema
Soktary plasmacyloma of bone

E.w-llOSSeCWJS (ell.tramedulary) p1aSlllaC)1Oma
Immunoglobulin depositiondiseases
Primaryamyloidosis
Systemic light andheavy cha in
deposrtoo diseases
Osteosclerotic rnyeIoma (POEMS $yrUome)
200
Mature a-cen neoplasms
Synonyms
Mo noc lonal g ammopathy, unattnbuted/
unassoctateo : Benign monoclonal gammopathy; Idiopathic paraproteinemia;
Noo-myelomatous gammopathy.
Ep;c'emioiogy
When sensitive techniques of deteclion
are use d, MG US is found in approximately 3% of persons ove r age 50 and in
mo re than 5% of individuals past 70
11232 1. MGUS is mo re common in men
than women (- 1.5:1) and more than twic e
as frequent in Afric an American s as in
Ca ucas ians 11 229 , 12491.
Etiology
No specific cause of MGUS has been
F"1g.10.29 Rodtyapliof(Aj Wja'ld{B) IernoraI hM:I

detnonslrcIle nulIlpIeIy1ic tOle lesions.
identified, It may be associated with connective tissue disorders, peripheral neurop athies. dermatological, endocrine and
liver d isea ses [ 12291. Transie nt oligoc lonal and mo noc lonal ga mmopa thies
have been described in patient s following
solid organ and 8 M/stem ce ll transplantation /1229. 149 1}.
The clonal plasma cells producing nonIgM MGUS are in the 8M ; Iymphoplasmacytic cells that produce IgM MGUS may
be in BM and other sites . such as spleen
and lymph nodes.
Clinical features
Patient s exhibit no symptoms or physical
findings related to MGUS. The typical taborator y and rad iog raph ic abno rmalities
associated with plasma ce ll myeloma are
lacking, The M-p rotein is usually discovered unexpectedly 00 serum protein electrophoresis . Approximately 70% are IgG.
Table 1D.G.(
Oi ll9';lOS ~C
criteria forMGUS
Booe f1'\llflOW donalplasma cells <10'4andlow

lel'8l ofplasma eel flNtrabon in a trephinebiopsy
No ~ organ 01' bfo$Ul rmpauTI'l8fl\

(CRAB: 1lypercalcemIa. renal nsufticiency.
a'\allIIlI3 , blwle 1e$IOn$)
Lblirled m 156}.
15% 19M. 12% IgA and 3% are biclonal
112291. UP to 20% 01 MGUS may consist

only of an 19 light chain that may be detected only with me serum free light chain
assay 11124 . 13741 . Reduction 01 un in'o'O'Jed ~ns is h.rld in 3)-4O'Jb
01 patients with MGU S and monoclonal
light chain in urine in nearly a th ird 112331.
Marrow aspirates contain a median o f 3%

plasmacells and trephine biopsies sho w
no or a minimal inc rease in plasma cells

that are inte rstitia l and evenly sc attered
throughout the 8 M, or occ asionally in

small clusters 1561- They are usually ma-
both nume rica l and struc tural abnormalitie s in most patients { 113, 430 , 717, 7 18J.
The abnormalitie s in non-lg M MGU S are
the same as those fou nd in myeloma although the p reva lence may d iffer. Iransocations involving the IGH@gene ( 14q 32)
are fou nd in nearly hall of the c ases with
differen t studies showi ng tha t t( 11; 14)
(q23:q 32) is present in 15-25%, t(4 ; 14)
(p 16.3:q32) in 2-9% and t( 14.16XQ32:q23)
in 1- 5% 1113, 7 171. De letion s of 13q are
pres ent in 40 - 50 % of cases of MGU S
compared to 50% of those with myeloma
{717 , 7 18. 11801. It is not clear if 13q deletions sometimes are associated with
progression of MG US (1125, 12291 Hyperdiploidy is o bserved in about 40% 01
MGUS with chromosomal trisomies similar to those in myeloma 14301. No obvious
cl inical correlations are associated wi th
chromosome abnormalities in MGUS bu t
this may refl ec t lack 01 sufficient data
17171. Ac tivating K- and NRA$mutations
are much less frequent in MGU S (-5%)
compared to myeloma (30-40%) 11 821 1.
Although genetic alterations and gene expression patterns prob ably can distingu ish
adv anced myeloma Irom MGU S there are
no uneq uivocal intri nsic differences that
d istingui sh MGUS from myeloma .

IgG and Ig A MGUS are p roduce d by
post-ger minal centre plasma c ells wit h
immunoglobulin genes that have somatic
hypermutation of the varia ble regions and
are class-switched . IgM MGUS is p roduced by B lym phocytes with somatic
hyperm utalion of the IG V genes but without class swi tch 112341.
Prog nosis and predictive tectore
The clinical course in most persons with
MGUS is stable WIth
Il M-protein
or other evidence of progression. However, there can be evolution to an overt
plasma cell myeloma . amyloidosis (in
non-lgM MGUS), WM or other Iymphoproliferative oisoeoer (in IgM MGUS) 156.
1229}. The risk of progression is aoout1%
per year and indefinite, persisting even
after 30 years 112331. Thus, MGUS should
be considered a p re-neo plastic condllion
116971. Size and type of M- protein and
serum free light chain ratio are significant
clinical risk factors 156, 1233. 16971. Risk of
prog ression lor patients with an M.prOlein
of 25 gil is >4 lime s mat of one with <5
gil. Patients wi th an IgM or IgA MGUS
are at g reater risk of progression (- 1.5%
per year) to a mali gn ant disord er than
noocrease
lUre appearing but mil d changes. inc luding cytop lasmic inclusions an d nucleoli,
areoccasionally observe d.
Irrmunophenotype
Staining tor CD 138 fa cil itat es enumeratio n
of plasma ce lls on 8M trephine b iopsies.
Detection of the p lasma c ells that express

monotypc cyto plas mic Ig of the same
isotype as the M-protein is often d iffic ult,
because the c lone may be small and in a
background of normal p lasma c ells:
moootypic light c ha in sta ining is not always detec tab le by im munohistochemistry [17311. Immuno phenotyp ing by trow
cytometry freq uen tly shows two po putatone of plasma cel ls , one wit h a no rm al
i'rmJnophenotype (CD38 brig ht+ , CD19 +,
CD56-) that is polyclon ar an d a mon oclonal population w ith an aberrant phenotype, most etten either CD 19-/CD56+
orCD19-ICD56- 11726 I. The monoclonal
population may exhi bit wea ker expression
at CD38 and other aberrant antigen
expressioo 11618, 1643. 17261.
Geretics
Abnormal karyotypes are rarely seen in
UGUS FISH studies have damonstrated
1_.'
. , :-:
< .~
J ;
.~.
' ....
~
Fig.10.30 Plasma cell myeloma. A Gross photograph af thevertebral column. showingmultiple IyticIeSiOOs. filledwith
grey, fleshy tumour. B V&rtebral c:oh;mn after maceration, showingr'r'll; ltiple lytic lesions.
Fig. 10.31 Plasma eel myeloma. low (A) and high lB) rnagMJealions of a bone marrow biopsy. There is
exler\SMl marrow repIacernenI WItllneoplastic plasma eels. The palIem of in'O("Ii l8l ~ is mixed. fIIerstitJal nl loc3.
The plasma eels embil mature Iea!lns WlIh abI.ntaA: ~. eeeenn: Ikldei MltI marse dJromBtrl; II'OSlladc
visible ru:leoI.
Plasma cea neoplasms
201
trose with IgG 11229. 1234 1. In addition,

the fraction of 8M plasma cells with an
abnormal irnmunophenotype. the detection of DNA aneuploidy and scorormar
levels of poIyclonal 19 also appear to be
significant clinical risk factors {17261_
Plasma cell myeloma

Definition
Plasma cell myeloma is a 8M-based , rntJltifoc al plasma ce ll neoplasm associa ted
with an M-protein in serum andlor urine.
In most cases there is disseminated 8M
involvement. The disease spans a clinical
spectrum from asymptomatic to aggressive forms and disorders due to deposilion of abnormal immunoglobulin cha ins
in tissues 113741. The diagnosis is based
00 a combination of pathOlogical, radiological and clinical features.
ICD-O code
9732/3
Synonyms
Multiple myeloma: Myelomatosis:medullary
plasmacytoma; Kahler's disease.
Epidemiology
Plasma cell myeloma comprises about
1% of malignant tumours. 10- 15% of
haema topoietic neoplasms and causes
20% 01 deaths from haematologic mauqnancies {1052, 16441. An estimated 2O,(XX)
cases were diag nosed and more than
10,000 patients died of myeloma in the
United States in 2007 110521. Plasma cell
myeloma is more common in men than
women (1.4: 1) and occurs twice as frequently in African America ns as in Caucasians 11844) Myeloma is not found in
children and only rarely in adults less than
30 years of age; the incidence increases
progressively with age thereafter, with approximately 90% of cases occurring over
age 50 and a median age at diagnosis of
about 70 years . The risk of plasma ceu
myeloma is 3.7 fold higher for individuals
with a first degree relative with the disease {2821.
\
Etiology
Chronic antigenic stimulation from infection or other chronic disease and exposure to specific toxic substances or
radiation has been associated with an increased incidence of plasma cell
myeloma {1289, 131 51 . An antigenic stimulus giving rise to mulliple ben ign clones
202
Mature B-eelt neoplasms
SymptOlTllltic plAma e.ll myelorTll
Bone marrow clonal
plasma eels orpIasmacylomI"
Related organ orlissue impalrment . (CRAB Irypertalcerma. renal nsutfioerq, AfIa6Wia,bone lesions)
Asymptomatic tsmoldeliogj myeloma
M-protein in S6f\J mat myeloma ~vels (>3OgIL)
AND/OR
10% or more donal plasma ~I s in bone mai'TOW

Norelated organ or bssoe impairment [end organ damage or bone IesionI(CRAB: hypercalcerria, nlIIaI
inSufticjency, anaema. bone lesions))orrnyeIom&-it!lat s~
No IeYeI 0( serum orume M-proIeIl is I1dlJl:led M-prolein in most cases II >3(91. 0( IgG or >25g.t 0( IDA or
>19''24 Iv 0( unne Igtt d\ain I:d some pab8nts WIll! S)'frPIomabc III)"!lDma I'aYe ItveIs lower than htse.
UonodcI'IaI plasma eels usuaIy exceed 10'% 01 nucleated eels i'llhe marT\1IfI' I:d no!1Onal1eWtl is
designaled because abl:M: 5% 01 pabenls WIth s~tic; myeloma Ilave < 1O"fe manow plasma ceh.
The mo5l impcItantcrilerlalor symptomaoc myeloma aremaru1estalions 0( eod organ damage I1cIudIng
8naen'ia, hypercak::erma.1ytJC bone lesions, renal insu!lioeoty. hypefVlSCOSlfy. amy\Oidosts orl ecurrent
i'llections.
Modified from ,56).
could be followed by a mutagenic event

initiating malignant transformation 18731.
Most patients have no identifiable toxic
exposure or known chronic ant igen ic
sterwlation 113151.
Genera lized 8M involvement is typ ically
present. lytic bone lesions and focal
tumour al masses of plasma cells also
occur . The most common sites are in 8M
areas of most acti ve haemetopolesls .
Extramedullary involvement is generally a
manifestation of advanced disease.
Clinica lleatures
Symptoma tic plasma cell myeloma is
defined by the presence 01 end-organ
damage (CRAB: hypercalcemia. renal
insuffic iency, anaemia , bone lesions) in a
patient with an M component and clonal
8M plasma ce lls. In most patients there is
a constellation of clini cal , laboratory, radiological and pathOlogical findings 113741.
Radiog raphic sludies reveal lytic lesions.
osteoporosis or fractures in 70% of cases
of myeloma at d iagn osis, often assoc iated with bone pain and hypercalcemia
156, 1224, 18401 Renal failure is due to
tubular da mage resulting from monodonal light chain proteinuria; recurrent intecuone may be partly a consequence
of depressed normal immunoglobulin
produ ct ion; and anaemi a (67%) results

from 8M replacement and renal damage
with resultant loss of erythropoietin. An
M-protein is found in the serum or urine in
abou t 97% of patients 112261 (lgG 50%.
IgA 20% , light chain 20% 1561, IgD. IgE.
IgM and bicl onal < 10% ); - 3% of cases
are non-secretory. The serum M-protelf"l is
usually >3Og/l of IgG and >2Og/l of IgA.
In 90% of patients there is a decrease in
polyclonallg 50% of normal). Otherlaborat ory findings include hypercalcemia
(20% ), elevated creatinine (20-30%)
112261. hyperuricemia (>50%) and hypoalbuminemia (- 15%) 1842, 12261.
Clinical variants
Asymptoma tic (smoldering) plasma cell
myeloma
In asymptomatic plasma cell myeloma.
the diagnostic criteria lor myeloma are
met but no related organ or tissue impairment (end-organ damage) is present 156,
12271. AsymptomatIC plasma cell myeIOrna
is similar to MGUS in its lack of clinical
manifestations. but is much more likely 10
progress to symptomatic myeloma 1582.
123 1, 12331, Patients with o ore -sanoo
stage I disease are included in this category and in some series so are asymptomatic patient s with an apparent solitary
plasmacytoma but with add itional bone
abnormalities detected only by MRI 156,
582). About S% of patient s with myeloma

areinitially asymptomatic 1123 11. The mao
Jority have between 10 and 20% 8 M
plasma cells and the med ian level of
serum M-protein is nearly 3OgIL. Normal
poIyclonal immunoglobulins are reduced
in >90% of patients and -70% have mono-Clonal light chains in urine 11 226 1. Patients
may have stable disease lor long periOds
bulth e cumulative probability of progression to symptomatic myeloma or amyloidosis is 10% per year lor the first 5 years.
3% per year for the next 5 years and approximately 1% for the subsequent 10
years (1231}.
Non-secretory myeloma
In approximately3% 01 plasma c elt mye1omas !hefe is absence of an M-protein on

rTmXIOIixalion electrophoresis 156, 12261.
Cytoplasmic M-protein is present in the
reopiasnc plasma c elts in about 85% 01
these when eva luated b y immunohistochemistry. consi stent with impaired secretion ollg 1561 . In about 15% 01 these
patients. no cytopl asmic Ig synthesis is
detected (non-prOduc er myeloma). Acquired mutations of the Ig light chain variable genes or alteration in the light cha in
constant region have been implicated in
the pathogenesis of the non-secretory
state 1477. 6221. In up to two-thirds of
cases. however, elevated serum free light
chains and/or an ab normal free light
chain ratio are detectable , suggesting
that manyare atreast minimally secretory
16101. The clinical features of non-secretory
myeloma are similar to other plasma ce ll
myelomasexcept tor a lower incide nce of
renal insufficie ncy and hyperc alc emia
and less depression of normal Ig (56,
20371
Ftg.10.32 Plasma cel myeloma. A PernnaIirMiemenl (e~ pIasmacyDna ). ~ assay

pefWenal pIasmacyloma B Section of kidney shoMlg renallIbAr lanMI ~
sitionWIth casts refteclt,g renallI.Witr Sera JMes ~ reabsorpIloo (1rmu1opero ~. ~ ighI chain).
~1s lambda IighI~
characteristic s of the leuka emic pla sma

cells span much of the morphologfc spectrum found in other myelomas but often.
many of the plasma c ells are small with
relative ly unte cytop lasm and may resemble plasmacytoid lymphocytes 1288 1. Typic ally, the immunophenotype of PCl
differs from that of most other myeloma s
by the lack of aberrant CD56 expression
{17191. An abn orma l karyotype is more
frequently found and there is a higher inc idence of unfavourable c ytoge netics
Macroscopy
In plasma cell myeloma. the bone defects
on gross examination are filled With a soft
gelatinous. fish-flesh. haernorrhagic nssce.
Urilr~
SeN M
~- I
I
.
1
~
Plasma cell leukaemia (peL)

In PeL. the number of clonal plasma cells
in the PB exceeds 2x1Q9A..or is 20% of the
leukocyte differential count {56}. In addi100 to PBand 8 M, the neop lastic plasma
cells may be found in extramedulla ry tissues. such as spleen and liver and in
pleural effusions, ascites and ce rebrospinal fluid. pel may be present at the
tsre of diagnosiS(primary PCl) or evolve
as a lale feature in the course 01 plasma
cell myeloma (secondary PCl) 17571. Primary Pel is found in 2-5% of cases of
myeloma 1112. 583. 7571 . Compared to
IgG Of IgA myeloma. a higher proportion
of ~g ht chain only. IgD . or IgE myeloma
present as PCl 1757. 916 1. The c ytologic
11121. Most clin ical signs of myeloma are

observed in PCl. aJthough osteo ivtc lesions and bone pain are less frequent and
lymphadenopathy. organomegaty and
renallailure are more often present!75n
PCl is an aggressive disease with short
survival 1112. 583, 7571 .
.\-...!'"<'C.
"
.1>
!::
'--
-.EL
.. ... ....
~
~ . 10.33 Serum and urW1e prolein el8dropholesis and mrudtxalion from a 65-year-old llfl)III(Ifl wrth plasma ~
who presented wrth bact. reo,arv:l peMc PlWl arv:l ge. .... iilized weakness.There was .., t1ypeicaloei'la,
laUe oranaemia; howeYer. a skeletal Sl6'o'9y' I'8'o'eIIed Il'UIipIeIytJc tesions i'I tle sJuA. nbs . peIYis. etaYides, sc:apda
em spI'le_ A bMe marrow biopsy slowed 13%plasma
Pro!er'I eledJophole$iS {ElP) f'YeIled a 31 !J'1- ~
IgGk M-proIein and a 341.4il'9'24 h.1oI'ine M-proIeln. The M-proIeil was il:lenbMd byirmulofiuIial ...... UlNes4
(IFE) as IgG kappa (C<u\esy ofO!1 Frank H. Wtln. ok. arv:l Demis C. Wooten).
..-..
"'"
'*_
203
Fig. 10.34 Plasma eel myeloma Ifl a bone marrow

biopsy, A discrete plasma eel mass dIsplaces normal
rnafTOW fat cellslWId haemalopoietJc eIemef1ls, I'4ear the
myeloma mass nole prtIfl1ineotosteodaslic activity in the
trabecular bone
Morphology
Bone marrow biopsy
In co ntrast to normal plasma cells, which
are typi ca lly found in small clusters
around 8M arterioles, myeloma plas ma
cells usually occur in interstitial clusters,
focal nodules or diffuse sheets 1152, 2881.
There is often conside rable 8 M spa ring
and preservation of normal naernaropoesis. with interstitial and focal patterns
of involvement With diffuse involvement,
expansive areas of the BM are replaced
and haematopoiesis may be markedly
suppressed. There is typically progres o
sion from interstitial and focal disease in
early myeloma to d iffuse involvement in
advanced stagesof disease 1152) , Generalfy,

when 30% of the 8M volume is comprised
of plasma cells, a diagnosis of myeloma is
likely, although rare cases of react ive
plasmacytosis may reach that level. A
tumoural mass of plasma cells disp lacing
normal 8 M elements strongly favours a
diagnosis of plasma cell myeloma, even
it the overall percen tage of plasma cells
is <30. Occasionally prominent osteoclastic
act ivity is observed in biopsy sec tions.
resulting in the bone lesions on radiographs .
Immunohistochemistry is useful in Quantifying plasma cells on biopsies, in
confi rming a monoclonal plasma cell
proliferation and in disting uishing myeloma from other neop lasms. A CD138 stain
is useful for quantifying plasma cells. and
ctonentv can usually be established with
stains for kap pa and lambda light chains
156. 17311
Bone marrow aspiration
The number of plasma cells seen on aspirate smears varies from barely increased to upwa rds of 90% 112261.
Myeloma plasma cells vary from mature
forms indistinguishable from normal 10ifn.
mature , ptasmabiasuc. and pleomofphic
1152.288, 8401 . Mature plasma cells are
usually oval. with a round eccentrc
---
Fig. 10.36 Plasma cel myeloma. cykIlogic features If1 marrow aspirations showing 'o'ariatJon from mature l A-B) kl immature (e ,0) plasma cells. The more mallJ'e ceRs haveckJnped I1UCIe<Ir dlrumatin. abllld1tcytIpIasm. lownuclearcytoplasmic ratiO and only rare nucteoli (Xll'l"'4I3red kl the less mature eels . whiCh havemore prominent nudeoIi, loose
reticular chromatin and a higtlernuclear<ytoplasmtC rabo. 0 P1asmablasts from a p1asmablastic myeloma with
promineot nucleoli. retictJlar chromalln and high nuaear<ytoplasmic rato.
204
Mature B-cell neoplasm s
,
Fig. 10.37 Plasma cell myeloma. rncwphoIogic vnrG
on ~~_ A So-called Mott c:el MIl
abundant "grape-like" c-,1OPIasmic indo.JSi)ns d
irnml.Jnoglobulin, B Numerous Russel tooes
based
nucleus and "spoke wheel " Or "cloc kface" chromatin without nucleoli . There is
generally abundant basop hilic cytoplasm
and a perinuclear ror. In con trast, immature forms have more dispersed nuclear
chromatin, a higher nuclear/cytoplasmic
ratio. and often, prominent nucleoli. In almost 10% of case s there is plasmablastic
morphology 18401, Muhinueleated, poIylobated. pleomorphic plasma cells are
prCml nent in some case s 11 52 , 2881. BeC8lJSe nuclear immalu rity and pleomorphism rarely occ ur in react ive plasma
cells. they are reliable indicators of neoplastc plasma cells. The cytoplasm of
myeloma cells has abundant endoplasmic reticulum (ER), which may c on tain ,
condensed or crystallized c ytop lasmic Ig
producing a variety of morphologically
osnrcnve hOdi ngs, includIng : multiple
pale bluish-white, grape-like accumulallOl'l (Molt cells, Morula cells), cherry-red
refracnve round bootes (Russell bodies),
~ stalr'Ii"Ig gtycogen-rich rgA (flame
cells). overstuffed fIbrils (Gaucher-like
ceas. thesaurocyt es) and crystalline rods
12881. Other than the presence of crystalline rods, these changes are not
palhognomonic of mye loma since they
may be found in reactive p lasma cells .
In about 5% of cases of symptomatic
myeloma there are < 10% p lasma cells in
ee 8M aspirate smears 1561, This may be
due 10 a sub-optimal BM aspirate or the
frequent focal d istribution of myeloma in
the 8M In such instances, larg er numbers of plasma cells and foca l clusters
are sometimes obse rved in the trephine
biopsy sections, Biop sies d irect ed at
radiographic lesions may be nec essary to
establish the d iagno sis in some pa tients.
Peripheral blood
Rouleaux formation is usually the most
striking feature on PB smea rs and is related to the quantity and type of M-protein.
Aeckoevmrobtasnc reac tion is obse rved
in some cases. Plasma cells are found on
PB smearsin approximately 15% of cases,
usually in small numbers . Marked plasma cytosis eccoroenee plasma cellleul<.aerm.
KK1ney
Bence Jones protein accumulates as aggregates of eosinophilic material in the

k.mna of the renal tubules. Renal tubular
reabsorption of Bence Jones p rotein is
largely responsible for rena l damage in
plasma cell myeloma .
.. .
COlO
CD20
FIg.1D.38 FlowcyDneIry tMstogams cia bcrle marlOWfrom, pabent WI01 plasma eel ~_ The l'lElq)Iaslic plasma
eels !We painB:! red: normal B~ _ bloe. The myeloma OllIs IlIPf8SS brlljlt C038and arenegatiY8 krano,
C019and COlO. They express CD56 and P<Wtial C045. arenegalI\'e lor surface igt4chains and eqJreSS cytIplasmic
IrmlUnophenotype
Plasma cell myelomas typically have
monotypic cytoplasmic Ig and lack surface Ig. They usua lly express CD79a,
VS38c, CDl38 and strong CD38, simila rly
to normal p lasma cells but in con trast 10
nor ma l p las ma c ells, they are nearl y
always CD19 negative ; CD56 is aberranll y expressed in 67- 79% of c ases
113 12. 1719, 19081. In add ition to CD56,
my eloma plasma ce lls may aberranuy
express CDl17. CD20 , CD52 and CO lO,
in decreas ing o rder of frequency , and
occasiona lly, myeloid and monocytic
ant igens are found (26, 850 ,131 21 Unlike
most myelomas. about 80 % of pl asma
ce illeukaemias are CDS6 neg ative 1757.
1719 , 19081. Some c ases are cy clin 0 1
po sitive , This fin d ing correla tes with the
p resenc e of 1( 11;14)( q13;q32) involvi ng
Ihe CCNDI g ene and has bee n associated with a Iymphopl asmacytic rrorpnologic appearance.
Genetics
Immunog lobulin heavy and ligh t c hain
genes are
rearranged. There is a
high load of IGHV gene somatic hypermutation consistent with de rivation from a
post-cerrnmar centre, ant igen-driven
B~II 11341. Immu nog lobu lin gene deletion is sometimes found ; in patients WIth
cloreuv
light chain only disease or Bence Jone s

proteinuria, JH seg ments and/or parts or
all of chromosome 14 may be lost 11401.
Genetic abnormalities and oncogenes
Abnormalities are detect ed by conventional cytogenetics in abo ut one third of
myelom as 156 1, 19471- Fluorescence in
situ hybr idizatio n (FISH ) inc reases the
proportion with c hromosomal abnormalities to >90% 111 1, 430, 718 , 1181 , 19471Both nume rica l an d structural abnormalities are found and includ e trisomi es,
whole or par tia l c hromosome d eletions
and transccatons: complex cytogenetic
abn orm aliti es a re co mmon 15611. The
mos t frequ ent c hromosome translo c ationa involve the heavy chain locu s
(lG H@)on chromosome 14q 32 and are
present in 55-70% of tumours 1113. 7181.
Five major recurrent onc oge nes are involved in 14q32 translocations: cvcun 0 1
(1 1q 13) ( 15 - 18%); C-MAF( 16q23) (5%);
FGFR3/MMSET( 4p16.3) (15%); eye/In D3
(6 p21 ) (3%) ; and MAFB (2Oq1 1) (2%)
1111, 199,200,12011 . Tog ether theseS
trensocanons are foun d in about 40% of
cases of myeloma , most of which are nonhyperdiploid
and/or >75 chromosomes). The rema ining tumou rs, which
only infrequently have one of the five
recurrent fGH@translocations.aremostly
hyperdiploid. usually with gains in the odd
numbered ch romosomes. 3, 5 , 7. 9. 11,
48
205
Table10.06
Group
Tra n~tion
and Cyclin 0 groops in plasma oeI myelomas.
Primal)'
"""
O-Cytlin
Ploidy
F~qu&IlCy
Progno.i.
transJoc.tion
"'1
6021
CCNDJ
03
HH
3%
eeee
l1q1J
11Q1J
CCNOI
01
O.NH
16%
Go
01
"'"
3"
Go
"'"
"'"
"'"
"'"
"'"
....
01
0 1+02
....
H,NH
11%
? ""
?
HH
'"
01+02
D2
D2
"'"
"'"
"p16
FGFR3IIIMSET
02
NH>H
"'"
16q23
""'"
02
NH
D2
NH
4016
21lq11
",,/8
..
,.
15\
'"
1>, diploid: H.~: NH. ~. UocifIed from (2OOJ
? Go
""
""
""
ce.
Fig. 10.39 IlI1eIpIIase FISH 31'1illyses of reoJrrent abnormalities in plasma

myeloma A FU$IOI1 signals for
U:".1")(p16:Q32)./gHprobes-geen; MMSETIFGFRJ probes-fed. Two fusion sigIaIsinlicated by ye/kM' ~ mosl
likely idefrtIlyderl"j and derl1") but txlUIlI represert two ccees oIllerj"). B Em copiesollhreedlromosomes 11 3 tly_
penjipIoId \l.fTllu. TIvee copies 01 chtol nOSOn. 5 (lSI D5S231D5S721"9f1!e11) alll cmmosome9 (CEP ~ [drded]
and bs copies 01 cMlmosome 15 (CEP 15-ted). CTwo copies 01 etrom:lsome 17 and doIefi:)n 01 one copy 01 TP5J.
TP53--fed, CEP 1111ll8fl. 0 Loss 01 one mpyolctrorrosome13/13Q. LSI13(CXI'lIiIining RB1}green. Dl3S319-fed. In
all flu p;wleIs. 11'18 C)'tIplasm is tu ck.Ie m irmuloslair'Wlg 0I 1gobppa Of ~ ex.pressed by lhe U'noI.rplasma
eels, and tie ptObe$ we mn Vysis. C1asy 01 Or SColt \laJ'I We and Or Ra1aeI Fonseca
206
15, 19 and 2 1 1430,431, 718,20991. Both

IGH@ uanstocations and hyperdip loidy,
appear to be early events in the genesis
of plasma cell neoplasms, unified by
associated upregulation of one of the
eye/in 0 genes (0 1, 02, 03) 1199, 201,
405 , 20991. Gene expression profiling
can determine the expression levels of
eye/in D " 02 and 03 and identify
myeloma that overexpress oncogenes
dysregulated by the five recurrent IGH@
translocations. Using patterns of nensocations (T) and cycnn (C) D expression
(TC groups) plasma cell myelomas can
be classified into 8 groups that are based
mostly on initialing ()( early pathogenic
events 12001 Some or all of these groups
may represent distinct disease enunes
that require different therapeutic approaches I2CXlI. Anothe r molecular classification is based on unsupervised
clustering of tumours by gene expression
profiles 124951. This identifies seven rrolecurar groups that are similar although
not identical to the TC groups, Withone at
the seven molecular groups being defined by progression events that lead to
increased proliferation .
Monosomy or partial deletion of ctrcrosome 13 ( 13q14), which is found in nearty
half of tumours by FISH, is another early
event in pathogenesis, although the precise timing of these various early events
is poorly understood 111t , 7181. Activating mutations of K-or NRAS are presentin
about 30-40% of tumours. and are
thoug ht to represent an early event in prog ression, perhap s mediating the MGUS
to myeloma transition in some patients
(718, 182 11. Some other recurrent genetic
chan ges associat ed with di sease progression in bo th non-hype rd ip loid and
hyperd iploid tumour s inc iude the following : secon dary IGH@ or IGL translocanons. deletion and/or mutation of TP53
(17p13), traosrocenons involving MYCor
less often NMYC, gains of chromosome
1Q and loss of t p , mutations of genes that
result in activation of the NF-kappa B
pathway, mutations of FGFR3 in tumours
with 1(4:14), and inactivation of p lIr"""or
RB 1145, 111, 200, 571, 880 , 1131, 1201,
2017,20991 . Epigenetic cha nges manifested by DNA memyianon also are associated with tumour proqression.
Although genetic events appear to
play the key role in initiation and progreso
son of plasma cell myeloma. the 8M
microenvironment is also important in
pathogenesis and progressioo 114891.
Extracellular. matrix proteins, secrete d

cytokines and growth fac tors, and/or
the functional consequences of di rect
interaction of the 8M stromal cells with
neoplastic plasma cells are major
constituents that influence the pathophysiology of myeloma 11 489/.
Postulated normaJ cou nterpart
Post-germinal centre long-lived plasma
cells in which the immunog lobulin genes
have undergone class switch and
somatic hypermutatiOn.

Plasma cell myeloma is usually incurable,
with a median survival of 3-4 years. but
the range varies from <6 months to >10
years 18421, The Durie and Salmon (OS)
staging system applies commonly avaaable clinical parameters to predict
myeloma cell turTlOUr burden - low, intermedia te and high tumour cell burden
1160, 6331 (Table 10.07). There is a
significant dlHerence in survival between
each of three tumour mass stages; normal
renal function versus renal insufficiency
further defines lower versus higher risk
patients in each stage 1633, 842. 18081.
Additional indicators of higher risk
patients include elevated serum 11-2
microglobulin (R2M), low serum albumin ,
elevated lactate dehydrogenase, high
O reacnve protein, increased plasma cell
proliferative activity , high degree of 8M
replacement, plasmabl astic morphology
and genetics PS9 , 160,84 1. 18081. An
international stagi ng system (ISS) for
plasma cell myeloma provides highly
significant prognostic correlations, using
acornbination of serum r..2M and albumin
level to define 3 stages (8421 (Tabl e
10.08),
Patients with abno rmal ities by conventional (metaphase) cytogenetics have a
significantly shorter median survival than
those without 1111, 4 16, 428, 787, 842,
880, 912, 1132, 1181, 2000, 20991. The
most important independent negative
prognostic indicato rs include: high risk
~4; 1 4) and the MAFtransJocations t( 14;16)
and t(14;2O), deletion of 17p/TP53 se
qcences and increased serum B2M. A
high-riSk molecular signature based on
the expression 01either 70 or 17 genes
provides perhaps the most robust , independent prognoslic indic ator 12001/.
F.g.10.40 5pectrakaryotypic(SKY)a'WysIsd~n1~l*smaoelrnyebna . ....C ~

spreads "lispIaycolcn. B,OQassdicalion dchOlllOlOl 'oes;A, B Hypenipklid Lm:u'Mlh 53 c:hOl 'iUSOIfIeS, n::t.d-
ing bs rearrnnged chDmDSQllleS IlYoIWlg two or fI'IOl'edtrerenl chOlllOSOllleS , trisOlnIesdchOlllOSOltleS 3, 9, u . 19

and letr'ascrT1es d c:MJmornes 15and 21. From f ISH MlaIyses (not$hDwrl), \here 1$no lGHor JGL ba lSkX:abol., tu ltYC
is i'lSerIed 0l'I d'nomosome 6p23. C,O ~ bnlU WlfJ 46dlOllllSOl1eS,1lckDrlqalleast hee ~
ctrcrnosomes invoMng two orfI'ICII'e dillerenl d1n:Jrros<:mes. antrtemally deleted dVomosome l.t, andbss d one CWI
ofchromosome 13. FISH anatyses (notshown)a:m.rm ltle presence d a l(2;1.tKp23:q32) iM:lIving N-M'fCanda karyoIypicaIly silent l(-4;1.tKp16;q32). Courtesy afDrAnna Rosdi;e and DrAna Gabrea
Table 10 07 Myeloma sIq1g syslem Mod.f1ed from DIn! and Salmon {633}
Stage I:
- lCM M-protein ~s : IgG <~ .1gA <3OgIt; Urine BJ ~4hr
- Absent or soitary bone lesions,
- ~ haerrogk:lbin, serum calCiwn, 1g Jevels (non-M protein),
Stage II: O'IeraU vanes between I and III

Stage III: Arry one ormore ollhe following :
- High M-protein: IgG :>70g1l, IgA :> 5Og/L: Urine lightchain :>12g124hr
- Acvanceo, multiple lytic bone lesions
- Haemoglobin <8,SgldL, serum calcium :>12mg1dL.
Subclassification: Based on renallunclion
A" serum creatinine <2mgldL
B " serum creabnine zz mgldL
Table 10.GB International staging system fof pasroa cellmyeloma.
s....
Criteria
Serum ~ <3 5 mg.1..

Serum albumin :>3.5 gldL
"
"'
Median 5urvival
"moo"
Notstage I orIll"
Serum ~ :>5 5 mg1l
"There are two calegorie$ Jar stage II: serun ~ <3.5 mgIl.. but seIVIl aItlumi'l <3.5 gll1.: or sen.m
~ 3.510 <5.5 mgIl.. rmpecbwe 01 the sen.rn all\rlWlleYeI.
ModIfIed from (842).
207
Table10.09
Cytogeneticprogoostic groups in plasma cell myeloma.
Unfivotll'lble risk:
Delellon 13IS ~ by meta(:tIa$& analysis

114,14) or11 14:16)or1(14;20) by FISH
Deleboo17p13 byFISH
Hypodiploidy
F~" risk :
Absence ollWlfavcuable risk geoetIC$ and presenceafhyperdiploilty.1( 11;14) or116,14) by FISH

Modified from {2099},

Definition
Solitary plasmacytoma 01 bone (osseous
plasmacytoma) is a localized bone tumour
consisting 01 monoclonal plasma cells,
Co mplete skeletal rad iogr ap hs show no
other lesions. There are no clinical feat ures
01 plasma cell myeloma an d no evidence
01 8 M plasmacytosis except for the solitary lesion 156, 20611.
ICD-O code
9731/3
Epidemiology
Solitary plasmacytoma of bone comprises
3-5% of plasma cell neo p lasms 1561. It is
more c ommo n in men (65% ); media n age
at d iag nosis is 55 yea rs 156, 5821.
The most common sites are bones with
active 8 M naema topole sle: in orde r of freq uency , the vert ebrae . rib s. skull, pelvis,
femu r, clavicle and sca pul a 15821. Thoracic vertebrae are mo re commonly involved than cervical or lumbar, and long
bone invo lvement below the elbow or
knee is rare 156. 5451.
ad d itiona l lesions and is c onside red a

prerequi site for di ag nosi s by some investigators 11296, 206 11
Mor phol ogy, irrmunophenotype

and genetics
Plasmac ytom as are usually ea sily recogniz ab le in tissue sec tions unless the
p lasma cells are very poorly d ifferentiated , e.g. pla sma bla stic or anaplastic .
Confirmation of a clon al p lasma ce ll lesion
can be ac complished by immunohisto chemistry Even when the d iagnosis is ap parent. oererrrsnauon of light c hain type
is suggested. The irrmunophenotype and
genetics are simi lar to those of plasma
c ell myeloma
Progn osis and pred ictive factors
Local con trol is achieved by radiotherapy
in most cases, but up 10 two third s of patients even tually evolve to ge neralized
myeloma or additional solitary or multiple
p lasmac ytomas 156, 545, 9551 Approximately one -third of patients remain disease free lor >10 years; median overall
survival is - 10 years 1561. Older patients
and those with a sol itary plasmacytoma
la rge r th an 5 cm or per sistenc e of an
M-protein following local rad iotherap y repOrled ly have a higher incidence of prog ression 156. 582 , 1296, 2272, 24031,
However. these unfavourable features have
not been consistent betwee n series
1206 11, Osteopenia and low leve ls of uninvolved immunoglobu lins . both 01 which
suggest occult plasma cell myeloma. are
also reported as adverse prognostic lactor s 1582, 10301. Measurement 01the free
lig ht chain ratio is usefu l l or predi cting
progression (5871.
Definition
Clinical leatures
Patients most frequently present with
bone pain at the site of the lesion or with
a pathological fract ure . Verte bral lesions
may be associated wi th symptoma tic
cord com p ression 15451 . Sofl tiss ue extension may p roduce a pa lpa ble mass
1561. An M-protein is toone in se rum or
urine in 24-72% of patients 156, 582 ,
206 1,24031, In most cases ooivcionar immunoglobulins are at normal levels 1582,
206 11. There is no anaemia, hyperca lcemia or rena l failu re relate d to the plasmacytoma 156 1. MAl is useful to exclude
208
Mature B..cell neoplasms
Exuaosseou s (ext ramedul lary ) pl asmacytomas are loc a lized plasma cell neoplasms that arise in tissues o ther than
bone. Lymphomas with prominent plasmac ytic d ifferentiatio n, partic ular ly extranod al ma rg inal zone (MALT) lymp ho ma,
must be excluded,
ICD-O code
973413
Synonym
Plasmacy toma. extramedullary.
Epidemiology
Extraosseous (ex trame d ullary) plasmacytomas constitute 3-5% of aU plasma
cell neoplasms 1221. Two thirds of patients
are ma le; the median age at diagnosis is
about 55 years.
Sites of invo lvement
Approximately 80 % of extraosseoos
plasmacytomas occur in the upper respirato ry tract , incfuding the oropharynx,
naso pha rynx, sinuses and larynx, but
they may occur in numerous other sites,
including the gastrointestinal tract (Gil,
lymph nodes. bladder, CNS. breast. thyroid . testis . parotid and skin 1221. Plasmacytomas of the up pe r respiratory track
sp read to cer vic al lymph nodes in - 15%
of cases 114601.
Clinical features
Symptoms are generally related to the
tumour mass and include rhino rrhoea,
ep istaxis and nasal obs truc tion , Radiographic and morphologic assessments
show no evidence of BM involvement. Approximately 20 % 01 pat ients have a small
M-p rotein, most commonly IgA 156. 20611
There are no c linical features of plasma
cell myelo ma.
The mo rph Ologic features are similar to

those of solitary plasmacytoma of bone,
However, in extraosseous sites, distinction be tween lymphomas that exhibi t extreme plasma cell differentiat ion and
p lasmacytoma may be diff icult 15801.
Ma rg inal zone lymphoma 01 MALT type,
Iymphop lasmac yt ic lymp homa and occ asionall y, immu noblas tic or plasmablaslic
large cell lym phomas may be misdiagnosed as plasmacytoma 1580, 9991 . Disnocton from a marginal zone lymphoma
with marke d plasma cell differentiation is
espec ially problematic , particu larly in skin
and G I, and may not be possi ble in some
instances. Areas With features of marginal
zone lymphoma may be identified in tissue sections in some cases and in others
a clonally related lymp hoc yte population
may be identified by flow cyto mefry
Irrmunophenotype and genetic features
The immuoopheootype and genetic teatures are not extensively studied. but appear to be similar to thos e 01 plasma cell
myeloma, Immunohistoch emistry or In situ
hybridization for Ig light chains can be
useful in d istinguishing neoplastic from
reactiveoiasma cell infiltrates. Expression

of CD20 by lymphocytes within the lesion
or by the plasmacytoid cells or expression of IJ rather than y heavy chain favours
a diagnosis of lymphoma over pla sma cytoma
Prognosisand predictive factors
In most cases the lesions are eradicated
with local radiation therapy. Reg ional
recurrences develop in up to 25% of
patients and occasionally there is met astasis 10 distant extraosseoue sites. Progression to plasma c ell myelom a is
infrequent, occurring in -1 5% of cases
1221, About 70% of patients remain
disease free at 10 yea rs 15791 , This indolent course may sug gest that many cases
are more c losely related to MALT lym phoma than to myeloma.
Monoclonal immunoglobulin
deposition diseases
The rrooodonal irrm..x'loglobulin oeooston

diseases (MIDO) are closely-related disorDers that are charac terized by visceral
and soft nssue d eposition 01 immunoglobulin, resulting in com promised organ
fLr1ction 1100, 304 , 934.1085, 1225, 1779,
1814. 1994.24331. The und erlying disorderis typically a plasma cell neoplasm, or
Fig. ' 0. t Plasmacytoma showlng absence dCOlO (A) iIfkl expressiorl dCD38IBI_
rarely a Iym phoplasmac ytic neoplasm

1785, 7861; however, the immunoglobulin
molec ule accumulates in tissue before the
development of a large tumour b urde n.
Thus. these patien ts typ ica lly do not have
overt myelom a. or rvmpncorasmacvuc
lymphom a at the time of the diagnosis.
The MIOO appear to be chemically di fferen t mani festations of similar pathological
p rocesses, resulting in clinically similar
but not identical countcoe. There are two
major c ateqones of MIDD: primary amyloidosis and lig hl chain deposition d isease (LCDD); rarely ligh t and heavy chain
deposition disease (LHC DD) and heavy
chain oeoositoo disease (HeDD) may be
seen
Primary amyloidosis
Definition
Primary amyloidosis is c aused by a
plasma c ell. or rarely. a Ivmoboorasmacvnc neoplasm that sec retes intact or
frag ment s of abnormal immunog lobulin
light chains, or rarely, heavy ch ains, wtuch
depo sit in various tissues and form a Bp leated sheet structu re (AL amyloid) that
b ind s Congo red dye with cha racteristic
bi refringence 1785, 786, 813, 1157,1225.
19941.
lCQ.O oode
9769/1
Epidemiology
The median age at dia gnosis of p rimary
<myloidosis is 64 years and >95% c:I pa1lE!fltS
are over 40; 65- 70%are male 11 225, 12281.
,...1&...~;:.La ili.&
fig. 10,. 2 Plasmacy1oma. Composrte figufe illuslrates immllooglobulin expression, A Typical plasma cell morphology B CyIoj)Iasmic kappa light chain posdlYity
CAbsenc8 01 lambda \ighl chaindiseaseexpl"llSSion. 0 Expression of cy10plasmicgammahea'IY chain, E.FAbsence 01 mil aridalpha hea'IY chains,
209
",
Fig. 10.43 PlasmaC811 grarUoma. A The "masselJed'oIp1asma cels SOlllates a neoplasm. ~ stamsl'lCM' poIytypiccy1qllasnic~Wilh someplasma
eels 8xpre$$1l'1Q (81 ~ 19l1 cham and somee~ (e) Ianbda i(;Tl d1aons
Approximately 20% of patients have

plasma cell myeloma but most have criteria for MGUS with production of a
M-protein that results in pathologiCal deposition 0119 light chains in various tissues .
Among patients with myeloma, up 1010%
have or will develop amyloidosis 156.
1225, 1226,1 9941,
AL amyloid ac cumulates in many tissues
and organs inCluding subcutaneous tat ,
kidney, heart, liver, Gr, pe ripheral nerves
and 8M. The diagnostic biopsy site generally is the abdominal subcutaneous tatpad. 8 M or the rect um 11225.1 994 1.
Clinical features
Clinical findi ngs are usually related to
deposition 01 amyloid in organs, resulting
in organomegaly Purpura (15%) (particularly periorbital or facia l). bone pain

(5%) , peripheral neuropathy (17%) and
carpallunnel syndrome (21%) are early
signs of disease. Haemorrhagic manifestation s are found in approximately one fifth of cases. Bleeding may occur due 10
inc reased frag ility of blood vessels from
am yloid deposits. binding of coagulation
factor X and/or vascular structures to
amyloid proteins. Symptoms referab le to
con g estive heart failure (17%), nephrotic
syndrome (28%) or ma labsorption (5%)
are all relatively common 112251. Hepatomeg aly is foun d in 25-30% of pa tients
and ma crogl ossia in about 10% {12251.
Ed ema is otten present in p atients with
congestive heart failure or neph rotic syndrome / 1225). An Mprot ein is found in
the serum and /or urine by immunofix ation
in >90% of patients with primary amyloidosis and with a combination of immunofixation and serum free light cha in ratio
analysis in 99% 157. 1123 . 12251. Thelighl
chain is lambda in 70% of patients 112251.
Palhophyskllogy
AL amyloid is composed of intact
immunoglobulin light cha ins or rarely,
heavy cha ins that are secreted by m0nocl onal plasma celts and then ingested.
processed and discharged by macrophages into the extracellular matrix . The
accumulated amyloid includes both intact
light chain and fragments of the variable
(V) NH2-terminus region . All tight chain V
region fragmen ts are potentially amylodoqenic. and all plasma cell neoplasms
that produce VAVI have AL 11225 . 1994),
Macrosc opy
On gross inspec tion amyloi d has a dense
"porce lain-like" or waxy appearance,
~ pIasmacybma 0( Ih8 skr1 wrlhabundard. Russel body tormabon (A B) wtidll3l prockIce

~ stanng by irmlullOhiSb:tletfislry. MonodonaIity is dem:nstraled by IlllIHadioacDve i'I situ hybridaabon
~ absence of kappa (e) and presence of Ian'bda mRNA ~ (O).
f ig. 10."
210
Morph ology
Biopsy section s of 8M vary from no
pathologi c findings to extens ive replacement with amyloid, overt myel oma, or
rarely. lymp hopl asmac ytic lymph oma.
The most com mon findi ng is a mild
inc rease in pla sma c ells that may appear
norm al or exhibi l any of the changes
foun d in pl asma cell myeloma 11 2251,
Amyloid is p resent in many other tissues
and organs. In H&E stained sectio ns, it is
a p ink. amorphous. waxy-appearing substance , With a ch aracteristic cracking artifac t. Typically, it is found foc ally In
thic kened blood vess el wans. on basement membranes , and in the mtersmnm
01 tissues such as tat or BM 124331.
Macrop hages and foreign-body giant
celts may be found around deposits
Organ parenchyma may be massively replaced by amyloid (amyloidoma). Plasma
'j'
f,,,
'(;,,<,.
,J ,t-'
I '"
"L
"Ii
I~
~
."
..
;it,,~~..'..a>:L:l...,i'
FIg. 10.45 APrrnaty amyIaIdosIs in a pabetIl withplasma eel myeloma. Grossp/K*)graph of a section of heal1shows !he Iiffuse rilrgement charactefiStlC 01 amyloid deposition,
es;e::.ally III !he left 'tllfllncle. Bone marrow biopsy of pnmary amyloidosis sha.Wng etIaraclerisbc pale. waxy arnotpl'lous deposits (BI and associated hlSbocyte$, otIen
1TUlrIucIea1ed. andneoplasbc plasma eels (C).
cellsmay be increased in the adjacent tissues. Congo red stains amyloid pi nk to

red by standard light microscopy and
under polarized lig ht p roduc es a c baractereuc "apple-green" birefring ence . Elec-
Iron microscopic studies will differentiate
Al amyloid from t c o n .
Irrvnunophenotype
The immunophenotypic features of the
plasma cells are simila r 10 lhose of
myeloma , Immunoh istochemical sta ining
of 8M seclions for kappa and lambd a
IigN chains shows a monoclonal plasma
cell staining pattern unless the clone is
IAlsually small and masked by rormat
poIyclonal plasma cells 1675, 2433,
24521 . Staining lor amyloid P componen t
is posmve. Immunohistochemical techniques using anti-amyloid fib ril antibodies
to At kappa and lambda are use lul in distinguishing prima ry and secondary amyloidosis (AA) in some c ases but are
definitive less than half the time {6751. AA
amyloid , however, can be rec og nized by
immunohistochemistry in essentially all
cases (571.
Genetics
The genetic abno rmalities reported ih pr imary amyloidosis are simil ar to those in
rm-lgM MGUS and plasma cell myeloma.
One exception is the unexplained observabon that lhet( 11;14) is p resent in >40%
01 individuals with amyloidosis but on ly
15-20% of those with a d iag nosis of nonIgM MGUS or myeloma 1718. 9121.
Parame ters that ha ve been associated

wit h poor pr ognosis include elev ated
serum c reatinine , hep atomegaly, major
we ig ht loss, excretio n of lambda lig ht
c ha ins in the urine (vs kappa light chains
or no M-protein), elevated 112 mic rog lobulin
levels an d a large whole bod y am yloi d
load {57. 784 , 1228/. The single most frequent c ause of death is amyloid rela ted
cardiac disease ( -40%) {122BI .
_ l i ght and heavy chain

deposition dis8ases
Definition
Monoclonal light and heavy c hain deposition diseases are plasma cell or rare ly
Iym phoplasmacytic neoplasms that sec rete an abnormal light or, less otten.
heavy c hain or both, which deposit in tissues causing orga n dysfunc tion but do
not form amy loid B-p leated sheets, b ind
Congo red or con tain amyloid P-component
[ 106,304, 580,934 , 1085, 1779 , 18 141.
These d isorders include lig ht chain deposit ion di sease (lC DD) (304.1 776, 1779,
18 141. heavy c ha in d eposition disease
(HC DD ) {106 . 934 ,1 08 51 and ligh t and
heavy c hain deposition disease (LH CDD)
1304.5801
Synonym
Randall d isease {18141.
Epid emiolog y
These are rare d iseases of adults (med ian
age 56 years. range 33 -79) which occur
in association with either myeloma (65%
01 cases) or MG US 1304, 1085 , 1776,
1779 1. There is no evidence of an ethnicity effect and the rnale.ternale incidence
is nearly equal{304. 1085. 1779/.
Sites of lnvotvement
lCDD and HCDD may involve many organs . IT'OSl <Xm'T'IOl'lIy the kiOOeys 117761.
The liver. heart. nerves. blood vessels and
occasionally JOints may be involved 1106,
:4,934, 1005,1779,181 4,2433I .Thereis
prom inent deposition of the aberrant 19 on
basement membranes, elastic and cotIagen
fibres . Pulmooary involvement, eitherdiffuse
or nodular. has been reported {214. 18751
Clinical feat ures
Patient s present w ith symptoms 01 organ
dysfun c tion as a result of di ffuse, systemi c imm unoglobul in deposits, usually
manifested by nephrotic syndrome and/or
ren al failure 1564 . 1776 1, Symptomatic extrarenal d eposition in lCDD is unco mmon
and involves the heart (21%). liver (19%)
Progoosi.
The median survival for patients with primary amyloidosis is approximately 2
years trom diagnosis 112281. Patients with
amyloidosis and plasma cell mye lom a
have a shorter survi va l than tho se wit h
amyloidosis or myeloma alone 11225 1.
Plasma ce ll neoplasms
211
. ...
o ."
and peripheral nervous system (8%) 1304,

1462. 1776 1. HCDO of IgG3 ex IgGl .sotypes result in nypocomoiemen terea
since the IgG3 and IgG 1 subclasses
most read ily fix complement 19341, There
is an M-prot ein in 85% of cases.
Pathophysiology
The M-p rotein in non-amyloid MIDD has

unde rgone structural change due to deletion a! and mutational events 1304 , 580 ,
1085, 17791. In LCDD the primary d efect
involves mul tiple mutationS 01the Ig ligh t
ch ain va ria ble reg ion wi th ka ppa lig ht
c hain of V"IV typ e nota bly over represented 1304. 580, 17791. In HCDD the cntlear eve nt is de letion of the CH 1 constant
doma in which ca uses failure to associate
with heavy c hain b indi ng protein, resulting in p remature sec retion 1106. 934.
1085 , 17791. In HC DD the variable regi ons also contain amino ac id subs titutions that ca use an inc reased propensity
for tissue dep osit ion and for bind ing
blood element s 1106, 304,10851,
Morphology
There are prom inent tissue d epo sits of a
non -amyloid , nonnbrtnarv amorphous
eosinophil ic ma teria l, which d o not stain
with Co ngo red. They are often see n as
refrac tile eos inophilic material in the

glomerular and tubular basement membranes . bu t may also be seen in BM and
other tissues. LCOD is usually diagnosed
by renal biopsy using fluorescent antilight chain antibodies and electron microscopy 11 776 1. Kappa chains a re
observed by immunoflourescence in the
renal glomerular and tubular baseme nt
mem brane. The hallmark 01the disease is
the p rom inent, smoo th, ribbon-like linear
per itubular deposits of monotypic irrrnunoglobulin alon g the oute r ed ge 01the tubular ba sement memb rane. These depo sits
by electron mic rosco py are typically discr ete. den se pu nct ate , granular, nonfib rillary deposits, with an absence of the
a-oreateo sheet structure by X-ray di ffrac tion. Althoug h in some ca ses plasma ce lls
are found in the vic inity of deposits, it is
more c ommon to find 19 deposition in visceral organs with few, jf any, plasma ce lls,
Bone marrow p lasmacyt osis is prese nt in
most cases; rarely, a Iymphoplasmacyt ic
or marg inal zone lymphoma has b een
repo rted 1214, 305, 23911.
Immunophenotype
In contrast with pr imary amyl oid o sis,
which has a predominance of lam b da
lig ht chain with overreoreser uaton of the
.-
''(5'
,
c:
V1IV1 variable reg ion , LCDD has a prevalence 01 kappa light chains (80%) with
overepreseotatco of the VICIV variable region 13041 Irrmunohistochemistry on 8M
sections may reveal an abe rrant kappa!
lambda ratio 124331.
Prognosis
The med ian ove rall survival lor patients
with LCDD is approximately 4 years.
Prognosis is correla ted with age. the presence of plasma cell myeloma and emarenat lig ht chain depos ition 11462 , 17761.
Osteosclerotic myeloma (POEMS

syndrome)
Definition
Osteosc lerotic myeloma is a p lasma cell
neoplasm c ha racterized by fib rosis and
osteosclerotic chan ges in bon e trabeculae, and often with lymph node changes
resem bl ing the plasma ce ll va riant of
Castleman disease, This disorder is often
a co mponent of a rare synd rome that inc ludes polyneu ropathy, organomega ly,
endoc rinopathy, monoc lonal gammopathy.
and skin c hang es (POEMS) 11483). The
relations hip of thi s d isease to typical
pla sma cell myeloma is not known .
Synonym
Crow- Fukase synd rome.
Epidemiology
This is a rare disease. occurring predominantly in adu lts, and estimated to c0mprise 1- 2% of plasm a celt dvscrasas
114831. Many cases have been reported
from Ja pan. Men are affec ted slightly
more often than women (M.F ratio 1.41)
and the median age is about 50 years
F~ 10,48 lighI chain depoSlbon disease in kOIeyshowring (A) pale anorphous palttIes IIo'Iltlin gIorroenAi (nodulaf
gIomenJosdetosi) and (81 ~ stain stlowing renalllMar andel1rabbJlar c\epOSlbOn ~ Il.ippa IicJ1l
chain in a smooIh inearpallem.
2 12
15901.
Etiology
An imbalance of p ro-inflammator y c ytokines is common in POEMS syndrome.
Vascular endothelial growth factor (VEGF)
produced by the tumour cells may be responsible for some of the symp toms of
the disease 1634. 23631 . Some cases of
POEMS syndrome . especially those associated with Cas tleman disease, have
been reported to be associated with
hll'laflherpesvirus 8 (HHV8) 1175. 14831
Q inica! teensee
Most patents do not present With all of the
manifestations of POEMS syndrome and
not all are requi red for diagnosis. The
map clinical feature is a chronic pr ogressive polyneuropathy 15901. O rganamegaly is present in at least 50% of
patients and enoocnocoamv and skin
changes each in two-thirds 15901. In
75-85% of patients ther e is a serum
M-protein that is either IgG lambda or IgA
lambda; the quantity is typic ally low (median 1.1 g/d l ) 15901. An M-p rotein is
found in urine in <50% of patients. Relatively c ommon clinic al findi ng s include
edema an d serou s c avi ty effusions, pap illedema, thrombocytosis. weight loss,
fatigue, clu bbinq. bon e pain and arthralgias. Hypercalc emia, renal insufficiency.
and pathological fractures are rare. nacographic bone abnor malities are found in
nearly all cases. These vary from single
sclerotic lesions in about ha" to more than
three lesions in one-th ird of cases 15901_
Morphology
The charac teristic lesion is an osteosclerotic plasmacytoma. which ma y be single

Of multiple. The lesion is comprised of focally thickened trabecular bone Wi th
closely associated perat-etecctar fibrosis
with entrapped plasma cells . The p lasma
cells may appear elongated due to distortion b y small bands of connective
tissue. The 8 M away from the osteosclerotic lesion usually con tains <5% plasma
cells, which are typically normal appearing. In a minorit y of p atients with more
generalized osteosclerotic myelona. > 10%
p lasma cells may be found in random 8M
b iopsies 120581. Two-third s of patients
with lymphadenop athy have ch anges
conserera with the plasma cell variant of
Cesneman's disease 15901.
Immunophenotype
The plasma cells con tain monoclonal
cytoplasmic Ig which may be IgG QII IgA.
The ligh t chain is lambda in almost all
p atients.
Prognosis
The median overall survival is 14.7 years
1590, 14831. The most corrmon causes of
death are cardiorespiratory failu re and
infection.
Plasma cet! neoplasms
213
Extranodal marginal zone lymphoma

of mucosa-associated lymphoid tissue
(MALT lymphoma)
P.G Isaac son

A.ChoU
S. Nakam ura
H.K. MOlier-Herme link
N.L. Harr is
S,H. Swerdlow
Definition
Extranodal ma rginal zone lymphoma of
rrocosa-asscctaiec lymphoid tissue (MALT

lymphoma) is an extranodat lymphoma
composed 01 morphologically heterogeneous small Bcens including marginal
zone (centrocvte-nke) cells . cells resembling monocytoid cells. smaJllymphocytes.
and scattered immunoblasts and centroblast-like cells. There is plasma cell differentiation in a proportiOn of the cases.
The infiltrate is in the marginal zone 01 reac tive B-cell follicles and extends into the
inlerfoIrictJlar region. In epithelial tesces. the
neoplastic cells typically inliltrate the epithe-
lilm laming tymphoeprtheliallesions 110 131.

ICD-{) code
9699/3
Synonym
Extranodal ma rg inal zone B-ceillymphorna
of mucosa-associated lymphoid tissue.
Epidemiology
MALT lymp homa compr ises 7- 8% of all
B-eeillym phomas 151). and up 1050% of
pr imary ga stric lym p homa [600. 1801 1,
Most cases occur in adults with a median

age of 61 and a slig ht female prep onderanc e (male: female ratio 1' 1,2) 151 1, There
appears to be a highe r incidenc e of ga stric MALT lymphomas in north-east Italy
16001 and a special sub typ e pr eviously
know n as alpha heavy c hain di seas e and
now c alled immun oproliferative small intestinal di sease ( IPSID) occurs in th e
Middle Ea st 117511, the Ca pe reg ion 0 1
South Africa 117811and a varie ty of othe r
trop ical and sub tropical loc ations,
Etiology
Hussell and colleagues 19981have shown
that contmuec prolif erat ion 01 gastric
MALT lymp homa cells lrom pat ients infected with Helicobacter (H.) pylori de pends
on the presence 01 t-eens specifically activated by H . pylori antigens. The enoortance of this stimula hon in vivo has been
clearly demonstrated by the induction 01
remissions in gastric MALT lym phomas
with antibiotic therapy to eradicate H .
pylori 124441. A role for antigenic stmJIation
2 14
Mature s-een neoplasms
Fig. 10.0 ExtranociaI m<II'ginaI zcne lymphoma of IIUXJS&o<IS5OCi ~ bsue. A Resedlon specimenal a
gastric MAlT Iynll/1oma BMALT Iynll/1oma of fie ~ .
by Chlamydia osittacr. Campylobacter

jejuni and Borrelia burgdorferi has been
proposed for some cases of ocular adnexal MALT lymp homa. IPSID and cu taneous MALT lymphoma respectively 1364.
695, 12641. Isaacson has suggested that
"acqoreo MALT" secondary to autoirrrnune
disease or infec tio n in these sites may
form the subst rate for lymphoma oeveto pment 11011}.
Precursor lesiorls
In man y cases of MA LT lymphoma, the re
is a history of a ch ronic inflammatory
d isorder that results in acc umulation of
extranocrat lymphoid tissue , The c hronic
inflammation may be the result of infec tion , autoimmunity o r othe r unknown stimulus. Examples of infec tious organism s
that may cause ac cumu lation of MALT
that preced es MALT lym phoma include H.
pylori (g astric MA LT lymphoma) (2445l.
Chlamyd ia osrnacr (ocular ad nexal MALT
lymphoma) 1394. 6951. Campvobacte

jejuni(IPSID) 11264. 1781, 18121 and Borrelia burgdoferi (cutaneous MALT 1ymphoma) 13641. At least in ocular and
cutaneous MALT lymphomas , there is
great varia tion in the strength of these
associations that might relate in part to
geographic dive rsity 1394. 1290, t898I.ln
the lirst study in which the association 01
gastric MALT lymphoma with H. pylori
inlection was examined. the organism
was presen t in over 90% of c ases 124451,
Subse q uent stud ies have shown a lower
incidence 115661 but also that the density
and detectability of H. pylori decrea ses as
lymphoma evolves from c hronic gastritis
(1562) The orga nism may be undetectab le using histopathological techniques in patient s who are seropositive
16361 . Auto immune based c hronic inflammatio n in the form of SjOgren syndrome
and Has himo to thyro id itis is known
respect ively to pre cede salivary gland
Fig. 10.5(1 Gaslnc MALT Iynll/1oma AThe\lmol.r oek SIIl'OUI'Id readNe IoIides al'lCl infjtraJe fie 1TIJCOSa. Thebkles have a twicaI staTy-sky appearanal. B The rna-gm zcne eels Itfillfaleltle IanwIa propria n a cIiIIMpaIIIm
a'ld haYe ooIaizedfie gemIIIiII oanIres d f8Idw B-alI",TheaJIonizecI kllIic:Jes donoI show a slaITy-sky ....
)
and thyroid . MALT lymp homa, Patie nts
with SjOgren synd rome (85) o r Iymphoepithelial saieoeruus (LESA) have a 44-fold
increased risk 01 d evelop ing overt lymphoma. com prisi ng a bout 4-7% of pa tients 111 14, 21501. Approximalely 85% 01
lymphomas in pa tients with SS/LESA are
MAlTlymphomas. Patients with Hashimoto
thyroiditis have a 3-lold excess risk of developing lymphoma and a lO- fold increased risk of thyroi d lymphoma, for an
overall lymphoma risk of 0.5-1 .5% 160.
958.11161_94%01 thyroid Iymphcmas have
evidence 01 lymphocytic thyroiditis 15581.
distribution and sprea d ou t to form larger

confl uent areas which eve ntually overrun
some or most of the follicl es 11018. 10 191.
The charac teristic marginal zone
have small to medium -sized , sli gh tly irreg ular nuclei with moderately d isper sed
a-cens
ch romatin and incons picuous nucleoli, resem bling those 01 cerurocvtes: they have
relatively abundant, pale c ytoplasm. The
accu mulation of more pale-staining cytop lasm may lead to a monocytoi d appearance. Alterna tively. the ma rginal zone
Sites 01 irrvolvement
The gastrointestinal(GI) tract is the most

common site of MALT lym phOma , compriSing 50% of all cases, and within the GI
tract. the stomachis the most common 10calion (85%) {18011 . The small intestine is
typically involved in patients with I?SID .
Other common srtes inc lude saliv ary
gland. lung ( 14%) . head and neck (1 4%),
ocular adnexa (12%), skin (1 1%), thyroid

(4%) and breast (4%) 121931.
OinicaJ features
The majorityof patients present with stage
I or II disease . A min or ity of patien ts
(2- 20%) have bone marr ow (8 M) involvement 179. 1802. 2 1941. The trecuencv 01 8 M invo lvem ent is low er in
gastric cases and high er in MALT lymphomas arising in the lung and ocular adnexa 12193. 2 194). Multip le extranooa!
sitesmay be involved in up to 25% of gastric cases and 46% of extragastric c ases
at the time of presenta tion 118021. Multifocal nodal invo lveme nt is rare (7.5% of
thecases) 121931 . App lication of stag ing
systems for nodal lymphomas can be
misleading in MALT lymphomas. since involvement of mult ip le extranod al sites ,
particularly of pai red org ans (e .g . salivar y
glands) or org an systems (e.q . ga strointestinal tract. skin) may not reflec t trul y
disseminated d isea se. Prasmecvnc differenneuoe is a feature of many of the cases
and a serum paraprotein (M-compo nenl)
can be detec ted in a third of patient s with
MALT lymphoma 124291. The majo r ex ception is IPSID. in wh ic h an a berran t
a.lpha heavy chai n ca n usua lly be found
inlhe peripheral b lood 1178 11.
The lymphOma cells infilt rate around reactive B-cell follicles. exte rn al to a preserved follicle ma ntle . in a ma rginal zone
Extranodal marginal zone lymphoma of mucosa-associated lymphoid nssoe
215
cells may more closel y resemble small

lymphocytes. Prasmecync diff erentia tion
is present in approxima tely one third of
gastric MALT lymphoma s. is frequently
found in cuta neous MALT lym p homas
and is a c onstant and often striking feature in thyroid MA LT lym phomas. The histological feat ures 01 JPSID are simi lar to
those 01 other cases 01MALT lym phoma.
bu t typi cally show striki ng p lasma cytic
d iffere ntiat ion 11 82, 101 2 , 1781 1. l arg e
cells resemb ling centrobtasts or irnmunoblasts are usually present, but are in the
minority. In glandular tissues. epithelium
is often invaded and destroyed by discrete aggreg ates 01 lymphoma cells resutting in the so-called Iymphoepithelial
lesions. Lymphoepilheliallesions are ag gregates of three or more marginal zone
cells with d istort ion or destruction of the
ep ithelium , etten together with eosroophilic degeneration of epi thelial celts The
lymphoma cells some times specifically
colonize the ge rminal centres of the reactive follic les and in extreme examples, this
ca n lead to a close resemblanc e to follicular lymphoma . In lym p h nodes, MALT
lymphoma invades the marginal zone with
subs eq uent intertonicula r expa nsion. D iSc rete aggregates 01 monoc yto id
may be presen t in a paratomcurar and
oensmusoioat d istribution . Cytological
heterogeneity is still pr esent and both
plasma c ell diff erentiat ion and fo llic ular
colonization may be seen.
MALT lym phoma as def ined is a lymphoma composed predominantly of small
celt s, Transfo rmed centrobtast- or immunobrast-uke cells may be pre sent in
var iab le numbers in MALT lymphoma but,
when solid or sheet -lik e proliferations of
a-ceus
transformed ce lls a re present, the tumour

should be d iagnosed as d iffuse large
B-ce Ulymp homa and the prese nce of ac com panying MALT lymp homa noted. The
ter m "hig h-g rade MALT lymphom a"
shou ld not be used , and the term MAl T
lymp hom a" shou ld not be applied to a
larg e Bccell lymphoma even if it has
arisen in a MALT site or is assoc iated w ith
tymoroeonreuauesons.
The d iffer ential diagnosis of MALT lymphoma incl udes the react ive inflammatory
processes that typically precede the 1ymphoma including Hencobacter pylori
gastritis, Iymphoeplthelial
Hashimoto th yroiditis and other small
B-c elf lymphomas (follicular lymphoma,
mantle cel l lymphoma, small lymphocytic
lymphoma). Distinction from reactive
proc esses is based mainly on the presence of destructive infiltrates of extrafollicular Bceus. typically with the
morphology of marginal zone cells
12444 1. In borderline cases, rrmcropbenotypi ng 0..- molecular genetic analysis to
ass ess s-een cronantv is nec essa ry to
he lp establis h or exclude a d iag nosis of
MALT lym ph oma, although molecular
studies may also de monstra te clonal Bcells in some non-neoplastic MALT proliferat ions or per sistent cl onal population s
in gastric MA LT lymphomas even afte r
histo log ic co m plete remi ssio ns 11502,
1792,2457 1. Distinction from other sman
Bccell lymphomas is based on a co mbination of th e c harac terist ic morpholog ic
and immuno phenotypic features .
sraraoenes.
Table 10.10
AnatomiC Site distribution and freq~ (%) ofd1romosoma1lrans.localioos and trisomies 3 and 18 in MALT ~s'
t(11 ;1B)
(q21;q21)
t{14;18)
(q32;q21)
t{3;14)
(pl t ;q31)
t{l;14l
(p22;q32J
'3
."
' -16
t-s
11
-.,"'"
12-56
0-13
75
25
0-10
0-25
0-20
38
13
0-5
0-16
0-,
55
19
31-53
6-10
2-7
20
o-a
0-"
0-10
20
""""
0-17
0-50
17
Silo
-.........
St.,...
....
"""'
"'"
-Data ~ ~ kI StreItleI Sf II. (2109A) rid Remstein at II {18J6}.
216
Immu noph enoty pe

Tumour c ells typi cally exp ress 19M, and
less ofte n IgA or Ig G. and show light
c ha in restric tion. In IPSID, both the
pla sma ce lls and marginal zone celts express alph a heavy c hain without any light
c hain 11 01 21. The tumour c ells of MAlT
lym phoma are C D20+, CD79a+, CD5-,
CO lD-, CD23-, CD43+f-, C D11c+I-(weak).
Infreq uent cases are CD5 +. The lymphom a c ells exp ress the marginal zone
ce ll-associated antigens C02 1 and CD35,
Staining to..- C02 1 and COOS also typically
reveals expande d mesh works of follicular
d endritic cells corres pon ding to COil>
nized follicles. There is no spectc marlier
for MALT lymphoma at present The
demonstrat ion of imm unoglobulin ligtt
chain restriction is important in the differential diagnosis with benign lymphoid
infiltrates. In the differential diag nosis with

othersmall B-ceillymphomas. absence of
the characteristic markers tor those neoplasmsis important: lack of C0 5 is useful
in distinction from most mantle ce ll and
small lymphocytic lymphomas , cychn 0 1
in distinction from mantle cell lymphomas
andCOl Oin the differential diagnosis with
many lollicular lymphomas.
Genetics
Immunoglobulin heavy and light chain
genesare rearranged and srow somatic
hypermutalion of variable regions, consistent with derivation from a post-germinal
centre. memory B-ceIl1618. 1789 1.
Cytogenetic abnormalfties and ona>genes

Chromosomal translocations assoc iated
with MALT lymphomas include t(11;18)
1021;021). ~ 1. 1 4Xp22;Q32I. X'4;18XQ32;q211
and t(3;14)(p 14. 1;q32). resulting in the
production of a ch imeric protein (API2MAl Tl) Q( in transcriptional deregulation
(Bel lO.MAlTl , FOXP1)respectively 1574.
1285. 1667.2110.2111 .2416,24461 . Trisomy 3, 18 or less commonly of other
chromosomes is a non-specific but also
not infrequent finding in MALT lymphomas. The frequencies at which the
nanslocations or trisomies occur vary
markedly with the primary site of disease.
The t(11 ;18)(q21;q21) is mainly detected
in pulmonary and gastric tumours, the
t(14;18)(q32:q2 1) in ocu lar ad nexae/orbit
and salivary glan d lesions and the
t(3:14)(p 14.1 ;q32) in MALT lymph omas
arising in the thyroid, ocular aonexae/orbrt
and skin. Similarly, geogr aph ic variability
inincidence and anatomic site specific ity
of the translocations has been noted, suggesting different environmental influences

such as infectious Q( other etiologic fac tors 11636. 2 1101.
Post germinal centre, marginal zone B-ceIL
Prognosis and predictive teeters
MALT lymphomas have an indolent natural cou rse and are slow to disseminate.
Recur rences. that can occur after many
years, may involve other extrancda t sites
and occur more often in patients with extragastric MALT lymphomas than in patients with primary gastric disease 11 8021 .
The tumours are sensitive to radia tion
therapy, and local treatment may be followed by prolonged disease-free intervals.
Involvement of multiple extranodal sites

and even 8M involvement do not appear
to coo ter a worse prognos is 121941. Protrac ted remissions may be induced in
H. pyIoi-associated gastricMAlT ~
by antibiotic therapy lor H. pylori 11587.
24441. Cases with the t(11;18)(q2 1;q2 1)
appear to be resistant to H. pylori eraorcnon therapy 113211. In IPSIO. remissions
have followed therapy with broad-spec trum antibiotics 11 82, 12641 . Antibiotics
have also been used to succ essiunv treat
selected other MALT lymphomas. Transformation to diffuse large B-ce ll lymphoma may occ ur.
ExtranodaJ marginal zone lymphoma 01 mocose-essocateo Iymphofd tissue
217
Nodal marginal zone lymphoma
E. Campo
SA Pileri
E.S. J affe
HK MOllerHermelink
B.N, Nalhwani
Definition
Nodal marginal zone lymphoma (NMZl)
is a primary nodal B-ceH neoplasm that
morphologically resembles lymph nodes
involved by MZL of exnarooet or splenic
types, but without evidence of extranodal
or splenic disease.
ICD-{) code
9699/3
Synonyms
Monocytoid Been lymphoma; peratonicutar s-een lymphoma: Nodal marginal
zone B-cefllymphoma.
Epidemology
Nodal MlL comprises only 1.5-1 .8% of
aillyrnphoid neoplasms 1195. 15781. Most
cases occur in adults with a median age
around 60 years and a similar proportion
in males and females 1731 _ This lymphoma may occur in children {21401.
Hepa titis C virus has been de tected in
20-24% of the patients in some studies

173, 25061, but has not been observed in
other series {2264 1.
Peripheral lymph nodes. occasionally
bone marrow and peripheral blood 1195.
1578/.
Clinical features
Most patients present with asymptomatIC.
localized or generalized peripherallymphadenopathy 173. 1951. Presence at a
primary extrarocar marginal zone 1ymphoma should be ruled out since approximately one third of the cases pesentrqes
nodal MZL represent nodal disseminalial
F'IQ. 10.59 SpIIlIlIc type nodal marg.naI zone IympI'loma AAlIow magnrfJcation. note the loIIic:aar!1OWlh pallemwdh pa/IlI C8II1haI1ocaIy SInOIRl porbonsofIeacllYe genrnI
ceees B The ll.m:u lli ~ d a proIiIerabon aIsmall eels exp;vvjng between a reactiYe g&mWIiJI oentrean:!an IItIenua1ed mantle cell wf, C IgD ~ sI'OlIIS .. _
positivity aI tile b'nol.r t8Is IhaIIlmUld !he negaIrW lIllfII'*laI oenIre..tlefeas the residIJaI manIIe CJ!JIs are ~ posiIi'ooe. DCOlO staI'ing. The ILfro.J" eelsare oegaIMt _ _
toe resOaI gemWIaI centre iI jIOSltrYe EBCl2 stainrlg, The hm:ltI' eels are posANe wtlefeastie reacM gerrrWlaI centre is I"lllgaM
218
Mat ure B-cell neoplasms
Mg. 10.60 NOOaI margnallOI18 ~. paediatnc typeCXIIllITIOIiy ex1Iibtts progressive ~sJormabon d gemW'IaI
0ilI'hS (A). The atypical eels are b..nd pnmarjyin !he irrtelloIiaAr areas andmay disrupt !he IoIices. B ~ SlaMWlg
hlfi\tIIIlhe lhr\4lI8d and elP'lnded manlle cvff: the lunJ::U eels are \gO negabve.
01 a MALT lymphoma. particularly in patents with Hashimoto thyroiditis or S;Ogren syndrome 1328.16011.
The tumour cells surround reac tive follicles and expand into the mtertomcutar
areas. Follicular colonization may be
present. In cases with a diffuse pattern.
follicl e remnants may be detected with
stains forfollicular denonnc cells and germinal centre markers . The tumour cells
are composed of variable numbers of
marginal zone (centrocvte-uke and monocytoid) Beene . plasma cells and scattered transformed B-c ells 1321, 1578.
1601 , 2264J . Cases with a predominant
rrcoocvtoio Been populatio n are uocommonoPlasma cell differentiation may be
prominent and the different ial diagnosis
with Iymphoplasmac ytic lymphoma or
even nodal plasmacytoma may be diff icult. Some of these cases may have
prominent eosinophilia. The presenc e of
remnants of follicul ar dendritic mesh works suggestive of co lonized follicles
would favour the diagnosis of noda l MZL.
Somecases have more numerous large
transformed cel ls (som etimes >20%).
However. these ce lls are usual ly mixed
with small cells and may be more common in the colonize d germinal centres
11578.22641 Some cases mimic splenic

MZl with the tumour cells composed of
small to medium size lymphocytes with
pale cytoplasm and occasional transformed cells gfO'Ning inside an attenuated
mantle zone and often around a residual
germinal centre 1328). Conccene nodal
MZl and Hl have been reported 124931.
Immunophenotype
Most nodal MZl express pan-Been markers with C043 coexpression in 50% of the
cases. C05, C023, COlO . BCl 6 and cyclin 0 1 are negative and BCl2 is positive
in most cases. IgO is positive in a minority of the c ases . Tumours mimicking
splenic MZl have a similar phenotype but
are usually IgO positive 13281 .
Genet ics
The imm unoglobulin genes are clonauy
rearranged with a predominanc e of mutated VH3and VH4fam ilies 1321, 2263),
Trisomies 3, 18 and 7 have been observed. The translooations associa ted
with extranodel MZl are not detec ted
1575, 22641.
Post-germinal centre marginal zo-e s -een.

60 - 80% of the pa tients survive longer
than 5 years 1731 The prog nosis ot mese
patients may be predicted using the follicular lymphoma international prognostic
index (FlIPI) 173 J. The number of isolated
large cells does not seem to be of prognostic significance 122641. Transformation
to a large B-ceillymphoma may occu r. Diagnosis of transformation requires the
identification of sheets of large cells .
Paediatric nodal marginal zona

lymphomas
Nodal MZl in the paediatric age have
distinctive clinical and morphological
characteristics 121401. They present predominantly in mates (ratio 20:1) with
asymptomatic and localized (90% stage
I) disease , mainly in the head and neck
lymph nodes . Histologically the tumour is
similar to that seen in adults except that
there are often progressively transformed
germinal centres in which the outer border
of the follicles is disrupted and infiltrated
by neoplastic cells. The immunophenotype is similar to adult NMZl 121401 . The
diffe rential diagnosis with atypical marginal zone hyperplasia with monotypic Ig
expression may be difficult because the
large cells in this con dition also express
C0 43 11 00 1. Althoug h this latter process
has been reported in extra noda l sites,
some ca ution is advised as a similar
process might also occ ur in the lymph
nodes. Particularly for these reasons.
studies for clonal rearrange ments of the
IGH@chain are necessa ry to help distinguis h paed iatric NMZl from reactive conditions (21401. The prognosis of paediatric
nodal MZl is excell ent with a very low
relap se rate and tong survival after conservative treatment.
Nodal marginal zone lymphOma
219
Follicular lymphoma
NL Harris
S.H Swerdlow
E.S. Jaffe
G.Olt
Definition
Follicular lymphoma (Fl ) is a neoplasm
compo sed of follic le ce ntre (ger minal

centre) e-ceas (typica lly both ceotrocy tes
and c entroblasts/large trans formed c ells).

wh ich usuall y has at least a partially
follicu lar pattern. If diffuse areas of any
size comprised predominanlly or entirely of
blastic cells are present in any case of follicul ar lymp hom a. a di agnosis 01 diffuse
large B-cell lymphoma is also made. Lym-
phomas composed of centrocytes and

cemootasrs WIth an entirely diffuse pattern
in the sampled tissue may be included in
this category. Primarycutaneous lympho-
mas 01 germinal centre cells are separately classified .
ICD-O codes
Foll icul ar lymp hom a
Grade 1
Grade 2
Grade 3A
Grade 38
BN Nathwani
D. de Jong
T. Yoshino
D. Spagnolo
969013
969513
9691/3
9698/3
9698/3
Epi demiology
FL accounts for about 20% of all lymphomas with the highest incidence in the
USA and Western Europe. In Eastern Europe , Asia and in developing countries the
incidence is much lower 1371. It affects predominantly adults, with a median age in the
6th decade and a maJe:female ratio of 1.1.7
{511. FL rarety occurs in individuals under
the age of 20 years ; paeeenc patients are
predominantly ma les 1707, 133 7, 1754,
2 132 1.
FIg.10.61 Ft6:Uar Iymphcma. The ~lcAdes

aredosely padled.locaIy snow M aIm:lst back~
pattern. and lad manIIe zone!
T.bl, 10.11 Follicular tympnoma grading.

Grlding
Definition
Grade 1-2 (low gl1lde) 0-15 centroblasts per hpl
o-s cenlroblasts perhpf
6-15 cenwotllasls per hpf
2
>15teIlIrobIIsls per ~
""'" 3
]A
JB
Reportingof pft1em
Follicular
Follicular and diffuse
Focally f~ l ieu lar
."'"
.......
~
Sold _ _ da~~"'''_b_
Proportion folliCul.
>75%
25-75%
<25%
"'..
Diffuse.fNI contIiining>15c:entrobla5t5 per

hpf are ~ n diffuse a.rgt lkell tym.
~ with foIIitu~ 1ymphomI1~ 1-2,
Gritde 3.A Ot Grade 381'.
rmr
"". hi!J1-power field 01 0.159

(-4Olc objective,
18 mm field 01_ oct&; counll 0 hpl and dMde
by 10),
If using 820 mm fiekl of view ocular, count 811pf
and divide by 10 0((::0"'11\ 10 hpfand divideby 12
10 get the numba\' of centrobiastslO.159 mml hpf
If using a 22mm field of viewowlar, counl7 hP
and lM:Ie by 10 or CW'Il 1D hpfand drVIde by 15
mQ8I: Itle nuntIer 01 ~.1591ff1'i 11Jf.
GiYe~"oleachi'l~
- If !he biopsy ~ is smaI. a rdlI shoIAd be

iIlkled thallhe absence d bides ma.,. refted
S<IITIPliI'Ig enor.
220
Matur e 8-cell neop lasms
Sites of inv olvement

FL pred om inantly involves lymp h nod es,
bu t also spleen, bone mar row (BM ), peripheral blood (PB) and Waldeyer ring. InIJOIvement ol non-haematopoietic extranodal
sites , such as the gastrointest inal tract
(GI) Of soft tissue may occur in a setting of
widespread nodal disease. Fl ma y occasionally be primary in extranodal sites, inc luding ski n , GI tract , pa rtic ula rly the
duodenum, ocular adnexa , b reas t an d
testis.
Clinical features
Most patients have widespread d isease
at diagnosis , incl Ud ing peripheral and
central (abdominal and thoracic) lymphadenopathy and splenomegaly The BM is
involved in 40-70%. On ly one third 01
patients are in Stage I or II at the lime 01
the di ag nosis 1511. Despite widesprea d
d isease , patients are usually othe rwi se
asymptomatic .
Morphology
Pattern
Most cases of FL have a p red om inant ly
fol licul ar pattern w ith closely-packed fol licles that efface the oocat architecture .
Neoplastic follicles are often poorty defined
and usu ally have attenuated or absent
mantle zon es . In contrast to reac tive
germinal centres where cen troblasts BOO

cenrrocytes occupy d ifferent zone s (pcranzanon). in FL the two types of cells are
rand omly distributed . Similarly, tingible
body ma cr ophages, c harac teristic of reac tive germin al ce ntres, are usually absent in FL. In some cases, follicles may be
large, irreg ular, and serp iginous, resembling diffuse areas . Staining for follicular
dendritic cel ls (FOC) (CD21K::D23) may be
necessary to d istinguish between large
foll ic les and d iffu se areas. Interlollieular
spread by neoplastic cells is cormm and
this does not constitute a diffuse pattern.
r.. IU3 FoIaAr IymJ:k.ma gradIlg. A Grade12 of], There is a monotonous pop,Aalion of smalleels 1IIidI irrelJJIar ru:Iei (oenb'OCyle$) WIth ody rare largeeels (cenlroblasts)
"'1lJ" II'O'W ~ oudeoI allda moderilIe amoum d tylopIasrn (amrov). Most of the largeru:Iei presentin this field are !hosed kAcular de!mlic cells (FOC) (amM16ad):
. . . DIlls IllrIe more dek:ate ru::lear merrtJranes and YIOIet-lXlloured 1'lJdri. alldare oIIen binucleate. B Grade 1-2d 3. The majority d the eels are centrocyles. but ~
fU1lfJIQII ter*obIasts all! present (arrows): several FOC WIth double nudeiall! present(arrowt1eatj). C Grade 31.. There all! more than 15 C8fIlrobIasls per high power field. bul
cnot)1eS in SIiI present. 0 GracIe 36. The majority01 tile cellsall! cerrtroblasls.
The interfollicular neoplastic cells are often

ceruccvtesthat are smaller than those in
the germinal centres, with a less irreg ular
nuclear contour, and they may show immunophenotypic differences from the
cells in thegerminal centres 15991.
Dffuse areas may be presen t, often with
sclerosis. par ticularly in mese nteric and

retroper itoneal infiltrates, A diffuse area is
defined as an area of the tissue completely
lacking follicles defined by CD2 1+/C023+
FDC. Distinction between an extensive interfollicular component and a diff use
c omponent may sometimes be arbitrary,
Diffuse areas comprised predominantly of
ce ntrocytes are not thought to be clinica lly sign ificant. Howeve r. the presence
of diffuse areas com prised entirely or predomi nantly of large blastic/transformed
cells (that would fulfill criteria for Grade 3
follicu lar lymphoma) in a FL of any grade

.....
'.~.~~'I:':'
Fig.IUI FoIcuIar lymphoma. Grade 1-2. with marginal zone dlfferentialion. A AI theperiphery d !he 1oI1ic:llls. ItIere is a pale rim lXlrT8SjXlIlding kl marginal zone tifferenlialion.
8 The centres oIlhe IoRides cootain tile typical mixture 01 cenlrocytes and cerllroblasl$, C The cells a1!he periphery 01 the IoIlides alll medill'l'l-SiZed cells wi1h slightly iflllQlAar
Q nI abI.nlao1ligh~y eosinophilic topale stainillQ C)1OllIasm, consistentwith marginal zone or monocytoKl fkells ,
Follicular lymphoma
221
is equivalent to diffuse larg e B-c ell lymphoma, and a separate dtagnosis of diffuse
large Be en lymphoma should be made
18971 (See grading of follicular lymphoma
qelowl Despite the unclear clinical significa nce of diffuse areas comprised predomina ntly of centrocvtes with ooly rare
centroblasts (Grade 1-2), It is recommended
that the relative pro por tions of follicu lar
and diffuse areas be noted in the pathology repo rt as follicu lar (> 75% follic ular),
follicular and diffuse (25 - 75% follicular ),
or foc ally follicular/pred ominantly d iffuse
25% follicular) 18971.
Diffuse follicular lymphoma
Rare lymphomas with the morphology al'ld
immunophenotype of FL have an entirely
dIffuse growth pattern. This p henomenon
is usually seen on small biopsy specimens.
and likely represents a di ffuse area in a Fl
that is not adequately sampled. In these
cases, the p athologist sho uld sug gest
that more tissue be obtained if possible.
A diagnos is of di ffuse FL may be mad e
when the lymphoma is c omposed of cells
resembling cen trocytes. with a m inor compo nent of centrobl asts and an entirely diffuse pattern ; both the small and large cells
must hav e the immunophenotype of germinal centre cells or presence of a classical
t(14:18) translocation should be demonstrated. Thus. a diagnosis of diffuse FL cannot be made without these ancillary studies.
Partial nodal involve men t and "in situ
follicular lymphoma
Non-neoplastic follicles may be pre sent in
lymph nodes involved by otherwise typic al
Fl, and their presenc e has been repor ted
to predict for lower stage at diag nosis 181.
Non-neop lastic follicles may also be partially colo nized by FL ce lls, both in lymph
nodes with area s of obv ious Fl, in lymph
nodes adjacent 10 those involved by Fl or
occasionanv in isolate d lymp h nodes in
patients with or without H, elsewhere. The
latter pattern has been called in situ"
follicular lymphoma (see be low) 14621.
Cytology
Fl is typically composed of the two types
of Bceus roemanv found in g erminal
centres . Small to medium-sized cells with
angulated. elongated , twisted Of cleaved
nuclei, inconspicuous nucleoli and scant
pa le c ytopl asm are c alled centrocvtes.
Large ce lls with usually round or oval, but
occasionally ind ented or mu ltilob ated
nuclei , vesicular chromatin , 1 to 3 peripheral nucleol i and a narrow rim of cytoplasm are c alled ce ntrobtasts. Typi cally,
they are at least 3 times the size 01 lymp hoc ytes, b ut they may be sm aller in
some c ases . Oentrocvtes p red ominate in
most cases; centroorasts are always pres ent. but are usually in the minority, so that
most cases have a monomorphic eppeeraoce . in contrast to reactive follicles .
The number of centroblasts varies from
c ase to case and is the basis 01grading .
In some c ases, neopl astic centrobleste
may have irregular or lobulated nuc lei resembling large centrocytes, and infrequent
c ases sho w nucl ei with very di sp ersed
c hromatin and a lymphob last -like appearance,
In about 10% of FL there may be disc rete
foci of marginal zone or monocytoid-appearing Be ene. typically at the pe riphery
of the neoplastic follicles 1816, 1577,

22521. These cells are part of the neeplastic clone 118531. Ptasmacvnc differentiation may be ma rked and signet ring
cells may also occur.
Grading of follicula r lymp homa
Fl has been graded in many classifications
(Rap papo rt 118201. Working formulation
147}. R EA L. (898}. WHO 3rd edition
110391) ac cording to the proportion of
larg e cells (ce ntrob lasts), and a number
of studies suggest that this histological
grading predict s clinic al ou tcome , with
ca ses with mo re larg e cells behaving
more aggressively an d having a higher
likelihood of progression to a diffuse large
celilymphonla than those with fewer large
cells 138, 47. 153. 748. 806 , 807 . 1070.
1102, 1335 , 1400 , 18201. However, the
optimal method and clinical significance
of grad ing have been deb ated , and no
met hod has shown high reproducibility
151, 1468, 15791 . The 3rd edi tion of this
series used the method of counting large
transformed cells (centroblasts) described
by Mann and Berard 11039. 1378, 15791,
to define 3 grad es. It has been suggested
that the number of grades could be reduced, since there are no important clinical
Fig. 10.65 Follicular lymphoma assooated WJltJ DLBCL A ~ JoIdes arepresent on the rY1Itc. ...... . dlse
on the Iefl The ddluse Nea is a:JIIllI1sed precbninamlyof large eels linse'll. so separale diagrUrs ~ Cx.BCt.
is 1T1<Ide. B Slaining b' C021 sIlows FOemesI1worts in the loIdes. bill not in !he arNS of0lBCl.
Nea
Bone marrow and blood

In BM, Fl ch aracteristic ally localizes to Ihe
par anabecurar region and may sp read
into the interstitial areas, A follicular growth
pattern with a meshwork of follic ular dendritic cells is rare but can be seen, The
morpholog y of the tumour cells most commonly resembl es that of the neoplastic intertomcutar cells in lym ph nod es. The
same cells may be seen in the PB.
222
Mat ure
a-cen neoplasms
Fig. 10.66 Bone rnarroIlt il'oUvement by loliaJlar~ . AAl kIwITIiIJ'Ilbbon .lhere lRpa'atr'abeo.*JlynllhcIl
BThe ~ are small cenln::JtyIe$
~.
for follic ular dendritic ce lls (FOC) may be

esse ntial.
The vast major ity of fo llic ular lymphomas
are grade 1-2 (80-90% in most unselected
series). Paed iatric ca ses are more likely
to be g rade 3 1707, 133 7, 1754 , 21321.
On ly a few stud ies have compa red the
fre quency of gra de 3A vs 3B cases, In
published studies 1883, 1 t 19, 16681, 3r'f'O'lQ
pt.6ety follicular casesof grade 3 FL.. the poportion of grade 3B cases is 20-25%. Areas
01 diffuse large B-cetllymphoma are present in 60-80% of grade 3B cases and less
frequently in grade 3A 1883. 1119 1.
rig. IU7 IrmulophenoIype of loIlicIAr~. AThe loIicIes and i1terlo1ioAar rtlgIORS contain CD20+ B-celIs.
BThe /oIIides are ISIilormIy BCl2+. C BCL6 is expressed by lhe follicles, but to a lesser degree by i1lerlollicular
neopIasbcceHs 0 COlOexpresslOfl is SII'l'Iilar 10 Ihat 01 BCL6.
oneercee between grades 1 and 2. Dishnchon of grade 3 cases from low-grade

(grades 1 and 2) cases is cl inically relevant Although it is still con troversial, there
is evidence that there may be im portant
clinical and biolog ica l di fferenc es between grade 3A and grade 3B c ases
(248,249, 1119, 16681 . The re is insuff icient evidence at this time to recommend
an alternative method or to recomm en d
eliminating grad ing a ltog ethe r.
FolliCularlymphoma is g raded by co unting
orestimating the absol ute numbe r of c enobasts (large or small) in ten neop lastic
foll icles, expressed pe r 40x high-power
microscopic field (hpf) 11039, 13 78 ,
15791. At least 10 high power fields within
dilterent follicles are eva luated; these
should be rep resen tat ive follicles, not
selected for those with the mos t numerous
large cells. Grade 1 and g rade 2 cases
have a marked predomin anc e of cen trocy1es and only few cen uo brasts (g rade 1
'" ()"5 centroblastS/hpf; g rade 2 '" 6 -15
cenuoblastS/hpf) . Since grad es 1 and 2
represent a continuum and are both clinically indolent, distinction between them
e not eocouraged, and a g rade of 1-2 of
3- can be reported. Grade 3 cases have
> 15 centrobtas tsmpt . Gra de 3 is further

subdivi d ed accordi ng to the propor tion of
centrocytes. In gr ade 3A, centroc vtes are

still present, wh ile g rade 3B follicl es are
co m po sed entirely of large blastic ce lls
(centroblasts or immunobl asts),
If dist inct areas of g rad e 3 FL are present
in a b iopsy of an ot herw ise g rad e 1-2 Fl,
a separate d iagn osis of g rade 3 FL
should also be made, and the approx imate am oun t of each g rade rep orted
Since bot h pa ttern and c ytology vary
among foll ic les, lymp h nod es mu st be
adeq uately samp led .
Any area of d iffuse large B-ceillymphoma
(Ol BCl) in a FL shou ld be repo rted as
the primary d iag nosis , with an estimate of
the proportion of OlBCl and Fl, p resent.
Thus , in grade 3 follicu lar lymphoma, the
presence of a diffuse c omponent warrants
a separate d iag nosis of d iffuse large Bcell lym phoma. In other words , it is never
correct to make a di agnosis of "follic ular
lymphoma, g rad e 3 (A or B) with d iffuse
areas": the di agnosis is: "1. Diffuse large
B-c eil lymphoma C%) 2. Fo llic ular lymphcma, g rade 3 (A 01 B) L %). To d istinguish
large , co nfl uent fo llicl es or inte rfollicular
invotvement from areas of DLBCL staining
Immunopheootype
The tumour cells are usually Slg+ (lgM+/IgD, IgG Of rarely IgA). express B-cell
associated antigens (C019, C020, C022,
C079a) and are BCL2+ . BCL6+, CDlO+ ,
CDS- and CD43-. Some cases, especially
grade 3B , may lack CO lO, but retain
BCL6 expression 1248, 346, 1111. 1239,
1668, 17601. COlO ex pression is often
stronger in the follicles than in interfollicutar neoplastic cells . and may be absent in
the mtertoucotar component, as well as in
areas of marginal zone d ifferentiation,
PB and BM 1599. 8991. BCl6 is frequently
downregulated in the jntertonlcutar areas .
IRF4/M UM 1 is typically abse nt in FL. Rare
c ases of predominantly Grade 3B, C01~
FL have been described that express
IRF4/M UM 1 and lac ked BCL2 rearrange
men t; 59% were associated with OLBCL
111111, Meshwork s of FOC are present in
fo llic ular areas 12508 ); thes e may be
spa rser than in normal foll icl es, and may
variab ly express C 0 21 and C023. so that
ant ibo dies to both ant igens may be
needed to de tect FOC meshwork s.
BCL2 p rotein is expressed by a variable
pro por tion of the neo plastic ce lls in
85-90% of cas es of g rade 1 and g rade 2
FL , but only 50% of gra de 3 FL using
standard antibodies 112381. In a proportion
of the cases, abse nce of BCL2 p rotein is
d ue to mutations in the BCL2 ge ne that
eliminate the epi tope s rec og nized by the
most commonly used antibody, and BCL2
ca n be de tect ed using antibodies to other
BCL2 epitopes 119731. BCL2 protein can
be useful in diSlinguishi ng neoplastic from
reac tive follicles, although ab sence of
BCL2 protein does not exclu de the diagnosis. It is essential for the d iagnosis of
"in sltil' Fl; in these cases and in partially
involv ed follicles, the expression of BCl2
is etten much stronger than in more typical neoplastic follic les. BCL2 protein is
FollICular lymphOma
223
. ..
w
w
w
w
>1'10
~llD'
01
O.
A ll
,)
>0)'"
O.
:10.......
1IO
...
..
..
B o.
--...
--
...
---,-- ,-----,-- .,----,--,.---,---,
Fig.10.61 Survival Q.fVM lor pabents .... loIic:ljar ~. gr.Ided according to !he WHO cnteria {237.cj. A 0veraISIIViYaI d pabents lreatedWJlh regimens nollX:l'llaiWlg am.
(pdiative Ihefapy):!here is no cllfterenc:e in ~ lor patients with!J'ilOe 1 'IS grade 2 toIicuIar lymphoma (o- SO and 51150 centl'ObIastsl10 hpf).
those Mlh!Jade
3 (>150cenIrtJblas3I1 0 ~ hada sigMicamIy worse oYefaI survival. B 0ieraI $UI"o'FvaI of patientstrealed WIlh adriamycin-alnI regmeos (ar.tIMl intoot): Ihe 3 StniYaI a.nes
areidentical. irdcaIlrlg lhallhent is 110 Slnival benelk lor pabents WI1Il grade 1 and !1acIe 2 FLIrealed .... ~ 1M Ihat!he adYefse PfO!1lOSis of pde 3 Fl is elirTwWd
by 8WessiYe therapy. C Faln-lree Sln'ivaI of pabenls trealed with adriaJTl)Ul: lhere isa suggestion d. plaleau in Ihe cuvelor pde 3 Fl (>150 ~10~. SUlpSlng Ih8 ~ 01 an lor some d It'lese pabeflls; in lXlIlIrasl, palierlls WIth !7ade 1 rod grade 2 Fl conlInue toexperience re6apse$.
""'*
8ITl)'QIl
not useful in d istingu ishing fol licular from

other types of k:lw-grade B-cell lymphoma,
mos t of which also express BCL2 protein.
The interpretation of BCL2 immunostainiog in germinal centre c elts req uires caution as r-ceus. primary follicles and mantle
zones normally expres s this protein,
Occasional cases of grade 3 follicular
lymphoma are C D43 +.
In ad dition 10 FOC, neop lastic follicles
contain numerous other non-neoplastic
cells normally found in germinal centres.
incl ud ing follicular t-eens (CD3+ , CD4+ .
CD57+ . PD 1+ , CXC L13+ ) and varying
numbers of t asnocvtes.
The pro life ration ind ex in FL generally
co rrelates with histologic grade; most
g rade 1-2 c ases have a proliferation
frac tion <20%. while most g rade 3 cases
have a pro liferation fraction >20%, altho ug h there is co nsi de rab le variation
among stud ies, prob ably du e to tec hnical
di fferenc es in immun ostaining 11 183,
1400 , 1668, 2358 BI. A subg roup of morp holog ica lly low -gr ad e FL with a hig h
T~ bIe
10.12 Genetic aboofmalities in fdliaJlar 1ympOoma.
Cytoge netic abnormalities

~1 4:18)(Q32;q21)
80%
.,
20%
. 16
20%
15%
15%
15%
3Q27-26
6Q23-26'
I7p'
~ abnonnalitln
BCL2 reafT8rged
IlO%
BCl6~
15%
40%
BCL6 S' muIabons
"Associated with a 'IlIOI'Se prognosis{2239}.
224
Mature B-ceU neoplasms
proliferative index ha s been described

11183. 23588 1. which behaved more
aggressively than those with a low proliferative index. and similarly to grade 3 Fl
123588 1. Thus , Ki67 staining should be
considered as an adjunct to histologiC
grading and its use is c linic ally jrsnned.
although not formally requ ired at this time.
Genetics

Immunog lo b ulin heavy and light c hains
are rea rrang ed ; variable reg ion genes
show extensive and ongoing somatic
hypermutation {448, 16701. As a result of
these mutations in the CD R-regio ns, PCR
prime r annealing may be hampered and
de pend ing on the primers used. immunoglobulin-PCR may not yield monoclonal
pro d ucts in a pr opo rt ion of FL cases
(10 - 40%) . Mu ltip lex PCR reactions using
B IOMED-2 expa nded pr imer sets d etect
cl ose r to 90 % of IGH(V-D-J) g ene rearrang ements, and clonantv det ection approximates 100% when p rimers detectin g
IGH(D-J) and light c hain g ene rearrang ements are inclu ded [652 1.

FL is genetically characterized by the
translocation t( 14:18)(q32 :q2 1) and BCL2
gene rearrangements. Alternative BCL2
translocations to imm unogl o bulin ligh t
chain ge nes have been re po rted . The
t(1 4; 18) is pr esent in up to 90% of the
gr ad e 1-2 FL 19 79, 18851but the proportion depends on the technique used 118.
93 . 1508 . 22801_ FISH see ms 10 be tre
most sensitive and specific method
122801 . BCL2 rearrangements are much
less freq uent in grade 3B Fl 116681 Geographic variation in the detection of
BCL2 tran slocatioos in FL between

Western and Asian populations has been
reported 121 51. The BCL2/IGHO rearrangemen t is found in the P8 of 25-75%
01 hea lthy donors . and also in reac tive
rooes. particutarty if using sensitive nested
or RT-PeR assays 11876. 1967, 21211. A
rece nt study suggests tha t rather than
be ing naive B-cells, these BCL2-rearranged ce lls are memory Beene 118771.
Abnorma lities of 3q27 and /or BCL6 rearrangement are found in 5-15% of FL.
most co mmon ly in gr ade 38 cases 11119,
16681. FL grade 3B associated with DLBCl
have been reported 10have a frequency of
BCL6 rearrangemen ts similar to that seen
in DlBCL 1248, 249 , 1119, 16681.
In addi tion to the t(14 :18) , other genetic
a ltera tions are found in 90% of FL and
most co mmon ly inc lude loss of to. 6q,
tcq an d 17p and ga ins of chromosomes
1, 6p , 7, 8, 12q , X and 18q/dup [954, 1621,
22 39 ), The numbe r of ad dit iona l alterations inc reases with histo logi cal grade
and transformation 11930}. Rare cases of
FL ca rry the t(8:14) or variants tog ether
with the t(14;18) [ 102, 23431.
Gene expression prof ile stud ies have
show n the im po rtanc e of the mic roenvironment in the pat hogenesis. evolution
and prog nosis of FL 1510. 8041 .
Transformation to DLBCL may totlOlN oneeragenetic pathways including inactivaticn
of TP53. p 1~, and activation of MYC
1513,637, 1338,1756. 19301.
Postulated oormaJ counterpart
Germinal c entre B-cei L
Prognos is and p redictive factors
Prognosis is c losely related to the extera 01
tbe d isease at diagnosis. The International
Prognostic Index (IPI) and especially the

International Prognostic Index for FL (FlIPI)
are strong predictors of outcome 149. 5 1,
20481
Histologicalgrade correlates with prognosis in follicular lymphoma, with grade 1-2
cases being indolen t and not usually CU"able, except for the infrequent localized
cases /40, 806. 1070 , 1335 1. The majority
of published studies show a signi fic antly
more aggressive clinical course for
ular lymphomas cl assified as large ce ll or
Grade3/40. 153. 1400. 14431; but the use
of regimens containing ad riamyc in and/or
rrtuximab may obviate these d ifferenc es
and requires further stud y 138, 153 ,752 ,
807,863 , 1102, 1860 , 2374, 23841.
Many stud ies have ind ic ated /47 , 1273 ,
1820, 23601 that the p resence of even
very large diffuse areas in fo llicul ar lymphoma classi fied as grade 1-2 ("small
cleaved" or "mixed sma ll and larg e ce ll")
doesnot significantly alter the p rognosis .
In most repoted studi es. cases 01g rade
3 Fl with diffuse areas >25% (no w rec ognized as areas of DLBCL) have a worse
prognosis than purely follicular cases 138,
153,752.807,883. 1860.2346.23841.
The presence 01 more !han 6 ctromosomal
breaks and a compl ex ka ryoty pe ha s
been shown to be assoc iated with a poor
outcome: in addition, de l 6q~26 , de l 17p
and mutations in TP53 as we ll as - 1p.
+ 12. +18p. - xp cooter a wor se prognosis
and a shorter lime to tran sformation
/1284. 22391. Rare c ases w ith both
14;18) and t(8;14) have a poor prognosis
[102.23431. Recent gene expression data
have suggested a role of the microenvironment, includi ng T-cells and accesso ry
cells including FOG and macrophages in
determining the clin ical behaviour of FL
1510. 804, 893J Currently, no spec ific
markers are available other than histo logicgrade and proliferation traction that
can be used in cli nica l prac tic e to predi ct
tome-
outcome or direct therapy.

In 25 -35% of pa tients w ith FL, tra nsformat io n or ' p rog ression' to a hig h grade
lymphoma oc c urs , usually DLBCL. bu t
occasio nally resembling Burkin lymp homa Of with features intermediate between DL BCL an d Burkitt lymphoma
128A. 748. 964A. l803A 1 This occurrence
is usually associated with a rapidly progressive cl inical cou rse and death from
tumour thai is refract ory to treatment {88 B,
748 1. Rare pa tient s develo p acute B-ee ll
lym p hobl astic leukaemia. whi c h in most
cases appears to repr esent blast transformation of the orig inal B c ell tumour
[5 18A. 764A. 1197A ). Transformation typically involves additional genetic abnorma lities , partic ularly MYC tranetccatrons:
the combination of a BCL2 and a M YC
rearrangement is associated with a partic ularly aggressive course {702A. 1266A.
2468 AI Rec ently. the occurrence of
histioc ytic/d endr itic cell sa rcomas has
been described in patients with FL, in which
the sarcomas shared both IGHtI and BCL2
rearrang ements With the FL. This ph enomenon may represent de-differentiation of
a B cell due to loss 01PAX5 activity /675A I.
Variants
Paediatric follicular lymphoma
This va riant often involves cervic al lymph
nodes. other periphera l lymph nodes or
Waldeyer ring ; however. other extrarooat
involveme nt also oc cur s, with FL of the
testis well des cribed 1707 . 1337. 1754,
2132 1. Ch ild ren with FL typ ically have
early-staqe d isease 1707, 1337, 1754 ,
21321 Paed iatric follicular lymp homas
have many features ind istinguis hab le from
those seen in adults, but demonstrate an
inc reased proportion that are loc a lized.
lac k BCl2 protein expressio n and 1(14:18)
and are grade 3 11337.21321. They also
tend to have larg e expansite follic les .

Rare cases of florid tomcutar hyperplasia.
particu larly in you ng ma les . may have
clonal populations of CD1O+ Beene detected by flow cytometry and molecular
analysis. A d iagnosis of lymphoma should
not be made in the absence of morphologic features of malignancy 11 21 11- The
prog nosis of paediatric patients ap pears
to be good, with the majority of reported
cases d isease free at the l ime 01 last
follow -up 1707. 133 7, 17541. Expression
of BCl2 protein in paediatric FL was associated in one report w ith hig her stage
at diagnosis and a worse out com e than
BCL 2 negative cases I 1337f.
Prim ary intestinal follicular lymphoma
The majority of cases of primary follicular
lymphoma in the Gt trac t occur in the
small intestine , and involvement of the
d uodenum is a freque nt feature 11486.
1939. 2005 , 24721. Duodenal follic ular
lymphoma is p red ominantly found in the
second portion of the duodenum, p resen ting as multiple small polyps. often as
an incidental findin g on endoscopy pe rformed for other reasons. The morpholOgy,
immunophenotype and ge net ic feat ures
are similar to those of nodal follicular 1ymphomas . Most pa tients have localized disease (Slage IE or liE). and survival appe ars
to be excellent even without treatment.
Other extranodal fol licu lar lymphomas
Follicu lar lymphoma s c an occur in almost
any extrenodel site (6971 . In many of these
site s. the morphology. immunophenotype
and genetic features appear to be similar
to those 01 nodal FL, although da ta are
spa rse. Despite this, patients usually have
localized ex tra nodal d isease, and systemic relap ses are uncommon . Testicula r
follicu lar lymphomas are reported with inc rease d freq uency in ch ildren but also
are reported in ad ults 11191.
F"'II. lD.69 PalKMtric follicular lymphoma. A Follicles of varying size and shape. many WJlh preserved mantle zones. extending beyond 1tle ~ rooe capsuie.
~ of centroblasts (Grade 3). C The folliCleS are negative Jar Bell.
Follicular lymphoma
225
..
'."'"~'
A large nodules 01 lymphoid eels are present in lhe rru::tl5a The lolIides are I.IiformIy posItIveb BCL.2 (8) a'ldposiIiye lor C010 (e).
Intrafollicular neoplasiann
situ- follicular
lymphoma
Cases occur in whiCh architecturally
normal-appearing lymph nodes and other
~ tissues haveone or more follicles
that demonstrate BCL2-overexpressing
centrocytes and cennootasts. with or
without a monomorphic cytologic ap-
pearance suggestive of follicular 1ymphoma 14621. Some of these patients are

found to have follicular lymphoma elsewhere, either before or simultaneously,
some develop overt Fl later, and others

have remained without evidence of Fl. In
patients with overt Fl elsewhere , this
phenanenon likely represents colonization
at pre-existing follicles by neoplastic follicle
centre cells. In patients without known Fl,
the significance of this phenomenon is
difficult to ascertain. It may represent the
tissue counterpart of circulating clonal Bcells with BCL2 rearrangement -lhal is. a
clone of cells that have the translocation
but not the other genetic abnormalities to
resu lt in overt progressive malignancy, Of

in some cases it may represent the earliest evidence of a true follicular lymphoma
that will progress 10 overt Iymphc:ma .
This phenomenon cannot be recogniZed
withoul BCl2 staining , The pathology report shou ld indicate that the significance
of the finding is unknown, and that c linical evaluation for evidence of overt H
elsewhere is suggested .
'.
226
Mafure
Been neoplasms
Primary cutaneous follicle

centre lymphoma
DefiMion
Prinary cutaneous follicle centre lymphoma
(PCFCL) is a tl.rnour of neoplastic follicle
centre cells, including centrocvtes and
variable numbers of cemrootasts. w ith a
follicular, follicular and d iffuse or d iffuse
gro.vth pattern, thai generally pr esen ts on
the headOf trunk 124071. Lymphoma s with
a diffuse growth pattern and a monotonous
proliferation of centrobasts and immunoblasts are. irrespective of site , cl assified
as primary cutaneousdiffuse large B-cell

Ijmphoma (PCLBCL). leg type 124071
ro.ocode
The provisional COde proposed lor the
fourth edhon oi ICD-Q is 959713.
Synonym
Peucuotnsnocvtoma or me dorsum
Ic rostrs disease) 12061.
_ohlgy
Prinary cutaneous follicle centre lymphoma
is the most common type of pri mary c uta-
neous B-cell lymphoma, acc ounting for

approximately60% 01 all cases, It mainly atJects adultswith a median age of onset of
51 years and a male:fema le ratio of
approximately 1,5:111993, 2502).
Siles of involvement
Primary cutaneous follicle cent re lymphoma
characteristically presen t with solitary or
localized skin lesion s o n th e sc alp , the
forehead or on the trunk. Approximately
5% present with skin lesions on the teg s.
and 15% with muttltocat skin lesions
(1170. 1993. 25021
Clinical features
The clinical presentation consists of firm
erythematous to violaceous plaq ues, nodlAesa nmocrsof variable size. Particu larly
on thetrunk. tumours may be surrounded
by erythematous papules and slightly
infiltrated . sometimes figu rate plaq ues.
which may precede the de velo pment of
1I.m:lurous lesions by mon ths o r yea rs
1200, 1933. 2409/. In the past PCFCL with
such a typical p resenta tion 00 the ba ck
'Nel"e referred to as "reticulohistiOCytoma
R, Willemze
SH . Swerdlo w
N.L. Harris
B. Vergier
of the dorSlfll" or "Crosus tymphcrna" 1200/.

The skin surface is smoot h and ulceration
is rarely ob served . Presentation with multifoca l skin lesions is observed in a small
minority of patients, but is not associated
with a more unfavourab le prognosis 1824.
1993/ II left untreated, the skin lesions
graduaUy incr ease in size over years, but
d issem ination to extrecutereoue sites is
lXiCOIlil 0 I (-10% of patients) 11993, 25021.
Recur rences tend to be proximate to the
initial site of cutaneous presentation
Fig. 10.72 PrYnary eutaneolIs lctide t'efWe~.

Characlerisbc clinical presentabon with bcailed $lli1
lesionson !he scalp.
Mo<phoklgy
Prmary cutaneous follicle centre Iyrnphcrna
show perivascu lar and oenacrexar to d iffuse infiltrate s with almos t cons tant sparing of the epi d ermis. The infiltrates show
a spectrum of growth patt ern s with a morphologic continuum from follic ular to follicul ar and d iffuse to diff use 11 933 , 2407,
24091. The lesions are composed predominan tly of med ium-si ze d and la rge
centrocy tes and variable proportions of
centrobtasts. In sma ll andlor early lesions
a cl ear-cu t fo llic ular gr owt h pattern or
more often remnants of a folli cular growth
pattern may be observed, In contrast to
c utaneous follic ula r hype rplas ias, the follic les in these PCFCL are ill-defi ned , show
a mo notonous p roliferation of BCL6+ follicle ce ntre ce lls enmeshed in a network
of CD21 + o r CD35 + follicula r dendritic
ce lls, lack ting ible body mac rophage s
and gen erally have an attencat ec or absent mantle zone (360, 818) Reactiv e Tc ells may be numerous and a prominent
strom al component is usually present.
Advanced tumours usually show a monoton ous population of large centrocvtes
and multilob ated cells and in rare cases
sp ind le-shaped c ells, with a variable ad m ixtu re of centro btasts 1206 . 36 2, 824,
1933,2409). React ive t-eens are less pronounced and follicular struct ures. if present before, are no longer visible exce pt for
occasional scattered CD2 1+ or CD35+
follicular de ndr itic cells.
Imm unophenoty pe
The neoplastic cel ls express C02Q and
C0 79a, but a re usua lly Ig negative ,
Fig. 10.73 Primary urtaneces follicle centre lymphoma

Characteristic clinical presentation with localized skin
lesions 00 th echest

consistently express BCL6, while CD10 is
often posi tive in cases with a follicular
grow th pat tern and gene rally nega tive in
cases with a di ffuse growth pattern 1522,
819.949,1146,1170,1 485, 19931 Most
cases do not express BCL2 or show faint
BCL2 staining (weaker than ad mixed
t-eens) in a minority of neoplastic Be ene
[360,363. 419, 768. 949, 1170. 19931. However, several studies report BCL2 expression in a signi ficant proportion of PCFCL
with at least a partially follicular growth
pattern 113, 819, 1146, 14851. Notw ithstandin g, strong expression of both BCL2
and CD 10 by the neoplastic B-eells should
always raise suspicioo of a nodal follicular
lymphoma involving the skin secondarily
Starning for IRF4/MUM 1 and Fox-P t is negative in most case s 11170. 1993/. Simi1arty
for CDS and CD43 is negative in the
tumour cells.
Pnmarv cutaneous follicle centre lymphoma
227
Fig. 10.74 Pmlatyeutaneous bide c:enn Iyn..,tonaWIth a cjtfuse growth pattern. A DrIfuse ~ inNIrate. BThe lI.rncU' ceIIlexpress CD2O. CAl tigher magIlIftcabon, aAllar iflfiltrllle containS many fTIIAt*:lbated
eees.
Genetics

Clonalty rearranged irrmunoglobulin genes,
with somati c hype rmutation are p resent,
but may be not detec tabl e by PeR.
dele tions of a small region on c hromosome

9p 21.3 co nta ining the COKN2A and
COKN2B gen e loc i are either absent or
only rarely foun d in PCFCL 15771.
Postulated IlOfmal counterpart

Cytogenetic analyis and oncogenes
In many studies , PCFCL, inc lud ing cases
with a follicu lar g rowt h pattern , do not
show BCt.2 rearrangements 1363, 4 19 ,
768,8 18.819. 2329}. However, other stud-
ies report BCt.2 rearrangements in about

10-40% of PCFCL with a follicular growth
pattern using PCR and/or FISH 113,1 146,
14851. Primary cutaneous tolticle centre
lymphoma show the gene expression profile of germinal centre-like large B-cel1lymphomas, and often show amp lil ica tion 01
the C.f1EL gene 11, 577, 948} . Deletion ol
c hromosome 14q32.33 has been reported
1577}. In contrast to PCLBCL, leg typ e ,
228
Matu re
s-een neop lasms
Mature ge rmin al
lymphocyte.
centre
d er ived

Irrespective at the growth pattern (follictJlar
or di ffuse) , the number of blast cells, the
presence at t{14;18) and/Or BCl2 expressian or the presence 01either loca lized or
multitocal skin d isease, PCFCL hav e an
excellent prognosis with a 5-yearsurvival
over 95% 1818. 824. 1485 . 1933 . 1993,
2502}. Primary c utaneous follicle cen tre
lymp homa p resentin g on the leg are reported to have a more unfavourab le prognosis {1170. 19931. Cuta neo us relapses,
o bse rved in - 30% of pa tients, do not

indi cat e prog ressive dis ease . Systemic
th erap y is only required in pa tients with
very ex tensive c utaneous d isease , extreme ly thick skin tumours or with
ext racutaneous d isease 16 11, 19931 .
Definition
Mantle cell lymphoma (Mel) is a B-eell
neoplasm generally composed of monorropnc small to medium-sized lym pho id

cells with irregular nuclear contours and
a GeNO' translocati on 1139. 329. 1253.
1276,1693.2134.2246/. Neoplastic transfOfmed cells (centroblasts), parairrmunoblastsand proliferation centres are absent.
C linical features
Most pat ients present with stage III or IV
d isea se w ith lym ph adenopat hy. hepatosplenomegaly and 8M involvement 1247.
329, 1605 , 2136 1. Per ip hera l b lood involv eme nt is common and present in almost all pat ients by flow cytometry 16911.
Some pati ents have a marked lymphocytosis mimicking p ro/ymphocytiC leukaemia (74, 247 . 1605 1
9673/3
SH Swerdlow
E. Campo
M. Seto
H .K. Mu ller-Herme link
t.1o<phology
Ep;demiology
Mel comprises approximately 3- 10% of

non-Hodgkin lymphomas 151/. 11 occurs
in middle-aged to older individuals with a
median age of abou t 60 and a va riably
marked male predominance (about 2 :1 Of
greater) 174, 247, 329. 1253 .2134,21361.
Familial aggregation of Me L or Me l with
other s-een neoplasms has been re-
eoneo 122551.
Lymph nodes are the most commonly involved site; the splee n and bone marrow
(BM), with or without per iph era l blood
(PBj involvement. are oth e r impor tant
sfes 01 disease 174. 24 7, 160 5 , 2 134 1.
Other extranodal sites are frequently involved, including the gastrointestina l tract
and Waldeyer ring 1772 , 1916) , Mo st
cases of multiple lymphomatous po lyposis represent mant le ce ll lymphoma
11203,161 1,19OO}.
Cl assical MC l is a monomorphic lymphoid p ro/iferat ion with a vaguely nodular.

diffuse. mantle zone or rarely follic ular
g rowth pattern 1139, 1253 . 1276, 2134.
22 46}. Infrequent cases may show involvement almost exclusively restricted to
the inner mantle zones or 10 narrow mantles pn situ MC l ) 11602 . 184 21 . Most
c ases are com pos ed of small 10 med iumsized lym phoi d c ells with slig htly to
marked ly irregu lar nuc lear co ntours. mosl
c losely resem blin g cenncc vtes. The nuclei have at least somewhat d ispersed
c hromati n but inconspic uo us nuc leol i,
Neop lastic transfor med cells resemb ling
cenncotaets. immunoblasts or paraimmunoblasts and p roliferation centres are absent.
Hvaunrzeo sma ll vessels are co mmonly
seen. Many cas es have sc atte red sing le
epit helioid bistiocytes which in occasional
cases ca n c reate a "starry sky" ap pearance. Plasma ce lls may b e p resent but
are almos t always non -neoplasti c (2475},
TIbIt 10.13 Morphologic variants of mantle cell lymphoma.

~.Iv.
vMlllnts
cells resemblelymphoblast's with dispefSed chromatin anda highmitoticrate (usually at !east

2!r3l}'10hpt),
fllasIoij:
PIeo:Jraphic: calls art pleomorphic: butmany are IafgeWllh CMlI to irregularnudear coolours, geoeraIty pale
~ and often prominent nudeoli 11 at leastsome of the ceHs.
--
- SrnII eel: SrTllll IOJnd ~ WIth IIIOlll dumped chromalin, either admiJled or predlmnant, ITWIDJng
SlfIII tymphocytic tymplloma.
I,l;rgnI zone.Ike: prominenI loci r:A eels withabu'ltIanl pale ~ reserrtIIrlg marginal zone or
~ 8-alIsIlWIIIdling a ma'gIIl8I zone ~; sometines these paIef locimay aisO reserrtJle
~ C8'lIres r:A dnlnic ~ IIlukaerriaIsma ~~ .
B
Fig. 10.17 Mand. cell ~ invotving the alIon
(~ ~ pcIyJxlsis). !Jt'S5 ~. A
Overview showing one large and muftiple smanpolypoid

mucosal lesions. B Closeup showing tiny polypoid
mucosal lesions.
Histolog ic al transformation to typical large

ce ll lymphoma doe s not occur; however,
loss of a mantle zone growth pattern , increase in nuclear size, pleomorph ism and
c hromatin d ispersal , and increase in mitotic activity may be seen in some case s
at relap se 174 , 1253 , 1605 , 2 134 1. Some
of the latter cases w ill fu lfil the cr iteria for
a bl astoid or p leomorphic man tle ceil lymphoma .
A spectrum of morphologic variants is
recog nized . The b lastoid and pl eomorphi c va riants are con side red to be of important clinical sign ificance (Table 10 .13 ).
Although MCl is not g rade d. eva luation
of the prol iferation fract ion either by
counting mitotic figur es or estimating the
proportion 01 Ki67 positive nuclei is important because 01 its p rog nostic impact.
Immunophenotype
The cells express relatively intense surface IgM/lgD. more treq uenny with
lambda than kap pa restriction 1329.2 134,
22461. They are usually positive for CD5,
Mantle celllymphoola
229
fig. 10.7' Mantle c:eI~ . ~ nodes. A There is dllfuse afChitedInI e!lacement and typical pale IIyaftzed vesseb . B in addl1JCl'l ~ ItfIuse areas. nofe!he prorrn!IC
vague neoplasbenodules. C A mantle zone QJOWlI1 pattem is seen II1ltis ~ node WIth an intacl artMBclure
230
FMC7 and G043. but negative for COlO

and BCl6. C023 is negative or weakly
positive. Aberrant phenotypes have been
described . sometimes in assoc iation with
blastoid/pleomorph ic variants, including
absence of C05 and expression of COlO
and BCl 6 {323. 1518, 2470l , IrTVTIUnohistological stains demonstrate loose me shworks of follicular dendrilic c ells. All ca ses
are BCl2 protein positive and almost all
expresscyclin 0 1, incl uding the m inority
at cases that are C 0 5 negative {4 12.
2135.2 137. 2250.2467.25091 . Cyclin 01
stainingmay be required to recognize the
casesof "in silli' MCL
BMI1
.1. -
INK4
Restriction Po int Control
G1
p16 1NK ....

p15 , p11. p1i
COK 4/6
Cyciin 01
------
pR B I!) + E2F
r ~
Cyclin E
COK 2
pRB/E2F
/
CiplKlp
Genetics
IrtYnunogtObu lin gene s are rea rranged.
Variable region g enes are unmutated in
the ma;ority 01 the cases. but in 15-40%
d the cases. /G g enes show somatic hypermutation although the load of mutations is usually lower than in mutated C l l
{322. 1143. 1652. 21921. A biased use of
!he VH genes is reported in MCl. suqgesting that these tumour s may originate
trom speci fic sub set s of a-ceus 1322 .
11 43. 1652. 2 1921. In cont rast to cu.,
VH3-21 gene usage in MCl occurs mainly
in cases that are uomuteted. have fewer
genomic imbalances and a better prognosis 121921 Also in contrast to Ct.t . the
VH gene muta tional status in MCl does
not correlate with survival or ZAP-70
expression 1322. 340. 11431.
The t(11;14){q13;q32) between IGH@an d

cyclin 0' (GGN01 ) genes is present in
almost all cases and considered the primary genetic eve nt (1291, 1866. 2281.
2308, 2410.24111. Variant GGN0 1 translocations with the immunog lobulin ligh t
enema have also been reported [11791.
The translocation results in deregulated
cverexpression of GCND 1 mANA and
protein [246. 515, 19951. Some MCl express aberrant transcripts resulting in an
increased half-life of cyc lin 01 . Tumours
w,ththese truncated transc ript s have very
high levels of cy clin 0 1 expression {246,
515. 19951. high proliferation and mo re
aggressive clinic al behaviour {18 711.
Deregulated expression of c yclin 01 is
assured to overcome the cell cycle suppressive effect of AB1 and p27k ipl , lead1'910 the development 01 MeL{1048. 17931.
W::l carries a high number of ron-rancon secondary chromosomal aberrat ions
J
INK4
Cell
death
H MOM2 11-
p 14 ARF
ATM
Fig. 10.10 CeI cyde and DNA damage repw palhways altetedin matllle cel lymphoma. The cydin Ol lcydin
dependent kinase (CDK) 4/6 CQrr4lIeJ promoteS phospIuyIation d!he relinoblastoma prolein (pRB). This leads10
release of ee ElF lransmption racIors Yoftctlltlen lead 10 prt9'eSSiOn of ee eel cyde inlo!he S phase . Thecydin
D11COt< 416 compleJ isinhibiled by p16-. 8MIl is a ~ repressor of !heINK4afARFIocus.AbnonnaIiIies
in MeLltJat lead kl progresslOO of cells from GI to S phase incUIe increased cydin 01 in amost aI cases and b&s of
pl6"""". RB deletions. increased CDK4 alld increased 8MII in a minority of casesespecially lhose lhal are more
aggressive_ Dere\r.Jlated E2F also induces p14'" 1rw11Crip1lon. p14'" leads lDsIabiliz.ation of p5J by iMibIbng 1Ile
activiIy of MOM2 whietlleadsIII 1hedegradationof p5J. The Iurnl:u'suppressor p53leads 10 ifIcrea:sed expteSSlOll of
p21 in addition 10 leading 10 eel cycle arrest or apoptosis. The AT'" gene is required lor activation 0/ p5J after DNA.
damage. Many Mel ha~ ATMabnormalilies and some pabents have gernine mutabons ollhis gene. SCme Mel have
loss or tran~1 repression oIlt1e INK4afARFlocus lacking p16-,p14.... 1oss or mutation 01 TPSJor high Ieves otMDM2. Finally. cycIin ElCDK2 coepexesalso lead 10 cellcycle progression andare inhiMed by p21Ip27kipl . ln
Mel. increased levels of cydil'l 01 lead 10 seqtleSlraliOn eteese ce~ cycleinhibitors and. in addition, they may increase
p27degradalion.
inclu ding ga ins of 3q26 (31 -50%), 7p 21

( 16-34%) and 8q24 (16-36%: MYG) , and
losses of 1p13-p3 1 (29-52% ), 6q23-q27
(23 - 38% ). 9p 21 (18-3 1%), 11q 22-q 23
(21 -59%). 13q11-q 13 (22 - 55%). 13q 14.
q3 4 (43-51 "!o) and 17p 13-pter (2 1-45%)
{165, 1890 . 19951. Trisomy 12 has been
repo rted in 25% of cases {496 1. In addition to chromosomal imbalances, MCl
may demonstra te tetraploid clone s that
are more common in pleomorphic (80 %)
and blastcid variants (36%) than in c ases
with typical mo rphology (8%) {16661. The
presence of a t(8:14)(q2 4;q32 ) with MYG
translocat ion occurs rarely and is associ ated with an agg ressive cl inica l course
{22831. BGL6/3q27 transrccanons also
oc cur uncorrrnonly and are reportedly associated with BCl6 protein expression
13231. Some cyt og enetic abnormalities
may also have associat ions With variou s
clinical parameters incl uding a leukaemic
presentation 169 1, 16931.
Oncogenic alterations have been found in

several genes targeting the DNA damage
respo nse pathway and c ell cycle regulatory eleme nts l 688) inact ivating mutations of the ATM g ene at 1tq22-23 have
been detected in 40- 75% of Mel [320.
19561. ATMmutations have been also detected in the germline of some patients
with MCl [3201. Highly proliferative variants 01MCl have frequent TP53mutations,
homozygous deletions of JNK4alARF, the
CDK inhibitor p l81NK4c, amplifications
and overexoresson of the BMll poIycanb
and COK4 genes and occasional microdeletions of the RBl gene {165, 166,329,
839 .930. 1341, 1755, 1757.2412,24131.
CycJin 01 negative Me L
Aare Mel are negat ive for cyelin 01 and
the t(11. 14) but have an expression profile
and other features indistinguishable from
con ventiona l MCl 1738, 1871, 19181.
These cases have a high expression of
231
Naive B
lymphocyte
GermHne
ATM
Classical
MCl
Early
MCl
Blastoid
MCl
. --
CHK2
t(11;14)
Cyclin 01
~
~
p16/CDK4/Rb
ARF/MdM2IQ53
Rb
Increased Genomic
Inst.bUIt)'
High
Proliferation
Fig.1U1 Proposed model of IIlCIlecWr patl10genEtSlS in Ihe deYeqmenl and progression of MCL The presence of ,A,1M or CHK2 ifIadivaIing nI.IlatiORS ifllhe gemWne 01 some
paller'll$ suggests Ihat they ITI3)' IacilrIale lhe ~ ofltle MrloIJ". The 1(11;14) transb:atiOn occurs in an immatJ.n 8-<:eII aI'lCIleads to Itl8 oonstitulive dereglJabon 01 cydln
01 _..,.,. ~ r:A IlnGur ~ on.............
of lymphoid ~ Acquqd inectrvaIion 01 DN " ~ ~ paIIlways may tac:iIRale!he dirteIoprt'Il
aI addJbmaI geneticalIeralions and expansion of MCt eels witha dassicallT'IOIphokIgy. Increased genomiC instal*y maytiWgel genesin the cJ3I C)'de and senesoence ~
pahways 1tIat \IlIOUd lead ~ JTOlI aggressi\'e Ya"IafIls of MCl. ModrIied WIth perrrissicrllrom Jes P. 8f aI. (1048A)
cyclin 02 ()( eye lin 03. Some 01 these

cases carry a t(2; 12)(p12;p13) translocation fusing cychn 02 to the kappa light
chain gene locus 17891. This diagnosis
must be made only with great caution due
10 the many lymphomas that may mimic
MeL.
Postulated normal count erpart
Peripheral Bccell of inner mantle zone,
mostly of naive pre-germinal centre type.
Mantle cell lymphoma has a median survival at 3-5 years, but the vast majority of
patients cannot be cured 1329 , 21361. The
impact of some of the newer therapeutic
approaches remains to be established
11917. 2487AI. The most consistently reported adverse nrstopatnoioqicat prognostic parameter is a high mitotic rate
232
Mature s-een neop lasms
(>10-37.5115 hpf. >5OImm") 174, 247 ,

2134. 22371. A high proportion of Ki67
positive cells, ego >40% or >60% . is also
an adverse prognos tic ind ica tor 11120,
22371. The most significant prognostic indicator identified in a major gene expression profiling study was the proliferation
signature score 118711. Although not necessarily all independent of the proliferation fraction, the following have been
rep orted in at least some studies to be
adverse progn ostic features: blastoidl
pleomo rph ic morpholog y. trisomy 12,
karyotyp ic com plexity. TP53 mutation/
overexpressionnoss and a variety of clinic al parameters including overt PB
involvement (at least in patients with
adenopathy) {165 . 247 , 329 . 496. 839,
1341,1761 ,1918.21341. Gains of chromosome 3q and deletions 01 9q are associated with a poor prognosis independent
of the proliferation fraction 119181. The

small cell variant appears to have a more
indolent course with the impact 01 a
mantle zone or nodular pattern less settled 1247. 1253. 1368. 1605, 1871, 2134.
2237l. Patients presenting with PB. 8M
and some times splenic involvement but
without adenopathy have been reported
to have a better prognosis (median survival. 79 months) 116521. Although not a
progn ostic ind icator, mutated IG genes
were associated with the long-term survivors in the latter study, Patients with in
situ MeL also may have a better prognosis with long term survival even without
therapy. although caution is advised as
this morphologic pattern may be associated with more overt disease and a rapid
course 11602. 18421.
Diffuse large B-cell lymphoma,

Definition
[Muse large EkelllymphOma (DLBCL) is
aneoplasm of large B lymphoid cells with

nuclear size equal to or exceecnq nomal
macrophage nuclei or more than twice

the size of a flOfma l lym p hoc yte . thai has
a diffuse growth pattern .
Morphological, biological and clinical

studies have subdivided diffuse large
B-<:eI tymphomas into morphological variants , molecular and irTvnunophenc>(ypical
subgroups and distinct disease entities

(Table 10 .14) . However. a large number of
cases remain that may be biologically
heterogeneous, but for which the re are no
clear and accepted c riteria for subdivision. These are classified as DLBCL, rot
otherWise specified (NOS). OLBCL NOS
cotonses all OLBCL cases that do not

belong 10 specific subtypes or d isease
entities mentioned in Table 10 .14
ICD-OCOde
9680/3
Epidemiology
DLBCl . NOSco nstit utes 25-30% of ad ult
non-Hodgkin lymphomasin western couneesand a higherpercentage in developing

countries. It is more common in the elde rly
The median age is in the 7th deca de but
it may also occur in c hild ren and youn g
adults, It is slightly mor e common in ma les
than in females 15 1, 79 1.
Etiology
The etiolog y of DLB CL , NOS rem ains
uOO1own.1t usually arises de novo {relerred
Fig. lU2 Spleen IIvoIYed by drfIuse large B-eeI
WOlllIIXlttaIlS largelumol.r nodlJes.
H. Stein
RA Warnke
W.C . Chan
E.S. Jaffe
to as prim ary) bu t c an represent progression or transformat ion (relerred to as second ary) of a less ag gressive lymphoma,
e.g. chronic lymphocytic IeukaemiaI small
lymphocytic lym phoma (CLLlSLL) . follicula r lymphoma, ma rginal zone lymphoma
Of
nodular lymphocyte predominant
Hodgkin lymphoma (NLPH L). Undertying
iTn'I..nxiefici is a sig1fficant risk tectoDLBCL, NOS occurring in the setting of
irTYrunodeficiency are more often EpsteinBarr virus (EBV)-positive than scoreorc
DLBCL, NOS. In DLBCL cases without an
overt irTVTlUnodefic iency. the EBV infect ion
rate is app roxima tely 10% 1993. 1690 1.
Patientsmay present Vv'iIh rKldaIlJ extranodal
disease wiItJ up to 40% being at least initially
confi ned to extranod al sites 18981 The most
common extran odar site is the gastrointestinal trac t (stomach and ileocoecal
region ) but virtua lly any extranodal loca hon
may be a prima ry she. Other common sites
of extranodal presentation incl ude bone,
tes t is. spl een, Wald eyer ring . sal iva ry
g land , thyroi d, liver, kid ney and adren al
g land . Cutaneous lympho mas co mposed
01larg e B lym phocytes are dea lt w ith separately in this volu me , Bone m arrow (BM)
invo lve m ent is reported in 11- 27% of
c ases 1327, 442 ) The de tec t ion ra te of
minimal invo lvement ma y be inc reased if
an ci llar y studies like immunohistochemistryor p e R are added to the mo rpnoioqical evaluation of the BM specimen (2 15 11.
Bone m arrow in volve ment may be with
J K C . Chan
K.C, Gatter
E. Campo
DLB CL (corcoroann but more commonly

discord ant 14421. wit h the p resenc e of a
low-grade B-c ell lym phoma in the BM.
The frequency of discordant BM involvement varies in d ifferent reports from rare
to 70% of the positive cases 167, 945 ,
11901, Mo rphologic examination of peripheral blood (PB) smea rs revealed that
approximately one third 01 DlBCL patients
with BM invotvement also ha d malignant
cells in the PS1671 .
Clinical features
Pat ients usuatty present with a rapid ly
entargu'IQIl.mOUr mass at single Of multiple
nodal or extranodal SIIes_Almost ha lf 01
the patients have stage I or II d isease.
Most patients are asym ptoma tic but when
symptoms are p rese nt they are highly dependent on the site of involvement 151, 791 .
Morpho logy
Lym ph nodes demo nstrat e a d iffuse p rolife ration of large lym phoid ce lls that have
tota lly (more common pattern) or par tially
effaced th e arc hitecture . Partial nod al
invo lvement ma y be mtert oulcuter and/or
less commonly sinusoid al. The perinodal
tissue is often infiltrated , Broad or fine bands
at sclerosis may be observed. Cytomorphologi cally, DLBCL, NOS is d iverse and c an
be d ivided into co mm on an d rare mo rph olog ic va ria nts. Cases pr ed om inated
by medium-sized c ells may require spe c ial stud ies to ex clude ex tramed ulla ry
teckaemta s. Bu rkitt lymphoma variants
and bl astoid m antle cell lym phomas,
Fig. 10.83 DdIuse large B--c:eI~. cenlrotllastic vlll"ia'1l A T)'PIClII appearance. B In llise~, h II.m:u
eels have a potymorpnic and ~ed appearance.
Diffuse large B-celf lymphoma . not otherwise specilied
233
..
Corrmon mo rpho logiC variants

Three common and additional minor
morphological variants have been recognized. All variants may be admixed with a
high number of t-e ens and/or btstrccytes.
These cases should not be ca tegorized
as T-cell/histiocyte-rich large B-cell lymphoma (TCABCL) as long they do not fulfil all the criteri a of this DlBCL subtype .
Centroblastic varian t: This is the most
carmon variant. Centroblasts are mediumsized to large lymphoid cells with oval to
round, vesicular nuclei containing li ne
chroma tin. There are two to four nucl ear
membrane-bou nd nucleoli. The cytoplasm
is usually scanty and amphophilic to basop hilic . In some cases, the tumour is
monomorp hic, i.e. it is composed entirely
(>90%) of centroble sts. In most ca ses.
however, the tumour is polymorph ic with an
admixtu re of cen troblasts and invnunoblasts 90%) 1645, 12741. The tumou r
cells may have multilobated nuclei which
predominate in rare instances , especi ally
in manifestations of the bone and other
extranodal sites.
Immunoblastic variant: Greater than 90%
of the cells in this variant are immuno blasts
with a single ce ntrally located nucl eolus
and an app reciab le amount of basophilic
cytoplasm. Imrnunoblasts with plasmacytoid different iation may also be pre sent,
Clinical and/or imm unophenoly p ic find ings may be e ssential in differenti ating
this variant from extramedullary involvement by a p lasmab lastic lymphoma or an
immatu re plasma cell myeloma. The distinction of the immunoblastic variant from
the common cen trobl astic variant has
generally met With poor intraobserver and
mreronserver reproducibility {8981.
Anaplastic variant: This variant is characterized by large to very large round . oval
or polygonal cells With bizarre pleomorp hic nuclei tha t may resemble, at least in
pa rt, Hod gkin and/o r Reed-Sternberg
c ells, and may res em ble tumour cells of
Table 10.1" DiI Me largeB-ceI tymphoma: variants, subgroups ancl SI.tJtype$Ienhlie$.

Dlffuselarlle B-eeillymphoma., not otherwise s peelf~ (NOS)
Common morphologic varilts
""""""'"
~astiC
ArlapiasliC
Rare rTlOI'phologicvereots
MoIeaJlar subgroops
GemWIaI~~e {GC8 1
Activated 8<:eI-ike (ABC)
ImmurdlisllXtiemicalsubgroops
CD5-posiliveDLBCL
Germinal oontre EkelI-like (GCB)
Noo-ge!minaI OlIfltrelk:eHke (non-GCa)
DifluHlargeEken Iymphom. subtypes
T<.ellfhlsllocyte-rich large B-OOllymphoma

Pnmary DL8Cld!he CNS
Pm1ary cutaneous Ct.BCl.1eg ttPe
E8VposiM OlBCl d eeeldeIty
Otherlymphomas of lerge B t elll
PrImary mediastinal (1hynIe) Iatge!k::eI ~
wmva:sa.w large !k::eI ~

OLBCL associated Wllh dIronic inftarrrnation
Lymphomatoidgranulomatosis
AlK-poslbve LBCl
PIasmabiaslie lymphoma
large 8-aII1y!r9'lcma arISIflg II HHV8-assooated rWIicenIrie C3slIeman disease
PrYnary el'lusioo ~
Borcl.rllneeases
!k::eIIymphoma, undassItiable ...,;ttlfeatures intermediate between dllMe 1arge!k::ellympOOma and
.....
B-<:eI~,
undassiflable. WJtllleatL.res IIIermediate between dJse largeB-eeI Jyrnphoma and
classical HoOgklfl Iympnoma
234
Mat ure B-c elJ neoplasms
anaplastic large cell lymp homa. The cells

may show a sinusoi dal and/or a cohesive
growth pattern and may mimic uncitterennated ca rci noma /8911 . They are biolog icall y and cli nica lly unrel ated 10
anaplastic larg e c ell lymp homa which is
of Cytotoxic t-een derivation and unrelated

to ALKpositive lBCL
Raremorpholog ic variants: Rare cases of
DlBCl. NOS have a myxoid stroma ()( a
libriIary matrix. A few cases show pseudoroselle formation . Occasionally the neoraaetc cees are spindle-shaped ()( display
features of signet ring cells. Cytoplasmic
granules. mic rovillous crojectone and
intercellular junctions can also be seen .
"""""""henotype
The neoplastic cells express pan s-een

markers such as C01 9 . C02O. C022 and
CD79a, but may lack one or more of
these. Surface and/or cytoplasmic immunoglobulin (lgM>lgG> lgA ) ca n be
demonstrated in 50-75% of th e cases
(1328) . The presence of cytop lasm ic immunoglobulin does no t correlate with the
expression of plasma cell ma rkers such
as C0 38 and C0138. Both markers are
rarely co-expressed in CD20 posmve
cells. CD30 may be expressed especially
III the anaplastic variant I 17581. The neoplasticcells express C05 in 10% of the
cases 121421 These CDS positive DlBCl
cases usually represent de novo DlBCl
Mdonly rarely arising from ClUSLL. COS
poseve DLBCL can be distinguished
from the otastoio variant of manne cell
lymphoma by the absence of cvcun 01
expression 11418.24631.
The reported incidence of CO to . BCl6
and IRF4/MUM1 expression va ries . Expression of CO 10 is found in 30-60%.
BCl6 in 60-90% and IRF4/MU M1 in
35-65% of the cases (3 1. 196 . 460 . 521 .
994, 1547). Unlike normal germinal ce ntre
in whic h the ex press ion of
IRF4/MUM1 and BCl6 is m utua lly exclusive. co-expression of both markers was
found in 50% of DlBCl in one study
16611. A uniform high expression of
FOXPI has been reporte d in OlBCl
cases that lack the germinal centre onerotype and express IRF4/MUM1 and
BCL6 n the absence of t(14 ;18) 11461. ExpressiOn of BCl6 varies in different reports. ranging from 47-84% 1460. 759.
Bceus.
925.9941.
The prollferatloo fraction as detected by
~7 stall'ling is high (usually much more
than 40%) and may be greater than 90%
n SOOle cases 114781. p53 is expressed
n2O- 60% of cases 1420.1171 . 1281 .
24761.
Subgrouping VL BeL, NOS by

immunoph enotyping
An immunophenotypical subdivision of
DlBCl, NOS into germinal centre-like
(GCB) and non-germinal centre-like (reoGCB) subgroups has been proposed by
dillerent groups using a combination of
antibodies toCD10, BCl6and JRF4!MUM1
/460 .8821. Cases with CD10 expression
by >30% of cells are regarded as GC
type as well as cases that are CDlO-.
BCl6+ , IRF4!M UM1 . All other cases are
regarded as of ron-Go type 18821. H0wever. this irTllTlunophenotypic subdivision
does not correlate exactly with gene exp ression-based sUbgrouping of OlBCl
1994. 1869 1. The add ition of other markers such as BCL2 and Cyclin 02 may
lead to an imp rovement in the imm unop henotypic subg rouping of DlBCl13 11.
This immunophenotypic subgrouping
does not currently determine therapy.
Gene tic s
Cionally rearranged irrmunoglobulin heavy
and light chain genes are detectable.
They show somatic hypermutations in the
variable reg ions .
between diffuse larg e B-cell lymphoma

and Burkilllymphoma".

AJizadeh et al1241 identified I'M> subgroups
of OlBCl. One subgroup (termed GCBlike) has the gene expression profile of
germinal centre B-cells (45-50% of cases )
and the other (termed ABC-like) has the
profile of act ivated peripheral Bceus. This
was confirmed by a subsequent study
118691 _1000ially. a third subgroup (termed
type 3) was defined. This proved to be a
collection of cases that cannot be class ified as the GCB- and the ABC-SUbgroup
and does not represen t a d istinct subgroup
(994, 24491. The two established subgroups
are associated with d ifferent chromosomal
aberrat ions. The ABC-Dl BCl subg roup
has frequent gains of ac, 18q 2 1q22 and
losses of 6q2 1q22, whereas the GCBDlBCL subgroup displays frequent gains
at 12q1 2 /167, 2 1421. A number of the
eca-ue cases carry a BCL2 rearrangement {526. 9881.
The immunoblastic variant and the centroblasti c va riant cases with a polymorphic
centrobrast-uke cells and/Of a higher
Galtenl of irTrTulobCastsare more corrmon
i1 the ~ blJ:werealsool::lservecl
Abenant somatic hype rmutations

Aberrant somatic hypermutalions targeting multiple genetic loci, including the
genes PIMI. MYC . RhoHITTF (ARHH) and
PAX5 are encountered in more than 50%
of OlBCl cases. These genetic alterations
may contribute to the oncogenesis of this
lymphoma group 116991.
Chromosomal translocations
Up to 30 % of cases show abnor malities
of the 3q27 region involving the BC L6
gene, which is the commonest fransocaton
in OlBClI 158. 1620, 16261. Transloc ation
of the BCL2gene. Le. 1(14:18), a hallmark
of follicular lymphoma, occurs in 20-30%
of cases 1994. 13 16 . 2379}. A MYC rearrangement was observed in up to 10%
of an unselected series 01 cases 124811
and is usually associated With a complex
pattern of genetic alterations 19941. The
MYC break certoer is an IG gene in 60%
and a ~IG gene in 40% of cases 19941.
Approximately 20% of cases with a MYC
break have a concurrent fGH-BCL2
translocation and/or BCL6 break or both
1994. 22781. These cases usually have a
high proliferation (>90% Ki67+) and may
be better categorized as "B-ceillymplunas.
uncl assified with features inter mediate
in the GCB-subgroup. This indicates that

the eca-me and ABC-like subgroups
cannot reliably be recognized by morphology. The correlation between the
gene expression subtypes of OlBCl and
those defined as GC and non-GC DlBCl
by immunohistochemistry is variable
1882 . 994 1.
Table 10.15
Intemational Prognostic Index fex aggressi\ltllymphomas
Unfavourable variables
Age >60 yaars
Poor petfonnance status (ECOO:a)
Advanced Ann Arbor stage (1II-N)
Extranodal invOlvement zz sites

tigh sen.rn lDH (>normal)
Risk group
Unfavourablt v"riables
AI patJeIlt$ Pati9nU SfU
0 1
2
3
0
1
2
45
' In patlel'Its s60year-okl fie age-.adjusted nternatiOnal prognosbc index (aaiPiI is caIcUated VIOIh
tnree unlavourable variables ltJal lOdude poor per.
formance slalus.aovancedAnnAibor stage and
higl serum l DH
Diffuse larg e B-ce il lymphoma. not otherwise specified
235
Postu lated normal cou nterpart

Peripheral B-cells of eith er ge rm ina l
c entre or post ge rminal c entre (ac tivated
B-cell ) origi n.
Prognos is and predict ive factors
In me pre-ritu ximab era the long- term
remissi on rate was betwee n 50-60% . Although Indi vidual prog nosis varies widely.
the Internatio nal Prognostic Ind ex (IPI)
based on clinical parameters has proved
to be hig hly valuable 1791 . However, the
IPI seems to lose some of JlS predictive
value in patients treated wilh rituximab
11985 1 whi ch has im p rOVed prognosis
signIficantly 14551.
Concordant BM involvement is associated
with a very PQOf p rognosis (5-year overall
survival . 10%) while oiscoecanr involvemen t does not influence the clinical outcome significanlly (5-year overall survival,
62%). The PQOf survival associated wi th
concordan l invotvement was independent
01 the IPI score {327, 442.1 65 11.
MoqJholcgy
There are many conflicting repo rts on the
prognostIC impact of ffinJnobIastiC leatures
{79. 275, 645 , 1453 . 19 15{. Some studies
lound an adverse orocrosnc impact of
inrnunoblastlCmorphology whereas others
d id not
Immunophenotype
A larg e num be r 01immuno histoc hemical
markers have been report ed to be assoc iated with prog nostic effects: the expression
01 BC l 2, X-li nked inh ib itor of apo ptosts
(XIAP), IRF4/MU M1, c vcnn 0 2, cyclin 03,
p53, C05, FOXP1, PKC-/I, ICAM1, HLA-OR,
c- FU P have been associated with an adverse p rogn osis and the exp ression of
acts, COlO , l M02 with a favo urable
outcome {10, 146, 196, 460, 526. 759 ,
88 1, 925, 1009, 1479 , 1546 , 23 18. 2463 )
However, the results o btained in thes e
different stud ies are often co nllic ting and
the ir interp retation is thus con troversi al.
Finally. the addit ion 01the anti-G020 antibody rituximab has improved the surviv al
of patients with OLBCl considerably {4551
and was repo rted to have elimina led the
nega tive impact of the expression of BCl2
and the positive impact of BCl6 on cli nical
outcome {455, 1528, 1529, 2423/. Patients
with EBV-infected OlBCl , as revea led by
EBER in Situ hybridization, have be en
found in one study to have a worse c linical
outcome tha n patients with an EBVnegative OLBCL 11690/.
236
Mature B-celf neoplasms
Proa re ssia n -free s u rvtvat

. ~
r.
,-
-.--
----
r.. ~
:-t"- I "
..
~-,
Low-risk
--
~-
overall survival
r..
1."
-.--
. 1\
High-risk
.
r..
--
1.."
~-
low-fisk
"' ~l)
H igh -ri sk
Fig.10.85 OvefaB al'ld progreSSiOn-free surrival in diffuse large B-cellymphoma according 10 the age.adJusted
Intemabonal Prognostic Index in patients trealed W11h CHOP WIU1 and IIII'I1houI ntuximab ao::udI'lg to the study em
dl.ded byIheGElA (courtesy of Dr8. Corffier).
Immunohistochemical panels
Hans et al. I882} reported that a combination
of CO lO, Be l 6 an d IAF4!M UM 1 expression, the so-ca lled "Hans cla ssifier". cou ld
subdiv ide OlBC l patients into long- and
short-term surv ivors; this result has been
co nfirmed by some studies b ut not by
others 131, 460 ,1 339 , 1526, 16 10, 230 1).
Whether the ad di tion of rituximab to
CHOP will eliminate its p rognostic value

needs to be further invest iga ted {l 6101 .
The study of other immunohistoc hemical
pa nels inc lud ing markers such as cyclin
0 2, BCl2 and LM02 may improve the
prognost ic pr ed iction {3 1, 15801, However, the use of immunohistoc hemica l panels to ass ig n prognostic groups does not
c urrently have a role in rout ine c linical
practice. One of the major limitations is

the well-documented problems with re producibility in the per formance and interpretation ot some immunohistochemical
stains (518, 2505 1.
Proliferation
A high proliferation fraction , as assessed
by the Ki67 index, has been associated
withworse survival in scme series 11478 1_
This is supported by one gene exp ression
study in which the proliferation signature
proved to be a strong predictor of an
adverse ootcome I1869J . However other
studies have failed to confirm a prognostic
value for the Ki67 index 1460, 1904.2423.
24961
Genebcs
In some studies, BCL6 translocation has
been reported 10 be associated with a
better prognos is, but not in others 1158.
1056.1188. t543 . 1596, 1620, t728.2339I.
In contrast. the presence of a MYC break
is ~nk ed with a very untavouratne outcome 19941. TP53 mutations have been
associated with poo r su rvival in some series of OLBCL incl udin g one study in
wh ich mutations in the DN A binding domain proved to be the most important predictcrj420, l OCXJ. 1171, 128 1. 2421, 24761_
p53 p rotein expression does not seem to
be of prog nostic value in DLBCL patients
11 187.1353,20431. Patients with a molecularly defined GCB-subtype of DLBCL
have been shown to have a significantly
better c linical outcome than those with the
ABC subtype 124. 994. 18691 Whether this
difference persists in patients treated with
rituximab remains to be seen . Other subgroups, i.e. oxidative phosphorylation".
- BC A/proliferation" and ' best response"
identified by gene arrays, did not predict
survival , but may suggest targets lor therapy 115071.
Microenvironment
The ilTYllUne response appears to have a

strong impac t on the clinical outcome
after cnerrotherapy The MHC cl ass II
gene expression signature correlates with
a favoorable outcome 11 479. 1869.23181 _
The loss 01 MHC class II gene and protein

ex pression in pa tien ts with OLBCL was
tound to correlate with red uced numbers
and a
ol lumour-infill rating C08+
poor outcome 11846 1. The lymph node
signa lure as identified by gene expression
proliling is associated with a good cl inical
outcome 118691- This signature is characterized by genes that encode components
of extracellular matrix and coooecnee tissue
growth factor.
t-eens
The"'PY
DLBCL are aggressive but potentially
cu rable with multi-agent chemotherapy.
The CHOP regimen has been the mainstay
of therapy for several decades. Whereas
attempts 10 improve ou tcome with more
intensive chemotherapy failed to show
additional benefit. The addition of the antiC020 monoclonal antibody rituximab to
CHOP (R-CHOP) has led 10 a marked
improvement in survival 14551.
Diffuse large B-celllymphoma , not otherwise specified
237
T ceillhistiocyte-rich large
B-cell lymphoma
C . De Wolf-Peel ers
J. Delabie
E Campo
ES. Jaffe
G, Delsol
Definition
t-cemusnocvte-nchlarge B-eelltymphoma
(THALBCL) is c haracterized by a limited

number of scattered, large, atypical B cells
em bedded in a backg round of ab und ant
T ce lls and frequently tusnocyres.
ICD-Q code
968813
Synonyms
t -een-non B-celt lymphoma 118131. large
8 -eefl lymphoma ric h in t-eens and simulat ing Hodgkin d isease {4261. histiocyte
rictVT-eell-nch large B-eeillymphoma 15441.
Epidemiology
THRLBCL attects main ly m idd le-aged
man . It accounts for < 10% of all diffu se
large B-eeillymphomas (DlBCL)
THRLBCL mainly affects the lymph nodes
b ut bone ma rrow (8M), liver and spleen
involvement a re frequently found at d iag-
nose .
Clinical featu res
Patients present w ith fever, malaise .

splenomegaly and/or hep atomeg aly. A l-
most half of them are at advanced Ann

Arbor stage with an intermed iate to high
risk Inter nat ional Prognostic Index (IP I)
score. The d iseas e is often refractory to
chemotherapy pre sently in use.
.....
.,.
....
b blt 10.17
T~
StageIII-/V
largeIk:eIIympIw)ma
12-61 )'Un
75%
64%
l iv&r inYOIvemeni
13-70%
Spleen in'lOlv&ment
33--67%
Bone marrowinvolvement
17-60%
Data based on277 cases of patients withT<.efLI

hi6tlOCyte-nCh large B-oaI !yn"VIoma illhe M_
lure {13A, 251, 252. 125, 1329A, 1361A, 1841A.
223M. 2273A.. 2358A}_
238
Morphology
THRLBCL has a diffuse or less comm only
vaguely nodular gro wth pattern replacing
most of the no rma l lymp h node parenchyma . It is comprise d of scattered. sing le,
large B cells embed ded in a ba ckground
of small lymphocytes thai represent T cells ,
and var iable numbers of tustocvtes. The
tumour ce lls are always d ispersed and do
not form aggregates or sheets. These
cells may mimic the neoplastic lymphocyte pred omina nt (LP) c ells of nodular
lymphocyte-predominant Hodg kin lymphoma (NLPHL), but usually show a more
pronounced variation in size and in some
c ases may resembl e centroblast s or more
pleomorphic ce lls mimick ing Reed -Sternberg or Hodgkin cells 1598, 12991 They
are typ ica lly found with in clusters of
bland-looking non -ep ithelioid taetiocvtes
thai may not be obvious on conventional
examinatio n. These histiocytes represent
a main and d istinct ive component of
THRLBCL and are useful for the diag nosis
161. The background lymphocytes a re
nearly all of r-cennoeaee. Eosmopnns or
p lasma cells are not founo. The histolog y
resem bles cases of NLPHL with a d iffuse
co mponent, in which the LP cells have infiltrate the exnatoulcutar compartment but
these THALB CL-l ike areas in NLPHL do
not represent a transition towards THRLBCL
and do not c arry a bad prognostic signific anc e {252 1. Nevertheless. the re are
some ca ses of histologi cal progression in
NLPHL , in wh ic h the process is en tirely
diff use and lhe histolog ical ap pea rance is
virt ually ind isting uisha ble from de novo
THRLBCL. The relationship between secondary THAL BCL and pr imary cases rema ins controversial . They may represent
distinct, but morphologically and immu~
ph enotypically similar entities.
In the spleen. a multifoc al or mcroncouiar
involvement of the w hite pulp is found and
in the liver th e lymphomatous foci are
local ized in the portal tracts 1598) In
these extranooet loc ations as wel l as in
the BM . the lym p hom a is characteri zed
by the same co mposition as in the lymp h
nod e .
On rec urrence. the num ber of atyp ic al
cells may incr ease, resulting in a pic ture

of DLBCL , The tatter heralds a bad outcome within a short time 17lSeveral studi es have recogni zed ca ses
with similar morpholog y but without histiocvtes. wneme r these cases represent
the same entity as typic al THRLBCL is not
still c lear. Studies incl udi ng cases rich in
T cells With and Without histocvtes have
defined a more heterogeneous group of
large Be en lymphomas. which p robably
include more than one entity 12, 836,
1195 . 1299 . 1813 . 186 11. Further studies
should clarify the relationship between
these lymphomas. At present. while cases
lacking sig nific ant numbers of histiocytes
may be incl ud ed in THRLBC L. the absence of histiocytes should be noted ,
Lympho mas co nta ining B ce lls with a
spec trum of cell siz e, mo rphology and
d istrib ution (clusters or sheets of medium
to large B cells), should not be included
within the category of THRLBCL. and may
be considered a subtype of DLBCL. NOS,
Immunophenotype
The large atypical cells ex press pan
B-cell ma rkers and BCL6 ; a variable numbe r stain for BCL2 and EMA and no expressio n of C0 15. C030 and C0 138 is
found The bac kg round is co mpos ed of
var iab le number of C068-po sitive histocvtes and C0 3, COS, positive T cells. T-cell
rosett es around the tumour cell s and ramnants of B foll ic les or clusters of small B
lym phoCytes are ab sent. Lack of residual
IgO positive mantle cells and follicular
d ntic cell meshwork are of turtner diagnostic hel p differentiating THRLBCL from
NLPHL 16. 7251. There are aggressive
B-ceillymphomas, ric h in reactive
in wh ic h the neoplastic cells are sparse,
and are EBV-po sitive . In such c ases. the
neoplastic cells may exhibit a Hodgk in-hke
morp hology , Suc h cases should not be
class ified as THRLBC L, and should be
co nsidered w ithin the spectrum of EBV
pos itive OLBCL 11 2991.
oeo-
r-cees
Genetics
The tumou r B cells have the same clonal
rearranged IG genes carrying high rurber
of somatic mutations and intraclonal diversity 12631as germ inal centres ce lls.
l imited karyotypic studies have not
shown recurrent abnormalities. Comparative genomic hybri dization on rrucrodesectec tumour cells demonstrated more
imbalances in NLPHL than in THRlBC L
wiltl common anomalies involving 4q and
19p (7311. Gene expression profiling has
identified a subgrou p of DLBCL characterized by a host immune response and a

very bad prognosis {15071 and includes
most of the cases diagnosed as THRLBCl,
Postulated norm al c ounterpart
Germi nal centre B ce ll 12631.

THRLBCL is cons idered an agg ressive
lymp homa although clinical heterogeneity is described Cases with t usto cytes
are reported to represent a more homogeneous group of pa tients with a very aggres sive lymphoma. frequent failure of
current therapies and with the IPI score
being the only parameter of prognost ic
significance 17, 2511.
T-celllhlstiocyte-rich farge B-eelllymphoma
239
Primary diffuse large B-cell lymphoma

of the eNS
P.M. Kluin
M , Dec kert
J.A. Ferr y
Definition
Diffuse large B-cell lymphoma 01 the
central nervous system (eNS DLBCL)
represents all primary intracereb ral or intraocular lym phomas. Excluded are Iym.
phones of the dura . intravascula r large
B-eell lymphoma. lymphomas with evidence of systemic disease or secondary
lymphomas. as well as all inYTlUnodeficercv-eesoclatec lymphomas.
ICD-Ocode
Synonyms
These cases arealso diagnosed as prinary
e NS lymphoma (PCNSL) or prima ry intraocular lymphoma (PIOL) .
Ep;dem;,1ogy
e NS DLBCL represents < 1% 01 all nonHodgkin lymphomas (NHLl and ap prox imately 2-3% 01 all brain tumours. The
med ian age is approx imately 60 yea rs.
and there is a slight preponderance of
male patients, Some studies suggest an
increase in the incidence of e NS DlBCl
1485 1. bu t it is unk nown whether this is
due to improve d diagnostic tools or reflect s a real increase.
Etiolog y
Epstein-Barr virus is generally ab sent from
CNS DLBCL in immunocompetent patients,
Exp ress ion or abse nce of c hemo kines
and c bemo une rec ept o rs or c yto kines
may co ntribute to the spec ific localization
(2038 1. Tumour ce lls and endothelial cells
may interac t via ac tivation of Il 4 to crea te
Fig. 10.81 Nuclear ~bc resorIafIC8 imaging (MRI) of CNSOlBCL 11 aller gadoIinit,I'n infection IA);n:I tid
attenuated iflvefSion re<XIYf!f)' (FLAIR) sequenceslBI, There are I'l1O eManclflg mass lesions ifl lhe basal gar9a
(Courtesy of Or. F Glaus).
a favourable mic roenvironment for tumo ur

grCM'ttJ {18891. CNS DLBCl show a restricted
homi ng to the main immune sanctuaries
(b rain , eyes and testis). Many DlBC L of
the CNS and testis show decreased or absent expression of HLA c lass I and II protein s allow ing the tumo ur ce lls to further
esc ape from immu ne attac k 1240 , 1843 ).
Appro ximately 60% of all CNS OlBCl are
loca ted supratentorially. In 20- 40%, multip le lesion s are p resent. Us ing NMR I,
CNS DlBCl may show a homog eneo us
lesion but also sig ns of centr al necrosis.
The leptome ning es are affec ted in 5% .
Approximately 20% of the patients develq:l

intraocular lesions. and 80-90% of patients
with intraocular DlBCl develop conlralateraltumo urs and parenchymal eNS
lesions, Dissemination to extraneural sues
including the bone marrow is very rare,
Cli nical feat ures
Foca l neurologi cal defi c its are observed
in 50-80% of the patients, Neurc osvcbarc
symptoms (20 -30%) and symptoms due
to inc reased intracr anial p ressure are also
seen, leptomeningeal involvement presents
with headache and asymmetric cranial
neuropathies. Intraocular disease presents
with a blu rred vision and floaters.
Fig. 10.88 Prmary cWIuse Iarge~ ~ oflhe CNS. A Aa:urIUalionof1u'nou" cells wtil ee perlVaso.b' space B More sold patIem. WIll stI scme ~ .
Ihe petivascUar space, C Strong IRF4IMUM1 stalnrog ifl JTDre than 7O'lIo of ee tumlu eels 1'1 CNS OLBCL
240
Deletion
'I
6p21.3
Gain
I
i
_..
6p21.3 (HLA r.... lon)
Testis hemizygous
...,11
Testis homozygoI.a ""'21 17
eNS I'lomozygous ~11.
"""" """"Ygouo not2l1S
CNS~
.-.
II
II
',II
III
_.
r~
I~ I
Fig. l0J9 Alrwy CGtl analysis 0# 9 ~CNS Dl8Cl. 17primaryleslicular OLBO. and 18 primary nodal(stage U11)
tlBa.. s/'IoIWIg (somelimes vwy small <Ieletions at 6p2U
Most intraparenc hymal lym phomas show

adiffuse growth pattern; cha rac teristically,
Il,r nCM cells are present in the perivascular
space, which is best appreci ated at the
periphery of the tumour or areas where
the tumour cells d issoc iate . The tumour
cells mostly resem ble c entrootas ts. b ut
slYinkage artefacts may hinder assessment
01 the exact nuclear size Tumour cel ls
may be intermingled wit h react ive sma ll
bmotoc vtes. mac rop hages, activated
microglial ce lls and rea ctiv e astro cytes.
large areas of nec ros is o r foamy
cvtes may be present , pa rticularly in
patients treated w ith high dose co rtic osteroids, This may result in so-called ' vanlShingtumours' ,
nrst.o-
Immu nophenotype
All tumou rs are positive for B-eell markers
C020, C022 or C079a, CO lO expression
is pre sent in approximately 10-20%,
BC L6 in 60 - 80% and strong IRF4/MUM 1
in appr ox imately 90 % 126 1, 324, 1305 1:
BCL2 express ion, not related to the
t( 14: t 8)(q3 2 :q21) , is freq uent 14531.
Cytogene tic abnormalities and oncogenes

Approximately 30-40% of CNS DLBCL
have BCL6 transiocattons bu t 1( 14;18 )
(q32:q21) and t(8: 14)(q24:q32) are ex trem ely rare 1453 1. There are common
de letions at 6q and gains at 12q , 22q and
18q 21 w ith co py number inc rea se or
amplification 0 1 BCL2 and MALT1 123681.
Homozygous or hemizygous d eletions at
9p21 freq uently affect CDKN2Alp1B"-'~
14531, Small deletions. not visi ble by convennonar comparativ e genom ic hybridization (CGH), affecl6p2 1.3 (HLA reg ion )
and contribute to loss of HLA class II and
I expression 1240 ,18431.

Ac tivated (late ger minal centre) B-eell.
The for merly poor prog nosis has been
rema rkab ly ameliorated by novel chemotherapeutic protocols that inc lude methotrexate . Most relapses affect the e NS. The
spo rad ic systemic relapses may involve
any organ but relatively frequently the
testis and b reast 110431. Ind ivid ual biological prog nostic fact ors have been desc nbed . but so far they have not bee n
va lidated in ind epende nt stu dies 1261.
324. 1767/,
Genetics
CNS DLBCL contalna very high load of
(ongoing) soma tic hypermuta tions (up to
27%) and a striki ng ma intenance 01 the
open readi ng frame 115031. A biased use
of VH ge nes , in pa rticu lar VH4/34 , suggests an antigen dependent prolifera tion.
Mutations also affect BCL6, PIM1 , MYC,
RhoH/TTFn and PAXS 115051 .
Primary diffuse large B-eelllymphoma of the eNS
241
Primary cutaneous DLBCL, leg type
Definition
A pr imary cutaneous diffuse large B-cel1
lymphoma composed exclusively 01large
transformed Beene. most corrmonly arising in the leg.
ICD-Ocode
968013
Epidemk>logy
Primary cutaneous diffuse large Bccell
lymphoma (PClBCL. leg type) constitute
4% of all primary cutaneous lymphomaS
and 20% of all primary cutaneous B-cell
lymphomas 124071 and typically occur in
elderly panents. in pa rticular in women,
with a M:F ratio of 1:3 - 4. The median age
is in the 7th decade 123341.
These lym phomas preferentially affect the
lower legs . bu t 10 - 15% arise at other
sites 11170. 1993,25021.

Clinica l features
PCLBCL, leg type presents with fed or

b luish-red tumo urs on one or both of the
lower legs 1824 . 1170, 2334, 25021. These
C,J. L.M , Meijer

B, Verg ier
L.M. Duncan
R. Willemze
lymphomas frequently disseminate to

extracutaneous sites ,
Histopatho logy
These lymphomas are comprised of a
monotonous, d iffuse, non-epidermotropic
infiltrate of confluent sheets of ceotrootasts
and immunoblasts, many with a striking
round cell morphology 1824, 23341 . Mitotic fig ure s are frequently observed.
Small B-ce Us are lacking and reactive
are relatively few and often conlined to perivascular areas
f ig. 1o.t1 Pnn1ar)' a.1aoeous DLBa., leg type, Typical

~bon WlIh Uro.n on a leg
t-eens
drical
1".,..mOllheootype
Genetics
The neo plastic Be ene express monotypic

Ig, C020 and CD79a, In contrast to primary
cutaneous follicle centre lymphomas
(PCFCL), PCL BCL, leg-type nearly always
strongly express BCl2, IRF4/MUM 1, and
FOX -P 11768 , 8 19, 826, 948, 950, t1701 ,
However, approximately 10% of cases do
not express either BCL2 o r IRF4/MUM l
11 170 . 19931. BCL6 is expressed by most
cases, wher eas CO l O staining is usually
neg ative 19501.
PCLBCL, leg-type show many genetic

similarities with diffuse large B-cell 1ymphomas (DLBCL) arisin g at othe r sites bU:
marked differences with PCFCL Interphase
FISH analysis 1874 1 frequently shows
na nstoceno ns involving c- MYC. BCL6
and IgH genes in PCLBCL. leg-type
Using array-based CG H and FISH analyses, high-level DN A amplifications of
18q 2 1.3 1-q 2 1.33 , including the BCL2
and MA LT1 genes, were d etec ted in 67%
of the cases 15771. Amplificat ion of the
BCL2 ge ne may well explain the strong
BCL2 expression in thes e cases, particularly bec ause the t( 14;18 ) is not found in
these lymphomas 1577 , 875 1. Deletion of
a small region o n c hromosome 9p21.3
co ntaining the COKN2A and CDKN28
gene loc i has been reported in 67% of
PCLBCL , leg -typ e,
PCLBCL, leg-type has the gene expressco
profile of activated B-eell-like DlBCll948l,
Peripheral B-cells of post-germinal centre
origin.
Prog nosis and predict ive factors
These lym phomas have a 5-year survival
ot ap p roximately 50% {82 4 . 23341. The
p resence of multiple skin lesions at diagnosis is a significant adv erse risk faclor
{8241. BCl2-negative cases have the
same prognosis. Inact ivation of CDKN2A,
either by deletion or promoter hypermethylatiOn. has been found to be an IS\'
favourable p rognostic tacto- 15771.
242
Mat ure B-c ell neoplasms
EBV positive diffuse large B-cell

lymphoma of the elderly
S. Nakamu ra
E.S. Jaffe
SH Swerdlow
Definition
70% of patients present with extr anodal
disease (most commonly skin. lung. tons il
and stomach) with or without sirrultaneous
lymph node involvement; 30% of pat ients
have lymph node disease alone /12 13.
16751,
EBV-POSlbve diffuse large B-cell lymphoma

(OlBCL) of the elde rly is an EBV. c lonal
B-cell lymphoid prolife ration that occurs
fl patients >50 years and without any
knOwn immunodeficiency or p rior lym-
11674, 1675.20111. Rare cases of

asiTlilar lymphoma may occur in younger
phoma
individuals; however, the possibility of an

t.r'ldiagnosed underlying immunodeficiency must be very strongly considered
e eese circumstances. Cases of lymphomatoid granulomatosis, infec tiou s

mononucleosis or other well-defined discoes (such as plasmablaslic lymphoma,
pnmary effusion lymphoma and DLBCl
associated with chronic inflammation) that
may be EBV + are excluded from this c atego<y
ICl>{) code
9680/3
Syronyms
Senile EBV-associated B-c elf Iympho-
proliferative disorder; age-related EBV.
Iymp hoprolifera tive disorder; EBV-associated B-cell lymp hoproliferative disorde r of

the elderly.
Epidemiology
In Asian countr ies. EBV. DlBCL of the

el derly accou nts for 8-10% 01 DlBCl
among p atients wi thou t a documented
p redisposing immunodeficiency 11675 .
16901. with little data for Western countries .
Among DlBCl. the proportion of EBY +
cases inc reases with inc reasing patient
ag e with the highest proportion seen in
those >90 years of ag e (20-25%) 116751 _
The median age is 71 years (range:
45-92 yea rs), with a male:female ratio of
1.4: 1.
Etiology
EBY-positive DlBCL 01the elderly is an
EBY-d riven Been lymphom a be lieved to
be rela ted to immunolog ic al de terioration
or senescenc e in immun ity that is a part of
the ag ing proce ss /1674, 1675, 20111.
Clinical features
The clinical features at presentation are
variable . More than half of the patients have
high or high-intermediate International
Prognostic Index (IPI) scores 11213, 1675,
1690.24731.
Morphology
The arch itecture of the involved tissues is
effa ced in contrast to infec tious rrooonucleosis. Although no longer considered to
be of clinical importance 116751. cases
were initially divided morphologically into
polymorphous and large-eell lymphoma
subtypes. both of which inclu de many
large transformed cellslimmunobl asts and
Hodgkin and Reed-Sternberg (HRSl-like
EBY posmve diffuse large B-eeillymphoma 01 the elderly
243
gian t cells. J he polymorphous subtype

shows a broad range of B-cell ma turation
and a variable component of reactive elements such as small lymp hoc ytes,
plasma cells, t usuocvtes and epithelioid
cells . In the targe-ceillymphoma sub type .
most of the cells appear to be transformed . Both subtypes may demonstrate
large areas of geographical necrosis and
the histology is often variable from area to
area. indica.ting a con tinuous spectrum
between the two subtypes.
lrrmunophenotype
The neoplastic cell s are usually positive
f()( C020 and /or C079a. and light chain
restriction may be difficult to demonstrate.
COlO and BCl6 are usually negative.
244
while IRF4/MUM 1 is commonly posi tive.

Cases with immunoblas l ic or plasmabla stic features may lack CD20 expression
and have delectable cytoplasmic immunoglobulin . The large atypical cells are
l MP1 and EBNA-2 positive in 94% and
28% of cases . respe ctively 11674.16751 .
The cells are variably CD30-positive . but
are CD 15-neg ative.
Genetics
Cnonanrv of the immunog lobulin genes

and EBV can usually be detected by
molecular techniques. These studies are
helpful for distinguishing the polymorphous
cases from infectious mononucleosis of
the elderly.
Postulated rormet cou1erpart

Mature B lymphocyte. transformed by
EBV
The clinical course is ag gressive. with a
median survival of about two years 11675.
16901. Neither IPI score nor histopatholog ic subtype affects prognosis. The
presence of B symptoms and age >70
years appear to be reliab le p rognostic
factors. Patients with O. 1 or 2 of these
factors have median overall survival limes
01 56 . 25 and 9 months. respectively
116751.
DLBCL associated with

chronic inflammation
J.K.C . Chan
K. Aozasa
P. Gaulard
Difluse large s -een lym phoma (DLBCl)

associated with chronic inflammation is a
lymphoid neoplasm occurring in the contextollong-standing chronic inllarTma tion.
and showing association with EpsteinBarr
(EBV). Most cases involve body
cavities or narrow spa ces . Pyothoraxassociated IyrrV'lcnla (PAL) is a prototypic
bm. and develops in the pleural cavity of
patients with long -standing pyothorax.
.,
wus
960013
Ep;demiology
The interval between the onset of c hronic
trfIarrwnatiOf1 and malign ant lymphoma is
usually over 10 years 1408, 1024, 10251.
PAL develops in pat ient s with a 20-64
(median 37) year history of p yothorax
resuning from arti ficial pneumothorax lor
treatment of pu lmonary or p leural tuber-
culosis 163. 1024 , 1568 . 173 4 1. Age at

dlagnosis ranges Irom 5th to 8th decad e.
W11t1 a median age around 65- 70 year s
l1568j. The mal e 10 female ra tio is 12 .3
11024) versus near unity for c hronic

~8.)(, suggesting thaI males are mor e
susceptible to this type of lymphoma than

females, Although most ca ses of PAL
beve been reported in Japan, this tymphona has also been desc ribed in the
West 188,1398, 17341,
Fig. 10.94 Pyoltuax-associaled~, MasM U!Iw' p ...... aw, SUffOlA'ldng !he'IIItoaie kJng
via Il-6 and u

. -s receptor 11095. 10981.
For OlBCl occurring in other sellings of
long standing chronic suppuralion/inl lammation, such as chronic osteomyelitis,
metallic implant or chronic skin ulcer, the
tested cases have been EBV-pos,tive
{408, 4711.
The com monest sites of involvement are
the pleural cavity (PAL), bone (esp ecially
l emur), joint and pe riarticular so ft tissue
14081. In PAL, the tumour mass is larg er
than 10 ern in more than half of the cases
1631. There is direct invasion of adja cent
structu res, but tumour is often confined to
the thoracic cavity at the time 01 diagnosis, with about 70% of patients presenting
with clinical stag e 111I d isease 115681.
PAL thus differs from primary effusion

lym phoma. which is charac terized by
lymphoma tous serous effusions in the
absence of tumour mass lormation.
Patients with rheumatoi d arthritis may
develop large Be en lymphoma around
chronically inflamed joints, but these
cases are EBV-negative. and probably best
not classified into this c ategory {8171.
Clinical features
Patients with PAL present with chest pain,
back pain , l ever, tumourous swelling in
the c hest wall , or respiratory symptoms
such as productive cough. haemoptysis
or dyspnea. Radiolog ic exami nation
reveals a tumo ur mass in the pleura
(80%), pleura and lung (10%), and lung
near the pleura (7%), The serum lactate
EOOIogy
ArMicial pneumothorax, used in the past
asa loon ofsurgical therapy for pulmonary

tuberculosis, is the only significant risk
factor for development of PAL amon g
ehronic pyothorax patient s (62. 960 1. PAL
is strongly associated with EBV, with
expression of EBNA2 and /or l MP1
klgethef with EBNA' 1739 , 1629, 1936,
2t471_The EBV latency pattern is type III
I'Irrore than 60% of cases 11734. 2 1461_
1hefe is probably a role for chronic
I'Iftanrnation at the local site in the pronterabOO of EBV-translormed B cells by
enabling them to escape from the host
rrm..ne surveillance through prod uct ion
d l1O,animmunosuppressive cytokine,
;ro~ autoeme to oeec-re growth
_l~
Tuberculous pleuritis
..
Ctvonic
pyOthOrax
(latent)
DevelOpment
otlymphoma
> 20 years
OlBCl associated with chronic inflarrrnation
245
...
.' .. ".
..
,. :. .
.,.
..
.
. . ,".. ,
, . ~.
.,
..
.'*
~~~r.i; I
..' . . '.V
. ;'.
~
-:.'"
~~~~~~~i , . .,. ..'~'
.
.
.
~
I
...~
t ..
, . ~
' ~"
io , .
..
....
-,
f . ...
.. I
. :
i S., . - I
. .
"'
. ": .
I
oo ,'
' \ lit' \
, '..
~.
..
\ .
... . .... '. '_"-ol. ' .t...

r.::::;-,;',;::::: : ' '. ., . "
,-
~.
"
f)
Flg.l0.96 Pyoltloralc-assoaated!yrT1lhoma. AMuse proliferatIOn al larye Iyrr1Ihoid cells WIth invrNJnoblastJc ~~. BTlIITll:U eels express COlO. C POSItive !q'lI15 It EBV
11 the nudeus of IurTna' eels by i'I situ hybrdzation WIth EBER probe.
dehydrogenase level is commonly elevated 11 568. 17341 .

Patients whO develop lymphoma in the
bone, joint, periar tic ular soft tissue Of skin
many years after lhe onset of chronic

os teomyelitis, insertion of metallic im plant
in a joint or bone, or chronic venous ulcer

usually pre sent With pain or mass lesion.
The invol ved bo ne typi cally shows lytic
lesions on radiologic e xa mination .
m!!I!lIHlmlll
.----
---.-- ,
--'-.
---e---
Flg.l0.t1 Patterns of gene e~ 11 PAL and I'kldal

dilluse larva lken lymphoma (OlBCl) are Signlficaly
dillel'lln\. ModrfJed Irom Nistiu et 1M. (15991_
246
The morphologic features are not different

from DlBCL NOS. Most cases ShOw cen troblastic{lfTVTlunoblastic morphology. with
round nuclei and large single or multiple
nucleoli. Massive nec rosis and ang locentric g rO'Nlh may be prese nt.
lmmunophenotype
Most cases express CD20 and C07 9a

However, a proportion of cases may shOw
plasmacytic differentiation, with loss 01
CD20 and/or C079a, and expression 01
IRF4/M UM 1 and CD1 38. CD30 can be
stimulation of jnterterco-c . in keeping Wllh

the role of chronic inflammat ion in this
cond ition. Down-regulalion 01HLA classI

expression. which is essential lor efficient
induction of host cytotoxic T lymphocytes
(ClL), and mutations of CTl e p tcoes in
EBNA-3B, an immunodomi nant antigen
for CTl responses, might also contl'lbutetl
escape of PAL cells from host CTlI1096,
1097 1.
EBV-transformed late ge rminal ce ntrel
po st-germinal ce ntre
a-cen
expressed. Occasional casesmay express

in addition one or more t- een markers
(C0 2, CD3 , CD4 and /or COl), causing
problems in lineage assignment 11516,
1568, 1734, 22471.
In most cases, ISH for EBV discloses

EBER expression, and a type III LMP1+!
EBNA-2+ latency profile 117341 .
Geneti cs
Immunog lob ulin g enes are clo nally
rea rran ged an d hy pe rmutated 114921.
TP53 mutation s are fou nd in about 70% of
cas es, usu ally involving dipyrimid ine
sites, which a re kno wn to be susceptible
to mutagenesis induced by ionizing
radia tion {960 I. Cytogenetic studies show
complex karyotypes with numerous numerical and struc tural abnormali ties 12 1471
The ge ne expression profile of PAL is d istinct from nodal OLBCl {15991. One of the
most d illerentially expressed genes is interferon-inducible 27 (/F/21). wh ich is
known to be ind uced in B lymphocytes by

OlBCl ass oc iated with chronic inflammati on is an aggressive lymphoma For
PAL. the 5-year overall su rviva l ranges
'r om 20-35% 11 568 , 15721. For those
achieving complete remission with
c hemotherapy and/or rad iotherapy, the
s-year survival is 50% 115681. Complete
tumour resection (pleuropne umonec tomy
wi th o r w ithout resec tion of adjacent
involved tissues) has also been reported
to give good results 115601. Poor performance status, high se rum levels of
lac tate dehydrogenase. glu tamyl pyruvic
transaminase or urea , and advanced
clin ical stage are unfavourable prognostic
fact ors 16 1, 15721.
l ymphomatoid granulomatosis (LYG) is
an enqccentnc and anctocestrucnve

tyr1ltlOprOIderative disease involving extranodal sites. composed of Epstein-Bar r
virus (EBV}-posilive 8 cells admixed with

rea;tJve Tcells . which usually preconoate.
The lesion has a spectrum of hislological
g"ade and clinica l aggressiveness, which
IS/elated to the proportion of large B celts.
with underlying immunodeficiency are at

inc reased risk {86 1. 8881. Pred isposing
conditions include allogeneic organ transplantation, wiskon-Aioncn syndrome,
human jrrmcrcoeucencv virus (HrV) infection and x-unkeo Iymphoproliferative
syndrome. Moreover. pat ients presenting
without evidence 01 underlying immunodeficiency usually manifest red uc ed immune function upon carelul clinical or
leooratov analysis 12053. 24201.
976611
Lymphomatoid granulomatosis is a fare

It usually presents in adult life.
blt may be seen in c hild ren with immuno-
conclr{lOI'l .
0Ektency disorders. It affects males more

often thanfemales (M:F ratio ~: 1 ) 11 1211.
appears to be morecommon in western
countries than in Asia.
EbOogy
L~toid granulomatosis is an EBVdnYen Iymphoproliferalive disorder. Patients
F'II_11.91 ll'ftlPhomalold granuIomalosis
A LlII19
MwIld bfWUr\iklid ~_ Large I'I:ll1JIe5

... tn'il cMallon. B Large nec:tOtIl: noduIe$ are
..,brd"lle k4'ley.
Sites of invotvement
Pulmonary involvement occurs in over
90% 0 1 patients and is usually present at
initial diagnosis . Other common sites of
invo lvement include brain (26%), kidney
(32%), liver (29%) and skin (25-50%).
Upper respiratory tract and the gastrointesunartract may be affected, but are relatively uncanmon 14931. Lymph nodes and
spleen are very rarely involved 11 04 2.
1121,1182, 14461.
Clinical featu res
Patients frequ ently present with signs and
symptoms related to the respiratory tra ct.
suc h as co ugh (58%) , dy spnoe a (29%)
and c hest pai n (13%). Other co nstitutional
symptoms are common , including fever,
malaise , weig ht loss, neu rologi cal sympto ms , arthralgi as , mya lg ias and ga strointest inal sy mptoms . Patients w ith cent ral
nervous system disease may be asymptomatic or have var ied pr esent ation s depe nd ing o n the site of invo lvement suc h
as hearing loss, d ip lopi a, dy sarthria ,
ataxia and/or altered mental status 1170 71
Few pa tients present with asym ptomatic
disease 5%) 110421
Macroscopy
Lymphomatoid granulomatosis most commonly presents as pulmonary nodules
that vary in size. The lesions are most
often b ilateral in distribution, involving the
mid and lower lung fields . Larger nodules
freq uent ly exhibit central necrosis, and
may cavitate. Nodular lesion s are found
in the kidney and brain. usually associated with central necrosis . Skin les ions
are extremely d iverse in appearance.
S. Pittaluga
W.H. Wilson
E.S. Jaffe
Nodular lesions are found in the subcutaneous tissue. De rmal involvement may
also be seen . sometimes with necrosis
and ulceration . Cutaneous plaques or a
rrecuooaouiar rash are less COlTVTlOI1 cutaneousmanifestationsl170. 1042. 1121.
14461.
L ymphomatoid granulomatosis is characterized by an angiocentric and anqooestructive polymorphous lymphoid infiltra te

11 121. 11821. Lymphocytes predominate,
and are admixed with plasma cells, immunoblasts and tustocvtes. Neutrophils
and eosinophils are usually inconspicuous.
The baCkground small lymphocytes may
show some atypia or irregul arity. but do
not appea r overtly neoplastic. Lymphomatoid granulomatosis is composed of a
variable, but usually small, number of
EBYpositive B cells admixed with a
promi nent inflammatory bac kg round
1861, 11221. The EBY-pos itive c ells usually
sho w some atypia. They may resemble
immunoblasts or, less commonly, have a
rroreoeonopnc appearance reminiscent
of Hod gkin ce lls. Mu ltinucleated forms
may be seen. Classical Reed -Sternberg
F*IQ. 1U9 l ympllomaDd granUomakJsis. Chestra

graph ldentifles rrdbpIe nodules, mainly aIIed;ng !he
tower U1gflekls.
247

cells are gen erally not pr esent. and if
seen. should raise the possibi lity of
Hodgkin lymphoma. Well-formed granulomas are typ ic ally absen t in lung and
most other extrarocat sites 11 3171. However, skin lesions often exhibit a prominent
gran ulomatous reac tion in subcutaneous
tissue 11701.
Vascular changes are prominent in lymphomatoid granulomatosis. Lymphocytic
vasculitis, with infiltration of the vascu lar
wall is seen in most cases. The vascular
infiltrahon may compromise the vascular
integrity, leading to infarct-like tissue
necrosis. More direc t vascular damage in
the form of fibrinoid necrosis is also cornmon, and is mediated by chemokines induced by EBV 121651. Lymphomatoid
granulomatosis must be dist inguished
from extranodal NK/T-cell lymphoma.
nasal type, which often has an aoqiodestrucnve growth pattern, and is also
associated with EBV 11037).
Grading
The grading of lymphomatoid qranuiomatosts relates to the proportion of EBVpositive B cells relative to the reactive
lymphocyte background 1862, 13 171. It is
most impo rtant to dis tinguish gr ade 3
from grade 1 or 2. A uniform population of
large atyp ical EBV-posilive B cells without
a polymorphous background should be
classified as diff use targe B-cell lymphoma. and is beyond the spec trum of
lymphomatoid granulomat osis as currently defined ,
Fig. 10.100 CutroeoA manilestabon aI ~

shorIwlg sutx:uIaroIlM inlihbon, WlIh
lal necrosis 1d a ~ response.
~.
248
Fig. 10,101 lymphomatoid granulomatosis. ... Grade I lesion of ltle king shows a potymorpnous infiltrate n lhe
vasculard . 8 A Qade mlesion oIlhe brlIlIl(X)rQlns runerous largelraIlSbll iid Iymp/loid eels, C These eels IN
positive lor Epstoo-Barr virusby in $Au Il)tInlZalJOO .... 1tle EBER prnbe. 0 ~ pleoo1aphic eels may be seen.
mostcommonly n Grade 111 lesions. rarety in Grade II.
Grade 1 lesions contain a polymorphous

lymphoid infiltrate without cytologic atypia.
Large transformed lympho id cells are
absent or rare. and are bett er appreciated
by immu nohistoc hemist ry. Necrosis is
usually focal, when prese nt. By in situ
hybridization with EBER probe only infrequent EBV-positive c ells are identified 5
per high po wer field) 124201 In some
cases, EBV-positive ce lls may be absent,
but in this setting the diagnosis should be
made with caution , with studies to rule out
other inflammato ry or neoplastic c ond itions.
Grade 2 lesions cont ain occ asional large
lymphoid cells or immunobla sts in a polymorphous background . Small clusters
c an be seen espe cia lly by C020 stain,
Necrosis is more commonly seen, In situ
hybridization for EBV readily iden tifies
EBV-positive cells, which usually number
5-20lhigh powe r field . A variation in the
number and distribution o f EBV-posi tive
cells ca n b e seen within a nodule or
among nodules. and occasionally up to
50 EBV-positive cells/high power field can
be obs erved.
Grad e 3 lesions still show an inflarrmatory
backgroond , but cont ain large atypical B
cells which are readily identified by COlO
eoo can form larger aggregates. Markedly
pleomorphic and Hod gkin-like cells are
often present, and necrosis is usually
extensive. By in situ hybri dization, EBVposit ive cells are extremely numerous
(>50lhigh power field) , and focally may
form small con fluent sheets. It is important to take into co nsideration that in situ
hybridization for EBV c an be unreliable
when large areas of necrosis are present
due to poor RNA preservation; additional
molecular studies for EBV may be help ful
Immunophenotype
The EBV-positive B ce lls usually express
C0 20 1862, 2159 , 24201. The c ells are
variably positive lor C030, but negative
for C0 15. LMP1 may be positive in the
larger atypi ca l and more pleomorphic
ce lls. Stains for cy toplasmi c immunoglobulin are frequ ently non-informative,
although in rare cases monoc lonal cytoplasmic immunog lobulin expression may
be seen, part icu larly in cells showing
plasmacytoid differentiation 1242O}, The
backgroond lymphocytes are C03-positive
T cells. with C04+ cells more frequent
than COB+ cells.
Genetics
In most cases of Grade 2 or Grade 3 disease . clonality of the immunoglobulln
genes can be demonstra ted by molecular
genetic techniques {861. 14461. In some
cases different clonal popul ations may be
identified in different anatom ic sites
11490. 24201, .Southern blot analysis also

may show clona lity of EBV {1448 1. Demonstration of c lona lily in Grade 1 cases is
more inconsistent, an observation which
may be related 10 the relative rarity of the
EBV-positive cells in these ca ses . Alte rnatively, some cases of lymphomatoid
granulomatosis may be poivctonar. t -een
receptor gene analysis srows no evidence
ofrnonoc looalily 11446 , 14481. Altera tions
at oncogenes have no t been identified.

Mature B lymphocyte. uenstorreo by EBV
Prognosis and predict ive factors

Some patients follow a waxing and waning
clinical course wit h rare spontaneous
remission s wi tho ut the rapy However, in
most patients the disease is more agg ress ive , with a median survival of und er
two years based on historical series 11121 1.
More recent series have shown responses
to aggress ive chemotherapy w ith rttuximab for g rade 3 lesions. Grade 1 and 2
lesions usually achieve durable responses
to mterteroo -c 2b 124201. l ym phomatoid
g ranulomatosis ma y progress to an EBV+
d iffuse large B-ceil lymphoma (DlBCl).
Althoogh some patients with grade 3 lympho mato id granulomatosis may show
spontaneous reg re ssio n with immunotherapy or modification of the immune
state. for clinical purposes these patients
should be approached as diffuse large
B-ceil lymphoma 124201.
lymphomalOld granulomatOSIS
249
Primary mediastinal (thymic) large

B-cell lymphoma
Definition
A diffuse large Bcemvmprorre aris ing in
the mediastint.rn from putative thymic Been
origin with distinctive clinical, immunophenotypic and genotypic features.
ICD-{) code
9679/3
Synonym
Mediaslinallarge Bc eli lymphoma .
Ep;demlology
Primarymediastinal large B<el11ymphoma
(PMBl) accounts tor 2-4% of non-Hodgkin
lym phomas (NHllI 150. 3501 and occurs
pre dominantly in young adults (median
age. -35 years) with a female predominanc e (M:F ratio, about 1:2) 1350. 1257,
1943, 25001.
PMBL most likely arises within the thymus.
Patient s p resent with a loca lized antero-
superior mediastinal mass. The mass is

often "bu lky and frequently invades adjacent struc tures such as lungs. p leura or
pe ric ardium. Sprea d 10 sup racl avicular
and cervi cal lymph nodes can occur
(150, 350, 1257}. Ab sence of other lymph
node or bo ne marrow (BM) involvement is
a pre requisite 10 excl ude a systemic
DlBCl with secondary med iastinal involvement.
Clinical features
Symptoms are related to the medi astinal
mass, frequently with supe rior ven a ca va
syndrome, B symptoms may be present.
P. Gaulard
N.l. Harris
SA Piled
J.L. Kutok
At progression, dissemination to distant

extranodal sues incl uding kidney, adrenal.
liver or cen tral nervous system is relatively
common but BM involvement is usually
absen t.
PMBl shows a wide morphologicaVcytological spectrum from case to case

117121. II is commonly associated with
compartmentalizing atveotar fibrosis 1150.
are
350. 1499.1712,17441. Tumour
medium-size d to large cells with abundant pale cytoplasm and more or less
regular round or ovoid nuclei. In some
cases, lymphoma cells have pleomorphic
and/or multilob ated nuclei which may resemble Reed -Sternberg cells and raise
suspicion of Hod gkin lymp hom a (Hl)
11712, 22651. Rarely, there are "grey
zone" borderline cases combining teatures of PMBl and classical Hod gkin lymph oma (CHl) or c ases 01 composite
PMBl and CHlI22651.
F"'ll.10.103 PnmatymeliastJnat1arge8<:el ~
cens
Irrmunophenotype
PMBL expresses B-cell antigens such as
CD 19, CD 20. CD22 and CD79a, but, as a
rule, lacks immunoglobulin (Ig) 1150, 1092,
1328, 17441. CD30 is p resent in mo re
than 80% of the cas es, however, usually
weak and heterog eneous, co mpared to
Hodgkin lymph oma 1938, 1744 1, CD 15 is
occasionally present 115001. Tumour cells
are freq uently posi tive for IRF4/MUM1
(75%) and CD23 (70%), have variab le expression of BCl2 (55 - 80%) and BClS
(45- 100%) and CO lO is less common
CIA weee str::Mlg Aeshy ILmw' \ffllh necrosis.
(8-32%) 1311. 520, 17441. Tumour cells

are also positive for MAL antigen, CD54
and CD95. coexpress ffiAF1 and nuclear
REL 1470, 472, 185 7l. Variable defects in
the expression 01 HLA class I and/or class
II molecules have been found in most 01
the cases 11498. 1500 1.
Genetics
Imm unog lob ulin genes are clonally rearranged with a high load of somanc
hypermutations without ongoing mutational activity 11 270 ).
Cytogenetic and oncogene abnormalities

Compa rative genomic hybr idization
(CGH) demonstrated gains in chromosome 9p24 (up to 75%) and 2p15
( - 50%), but also in chr omosomes
XP11.4-2 1 (33%) and XQ 24-26 {33%l
[192, 1072,23931. Candi d ate genes include REL and BCL 11A (at 2p ), which are
amp lified in a pro po rtion of PMBL [2387,
Fig, 10,11)2 Pnmaty meciII5tlrl8I large 8<:eI ~, A Nuclei are lW'ld (centroI:llasl-Q) or someIines rTJ.IIlIlobated.
by ooIlIgenous Iilrosil. C Medium-silecI eels with large pale cyklplasm.
$epllIil1ed
250
H. Stein
A.M Kovrigina
E S, Jaffe
P. MOiler
2389). and J/iK2 , POL 1and PDL2 (at 9p)

11072,1459,18701. Nuclear acc umulation
of REl protein is common 11 857 , 23871
with an impe rfect correlation with REL
amplification and AEL transcr ipt ab undance 1701, 23871.
PMBL has a unique transcriptional signature, but shares featu res with CHL 11870,
19441. PMBL has consti tutive ly ac tiv ated
NFt;B 17011 and JAK-STAT signaling pamways 1864. 1459 1, frequently related to
Inactivating muta tions 01 SOCS111459,
23881.
Rearrangements 01 BCl2. BCL6 and M YC
genes are absent or rare 11944 . 1953 .
22711 whereasoecnvatco 01 P
and
TPS3genes have been reoortec {19531.
The discordant expression of components
of the B-cell receptor (BC A) (CD79a +.
slg-) is characteristic 01 PMBL 11092 .
'fI'-
1328. 17441. It cannot be ascribed to a
lack of functional/G gene rearrang ements
nor to a defect
in the transcription lactors
BOB.t , OCT2 and PU. 1{ 1328, 17441 but,

rather, to a downregulation of the intronic
heavy chain enhancer 118481 or posteenecrouonnar blockage / 13281.
~ medullary, asteroid , (AID-positive) ,
8-<:eIl 1953. 1016, 1494 J.
Variations in mic roscopic appe aranc e do
not predict d ifferences in survival 11712/,
Response to inten sive c hemo therapy ,
with or without rad iothera py, is usually
poco. Extension into ad jacent thorac ic
vscera, pleural or perlca roial effus ion and
poorperlormance status (350, 1257,1943)
Mas been associat ed with a poo r prognosis, According to recent stud ies, outc ome
ofPMBL patients is at least equ ivalent to
or superior to that 01other DLBCL pa tients
(350. 1943, 25001with a pla teau seen in
the sorvivat c urves bey ond 2 year s
/1943), In addi tion, the PMBL mo lec ular
signature was associat ed wi th a more
favourable survival (compa red to Gce
ar.cl ABC DLBCL) 118701. su p po rting a
esect naiurat history for PMBL.
Fig. 10.107 Primary mediaslinal Iafge Ek::eIIlympl'loma A Most tumour cells express
express MAl. with a L)'loplasmlc re.nloroemenl in lhe Golgi area
con
8 Tumour cells also
Primary mediastinal (thyrmc) large B-celllymphoma
251
Intravascular large B-cell lymphoma
S, Nakamura
M. Ponzon i
E. Campo
Definition
ratio of 1.1:1. The frequency and clinical

p resentation differ accord ing to the geographical origin of the pa tients between the
West and the Far East {621. 694 , 15451.
h.mina of vessels , particularty capillaries,

with exception of larger arteries and veins.
Intravascular large a-cen lymphoma

(lVLBCL) is a rare type of extranodallarge
B-ceil lymphoma characteri zed by the selective growth of lymphoma cel ls within the
ICG<l code
97 1213
This lymphoma is usually widely d isseminated in exnarooat sites including bone

ma rrow (8 M) and may present virtually in
any organ. However, lymph nodes are

Synonym
usually spared ,
Angiotropic large cell lymphoma.
Clinical features
Epkl~
This tumour occurs in adul ts (median. 67

years; range, 13 - 85 years) and with a M :F
Two major patterns of clinical presentation

have been rec og nized , a Western form
c harac terized by symp toms related to the
eels .
main organ involved . predominantly neur0logical or cutaneous, and an Asian variant

in wh ich the patients present with mumorgan failure, hepatosplenomegaly. pancvtcoeoa and _ _ syrd"""".
These presentations are seen more treQuently, although not exclusively. in Western and Far East countries. respectively
162 1, 69 4. 1544, 1545 , 17681. B symptoms are very common (55-76% of patients) in both types 01 presentation. An
isolated cutaneous variant has been identified invaria bly in Western females; it is
characterized by limitation of the turncu
to the skin and is associated with a better
p rognosis 16931. Conventional staging
F'15I10.1081nr.tYasoAar large B-oaIIyrlVana. A The largeWona

!he llin lrir/II~) n capIaty (I8ft~. B The Iarglluncu eels are presenl,, !he SQISe5
fA hl booe marrow. hMlg abl.nQInt t)'tIpIasm ~ a Il'O'e 01 less JTecPar rudeus. C The large~ celliNIh ID.Jses 11 tle adrenal gland. 0 The IiIrge Uro:r
eels Ir8 P'esenl ll !he Unen fA smaI ~ 11 !hecernI rlllI"IWS syslem
252
Mature
a-ces neoplasms
'...->.
procedures are generally associated with

a high proportion of false neg atives b ecause of the lack of detectab le tumour
masses.
~
The neoplastic lymphoi d cells are mainly
lodged in the lumina of small or intermediate vessels in many organs. Fibrin
ttrombi , haemorrage and necrosis may be
observed in some cases. The tumour
cells are large with prominent nucleoli and
trequenl mitotic figures. Rare cases have
cells WIth anapl astic featu res or smaller
size 117691. Minimal extravascular joceIial 01 neoplastic cess may be seen. SirosoidaI involvemen t occurs in the liver,
8M 117691. Malignant cells are
occasionally detected in peripheral blood
sceenard
""'-'>op/lero
Tumour cells express B-cell-associated
antigens. Co5 and CotO coespresson is
seen in 38% and 13% 01 the cases,
respectively. Almos t all 01 Co1~neg ative
Fig. l0.l 09 Skin involved by intravascula r

....,..,.
large B-cell
cases are IRF4/MUM 1 positive. Anecdotal

cases of intravascular T-cefl or NK-eell ~
phoma have b een report ed 12145 1. bu t
they shou ld be considered a different
entity.
The intravascular growth pattern has been
hypothesized to be secondary to a defect
in homing receptors on the neooiasnc cells
1698}. such as the lack of C029 (lJ1 integrin) and C054 (ICAM-1) adhesion P-moIaculesj 1766}.
Genetics
Immunoglobulin ge nes are clonally rearranged. Karyotypi c abnorma lities have
been described but too few cases have
been stud ied 114951 .

Transformed peripheral B-cell .
This is an aggressive lymphoma which responds poorly to chemotherapy 1692}. The
poor prog nosis reflects in part frequent
del ays in diagnosis due to the protean
pr esentation. Neither clinical types 01
prese ntation nor clinical parameters predicts patient survival, with the exception 01
the b etter prognosis for the c ases with
disease limited to the skin 1693, 17681 .
Intravascular large 8-celllymphoma
253
ALK-positive large B-cell lymphoma
G_ Delsol
E. Campo
AD. Gascoyne
Definition
ALK positive large B-ce ll lymphoma
(ALK-positive LBCL) is a neopl asm of
AlK-posi tive mooomorphic larg e immunoblast-like B cells, sometimes with erasma blaslic di fferentiation.
ICD-O code
9737/3
Synonyms
Large B-eell lymphoma expressing the
ALK kinase and lacking the 1(2;5) transl ocation; AL K-positive piasmatnesnc B-eell
lymphoma.
Epidemiology
This lymphoma is very rare 1% of
DLBC L) . w ith less than 40 c ases so fa r
been repo rted 1183 11. It seem s to occur
more frequ ently in ma le adu lts (M :F ratio,
3:1) and sp ans all age group s (9-70
years ) (med ian, 36 years) 118311.
The tumour mainly invotves lymph nodes
{9, 553, 761 , 1023, 1831,20751 or present s
as a medi astina l mass {527. 7881. Involvement of extranodal sites have been
also reported includin g na sop har ynx
11 644 1. to ngue 1527f, stomac h {1444j.
bone 1164-t) and soft tiss ues 14 171,
Cl inical featu res
Most pat ie nts prese nt with advanc ed
stage Ill/IV.
na.
10.112 ALK-posibve large B-eeil lympnoma, morpnologic features A T~re is massive invasion of lymphatic
sinuses B Neoplastic cells show immunoolastic and pla smablastic features
MO'Phoklgy
This lymphoma shows a sinusoid al growth
pattern and is composed of rrooororptuc
larg e imm unobtast- like cells with round
pa le nuclei co ntaining la rge central nu c leoli and abundant cytop lasm. Some
cases show plasmablastic differentiation
{553 . 761 1_Atypical multinucleated neop lastic g iant cells may be seen .
Immunophenotype
Lymphoma ce lls are strong ly positive for
ALK prot ein wi th a restricted g ranul ar
c yto pl asmic stainin g pa ttern highly ind icative of the exp ression of CLTCAL K
p rote in. Few c ases may show cytoplasmic, nucl ear and nucleolar ALK staining
associated with the NPM-Al K protein. In
adcIition,lhey also characteristically sl1rXr:jy
express EMA and plasma cell markers
such as CQ138 and VS38, being negative
for lineage-associated leukocyte antigens
(COO, C020, C079a) 1283, 553, 1962, 1963.
2075} . C0 45 is wea k or negative 1553.
761}. C030 is negative 1553}, although focal
and weak staining has been reported in
few cas es (2075] Most tumours express
cy top lasmic Ig (usually IgA, mo re rarely
IgG) with ligh t ch ain restrict ion 1553). As
de scri be d in some p lasma c ell tumours,
FIi- 10.111 IrrmJnoptlenoIype ofALK-posilive Iaf9lI ~ 1)mI:tloma. The turroor eels arepositive forEMA (A)WIth a CjIOpIasmiCmembranous pattem.IgA(BI. and ALI( (C} .....
a ntStricled CjIOpIasmiC~ pattem tir;;IIy iJclic3Iived \he e~ of \he CLTC-ALK fusion protein.
254
occasion al c ases are positive for c ytokeratin which, in addilioo to EMA posi tivity
and weak/negative staining for CD45,
may lead to the mista ken diagnosis of
carcinoma 120751 The tumours may be
also positive for CD4, CD57, IRF4/MUM1
120751. focally for CD43 120751and perIorin120751.
These tumours shoul d be distinguished
from CD30-po sitive AlK-positive T/null
eneoiastc large cell lym p homa and other
large B-ceil lymphomas with a sinusoidal
growth panern . and AlK-negative imrronoblasticlplasma blastic lym p homa s,
such as those involving the oral ca vity in
Hrv+ patients 14591.
Genetics
The immunog lobulin genes are clonally
rea rrang ed 1417, 761}. This tumo ur may
ex press full-leng th ALK 1553} b ut the key
oncogenic facto r is the AlK fusion p rotein
due to genetic alteration of the ALK locus
on chromosome 2. The most freq uent abnormali ty is the t(2;17Xp23;q23) respo nsible for Clathrin-ALK (CLTC-ALK) fusion
protein 1417 , 527 , 761 , 788 , 1023, 1444,
1831}. Few cases are assoc iated with the
t(2;5 Xp23 ;35) as de scr ibed in AlK-posjrive TlNull anaplastic large cell lymphoma
(AlCl ) 19, 16441. A c ryptic insertio n of
3'ALK gene sequences into chromosome
4q22-24 has a lso been repor ted 120751,

Post-germinal centre B cell with plasma
cell differentiation .
The overall median survival of high stage
III/IV patients was 11 months 118311. Long
survival (> 156 months) has been reported
in children 1553, 16441. These tumour s
are usua lly negative for CD20 antigen and
are thus insensitiv e to ntuximab.
AlK-positrve large B-eeillymphoma
255
H. Siein
N.l. Harris
E. Campo
Definition
P1asrnablastic lymphoma (PBL) is a diffuse
proliferation of large neoplastic cells most
of 'Nhich resemble B immunoblasts, but in
which all tumour cells have the immunephenotype of plasma cells. It was origina lly
described in the oral cavity but may occur
in other, predOminantly extrarooat sites .
ICD-O code
973513
Epidemiology
PSL is uncommon. It has its highest incidence in j-uv-ocenve individuals. predominantly males It may also be associated
with other immunodeficiency sla tes, including advanced age. The median age
at presen tation is around 50 years , with a
broad distribution, but mainly anecnnq
adults. Rare cases are seen in chi ldren
with immunodeficiency 1459. 5471.
Etiology
Immu nodefic iency. caused in the majority
of cases by HIV, predisposes to the

development of PBL Other causes 01
immunodeficiency such as iatrogenic
immunosup press ion for autoimmune drsease or prevention of po st-transp lant trie rapy a llog raft rej ec tio n may also be
impl icated, There are also cases w ithout
any history of immunodeficienc y, but those
pa tie nts tend to be elde rly. The t umo ur
cells are EBV-infected in the majority of

patients 124 1, 459 . 547 , 6041 .
PBl presents most frequentty as a mass in

the oral c avity, but it is also encountered in
other extrarocat sues -particularly mucosal sites- including the sinonasal cavity. orbit . skin. bone. soft tissues and
gastrointestinal tract. Nodal involveme nt
is seen but it is not corrvnon 1459 . 547 ,
6041. Ptesmabrestc lymphomas not associ ated with HIV-inlection present more
commonly in lymph nodes.
Clin ical features
Most pati ents are at an advanced stage
(ItI or IV) at presentation 1459, 547 , 6041 .
The inte rnational oroqrosnc index (IPI) is
01 inte rmediate or high risk score. Computed tomography an d positron emission
tomogr aphy may show d isseminated
bone involvement 121841 . Tumours with
features of PBL may occur in patients with
p rior plasma celt neoplasms, including
p lasma c ell mye loma . Such cases should
be co nsidered p lasmab lastic transform ation of my elo ma and d isting uished from
primary presmabrastc lym phoma.
Morp holog y
PBL show a morp holog ic al spec trum
vary ing from a ditluse and c ohes ive
prolife ration of cells resembling immunoblasts to cells with more obvious plasmacync differentiation, which may resemble
cases of prasmabtasnc p lasma ceM
myeloma. Mitotic ligures are frequent
Apoptouc cells and tingible body macrophages may be present. but are generaly
less prominent than in diffuse large B-eel
lymphoma. Cases with monomorphic
p1asmablastic cytology are most cx::mnc:ny
seen in the setting of H IV-infec lion and i'l
the oral. nasal and paranasar area (oral
mucosal type). Conversely, cases 'Mth
plasmacytic differentiation tend to OCClJ"
more corrmonly in othe r extranodaJ sues
as well as lymph nodes 1459 . 5471. The
differential diagnosis in the cases with
crasmacvnc differentiation may incluce
anaplastic or plasmablastic p lasma eel
myeloma, The presence of a high prolif
eranon fractioo, extranodallocalization, a
history of immune de fic iency. and the
presence of EBV by in situ hybridizahO"l
for EBER are useful in esta blishing the
d iag nosis of orasmabtasnc lymphoma
Immu nophenotype
The neoplast ic cell s ex press a plasmace ll ph enotyp e includ ing positivity for
CD t38 , CD 38, Vs38c and IRF4/MUM1
and are negative or only weakly positive
for CD45, C0 20 and PAX5. CD79a is pas.
itive in appoximately 50- 85% of the cases
F"tg. 10.tt3 It Plasmablaslic Iyr'I1Ihorna of the orallTUCOSilllrilh a ITlOlllJlmlll/liC prokIefalion of large.1mulobIastIc eels MIl promrlflflI oocleoIi. B PIasmabIasbc lymphoma"
plasmacytic dlllerenlialiOn. The Iur'ncU cells are large with rtu'Id nudei and showing coarse d'lnlfIIIbn and smaller or unapparenl nudeoIi. Smaller eels wrlh ~
<i!Ieranliabon arepresent.
256
Mature B-ceU neoplasms
Cytoplasmic immunoglobulins are expressed in 50 -70% of the cases, most

Ireqoefltty IgG and either kappa or lambda
ig ht chain. C056 is usually negative in
ee oral mucosal type of PBl , bu t may be
seen in cases with plasmacytic differentiation. The expression of C056 should
rai se suspicion for underlying plasma cell
myeklma. EMA and CD30 are frequently
expressed. K167 index is usually very high
(>90%). EBV EBER in situ hybridization is
in 60-75% of the cases but LMPl
ccseve
is rarely expressed. The rate 01 EBV-positivity is nearty 1(}()% in the oral mucosa!
type 01 PBL, in association with HIV-infeclion. H HV8 is consistently absent 1459 .

Plasmablast. r.e. a blastic proliferating
B-celt thaI has switched its phenotype to
the plasma cell gene expression program.
547,604,23191_
Genetics
Clonal IgH chain gene rearranqement is
demonstrable , even when irrmunoglobulin
expression is not detectab le , and the IgH
genes may show evidence of somatic
hypermutation or be in an unmutated
con figu ration 1744 1.

The c linical course is very aggressive Vvith
most of the pat ienls dying in lhe first year
atter diagnosis 1459, 547, 6041, although
the outcome may have imp roved more
recenuv possibly due to a better management of HIV infect ion 121841.
Ptasmablastic lymphoma
257
..
Large B-cell lymphoma arising in

HHV8associated multicentric
Castleman disease
De finition
Large B-cell lymphOma arising in human
herpes virus 8 (HHV8)-associated multicentric Castleman disease (HHV8 MCD) is
composed of a monoclonal proliferation 01
HHV8-infected lymphoid cells resembling
plasmablasts expressing 19 M and arising
in the selting of multicentric Castleman
disease (MCD) . It is usually associated
WIth nenan immunodeficiency virus (HIV)
infec tion . The term plasmablas tic is used
for this lymphoma because the cells mor-
phologically resemble plasma cells and

have abundant cytoplasmic immunoglobulin : however II corresponds to a naive,
19M-p roduc ing plasma cell without fG
somat ic hypermulation . This lymphoma
must be distinguished from p lasmablastic
lymphomas presenting in the oral c avity
or other extrenooat sites that frequently
sho w class-switched and hypermutated
JGgenes
ICD-Ocode
The p rovisional code proposed for the
fou rth edition of ICD-O is 9738/3.
PG , Isaac son
E. Campo
N .L. Harris
in 'Nhic h rarely It mani lests as a leukaemia

1627, 16381.
Clinical featu res
On a ba c kg round of the cnorcatteamres
of HHV8 CD , patients 'Nho are developing
HHV8 PL present with p rofound immunod efic ie ncy, enlarging lymph nodes and
massive splenomegaly otten eccoroanec
by manifestations of Kaposi sarcoma
1627, 1638}.
MOfIlhology
HH V8-positive mufticentric Castleman
disease
The B-eell follicles of lymph nodes and
spleen show varied degrees of involution
and hyalinization of their ger minal cen tres
with a pr ominent mantle zo ne that may
int rude into the ger minal cen tres and
complete ly efface the m . Amo ng these
mantle zone cells, there are variable numbe rs of larger plasmab lastic c ells with
dense amphophilic cytoplasm and vesicular, oflen eccentrfcenv p lac ed , nuclei
Fig. to.m HHV&-pos4lYe pIasmabIastlC Iyn'VlI:ma

Wrighl.Qemsa stained UnOlJ' eels in pefllIleraI blood.
con taining one or two prominent nucleoli.

Similar cells may be scattered in the
interfomcurar area which, in addition, is
heavily infiltrated by mature plasma cells
As the disease progresses, the ptasmablasts coalesce to form confluent
mic roscopic clusters (so-called microlymphomas) and sheets both within and
outside the germinal centres 16271.
Synonyms
HHV8-p ositive p lasmab lastic lym phoma
(HHV8 PL), Kap osi sarcoma herpes virus
(KSHV)-po silive p lasmabl astic lymphoma ,
Epidemio log y
HHV8 PL occurs worldwi de in HIV-po sil ive
patients who have develop ed HHV8 Mc a ,
It less commonly occurs in HIV-neg ative
pat ients who have d evelop ed HHV8 MCD
usually in reg ions whe re HHV8 is end em ic
(Af ric a and Med iterranea n coun tries)
12501.
Etiolog y
The neoplastic cells are positive for HHV8
in all cases. HHV8 encodes more than ten
homologues to cellular genes that provide
proliferative and anu-aooptouc signals
159,84 ,9 1, 10491.
The lymphoma characteristically involves
lymph nodes and sp leen but can crsseminate to other viscera via the blood stream
258
Mature B-c elt neoplasms
f$;~:li"":':"''::-'",,~;j~il-lioi:lIll' """"...",,0iiI'. . '. . ..
Fig. 10.116 HHV6-positive n1J1bc:errtrJc cas1l9man lisease. A The Ik:8I tilde WIth a IIOITlIiII genIWIII cenR ISU
I"OI.I'lded by a broad mantlezone. B ManIIe zone corUInsscattered plasmablasts. C This B<:eI lolIide shows pai1II
hyalftzalion 01 the germnaI centre WIth Bn atleoual8d manlle zone, D Gem.1aI centre contaiIWlg l'UTleI'OUl
...
~""",-
HHV8-positiv,e plasmablastic lymphoma

The emergence of frank lymp homa is heralded by expansion of the small confluent
sheets of HHV8 latent nuclear an tigen 1
(LANA- 1)-pos ihve plasmablasts to completely efface the lymph node and splenic
architecture. with massive splenomegaly.
Infiltrates may also be present in the liver.
lung. qastromtesunat tract and in some
cases there is leukaemic involvement of
the peripheral blood 1627, 16381
""""'phenotype
The p1asmablasts described above {16381
..1' . "
I
.-. .
",.
show stippled nuclear staining for LANA- 1,

VIla! Ainterleukin-6 and strongly express
c1gM Wllh Alight cha in restriction , They are
C02O+ or -, C079a-, COl38-. C038-/+.

C027 and Epstein-Barr encoded RNA
(ESER~tive. The interlotlicular plasma
cells are typically clgM negative. c lg A
cosmve.
express polytypic light c hai ns
and do not shc:rN rocear expression of

~- 1
anIlQ8O.
.r..f....."-.
,
~c~:.
, .'
..
.noW....
.,...,
~ "
!u
.:~
...
'
. I .
.:.. ....;:!o..
Fig. 10.117 HHVS posltMll'flllllcenlric CaslIeman disease Wmulostained u HHV8 (A1. 1gM (8). (~d'Iafl (C)and
A light chain (D). The plasmablasts e.press ntranudear HHVS lANA. c1gM and show AIiI;;lt chain teSlrictIon.
InIeffoIK:uIar plasma cells e~ poIytypic IgIgtrl d'Ians.
Genetics
AntJgen receptor genes
Despse constant expression of monotypic
IgM by the plasmablasts in HHV8 MCO.
careful molecular studies have shown that
trey constitute a poivcionar population
161 91. The mic rolymphomas thai develop
asthedisease progresses may be monoor polyclonal and the frank HHV8 PL are
moooc ionai. In both disorders. the IG
genesare unrnutated.

Activation of the IL6 rec eptor sig naling
pathway has been prop osed to p lay a role
ntte development of HHV8-infected naive
Blymphoproliferative lesions (619 ). There
is no information abo ut c ytogenetic ab normalities in the tumours
Postulated normal co unterpart
Naive Bcell.
Prognosis and pred ic tive factors
Botti HHV8 MCO and PL are highly
aggressive disorders with a median
survival 01a few months.
Associated con d itions
Kaposi sarcoma is freq uently present in
eerents With HHV8 PL and MCD . Primary
etfusion lymp homa (PEL) and its extracavitary cou nterpart may complica te
HHV8 MCD b ut unlike HHV8 PL. the
neoplastic cells do not express Ig and are
Fig. 10.118 HHVBilositive p1asmablasticlymphoma. A Sheetsof p1a$ffi3bjasls efface normal lymph node archilectlJl1l
B High magnificaton of p1asmahlasts in (A),TUITlOIJ" cells immunostained !of ( 1g lightchain (C) and Achain(0) stow
Alightchain restriction ,
usually co-infec ted with EBV.

In the g erminotropic Iymphoproliferative
disord er. ano ther monotypic HHV8-posinve lymphop ronterauve lesion that occurs
in HIV neg ative individuals. HHV8-posItive
prasmabrasts infiltrate ge rm inal centres
{6 18AI. The plasmablasts show either l(
or A lig ht chain restr iction but . like
HHVB MCD , these cells are polyClonal.
Co-infection with EBV is also characteristic.
Large B-eeU lymphoma ansmq in HHV8-assoclated multicentric Castl eman disease
259

J. Said
E. Cesarman
Definition
Primary effusion lymphoma (PEL) is a
large B-cell neoplasm usually presenting
as serous effusions without detectable
tumour masses. It is universally associated with human herpesvirus B (HHVB).
also named Kaposi sarcoma herpesvirus
(KSHV). It most often occurs in the setting
of immunodeficiency. Some patients with
PEL secondarily develop solid tumours in
adjacent structures such as the pleura.
Rare HHV8-positive lymphomas indistinguishable from PEL present as solid lumour masses, and have been termed
extracavitarv PEL.
ICD-O code
in elderly patients (both men and women) ,

mostly from areas with high p revalence
lor HHV8 infection such as the Mediterranean 121881. In these tetter patients the
lymphoma cells con tain HHV8 and may
lack EBV 1454. 191 11.
Etiology
The neoplastic cells are positive for HHV8
in all cases. Most cases are co-infected
with EBV 158, 85. 963 . 19121, but EBV has
restricted gene expression and may be
not required for the pathogenesis. HHV8
encodes more than ten homoIogues to
cellular genes that provide proliferative and
anti-apoptotic signals 159. 84, 91.10491.
Synonym
Epidem iology
The majority of cases arise in young or
middle-aged homosexualor bisexual males
with hum an immunodeficiency virus (HIV)
infection and severe immunodeficiency
11 555. 19 12). There is co-infection with
monoclonal Epstei n-Ba rr virus (EBV) 1372,
1555, 19121 . PEL has been repor ted in recip ients of solid org an transp lant s 1606,
1066, 13491. The disease also occurs in
the absen ce of immunod eficienc y, usually
_ ....
Fig. 10.120 Prirnafy e!Iusion ~ (PEl). PBnI

b::I CfDotJ1.There is rra1led.......' 01109 ptri'e1:
Iu::teoIi and a pIasirac:ybd appear;n::e in lie cytlpIaslIl
W'9'JIstarl.
patients have pre-existent or develop Ka-
967813
Body cavity based lymphoma.
.A
The mo st common sites are the pleural.
pe ric ardtal and peri toneal cav ities. Typ ically only one body cav ity is involved
{169.556, 16651. Extracavitarv tumours
with morphologic and phenotypic cha rac teristics simila r to PEL occur in extranod al sites inclu ding the gastrointestinal
tract. skin. lung and CNS. or may involve
lymph nodes 1377, 487. 556},
Clinic al features
Patients typi cally present with effusions in
the abse nc e of lymphad enopathy or
organomega ly. App roximately half of the
pest sarcoma 1581. Occasional cases are

associated with multicentric Castleman
disease 121881. PEL cases should be distinguished from rare cases of HHV8negative effusion based lymphoma
morphologically similar to PEL that have
been described in ascites from patients
with liver disease 11Q01, 1604. 18621: and
the EBV associated HHV8-negative large
B-cell lymp homas also occurring with
ch ronic sup purative inflammation , such
as pyo thorax associa ted lymphoma 163,
47 11.
Fig. '0.'" PmIafy eIlusion ~ (PEl.). A SokIlissue mass tomI'Ie ITIllliasIn.rn of an HIV+ patIenl WI\h PEl presenIing WI\h pINal elIusicln$. The 03Is<We Iar9t n
WI\h eosiIlOphIcIIIICfOflUdeoI and abundanl. cytoplasm. Mq ha\oe an anapIaslie or pIasmacybd appeatlI"It8. B ~ PEL
asa INl$$ in
lht Ilwgtbowel of 8fI HIV+ palJlri. The ru:Iei _ sml'jy positiYe lor IaIenlI*f\l8 Iltl1d1cn 'IIIilh nbocty m0RF13l..NA-1 f1.ANA).
'*"*.0.. ...
260
presenIilg""""
Morphology .
In cytocentrifuge preparations, the ce lls
exhibit a range of ap pea rances, from
large immunoblastic or plasmab lastic
cells to cells with more anaplastic morphology. Nuclei are large, rou nd to more irrequtar in shape, with promi nen t nu c leol i.
The cytoplasm can be abundant and is
deeply basophilic with vacuoles in occasional cells. A pe rinuclear hoI consistent
with plasmacytoid differentiation may be
seen. Some cells resemble Reed-Sternberg

cells. The cells often appear more uniform
in histolog ical sec tions tha n in cvtoeoln
preparations 158. 556.15551.
inmJnopheootype
lymphoma cells usually express CD 45 .
but lack pan-Been markers such as
CD 19, CD2Q and C079a 11167. 15551.
Surface and cytoplasmic irTllTMJnogtobutin

is absent. Usually, BCl6 is absent. Activaton and plasma cell-related markers
and a variety 01 non lineage-associated
antige ns such as HLA-DR, CD30, CD38.

Vs38c, C0 138 and EMA are onen demonstrable. "Phe cell s usually lac k l IN K-c eil
antigens . although abe rrant ex pression of
T-cell markers may occur 1169. 254. 19 10 1.
The ab errant phe notype frequently makes
it difficult to assign a lineage with immunophenotypi ng. The nuclei of the neoplastic
cells are positive for the HHVB-associaled
latent protein lANA (ORF 73) 16281. This
is very useful in establish ing a diagnosis.
Despite the usual presence of EBV w ith
EBER in situ hybridization. EBV LMPt is
absentl58. 454. 963 . 21881. Solid tumours
rep rese nting the extracavitary variant of
PEL have a phenotype similar to PEL but
express B-c e lt associated ant igens and
immunoglobulins slightly more often than
cases 01 PEL 13771.
Gooetics
Immunoglobulin genes are cl ona lly rearranged and hypermutated 11 4 19. 23531.
Some cases also have rearrangement of
f- c eu rec eptor genes (so-called genotypic infidel ity) 1956. 19101. Rare cases di ag nosed as TPEl have been reported
{487. 1263 1. No rec urrent chromosomal
abnormali ties have been identified. Compa rative genomic ana lysis has revealed
gains in c hromosomes 12 and X 115371HHV8 viral genomes are present in all
cases. Gene expression profiling of AIDSrelated PEL shows a d istinct prof ile with
features of both plasma c ells and EBVtransformed Iymphoblastoid cell lines
11 1591.
Post-qermoat centre Been.
The clinical outlook is extremely unfavourable. and median survival is less
than six months. Rare cases have
responoec to chemotherapy and/or
immune modulation 17931.
261
Burkitt lymphoma
Definition
Burkrtt lymphoma (BLl is a Ekeillymphoma
with an extremely short doubling time that
often presents in extrenodet sites or as
an acute leukaemia. It is composed 01
monomorphic medium-sized transformed
cells. Translocation involving MYC is
highly characteristic bu t 001 specrtc. N o
single parameter (such as morphology,
genetic analysis or immunophenotyping)
can be used as the gold standard for the
diagnosis of BL but a combination 01 several di agnostic techniques is necessary
ICD-Ocode
Burkitt lymphoma. NOS
9687/3
Epidemiology
Three cli nical variants of Burkin lymphoma
are rec ogn ized , each mani festing d ifferences in cli nic al presentation, morphology and biology.
Endemic BL: This varian t occurs in equatorial Afr ica , rep resenting the most common c hild hood mal ign anc y in this area
with an inci dence peak at a 10 7 year s and
a male.female rat io of 2: 11301, 24471. BL
is also endemic in Papua. New Guinea. In
endemi c region s there is a co rrelation between the geographical occ urrence and
some climati c fact or s (rainf all, altitude.
etc.) which correspond to the geog raph ical dis tribu tion of end emi c ma laria 1301 ,
656 ,2447 1.
Sporadic BL: This variant is seen throughout the world , mainly in ch ild ren and
young adu lts 1301,1 364,24471, The inc ide nce is low, representing only 1- 2% of
all lymp homas in Western Europe and in
the USA. BL acc ounts for 30 -50% of all
ch ildhood lymphom as. The med ian age
of the adul t pa tients is 30 years 1898 1. The
mare.temaie ratio is 2 or 3: 1, and in ch ild ren it is even mo re common among
males 12301. In some parts of the world,
for example, in South America and Nort h
Africa, both true sporad ic and endemic
variants are seen.
262
Mature Been neoplasms
L Leoncini
M. Rap h a~1
H , Stein
NL Harris
E.S. Jaffe
P. M. Kluin
tmmunoaeticiencv-s ssoos tea BL : This

vari ant is pr imar ily seen in association
with the human imm unodeficiency virus
(HIV) infection. often occurring as the initial
manifest ation of the ac qui red immunodefici ency syndrome (AIDS) 118181.
Etiology
In endemic BL, the EBV genome is present in the majority of the neoplastic cells in
all patients 12161, 24471 and there is
strong e pidemiological link Wi th hoIoendemic malaria 15281. Recen t data provide
insights into the emerging concepts of
polymicrobial disease pathogeneSiS
118551. In pa rticular, the potential mechanisms, by which Plasmodium talciparum
infections cooro impact on immunity and
viral persistence. include the exhaustion
of Epstein-Barr virus (EBV)-specific t-een
resp onse and To ll-like rec eptor (TLR) 9mediated react ivation ottarenuv intec ted
memo ry B cells 1203. 18551. This is in line
with evi dence that EBV-po sitive tumours
may de rive fro m memo ry B cells 11 80.
2232). However. epi demiolo gical studies
suggest that malar ia and EBV alone cannot ac co unt for the d istribution of endem ic Bl in high risk reg ions (1807,
229 11. Arbov iruses and plan t tumour promoters are othe r possible local co tacto rs
that cou ld exp lain suc h c harac teristics
Fig. 10.121 EI'Idemic Burkitt lymphoma, This Atncan

patient presented witha Iwgejaw tul11Ol.l'.
122911.
EBV may be detected in approx imately
30% of sporadic BL cases, howev er, a
low sccio-economio status and early EBV
infec tion are asso ciated with a high er
p revalence of EBV-positive sporadi c BL
In imm unod efic ie nc y-assoc iated c ases,
EBV is identified in onl y 25-40% o f the
c ases 18 77, 18181_BL is mo re co mmon in
HIV than in other forms 01 imm unosup pression and BL appears early in the prog ressio n of H IV infection when CD4 .
t-een counts are still high 11 301 1. This
sug gests that immunos uppression per 58
d oes not exp lain the incre ased risk of BL
A potential mechanistic link between ende mic and HIV-assoc iated BL lies in the
polyclonat Been activation that occurs
afte r mal aria and HIV infection. However,
the oncogenic role of HIV itself cannot be
Fig. 10.122 Sporadic Burkitt lymphoma with lJj lateral

ovarian tul1lOl.lf'S
Fig. 10.123 BlIaleral breasl fflolvemenl may be ..

presentrng manrIesIaIion dln1g ~. n Il'blrlr.
BL eels haYe proladIn receptOr$
rtg-10.124 &ni1l1ymp/lOma. loucl1 impmt. A The deeply basophilic cytoplasm can be appreciated as well as
abI.n1riipd vacuoles II the C)1OPIaSm. B The cells II It'is case are relatively S1rri1ar kI{Al.e:::ept !hey' havemore
~nudei.
nJed out 11781. In conclusion, one of the

paradoxes in expla ining the etiology of BL
is the occurrence of this tumour in many
Oi!1erent populations and settmqs . II is
posstse that drsuoct pathogenetic mecheusms exist among BL subtypes 11791.
On tOO other hand . different and mult iple
environmental exposures may converge
II a corrvnon pathogenetic mechanism
flVOMng the M YC gene at chromosome
8Q24 1201 41 .
ExtrallOdal sites are most often involved
'Mth some variation according to the clinical variants. However. in all three clinical
variants. patients are at risk tor cent ral
nervous system involvemen t. In endemic
BL.the jaws and other facial bones (orbi t)
are the site ot presentation in about 50%
01 the cases (301, 24471 The distal ileum,
caecum and/or omen tum, gonads, kidneys. lonq bones, thyroid, salivary glands
and breasts may also be affected either
w,th or without jaw involvement (302,
24471. Although loc alization may sometmes be found in the bone marrow (BM),
manifestation of leukaemia in the peri.
pheral blood (PB) is not present 1302,
24471. ln sporadic BL. jaw tumours are
very rare 11612). The majority of the cases
presents with abdominal masses 11 3641.
The ileo-caecal region rep resents the
most frequent site of involvement. SimiIar~ 10endemic BL, ovaries . kidneys and
breasts are also frequently involved.
Breast involvement totten bilateral and
massive) has been associated with onset
during puberty, pregnancy or lactation.
Retroperitoneal masses may result in
spinal CCH'd compression Wi th paraplegia,
l'yfTlph node presentation is seen more
ccmrnonly in adu lts than in chi ldren .
WaIdeyet mg and mediastinal involvement
ire rare. In invnunodelicieocyassociated
BL. noda l localization is frequent as well

as 8M involvement 1877, 18 181.
Clinical features
Clinical presentation varies acCOfding to
the epidemiologic subtype and the site of
involveme nt. Patients often present With
bulky c nsease.ano a high tumour burden
due to the short doubling time of the
tumou r. In the typical paediatric cases.
the parents of affected children will report
symptoms for only a few weeks. Paediatric 8 L palients are staged according 10
the system of Murphy el al.I15511. 70% of
patients present at advanced stages (III
and IV). Upon institutio n of therap y a
tumour lysis syndrome can occu r due to
rapid tumour c ell death /2381 1
Burl<ittleukaemia variant
A leukaemic phase can be observe d
in p atients with bulky disease. but only
rare cases (mainly males) present purely
as acute leukaemia with PB and BM
involve ment 11 363, 1364. 20601. This
Burkitt leukaemia. or acu te lymphocytic
leukaemia-l3. according to the lormer FAB
classification. tends to involve the CNS at
diagnosis or early during the disease
course. Its rapid chemosensitivity easily
leads to an acute tumour lysis syndrome.
--
The prototype of BL is observed in endemic BL and in a high percentage of

sooadc BL cases . particularly in childr6l1
1898,24471 . The tumour cells of BL are
medium-sized cells (nuclei similar Of
smaller to those of histiocytes) and show
a diffuse monotonous pattern of growth.
Some tumours surround and invade
otherwise uninvolved lymph nodes, The
celts appear to be coh esive but sometimes exh ibit squa red-off borders of retrac ted cytoplasm. The nuclei are round
with finely clumped and dispersed chromatin. with multiple basophi lic mecumsized , paracent rally situated nucleoli. The
cytoplasm is deeply basophi lic and usually contains lipid vacuoles. These cellular
details are better perce ived in imprints.
The tumour has an extremely high proliferation tract ion (many mitotic figures) as
Fig.10.125 Burkitt IympIloma statned lor Goernsa ' AI and H&E (B) has lI'liform IumolJ" eels wdtl multiple smaI
ru:leoli and Ii'oeIy ~ chrornabn II theirradii ,In hs &.nIa ~ slaIned b Giemsa (C)in! H&E (D). 1lere
is !1Nternodear~
Burkitt lymphoma
263
...~
Fig. 10.126 BtnJn lymphoma. Imrnunohis1odlemistry shows a strong and homogeoeous stam.ng lor KJ67/MIBl (A) and C010 (Bl. C FISHfor MYC IIarmg probes {891"1.
~ one8Iellt..., ookx:aization aI bott1 probes (ted and greerl) a"Id oneallele WIth segregatJon aI boIh probes.
well as a high fraction of epootosis. A

"starry sky pattern is usua Uy present .
which is imparted by numerous ben ign
macrophages that have ingested apoptote tumour cells . Some cases may have
a florid granulomatous reaction that may
cause difficulties in the recognition of the
tumour 189161. These cases typ ically
present with limited stage disease and
have an especially good prognosis 11973AI
In some cases, turnour c ells exhibit eccentric basophilic cytoplasm often with a
single central nucleolus. Such cases, defined as BL with plasmacytoid differentiation , can occasionally be observed in
children but are more common in irrmunodeficiency states 118181. Other cases of BL
may show greater nuclea r pleomorphism
and the nucleoli may be more prominent
and fewer in number 18981. In the past.
these cases have been referred to as
atypic al BL However, these morphologica l variants share a similar gene expression profile, which suppor ts the evidence
that the morphological spect rum of BL is
relatively wide (509. 9941,
Immunophenotyp e
In Burkitt lymphoma. inclUding cases presenting with leukaemia. the tumou r cells
express moderate to strong levels of
membrane IgM with ligh t cha in restric tion
and Bcen-assoc tateo antigens (e.g.
CD19, C020, C022) , COlO, BCL6. CD38,
and C043 ]15t . 898, 244n The
neoplastic cells are usually negative or
only weak ly positive (in -20% of the
cases) for BCL2 and are uniformly Td T
negative 1264. 890, 1104. 1307. 14381.
Nearly too% of the cells are positive tor
Ki67 18981. There are very few admixed
t-eens. Cases with a more atypical phenotype such as BCL2-positlve, as seen in
some adu lt patien ts. require s that the
case otherwise has all the characteristic
features of Burkitt lymphoma , incl udi ng
con
264
IG:M YC trans locat ion without BCL2 or

BCL6translocation.
Genetics
The tumour cells show clonal IG rearrangements with somatic hypermutation.
Cytogenetic abnormal/bas and oncogenes

Most of the cases have MYCtranslocation
at band 8q24 10 the IG heavy chain region , 14q32 or, less commonly, at the
lambda. 22q1 1or kappa, 2p12 light chain
loc i. Up to 10% of the cases may lack a
demonstra ble MYC translocation by FISH,
the explanation for which is uncertain
1890, 994 1. These cases may have MYC
translocation demonstrated using other
techni ques and must be otherwise completely typical to make a diag nosis of BL.
Furthermore , M YC translocations are not
specific for BL Most MYC/IG breakpoin ts
in endemic BL originate from abe rrant somatic hypermutatlon. In sporadic cases.
on the other hand , the transloc ation
mostly involves the IG switch regions of
the IgH locus at 14q32 1860, 20141. These
d ifferences in MYC breakp oint may well
be acc ounted for by the different maturational stage of the of EBV positive (mainly
endemic) and EBVnegative (mainly spo radic) BL \1801. Mutations in M YC may
enhance its tumourigenicity and some of
these mutations may lead to decreased
exp ression of BIM whic h binds and inactivates BCL2 1917. 24681. Other genetic
and epigenetic alterations occurring in a
subset of BL, involving p16""".... TP53,
p73, BAX, pl3O!RB2and BCL6, may promole cell growth and/or inhibit apoptoee
1179, 5 17, 1158, 1314, 19251
Gene profiling studies have demonstrated
a consistent gene expression signature
tor BL, which is clearly distinct from that
of DLBCL 1509. 994 1. Howeve r, intermediate cases were also found 1509. 994 1.
Postulated normaJ cou nterpart

Germinal centre or post germinal centre
BceUs.
In endemic and sporadic BL, the tumour
is high ly aggressive but potentially curable . Staging is performed according to
the scheme proposed by Murphy and
Hustu (155 11 and modified by Magratt!
113631. Staging is largely related to til"
mour burden , and identifies patients witt!
lirmted stage disease and patients with
extensive intraabdominal or intrathoracic
tumour 123811. Bone marrow and central
nervous system involvement. unresecteo
tumour> 10 em in diameter, and a high
LOH serum level are recog nized as poor
prognostic factors, particularly in sporadic BL. Intensive combination chemotherapy regimens result in cure rates of up
to 90% in pa tients with low stage disease
117081 and 60-80% in patients with advanc ed stage disease 11363, 20601 , The
results are better in children than in adults
1591f. However, even patien ts with advanc ed stage disease, including BM and
central nervous system involvement, may
be cured with a high dose treatment program 13101 With high intensity treatment,
most pa tients presenting with leukaemia
also have a very good prognosis with
80-90% survival 12060, 238 11.
Relapse. if it occu rs, is usually seen within
the firsl year arter diagnosis 11363. 23811 ,
Recently it has been reported that rrtuxirnab may be a useful additional therapeutic agent 1531 . 22291 . Although BL is
curable. many patients still die of the disease mainly in Africa 18921.
B-celllymphoma, unclassifiable,
with features intermediate between
diffuse large B-cell lymphoma and
Burkitt lymphoma
Definition
Bcetl lymphomas with features intermeoete between dutuse large B-cell lymphoma (DlBCl) and Burkitt lymphoma
(BLl are aggressive lymp homa s that have
morphological and genetic features of

both DLBCl and Bl, but for b iolog ical and
clinical reasons should not be included in
mese catego ries, Some of these cases
were previously c lassi fied as Burkitt-like
lymphoma (BlL).
The majority01 the cases in this category
have morpholog ical features that are
orermeotete between DLBCL and BL,
with some cells that are smaller than typ-
ical DlBCl. resembling BL, and some

cells that are larger than typical BL. resembling DlBCL. as well as a high prolif-
eraoon fraction. starry-sky pattern , and an
PM. Klu in
NL Harris
H . Stein
L. Leoncmi
immunophenotype consistent with BL.

Some cases may be morphologically
EpidemkJk>gy
These lymphomas are relatively infrequent
more typical of BL but have an atypical

immunophenotype or genetic features
that preclude a diagnosis 01 BL The d iagnosis 01 this type of unctassifiable
Bcentvrnoboma category should not be
made in cases of morphologically typical
DLBCL that have a MYC rearra ngement ,
or in otherwi se ty pica l BL in w hic h a MYC
rearrange me nt ca nnot be demonstrated
Some transformed follic ular lymphomas
may fall into this category. This is a r eterogeneous category that is not consroered a distinct disease entity. bu t is use ful
in allowing the c lassification of cases not
meeting c riteria lor classical BL or DLBCL
and mainly diagnosed in adults.
ico-o code
-..,.""...
6L
N,,,
""""""
V..
No
Sometimes
""~
cormcn
V..
No
Sometimes
Sometimes
Sometimes
Sometimes
.,,,,,
No
8CL2expr..elon
~eg8tiVfl / weak
S"..
Gtnetic Into,.,
WYC rearrallg8ll1el1l
YIS'
""Ye"o
V..
"'"1G..uvc-
No
No
8CUbut no UYC reanangement

8Ct6but no UYC~
"""" to!'
--
~ _ ooo
"""""""
No
No
V..
Prdiltrltion (KI61/MIB1)
>00% and tIor'roopene<H/s
~ orheterogerlElOOs
Iflte'
""""""
seeeeres
Only smaIo'mediUm-siZe cells
No
No
....
Yo.
No
N,,,
--........ --...... ,
-.... ........
""""""
More than half 01 the patients present with
widespread. etten extranodal disease.
Unlike BL , the re is no prefe rential localization in the ileocecal reg ion or jaws. The
bone marrow (BM) and perip heral b lood
(PB) may be involved as well.
Clinical leatures
Patients present with lymphadenopathy or
mass lesions in extranodal sites. Some
patients have a leukaemic presentation.
-ogy
968013
r.10.11 Iobpl'OClklgiCo. ~ and genetic Ieabns tlat may beusefIA ., <btl~ BL !romDLBCl.
ti51ic
M. Rapha~1
E. Campo
E.$. Jalfe
....
....
""""""
"
~ 5'4 r:J 0ChlItwise dassicaI BL 'Wl a cleltable ILYC~ {891A. 994}

I(;..,VYC juxtIposilioo of UYCIo oneof lhe IG loa: lGH@atl4q32./GL@al22q 11 or IGKO al 2p12. NoI'I
JG..,\IYC ~ 0Dl\taIn a MYC rearratl{IlIIll but no juxtaplMon 10 oneof!hlllG loci.
'DO!Jlle hi! ~$afllain a AIYCIllq24 brlIakpoint lflcombination wiltl a BCt.2Il8q21 (by Iar most
\'tQuenIl and/or BCL6J3q27 breakpoint. The partner of BCL2I18q21 breakpointmostty i5 ltle lGHiotus a114q32.
nllQlllll cases a 1(8.14 t8) is presefl1 (132OA).
...SImplt karyotype noor ontv few cy10genllic or (array) CGH abnormalibe5O\t1er!han the MYe rearral'lgeme'!Jl.
For.-ray CGHa lymphoma WIth 6 or ITlOfI abnormalities has beefl asslgned as "MYC-eomp~~-l994l.
These lymphomas are typically composed

of a dilfuse proliferation of medium- to
large-sized transformed cells with few
adrTixed smalilymphocyles and 00 stranal
reaction of fibrosis . Starry sky macrophages are typically present, as well as
many mitotic ligures and prominent apootests. causing a resemblance to BL The
cellular morphology is variable. In some
cases, the cells resemble those ot BL, but
with more varia tion in nuclear size and
contour than is considered acceptable lor
BL: some cases are co nsi stent with BL
mo rpholog ica lly but have an atypical immunop henoty pe and/or ge netic features;
othe r cases with an imm unophenotype
that is consistent with BL have a variable
nuclear size that is intermediate between
BL and DLBCL. otten with either irregular
nuclear contours or relatively large nucleoli. In rare cases the nuclei are relatively
small and the chromatin is finely granular.
resembling lymphoblastic lymphoma
Some of these tatter cases have been
classified as 'taestc" or blastoo-.lfl"lll.X'K)histochemistry lor TdT is required to exclude lymphoblastic lymphoma.
Cases 01 morphologically Iypical DLBCL
With a very high proliferation index should
not be included in this category /44 11 .
Irrmunophenotype
These lymphomas express B-cell markers. CD19, CD20, CD22 and CD79a and
B-cell lymphoma , unclass ifiable . with features intermediate between DLBCL and Burkitt lymphoma
265
a.:
Fi~ 10.121 TI'nle ~ 8.14~ .. T~ BL tJ)ll'I(X)SllCI 01 fI'IlidI.m-sizl. IloulolllOUS eels wGI ftUId rlld8i.1TUIIPt ru:leoIi. ;n:l a rTD:letaIe an'lOI.Ill 01 ~ wIid1
1m a ~ awe<r.n. Prtrrnlnl apopUis is MIln:8d bythe presence 01 ~ 8l'9JfI'lg ~ daMs. oealJlg hi "stairy-skf patIlvn. NIne 0/11 expem v.tID IWirwed
hs case i1depeIldelltt Il'IlIde diqosis 01 BL..: 1 made a ~ cI ~ BL BIw:JJtB case will similar a.waI ~. tu WIO'l */'fI1 noe wriaIol., sizein! shape 01 reels. SiJ: ~ caIedIhrs BL and 5 caIed ~ atypical BL. CDLBCL WIIh a 1(8:'-4) has a pnmnenI starry-sky panem. The eels are Iargel' 1d more pIeomol~ 1hafl1he BurUI
and alypicaI BtnAI aISJllS. " " e4*1ScaIed lis CUlClMd2 caIed l at)'Ilc:aI BL ~ from tan tarns to.;n:I Homng SJ ~
typically 51g. but so-called double hit cases

may be 51g negative. In general . cases
will be placed in this category when the
immunophenolype is suggestive of BL
(COlO. , BCLS+ . BCl2 and IRF4iMUM1or very weakly positive). Cases that morphologically resemble BL may be p laced
in this category when BCL2 is moderately
to strong ly positive. BCl2 positivity in a
case that otherwise might be classified as
Bl should suggest the possib ility 01 a
double hit lymphoma with both MYC and
BCL2lranslocations. The Ki67 lab eling
index is usually high. again raising the d ifferential diagnosis 01 Bl, bu t in reported
cases it varies between 50 and 100 %
\26 4, 890, 1438 1. Rare tumours with a
MYCwith or without BCL2rearrangement
are TdT positive; classification of these
cas es is con trove rsial , and the diagnosis
of lymphob lastic lymphoma may be preferre d 11 561 , 2 19 11 .The use fulness of
other markers rema ins to be estab lished
1922, 1858 ,2 179],
Geneti cs
IG genes are ctonauy rearranged.
Ap proximately 35-50% of the cases have
8q2 4/MYC transiocatioos 1890. 994, 14381.
However. whereas M YC in 8 L is juxtaposed to the one of the immunoglobulin
genes (IG- MYC). many of these cases
have other transiccauons (non IG-MYC).
Approximately 15% of the cases have a
BCL2 translocation, sometimes together
with a MYCtranslocation ("double hitlymphoma"). Cases previously classified as
Burkitt-like lymphoma may have a higher
frequency 01 MYC and BCL2 trensrocatons as well as double hits 11104, 1359 1.
Less frequently. BCL6 transiocanons are
seen , sometimes together with MYC andJor
BCL2. The relative incidence of double and
triple hit lymphomas increases w ith age.
266
Mature 8-cell neoplasms
up to more than 30 % in elderly patients

(http JIcgafJ.nci.ntl_gov~llel
man). Cytogenetic analysis of both the

non-IG-MYC and double hit cases often
shows a complex karyotype with multiple
abnormalities . in contrast to cl assic al
Burkitt lymphoma /12591 . Dependent on
the algorithm used, gene profiling stud ies
have shown that some double-hit cases
have a profile intermed iate between BL
and DLBCl\9941 or more similar to BL
\509}. Cases of otherwise typical DLBCl
with a MYC translocation should no t be
placed in this cateqo rv Conversely. Iym
phomas with a IG-MYC rearrangement as
the only ab nor mal ity likely rep resent Bl
even if they are morphologically atypical.

B-cell . most cases related to a germinal
centre slage 01 differentiation.
Prognosis and peedlceve factors

These are aggressive lymphomas, for
which the most appropriate therapeutic
approach is not established . The double
hit lymphomas show frequent involvement
of the 8M . PB and CNS; most cases are
resistant to current therapies. which
seems to be independent of the complexity 01 the other cytogenetic abnormaJ.
ities 1501 , 994 ,1259, 14381.
Fig.10.128 Malepabent, 61 ~. WiCh a rapdy tJOlWlgCllltW3noda1lTli1SS. "DouI*t ht'~ . boIh8q24.urc

lnl1 Bq21/BC1.2 breiIkp:lfIls A SlaJTysky paIlem. B ~ ~I showI'lg a IT"ixtIn d~ ..
dei will Mtle pIto,o!i....l llU pIOTftnl ruiIoI, absence d ~ cM:maIrlln:l tTWlyrTltJlic ipes. C Strtrg 8Q2
staII'lI'9 is vety In.ISl.I3I b BL 0 Ki67 stanng Will ~ IU elseWtln flete M:!te doseto100'.4 poSIM __
B-cell lymphcma, unclassifiable, with

features intermediate between diffuse
large B-cell lymphoma and classical
Hodgkin lymphoma
E.S. Jaffe
H. Stein
S.H . Swerdlow
E. Campo
SA Pileri
N L. Harris
DeIini1icn
A B lineage lymphoma that demonstrate s
Imm unophenotype
The lymphoma cells exhibit an immunop heno type With transitional features
between CHL and PMBL (758 . 2265} .
Neopla stic cells typically express CD45.
In contrast to CHl . the B-eell program is
often preserved. but is aberrantly expressed
in concert with Hodgkin ma rkers. such as
CD30 and CD 15. CD 20 and CD79a are
frequently positive, and may be strongly
expresse d on the majorily of the tumour
c ells. C030 is pos itive and C015 is oosrtive in the majority of cas es. Surface or
c ytop lasmic immunoglob ulin (Ig) is absent. The transcription factors PAX5. QCT-2
and BOB.1 are usually expressed, BCl6
is variably positive but C010 is generaHy
negative. ALK is consistently negative.
The background lymphocytes are predominantly C03+ . CD4+ . as seen in CHL
In cases Ihat morphologically resemble
oodular sclerosis classical Hodgkin rym.
phooIa: (NSCHL). lSiform streng expression
01 C020 and other Be en markers and absence of CO 15 would favour the diagnosis of grey zone lymphoma. In cases Ihat
resemble PMBL. absence of C020. expression 01 CD 15 or p resence of EBV
would favour this diagnos is as welt.
MAL. a marker associ ated with PMBL, is
exp ressed in at least a subset of the cases
presenting with med iastinal disea se 1472.
2265). Suppo rting a relationship to PMBl .
nuclear c-REU p65 p rotein has been id entified in those cases tested [758. 1857}. In
one series. p53 was expressed in Ihe
overlapping clinical, morphological and/or

IfMl unophenolypic features , between
classical Hodgkin lymphoma (CHL) and

onu se large B-cell lym phoma (DLBCL) ,
especially primarymediastinal large B-cell

Iyrrt:lhoma (PMBL), While these lymphomas
aremost commonly associated with mediastinal disease, similar cas es have been
respiratory distress. Another phenomenon which mayor may not be related to

-grey zone lymphomas is the occurrence
of CHL and PMBl as composite lymphoma
1815}. or sequentially. at ornerent points in
time 117271. While either lymphoma subtype may present first it is somewhat
more common for the initial presentation
to b e CHL with relap se as PMBL. often
within the first few years 12487f.
Of
reported in pe ripheral lym ph nod e g roups
as a primary site.
IC().()
code
959613
Synonyms
Grey zone lymphoma 11895, 22651 , large
Been lymphom a with Hodg kin features
175B1. Hodgkin-like anaplastic large cell

~ 12499. 25011.
EpidemoIogy
These lymphomas are most common in
young men, usually presenting between
the ages 01 20-40 yea rs of age 1758.
22651. However, they have been reported
tI Individuals as youn g as 13 yea rs of
age. and in older adults beyond the age
of 70 Most cases have b een reporte d
trem Western countries like CHL, they are

less common in Black s and Asians.
Etiology
The etiology is unknown. Eps tein-Ba rr
war sequences have been ide ntified in
20% or fewer cases.
Morpho log y
The lymp homa is typic ally composed of a
confluent, sheet-like growth of pleomorphic
tumour cells in a diffusely fibrotic stroma
1758.22651. Focal fibrous bands may be
seen in some cases . The cells are larger
and more p leomorphic than in the typical
case of PMBL. although some ceoucotastlike cells may be present. Pleomorphic
cells resembling lacunar cells and
Hoclgkin cells comprise the majOl'ityof the
infiltrate . A characterisnc feature is the
broad spectrum of cytological appearances with different areas of the lumour
Showing variations in cytological appe arance. i.e. some areas may mo re closely
resem ble CHL an d others ap pear mo re
like diffuse larg e B-eeil lymp homa. There
is usually a sparse inflamma tory infiltrate.
although scattered eosinop hils. lymphoc ytes an d histocyt es may be p resent.
Necrosis is frequ ent. but unlike CHL, the
necrotic areas do not c ontain neutrop hilic
infiltrates.
Sites 01 Involvement
The most common p resentation is with a
large anterior me diastinal mass. with or
W1lhout involvement 01 supraclavicular
trTllh nodes 1758. 22651. Other peripheral
~ node groups are less commonly
1'lYoIved. Theremay be spread to lung by
Orect extension. as well as spread to liver.
spleen and bone marrow. Non-lymphoid
l)'Qans are rarely involved. in cont rast to
PMBl.
CIncaI features
A. large mediastinal mass may be associ-
ated with a superior vena caval synd rome.
Fig. 10.129 B-ceII ~ WlIh features I1lermediate be'- dI1Iuse large B-ce. ~ and dassicaI HodglIIrl
lymphoma. Mediasbnalmass. A Lyrl'4Ihoma is composed of sheets 01 cells WJIh dearcytoplasm aoofine sderosrs. The
appearance resembles that of primary rnediastinallarge B-ceRIyrT'4)homa (PMBL). BTurrour cellswere stroogIy COl 5
positiveandalso CD30positive {nol shown).
B-ce illymphoma. uncla ssifiable, with features intermedi ate between DLBCL and Hodgki n lymphoma
267
relationship between CHL and PMBL has

been shown by gene expression p rofiling
studies. but specific g enomic studies of
"grey zone" or transitional lymphomas
have not been performed 11 870.1 9441.
Postulated normaJ coun terpart
A thymic B-cell is the likely lor those
cases arising in the mediastinum 122651.
For cases ariSing in the pe ripheral lymph
nodes. an alternative Be en origin is proposed.
fig . 10.130 Ik::eIIynlJ/lOma WIltIleallns inIemIe<iale betvIoeeo dtIfuse largeIk:elIIynlJ/lOma In! cIassi:aI Hodgkin
~. MediastJnaI mass. The ~ is COfT9)5ed rJ a sheel4e growth rJ eels wi\tI"i~ C)'t:lpIasm.
The inlrrnatay backgrol.nd is minimal. The phenotype resen'tIIed!hat rJ CHI.. WIth expression rJC030andC015.
bU: ~ lactn OCT21n! BOB 1 'fl'llnl po5Ilive
majority of cases 17581.

In instances of composi1e Of metachronous
lymphomas. the venous components
exhibit a phenotype charac teristic of that
entity. either CHL Of PMBL
Genetics
Only a few cases of me tachronous CHL
and PMBL have been studied at the
genetic level; a clonal relationship has
268
Mature
a-cen neoplasms
been shown between the two components 122651. Specific genetic changes
have not been associated with trenstormation of the lymphoma Of its components
to either CHL or PMBL Because the
mo rphological and phenotypic changes
are reversible, it is likely that epigenetic
rathe r than genetic alterations are
responsible for the change in morphology
an d immunophenotype 19331. A close

These lymphomas generally have a more
aggressive clinical course and poorer
outcome than either CHL or PMBL There
is no consensus on the optimum treatment, although in some series therapy lor
an aggressive large B-celllymphoma has
been proposed as effective 12265. 25011
Others have proposed use of a Hodgkin
type regimen 13491. Among CHL patients.
strong expression of CD20. as seen in this
transitional lymphoma, has been proposed as a poor prognostic indicator in
Hodgkin lymphoma trials 117741. However. other studies have reached an
opposite conclusion 122751.
CHAPTER 11
Mature T and NK-cell Neoplasms
T-<:eII prolymphocytic leukaemia

T-eelliarge granular lymphocytic leukaemia
Chronic Iymphoproliferative disorders of NK ce lls
AggressiveNK cell ktukaemla

EBV-positiYe Pcell Iymphoproliferative disofders of childhood
Adult T-eeilleukaemialtymphoma
Extranodal NKIT cell lymphoma, nasal type

Enteropathy-associated T-<:ell lymphoma
Hepatosplenic T-eelllymphoma
Subcutaneous panniculitis-like T-eell lymphoma
Mycosis fungoides
Sezary syndrome
Primary cutaneous CD30 positive T-eeillymphoproliferative disorders
Primary cutaneous gamma-delta T-eell lymphomas
Peripheral T-<:ell lymphoma , NOS
Angioimmunoblastic T-eelllymphoma
Anaplastic large cell lymphoma (ALCL). ALK positive
Anaplastic large cell lymphoma (ALCL). ALK negative
T-cell prolymphocytic leukaemia
D. Catovsky
H.K . Muller-Hermelink
E. Aalfkiaer
Definition
t -een prolymphocytic leukaemia (T-PLL) is
an aggressive t-een leukaemia characterized by the proliferation 01 small to
medium-sized prolymphocytes with a
mature post-thymic T-cell phenotype involving the peripheral blood (PB), bone
marrow (8M), lymph nodes. liver, spleen
and skin .
ICD-Ocode
9834/3
Synonym
t-een chronic lymphocytic leukaemia was
used historically as a synonym to- some
small cell variants
Epidemiology
T-PLL is rare. representing approximately
2% 01 cases of mature lymphocytic
leukaermas in adul ts over (he age of 30
I 1424 J; medi an age is 6S yea rs (range,
30-94 years).
Leukaemic t -eens are found in the PB.
8M, lym ph nod es. spleen. liver and sometimes skin.
Clinical features
Most patients pr esent with hep atospl enomegaly and genera lized lymphadenopathy.
Skin infiltration is seen in 20% 01pa tients,
and serou s effusion s, c hiefly pleural , in a
m inority ( 14241. Ana emi a an d thromboc ytopenia are co mmon and the lymphoc yte count is usually >100x 109/L and
> 200x 109/L in half of the patients. Serum
immunoglobulins are normal. Serology for
HTLV-1 is negative.
coa. a
outlin e is very irregular and can even be

cerebriform 117131. Irrespective 01 the nuclear features. a common morphological
feature is the presence of cytoplasmic
protrusions or b le bs. The 8M is diffusely
mtnuateo. but the di agnosis is dllflcult to
make by 8 M histology alone.
feature almost unique to T-PLL;

15% are C04-. C08+ 114241. The overexpression 01 the oncogene TCL' can be
demonstrated by immunohistochemistry
19211 and this method is useful for detecting residual T-PLL on 8M sections
after therapy.
Other tissues
Cutaneous involvement consists of pe rivascular or more dilfuse dermal infiltrates
without epi de rmotropism 11373, 1424 1.
The spleen histology shows d ense red
pu lp infiltration. whic h invades the spleen
c apsu le, b lood vess els a nd atrophied
white pulp 11663 1. In lymph nodes, the
involvement is d iffuse and tend s to predominate in the oaracortrcat areas , sometimes with sparing of tourcres Prom inent
high-endothelial venues may be numerous
and are often infiltrated by neop lastic c ells.
Ge netics
t-een receptor (TCR) genes , TRB@ and
TRG@, are clenatly rearra nged.
Cytoc hemistry
T orotvmohocyt es stain stron gly with
(I -na phthyl ac etate este rase and
acid
p hos phatase with do t-like stainin g in the
Golgi region 114251. f--iov.Iever, cytochemistry
is rarely used for routine diagnosis currently.

The most freq uent ch romosome aonomanty in T-PLl involves inversion 01chromosome 14 with breakpoints in the long
arm at q 11 and q32 , seen in 80 % of patients. In 10% there is a rec iprocal tandem
translocation t(14;14)(q11;q32) 1272, 13721.
These tran slocations juxtapose the TRA@
locus w ith the oncoge nes TCL 1A and
TeL 18 at 14q32 ,1 which are activa ted
throug h the translocation (17181. The translocation t(X; 14)(q 28;q 11) is less common,
"'",p"o<ogy
Peripheral blood and bone marrow
The d iag nosis is made on P8 films which
show a predominance of small to
medium-sized lymphoid cells with nong ranular basophilic cytoplasm, round .
oval or markedly irregular nuclei and a
visible nucleolus. tn 25% of cases the cell
size is small and the nucleolus may not be
visible by light microscopy (small cell variant) 114261. In 5% of patients the nuclear
270
Mature T- and NK-celt neoplasms
Immunophenoty pe
r-proiymonocvtes
are peripheral t-ceue

which are TdT and CD1a negative while
C02. C03 an d C07 are positive; the
membr ane expression of CD3 may be
weak. C052 is usually expressed at high
density. and can be used as a target of
ther apy 15351.
In 60% of patients the cells are CD4+ .
COB-, and in 25% they coexpress CD4 and
Fill- 11.02 T-<:eI proIymph:lcylic 1elNemia, P"" kiryotype s/'ll:MWIg ml 4q (q11;q32)
----l...

Unknown T-cell with a mature (pos tthymic) immunophenotype. Strong C07
and coexoresston of Co4 and COB and
weak membrane C03 may suggest that
T-PLL arises from a t-een at an intermediate stage of differentiation between cortical
thymocytes and mature T lymphocytes.
f"i- 11.C3 T-<eI ~ IeuIo:.aemia " l~ node is ddfuseIy inIiIlrated, t:U: a IoIic:le is l.I\aIIeded. GIemsa
B F'forrWlenl I'io;tI encIolheliaI verUe shorImg Iu!lloos cees in tile Unen , in I!le waI aIld the aqacent
pnro1el Giemsa stall.
1QIl.
bu1 it also involves the TCAtJ locus at

14q11Wlth the MTCP7 gene. 'htlich is h0mologous to TCL I, at Xq28 120971. Both
TeL I and MTCP7 have oncogenic prop etc e as both can induce a 't-een leuk aemia (CD4-IC DB+ ) in transgenic mice
1849. 23381. TCL 7 inhibits activationinduced death in the neoplastic t-eens.
further contributing to the neoplastic
process 15601.
Abnormalities of chromosome 8, id ic
(8p l 1), t(8;B)(p1 1. 12;q 12) and trisomy 8q
are seen in 70-80% of cases 1171BI.
Deletions at 12p 13 are also a featur e
of TPll when studie d by FISH 19371.
Molecular and FISH studies also show

deletions at 11q23 , the locus 101 the
Ataxia Telangiec tasia Mutated (ATM)
gene. and mutational analysis has shown
missense mutations at the ATM locus in TPLL \2100 , 23441. TPLL is not an uncommon secon dary neoplasia in patien ts with
ataxia telangiectasia \2721. Abnor malities
of ch romosome 6 (33%) and 17 (26%)
have also been described in T-PLL using
conventional karyotyping and CGH studies
1272,4831. The TP53gene (al 17p 13.1) is
deleted with overexp ression of p53 protein in a number of c ases 12731.
Progoosis and predictive factors

The course of the disease is aggressive
with a median survival of usually less than
one year. Cases with a more chronic
course have also been reported \7541.
Such cases may show an accelerated
ccese after 2-3 years. The best responses
have been reported with the monoclonal
antibody alemtuzumab (anh-Co52) 1536,
11301. Both autologous and allogenei c
stern cell transplants lor patients who
achieve remission are being explored. in
conjunction with immunotherapy. Recent
studies have identified both high expression of Tell and AKT as poor prognostic
markers 19231.
T-eeft prolymphocytlC leukaemia
271
T-cell large granular lymphocytic

leukaemia
W C, Chan
K. Fou car
W G. Morice
Definition
r-cea large granular lymPhocytIC leukaemia
(T-lGll is a heterogeneous disorde r char-
of autoanti bodies. circ ulating immune

complexes and hypergarrmaglobufinemia
are also common 1390, 1247f. Cases that
are CD4+ have been reported to be frequently (30%) associated with an underlying mali gn ancy 113031. Morbidity and
mortality are mostly due to the accompanying cytoperaas or other accom panying
diseases.
acterized by a persisten t (>6 months) increase in the number 01 per ipheral b lood
(PB) large granular lymphocytes (LGl),
usually between 2-20x 1()8i\... without a
clearly iden tified cause.
ICD-O cod e
as lymphocyte reconstitution occurs

1732A, 14 14AI . Clona l populations of
T-l Gl are also otten seen in association
with low grade Bccell malignancies, inclu ding hairy cell leukaemia and chronic
lym phocytic leukaemia. These are usually
stabl e and d o not p rogress to clinically
signilicant disease. They appear to represent a type of host respon se 182, 14031.
9831/3
Ep;demiology
Tl GL leukaemia rep resents 2-3% of
cases of mature lymphocytic leukaemias.
There is an approxima tely equal ma le:lemale ratio with no clearly de fined age
peak . The disease is rare 3%) before 25
years and the majority of cases (73%)
occur in the 45-75 years ag e group _
Etiology
The und erlying palho p hysiologic mechanisms for T-LGL leukaemi a are not well
und erstood. This disorder is fairly unique
in that the cl onal T-LGL cells retain many
phenotypi c and functi ona l pr op ertie s of
normal cytotoxic effector r-ceus 12201,
One theory po stulates that T-LGL leukaemia arises in a selt ing of sustained
immune stimulation. The frequent assoc iation of T-LGL leukaem ia with autoimmune disord ers sup ports this hypothesis
1220, 2428 1. Absenc e of homeostat ic
apo plos is is also a feature of the T-LGL ,
as these cel ls exp ress high levels of FAS
and FASL , lead ing investiga tors to pr opose ac tivation of pr o-survival pa thway s
in T-LGL whic h p revent s FAS signaling
[648, 1954 1. FASL levels are ele vated
in sera of many patien ts, which may be
impo rtant in the pathogenesis of neutropen ia 113231.
Clonal expa nsions of T-LGl can be observed following allogeneic bo ne ma rrow
(BM ) transplantation, usually reflec ting a
restricted t-een reper toire. However, rare
cases of T-l Gl leukaemia have also been
observed as a torm 01 post-transplant
Iymphoproliferative disorder 1103, 15731.
A pitfall in diagnosis is the frequent d evelopmen t of oligoclonal T-cell populations
following anooeneic BM transplantation
272
Mature T- and NK-cell neoplasms
T-lGl leukaemia involves the PB, BM,

liver and spleen. lymphadenopathy is
very rare .
Clinical features
Most cases have an indolent clinical
cou rse 1390, 563, 1247, 16831. Severe
neu tropenia with or withou t anaemia is
frequent while thrombocytopenia is
not; lymphoc ytosis is usu ally between
2-20x 1Q91l. Severe anaemia due to red
cell aplasia has be en repo rted in assoc iation with T-l Glleukaemia 112471. Mod erate splenomegaly is the main physical
finding, Rheumatoid arthritis, the presence
D. Catovskv
" "_
The predominant lymphocytes in PB and

8M films are lGL with moderate to abundant cytoplasm and fine or coarse azcrophi lic granules 1278, 390, 14411. The
granules In the LGL often exhibit a characteristic ultras tructu ral ap pearance described as parallel tubul ar arrays 11441 1
an d contain a number of proteins that
p laya role in cytolysis such as pertorin
and granzyme B. There is no agreement
on the level of lymphocytosis required tCJ"
dia gnosis of T-LGL leukaemia 119921, but
a l Gl count of >2x 1Q91l is frequently associated with a clon al proliferation. However, cases with l Gl lower than 2x10"n.
F"IQ.tt.G4 The various na phologic 'IlWla"IIs of LGl. in !he perVoeraI bk:lod (Wriltlfs slain).
- .
f.. l1,D5 Bone marrow lindn;Js in H.Gl.Ieukaerria. A ~ceIs ridlr.rte mrslibaly. as dernalstTaIed by 5lai1b TlA1. B,C ReadiYe ~ iJW'e9iItes.l~
lDUesin... bone marrow irnrIuIostainec wrth iII'l..cD2O (S) Md ri-C03 ie). !k:eIs in ltle nodule /If1I8O'Ined wrth C03 poS/lro'e T<eIs lNl predominate iIllhe~.
but which mee t all other appropriate crtene. are consistent with this dia gnosis.
Despite the cvtopenlas. the 8M is norrrocellular or twoocenurar in about 50% of
cases; in the remainder, the 8 M is typically slightly hypercellular 1152 1, 1662} .
The granulocytic ser ies often show left
s meo matu ration and mild to moderate
-etccnn fibrosis is present 13901. The extent 01 8 M invo lvem ent is va riable and
LGL usually comprise less than 50% of
j-e cellula r e leme nts w ith inte rstitial/intrasinusoi da l infiltra tes which are d ifficu lt
toidentify by mo rpho logic review 11 52 1).
Non-neoplasl ic nod ular lymphoid agg regates containing many
surrounded
bya rim of CD4 + T-cells are also freq uently
present 11662 1. Sp lenic invo lvement is
characterize d b y inf iltration and exp ansco of the red pulp cords and sinuso ids
by T-LGL with spari ng of the often hyperplastic white p ulp 116631.
express C08, the remainde r are C04/

COB-negative 11303. 1926, 19921. Abnormally d iminished or lost expression 01
COS and/or C07 is common in TlGl
leukaemia 11348, 15201_Co57 an d C0 16
are expressed in over 80% of the cases
11247 , 1520 1. Expression of the C0941
NKG2 and KIA families of NK-assoc iated
MHC-class I recepto rs can be d etec ted
in 50% or more of T-lGlleukaemias. KIA
positive cas es usua lly sho w uniform
expression of a sing le rsotorm and thi s
finding can serve as a surroga te indicator
of cronanty 11 348, 15201, The r-t.e t, express the cytotoxic effecto r proteins TIA 1,
gr anzyme Band g ranzym e M. Bone marrow co re b iop sy immunohistoch emi stry
using ant ibodies to th ese antig en s a nd
COB can be used for c onfirmation of the
diagnosis by revea ling the mainly interstitial o r intrasinusoida l T-l G l infiltrates
11519, 1521,16621.
Cytochemistry
The granules are aci d phosphatase and
~ ~idase positive. However, enzyme
cytochemic al stains are rarely used for
rc:utine diagnosis.
Genetic s
Cases classified as T-lGlleukaemia are,
as a rule, clonal. as documented by TCR
gene rearrangement studies 11247f. The
TRG@gene is rearrang ed in all cases regardless of the type of receptors expressed. The TRG@gene is rearranged
in cas es expressing the TCfbP receptor,
but the TRB@ gene may be in ge rmhne
connquranon in cases expressing the
TCR')'l5 receptor 123361.
a-ceus
~
RGL leukaemia is typically a disorder of
mature CD3, COB and t-een receptor
(TeA) o il-positive cytotoxic t-eens 1390.
16831. Uncommon va riants include C04
TCfbIl-positive cases and TCfTr,S-positive
cases; approximately 60% 01 the ratter
Thefe is no unique karyotypic abnormality,
but nume ric and structural chromosomal
abnormalities have been described in a
small number of cases 112471 _
Postu late d normal counterpart
COB-positive t-een subset for the common type and a subset and T lymphocytes lor the rare typ e expressing the
'" TCA
Prog nosis and predi ctive factor s
The tvmobopronterauon is typ ically indolent and non- prog ressive and some
investig ators feel that it is bett er regarded
as a c lonal d isord er of uncerta in sig nificance rather than a leukaemia. Morbid ity
is associated with the c ytopenias especially neutropenia, but mortality due to this
cause is uncommon. In a series of 68
pat ients, median survival was about 13
years 15631 . Rare cas es with an agg ressive course have been described 1773,
22491. Patients who require treatment
may benefit from cvcrosponne A, cyclophosphamide and corticosteroids, low
dose methotrexate or pen lostalin 11247,
16641.
t-een large granular lymphocytic leukaemia
273
Chronic Iymphoproliferative disorders

of NK cells
N Villamor
W G . Moric e
W C . Chan
K. Fouc ar
Defin ition
Chronic Iymphoprolileralive disorders of
NK cells are rare and heterogeneous.
They are characterize d by a per sistent
(> 6 months) inc rease in peri pheral blood
(PS) NK cells (usually ~2x 109/l ) w ithout a
clearly identi fied ca use. It is d ifficult 10 d istinguish between reacti ve and neoplastic
conditions. without hig hly specialized
tecnoques. Chronic NK-ceU Iymphoproliterative disorder (ClP().NK) represents
a proliferat ion of NK cells associated with
a chronic c linic al course , and is co nsidered a provisiona l entity.
ICD-O code
9831 13
Synonyms
Ch ronic NK-cell lymphocytosis , chronic
NK-Iarge g ranular lymphocyte (LGL) tyroobopronterauve disorder. Nk -ceuuneaoe
granular lymphocyte prolifera tive disord er, Nk-ceu LGL lymp hoc ytos is. indolen t
larg e g ran ular NK-eeil lympho prol iferative
dis orde r.
Ep;dem;ology
CLPO-NK occurs predominantly in adu lts
with a median ag e of 60 yea rs without sex
p redominance 11248, 1304. 1799 1. Unlike
Epstein-Barr vi rus (EBV)-associated agg ressiv e Nc-ceu leukaem ia . there is no
rac ial or ge netic pred isposition .
Etiology
A transient increase in circul ating NK cells
may be encountered in many conditions
such as autoimmune d isorders Of viral infections 11248, 17991. NK-eell activation
d ue to an unknow n stimulus, presumably
v iral, is postulated to pla ya role in the
early pathogenesis of chronic IymphoproIilerative d isorders of NK cells by selecting NK-eell clones, althoug h no evidence
of direct NK-eell infection has bee n observed 113)4 .1340.1799.24831 , Agenetic
susceptibility may be linked to haplotypes
containing higher numbers of activating
kille r immunoglobulin-like rec ep tor (KfR)
genes (649, 1982, 2482),
274
Mature T- and NK-eeHneoplasms
Fig. 11.06 ChroniC tymphoproIifetative disorders of NKcells. Penpheral blood ftlms show the lymphocy1e 'Mth coarse
azlJfOPhilic granulation(A), ~mphocyle withnumerous ftne granuiations (8), lymphocyte withscarce granlriaoon ;,,\IlI
limit of~isi bility (e). 0 Intrasinusoidal marrow infiltrationby granzyme B positive cells, Note the bland nuclearcytology
of the antigen ~ti l'El cees.
Predominantly PB and bone marrow- (BM) .
Cl inic al features
The majority of patients are asymptomatic ,
but som e may present with systemi c
sym p toms and/or cytopenia(s) (mai nly
neutropenia and anaemia ). Lymphadenopathy, hepa tomegaly, splenomegaly and
cutaneous lesions are infrequent 11304.
1661, 1799 /. Chronic Iymphoproli le rative
disorders of NK cells may occur in associanoo with other med ical conditions such
as solid and haemato log ic tumours, vasc ulitis, splen ec tomy, neuropat hy and autoimmune d isorde rs 11304, 166 1, 1695,
1799 1.
The ci rculating NK cells are typically intermeot ate in size with round nuclei with
con d ensed ch romatin and moderate
amounts of slig htly basop hilic cytoplasm
co ntaining fine or coarse azurop hilic
gr anules. The BM biop sy is ch arac terized
by intrasinusoid al and interstitial infiltration by ce lls with small. minimally irreg~

nuclei and modest amounts of pale cytoplasm , These infiltrates are difficult to
de tect w ithou t the aid of imm unohistoc hemistry.
Immunophenotype
Surface C03 is negative. while cytoplasmic C03t: is often positive. CD16 is positive , while weak C056 expression is
frequently observed 11304, 1519 , 1520.
1695. 236 11, Cytotoxic markers including
TIA 1, gra nzyme B and granzyme M are
positive , There may be d iminished or lost
expression of C02, C07 and C057; also
seen are aber rant cce xpression of CDS
and abnormal uniform expression of CDS
11517. 15201, Expression of the KIA family of NK-eell receptors (NKA) is aboorrrl<4
in CLPD- NK ; eithe r restricted KIA tsoto m
ex pression or a com plete lack of detec tab le KIA may be seen (649. 952,
1520 , 1695 , 2482, 2485 ) KIA-pos itive
cases p referent ially e xp ress ac tivating
receptor tsotcrms 1649. 24821. Other abnormalities of NKR incl ude uniform. bright
CD94/NKG2A heterodimer expression
and diminished CD 16 1 expression 11304.
1520. 1982. 236 11.
Genetics
Karyotype is norma l in most cases 11661.
1799. 21731. There are no rear rang ements of the immunoglobulin and
receptor genes. as expected fOf NK c ells.
In female patients. It is possible to exploit
x-cnrorosome inactiva tion as an indi rect
marker of c lonali ty. A skewe d ratio of
t-een
x-cnromosome inactivation restric ted to

is indicative of the presence of a
NK
clonal population, With such methodologies. cionantv is confirmed in some but
not in all pat ients 11135. 1304 . 15 75 1. Unlike aggressive NK-eeil leukaemia. EBV is
negative {1248 , 1340.24831.
cess
Postulated normal counte rpart

Mature NK-cell.
Prog nosis and p red ict ive factors
In the major ity of pat ients the c linical
course is indolent O'IIer a prolonged period
Disease progre ssion with inc reasing lymphocytosis and worsening of cvtocemas
is ob served in some cases. The presence
of cv tcoeruas. rec urrent infec tions and
comorbi di ty may be harbingers of a
wor se prognosis. Rare c ases with either
spo ntaneous co mplete remission {1304.
1661, 1799. 2484 1or transtomaton toan
ag g ress ive NK -c ell d isorder have been
desc ribed 1990. 1628. 18781 The p resence of cytogenetic abnormalities may
imply a worse p rognosis and cou ld be related to ra re transformations reported in
the literatu re 11628 1.
Chronic lymphopfoliferatlV8 disorders of NK cells
275
Aggressive NK-cell leukaemia
J .K,C , Chan
E.S. Jane
E. Ra lfkiaer
Y-H . Ko
Definition
A systemic neoplastic proliferat ion of
Nx-cens almost always assoc iated w ith
Eps tein-Barr vir us (EBVj and an aggressive cl inical cour se .
ico-o eeee
9948/3
Syrooym
Aggressive NK-ce ll leuka emiaJlymphoma .
El' derr1iology
This is a rare for m of leuka emia which is
other ethn ic populat ions 119011. Parents

are mos t commonly young to midd leaged adults. with a med ian age of 42
years 1205 2, 2 128 1. There is no sex
pred ilecti on or a slight male predomi-
nance 1381. 386. 1004, 1221 , 1223. 1659.

190 1, 1902,2052, 21281 .
Elioklgy
Little is known about the etio log y of ag gressive NK-ceilleukaemia . but the strong
association with EBV suggests a pathogenetic role of the virus . Rare patients
may mani fest features of hypersensitivity
to mosquito b ites or ch roni c ac tive EBV
infecti on 11020, 1021J, leading to overlap
with EBV+ r-eef Iyrnp hcprohfera tive disorders of chi ld hood,
The most commonly involved sites are
pe rip heral blood (PB), bone marrow (8 M),
liver and spleen, but any organ can show
involvement in addition, Since the number
of neoplastic c ells in the PB and 8 M can
be limi ted, the disease is different from
the usual teukaemtee and thu s als o has
been called "aggressive NK-eeilleukaemiaJ
lymphoma". There c an be overla p wit h
extranodal NKIT-eeillymphoma showing
multiorgan involvement it is unclear
whether ag g ressive NK-cell leukaemi a
represents the leukaemic cou nterpart of
ext rarooa t NKIT-ceil lymphoma 138 1/.
Clin ical features
The pa tients usually p resent with feve r,
ccoeutunon et symptoms and a leuka emic
276
Mature T- and NK-ceH neoplasms
.1. ..
much more prevalent among Asians than
...
.....
Fig.11.07 Aggressive NK<e/l leukaemia A In !his blood smear. the neopIas1ic cells are IIefY similartl normal large
granular lymphocy1es, B In !his case, the neoplastic cells have basophiliC cyloJlIasm. and nuclei wiIh more open
chromatin and disbnd nudeoli. AzurophiliC I13nules can be observed in the cylopIasm, C The neoplaslic cells are
negative for s~ CD3 (leLl4), wtIiIe ee normal T lymphocytes are staifled. D The lleOPlastic cells show ~
illmunoreactivity lor C056.
blood p icture. The number of c irculating

leukaemic cells may be low or high (a few
percent to >80% of all leukocytes); anaemia.
neut ropen ia and throm bocytopenia are
c ommon , Serum lact ate de hydrogenase
leve l is ofte n marked ly elevated Hepatospl enomegaly is commo n, sometimes acco mpa nied by lymphadenopathy, but skin
lesions are uncommon. The d isease may
be complicated by coagulopathy, haem ophagocytic syndrome or multiorgan failure {386 , 1004 . 1223 , 1515 , 1639 ,2052,
2128/. Rare cases may evolve from extra nodal NKIT-ceillymphoma or c hronic Iymphoproli lerative d isorders 01 NK cell s
1911 ,1628,1661 , 2049 1.
While it has been sug geste d that ag gressive NK-ceil leukaemia may merely repr esent the leukaemic manifest ation of
extranodar NKIT-cell lym phoma , the following fea tures are d istin ctive for the former: younger median age by more than a
decade ; high frequency of hepatos plenic
and 8M involveme nt; low freq uenc y of
c utaneou s involvement : di sseminated
dis ease with uniformly fatal outcome irrespective of treatme nt; and freq uent ex
pression of CD 16 11582, 2128 1.
Morpholog y
Ci rcula t ing leukaemic cel ls can show a
range of appearances from cells indistinguishable tram normal large granu lar lymphocytes to cel ls with atypical nuclei
featuring enlargement, irregular fold ings.
open c hromatin or distinct nucleoli. There
is an ample amount of pale or lighlly besophilic c yto plasm con taining fine (X
co arse azu rophilic granules , The 8M
show s mass ive, focal or subtle infiltratioo
by the neoplastic cells and there can be
intermi ng led react ive tuenocvtes wilh
nae rroonac ocvtoeis. In tissue sections
the leukaemic c ells show d iffuse or
pat chy destruct ive infiltrates. They often
appear monotonou s, with round or irregular nuclei, c ondensed c hromatin and
small nucleoli , but the y can sometimes
show sig nificant nucl ear pieororphem
There are freq uentty ad mixed apoptobc
More than 90% of cases harbour EBV,

wh ich occ urs in a c lonal epi soma l form
1386.903. 11261.
A
Ft.l1.oaAgpssMI NK<el IetAaema. A Giemsa-stained I'I\TOW asprate. The neoplasllccels show pleolnoqnc
~ b*l ru:IIi. prorrinenI ru:illoli lWId cytopla:stric 3lIftlPhIc granJes in ltle basoIt*~ , Bl~
IIlde. The neopIastJc eels appear mOlloD lOUS. and poss.e$$ l'OI.I'ld nudei. There are many inl~
--
bodies Necrosis is co mmon, and there
mayormay not be ang ioinvasion .
IrrmLllOphenotype
The neoplastic ce lls are CD2 +, surf ace
C03-. COOt: +, CD56+ and positive for
~ molecules. Thus . the irrmunopheoo-type is identical to that of exnenodet
cvto-
neg ative 1381. 1659 ). The neoplastic cells

express FAS ligand . and high levels of
FAS ligand ca n be found in the serum of
affect ed pat ient s 11117, 1369. 2 156 1.
Genetics
NKIT-ceil lymphoma, except that C0 16 is
j-ceu receptor ( TeR) genes are in germline

configuration . Clonalily therefore has to
be esta bl ished by other methods, such as
frequently positive (75%) 121281. CD 11 b

may be expressed. while CDS7 is usually
cytogenetic stu dies and patt ern 01X c hromosome inaclivation in female pa tients.
A variety of clonal cytog enetic abnormalities have been reported , such as

d el{6){q 2 1q25) and 11q deletion 119021.
An array -based com pa rative genomic hybr idizat io n study has shown signi ficant
d ifferenc es in genetic ch anges between
aggressive Nx -cenre ukaemta and extranodal NK/T-celilymphoma: 7p-, 17p. and
1q ... are frequent in the for mer but not the
latter, while 6q- is comnon in the tatter but
rare in the former 115671.
NK ce lls.
Prognosis and predict ive factors
Most cases pur sue a fulminant cli nical
course frequently complicated by mult iorgan failure . coag ulopathy and haemophagcx;ytic syndrome . The median survival
is less than 2 months 1381, 1902,2052,
2 1281. Response to chemotherapy is usually poor, and relap se is almost lhe rule in
patients ach ieving remission with or withou t BM transp lantation 12 128 1.
,
,
,
j
,.
Agg ressive NK-ceil leukaemia
277
EBV-positive T-cell Iymphoproliferative

disorders of childhood
L. Ouintanilla-Martmez
H. Kimura
E.S. Jaffe
Two maiO' types of Epstein-Barr (EBV)-
extensive lymphadenopathy. and careytoc enta has been described in Japan

{11 49. 1150. 21271. These patients have
higher viral copy numbers in peripheral
blood (PB) , and inste ad of
or natura l killer (NK )-cells are EBVinfected. These cases frequen tly manifest
monoclonal t -een populat io ns and prog ression to ove rt malig nant T-cell maliqnan cy is the rule. CAEBY with monoc lonal
EBY+ r-eef proliferati on rep resents partct
the spectrum of systemic EBY+ T-cell LPD
of childhood 117971. and to avoid confusion should nOI be referred as to CAEBV.
associated T-cetllymphoprolilerative disorders have been reported in the

paediatric age group . Both occur wi th
IC().() code
fou rth edi tion of ICO-Q is 972413.
increased frequency in Asians. and in
Synonyms and historica l annotation
Native Americans from Cen tral and South

America and Mexico . Hydroa vaceiniformelike lymphoma is a c utaneous ma lign ancy
with an indolent c linic al cou rse, but it usu-
Historica lly this p roc ess has been d escri bed und er a variety of terms inclu di ng:
fulminant EBY+ t-een LPO of chil d hoo d ,
sporad ic fatal infec tious mononuc leosi s
(FIM); fulm inant haemophag ocytic syn d rom e in c hild ren in Taiwan 121151: fatal
EBV-associ ated baemopn aqocvttc syn drome in Japan 11 144 1: an d severe
CAE BV {1149, 1636,21271.
The term fulminant or fatal haemoph agocytic syndrome has been used to
describ e a systemic d isease secondary
to acute primary EBV infection affecting
previously healthy children . It has been
shown to be a monoclonal COB+ EBVassociated Iymphoproliferative disorder.
and therefore is now considered equivalent
to systemic E8V+ T-celllPD of childhood
ally progresses over time Systemic EBV+

f-cemvmoro oronterauvedisease (LPD) of
childhood t ies a very fulm inant clinical
cou rse. It may be associated with ch ronic
ac tive EBVintec tion (CAEBV ). and in
these patients is p reced ed by a p rodromal phase 01 ootycronat or oligoclonal
expansion of EBV-infected T-cells .
Systemic EBV-positive T~II

IymphoprolifBrativB disease of
childhood
Be ene.t-eens
Epidemiology
Systemic EBV +
LPO of childhood is
most prevalent in Asia . primarily in Japan
and Taiwan 111 44 , 1149 .2115.21271 , It
has been reported in Mexico and rarely in
Western countries 117971. It occurs mosl
often in children and yCM.mg adults. There
is no sex predilection .
t-een
l179n
Definition
t-een
Systemic EBV+
LPD of childhood is
a hfe-threatening illness of children and
you ng adults c haract erized by a c lonal
proliferation of EBV-infec ted
with an
activated cy toto xic ph enoty pe , It c an
occur shor tly after primary ac ute EBY infec tion or in the sell ing of chronic ac tive
EBV infe ction (CA EBV), It has a rap id progre ssion with mul tiple organ fa ilure , sepsis and death, usua lly from days to weeks.
This entity shows some overlapping clinico pathologic features w ith ag gr essive
NK-cellieukae mia.
t-eens
278
Mature T- and NK -cel l neo plasms
The term CAE8V was coined to describe

an infectious monooucleosis-like syndrome
persisting for at least 6 months, and associated w ith hig h liter s of antibodies to
EBY-cap sid antigen (VCA.lgG) and early
antigen (EA -lg G) wit hout assoc iati on to
malignancy, autoimmune d iseases or
immunodefic ienc y 121071. These cases
are mostly seen in West ern popu lations ;
pr og ression to EBV-po sitive T-ce ll LPO
ha s been rep or ted rarely in suc h patients
11069, 109 4, 17971.
A more severe form of CAEBY ch aracterized by high feve r, hepatospl enomegaly.
Etiology
Alt hough the etiology is unknown, its
association with primary EBV infection,
and the racial predisposition, strongly
suggests a genetic defect in the host
immune response 10 EBV 11 144, 1149,
1797, 21 15, 2127) ,
Sites of Invo lvement
It is a systemic di seas e. The mos t commonly involved sites are liver and spleen
followed by lym ph nodes, bone marrow
(BM) , skin and lung {1 144, 1149 , 1797
2115,21271
"_.1Ii
_ G .. .
Fig. 11.12 Systen"ic EBV. T<el lPO of childhood A The liver shows a subde sinUSOIdal lymphoid infiltrate Iac:U'lg cytOlogIc atypia EIyIhrqlhaglxyts is pronWIenl.
BThe rlliIlrabng Iyl'npI'locyfes are C08-positive. C Nearlyall ~ in the S1llUsoids are EBER-posb'te.
CDcaI features
Mmphoklgy
Previously healthy patients present with
The infiltrating t-eens are usually small
acute onset of fever and general malaise

S:.Jggestive of an acute viral respira tory
illness. Within a period of weeks to
months. patients develop hepa tospleno megaly and liver failure. sometimes
and lack signif icant cytologic atypia

117971. However, cases with pleomorphic
med ium-sized to large lymphoid cells,
irregular nuclei and frequent mitoses have
been descri bed 121271. The liver and
sp leen show mild to marked sinusoidal
infiltration with striking baerroobaoocvtosts.
The spl enic white pulp is dep leted , The
liver has prominent porta l and sinusoida l
infiltration. cr orestasrs. steatosis and nec rosis, The lymph nodes usually show
preserved architecture with open sinuses.
A variable deg ree of sinus histiocyt osis
with erythrophagocytosis is presen t,
Bone marrow biops ies show histioc ytic
eccoroaned by lymphadenopathy. tate-
rat(l(Y tests show panc ytopenia, abnormal

Iver uncton tests and often an abno rmal
EBV serology with low or absent anti-yeA
19M antibodies. The d isease is usua lly
complicated by haemophag ocyl ic syndrome, coagulopathy, mulli organ failure
ant! sepsis (1 7971. Some cases occu r in
patients with a we ll-d oc umented his tory
cfCAEBV infection 11 069. 10941.
hyperplasia with prominent erythrophagocytosis,

Immunophenotype
The most typical phenotype of the neoplastic ce lls is CD2+ CD3+ CD56- and
TIA 1+ Most cases secon dary to acute
prima ry EBV infection are CD8+ 11113,
1797, 21151, whereas cases in the setting
of seve re CAEBV are CD4+ 11069, 1094,
1797). Rare c ases show both CD4+ and
CD8 + EBVi nfected T-ce lls 117971. EBVencoded RNA (EBERl is positive,
Genetic s
The cells have monociooauv rearranged
t-een receptor ( f eR) genes. All cases
72 bp
TeRr
~ 11.13
lPO fA etill:tlOOd A The spleen sIJ:Ms depIebon fA tIM! ~e!up and prorninenl
inMrales. The nodules are composed predomil'Iaolly DI CQ4.poWte eels
I EBER inSCU ~ shcM t'lal 1tle C04-positiye eels are also positivelor EBV RNA.
SysIerNc EBV.
-ada! <n:l
T~
~ ~
EBV-~il jve
Fig.11.1' Systemic eev- T<8I lPO DI ct*tlDod. PCR

lor TRG@ gene. PeR derrmstrales an idenIicaI T~
etJne i'l h iYer. spteen n ~ nodes
T.celllyrnphoproliferatrve disorders of childhood
279
harbour EBV in a c lonal episomal form

11069. 1144. 1149.2 127 1. All c ases analyzed carry type A EBV. either with wildtype or the 30 bp deleted product of LMP1
gene 11 113. 1797,2 1271. In situ hybridIzanon for EBER shows that the majority of
the infilt rating lymphoid cells are positive .
No con sistent ch romosomal aberration s
have been identi fied 1402, 11491 .
Cyto toxic CD 8+ T lym phocytes or ac tivate d CD4+
t-eens.

Most cases have a fulminant cli nical
cou rse resul ting in death. usually from
days 10 week s . How ever, some cases
srow a subacute course of several
months to a year.
Hydroa vaccinfforme-Iike
lymphoma
Definition
Hyd roa vaccinnorrre-uke lymphoma is an
EBV-positive cutaneous t-een lymphoma
occurring in ch ildren, and associated with
sensitivity 10 insect bites and sun sensitivity.
Etiology
The neopl astic cells, usually T-eens. bu t
sometimes NK-cells, are nanetoerrec by
ESV. Patients exhibit hy pe rsensitivity to
sunlight, and insect bites , often mosquito
b ites, which precipitate cl inical symptoms
11582/.
This is a c utaneo us co nd itio n that p rimarily affec ts sun-expo sed skin, in particu lar
the fac e 1596 , 10271.
Clinical features
It is characterized by a p apulovesicular
er uption that generally proceeds to ulce ration and scarring. In some cases. systemic symptoms including feve r. wasting.
lym phadenopathy and hepatosplenomegaly may be present. partic ularly late
in the course of the disease {147 . 3991.
Mmpoology
The neoplastic
are generally small to
med ium in size w ithout sig nifica nt atyp ia.
The infiltrates show extension from the
ep id erm is to the subcutis , showing necrosis, angioc entric ity an d anqioin vasion.
The ov erlying epidermis is freq uen tly
ulcerated 11471.
cene
ICD-O code
The provisional code proposed lor the
fourth ed ition oflCD-O is 972513.
Irrrnuno phenotype
The cells have a cytotoxic
Of, less
often, NK-ce Uphenotype. with expression
of CD56.
Epidemiology
This co ndi tion is see n mainly in c hild ren
and ad ole scents from Asi a , or in Nat ive
Ame rica ns from Central and South Am erica , and Mex ic o. Like other Eb v- pos itive
and NK-c eillympho mas, pred isposition for this cond ition ma y be related to
a defec tive cytotoxic immune res ponse to
EBV. It is rare in adults 11 47, 432 1.
Genetic s
Most ca ses have clonal rearra ngements
01 the TCR ge nes Some c ases of NK
de rivation w ill not show TCR ge ne rearrangement 1399, 2455 1.
EBER in situ hybri di zation is expressed in
all 01the atyp ic al cells, but LMP 1 is generally neg ative . EBV is monocl ona l by
term inal repeat analysis.
t-een
280
Mature T- and NK-ceU neoplasms
Fig. 11.15 Hydroa vaccini!orme-like lymphoma. Sunexposed areas of the skin exhibit a papulO'lesiaJtar
eruption. Many of the lesions are ulcerated WltIl a
haemoo!lagic crust.
t-een
Skin homing cyt otoxic T-cell Of NK-cell.

The clinical course is variable, and patients may have recurrent skin lesions fer
some time , up to 10- 15 years . belore
progression to systemic involvement. With
systemic sp read, the clinical course is
much more agg ressive {1600 1.
Adult T-cell leukaemia/lymphoma
Definition
A peripheral T-cell neoplasm most ott en
composed of high ly pleomorphic lymphoid cells. The disease is usually w idely
disseminated. and is caused by the

tunan retrovirus known as human T-cell
lelJ\aemia virus type 1 (HTLV- l).
roo code
9827/3
MJIt T-cellieukaemia/lymphoma (ATlL)

isendemic in several regions of the wor1d.
11 particular Southwestern Japan, the
Caribbean basin and parts of Centra l

Alrica The distribution 01 the disease is
Taillt 11.01 Clinical and morphoIogocai speclrum of
tffi.\Ll-4e1ated diseases.
~lit
difotd.rs
Pe/tlheraI ti:lod lleukaerlia)
-..""
""'" ""
-""
l~
reoe(lymphoma)
~ ikll type
Pleomorphic small celllype

Pleomorphic (medium and large cells) type
ArlapIasticlarge cell type
&,
P."".
-,'''''''"
closely linked to the prevalence of HTLV-1

in the po p ulation .
The d isease has a lon g late ncy, and affected individuals usua lly are exposed to
the virus very ear ly in life . The viru s may
be transmitted in breast milk. and through
exposure to pe ripheral b lood (PB ) and
bkx>d products. The c umulative inc idence
of ATlL is est imated to be 2 ,5% among
HTLV-1 carriers in Japan 121441. Sporadic
cases are described, but the affected paIients often derive from an endemic region
of the wor ld. ATLL occurs only in adults
and the age at onset ranges from the 20s
to the 80s , with an average of 58 year s.
The male to fema le ratio is 1.5; 1 12462 1_
K. Ohshima
E.S, Ja ffe
M . Kikuchi
Fig. 1U 7 Adull T<elIleu kaemiahymphoma. A r3lio-
lrc'Ph shcIws extensive ic bone lesions.
Etiology
HTLV-1 is causally linked 10 ATLL, but
HTLV-1 infection alone is not sufficient to
resull in neoplastic transformation of infected cells. The p40 tall: vital protein
leads to tra nscri ptional ac tivation of many
genes in HTLV-1 infected lymphoc ytes
1726}. In add ition. the HTLV-1 basic leuc ine
zi pper fac to r (H8Z) is thought to be impo rtan t for T-cell proliferation and oncogenesis 119401. f-iowever, add itional genetic
alternations acquired ove r time may result
in th e dev elopment of a ma lig nanc y,
HTLV-1 also ca n indi rectly cause other
d iseases, suc h as HTLV-1 associate d
myelopathy /tropical spas tic parap a resis
{21481.
Gastroilleslinal lraC!
'-
Ulcersfu!1
T"m. ..
""
.... """""
Portal orSinus inliltfation
IJ*traIion "Mill or Wllhout fibrosls
~ dilO rden
""""""
HTlV-l-woaa1ed myelopathy (HAM)

HTlVl-1UOCill!ed lIVefbI
HTlV1-associa1ecl tyrnpnadenrtlS
.......
HTllJ.l..as:sociB\ed ~(HAB)
HltV-l~ 8l'thnlpIthy (liMP)
IfTtVl-a&SOCia1ed ,.eptwopaltly
Most ATLL patients present wit h wid espread lym ph node involvement as well
as involvement of PB , The number of cirdoes not correculating neopl astic
late with the degree of bone marrow (8M)
involvement, sug ges ting that ci rculating
cells are recru ited from other org ans suc h
as the ski n. In fact , the skin is the mos t
common ext ralymphatic site of involvemen t (>50%).
The distribution of the d isease is usually
syste mic, involving the spleen and extranodal sites including skin. lung , liver. gastrointestoatnact and central nervous system
1298 1. Epidemiologica l differences occur
in patterns of presentation. For example.
cens
Mao.........,...
fC.p.11.11 MAT-<8I ~.
fir'odIngs of cutaneous lesions have been dassrlied as
~ (A). paplAes {Sl n:I nrxUes (e).
Adult T-eellieukaemia/lymphoma
28 1
T-celIeu~ . PeftpheralbIoodl*ns. A klttle acute vanant, the leukaemic eels are

medlum-sazed to large ~ eels with inegular nuclei and basopIliIic cytoplasm . The dWaetensbc AduN T-cel
~ cellshavebeendescnbed as"1lower cells", with mallY ru:lear COI'IYCIIutiOnS and lobules. BMAl
T-<::eI ~ eels in Itle etwonic varWit are generaIy small WIlh sJ9'IIl'I.Idea' abnormal",", sud! as
nothng. indeoIation. and c::orrvoMIon
Fig. 11 .19 Adult
Fig. 11.20 -'dun T-cell Ie~ emiahy'mpholna eels

trequenlIy eJPreSS FOXPJ. The roelqlreSSlOfl 01 fOXP3
and C025 is d'laraderiStk:oI ~ T<eIs(Treg).
PB involvement is much less c ommon in

canents from the Caribbean basin than
from Japan 112861.
Clinical features
Several clinical variants have been iden nfied: acute, lymphomatous , chronic and
smoldering ATLL 1201 01 . The acute vanani is most common and is charac terized
by a leukaem ic phase . otten with a
markedly elevated while blood cell (WBC)
count. skin rash and generalized lymphadenopathy Hypercalcaemia, with or
without lytic bone lesions. is a common
feature. Patients with acute ATLL have a
systemic disease accompanied by hepa tosplenomegaly, constitutional symptoms.
and elevated lactic dehydrogenase Leukocytosis an d eosinophilia are common .
Many pati ents have an associated T-cell
immun od efici ency, with frequent op portunistic infections such as Pneumocystis
c arinii pn eumonia and Strongy loidiasis ,
The lymphomatou s variant is charac terized by prominent lymphadenopathy but
without PB involv ement. Most pa tients
pre sent with ad vance d stage d isease
similar to the acute form , althou gh hype rcalcaemia is less allen seen. Cutaneous
lesions are common in both the acute and
lymphomatous forms of ATLl. They are
clinically diverse, and inc lude erythematous rashes, papules and nodules. Larger
nodules may show ulceration.
The chronic variant is frequently associated with an exfoliative skin rash. While an
absolute lymphoc ytosis may be present.
atypical lymphocytes are not numerous in
the PB. Hype rcalcaemia is absent.
In the smol dering variant, the wac count
is normal with >5% ci rculating neoplastic
cells , ATll cells are generall y small w ith a
normal appearance. Patients frequently
282
,- _
Table 11.G2
lXaglW)Slic mlefia fordiniCal subt)1les 0( Ad~ T<8llIeu~, Moddied from Shimoya-na at ai. {2010}.
Smoldering
N,
Bklod abnormal ~
LIlH
"""'"
"""'"
l~nopalhy
"'~
Bone marrow i'lliraIion
>"
""""
"""".......
No
No
No
Clu"onlc
Acut.
have skin or pulmonary lesions, but there

is no hyperca lca emia. Progression from
the chronic or smo lde ring to the ac ute
variant occurs in 25% of the c ases, b ut
usually aner a long durat ion 120 101.
I.1o<phology
ATLL is charac terize d by a b road spectnm of cytological features 116301. Several
morpholog ic al variants have been described, reflectin g this varied cytology

and referred to as pleomorphic small ,
medium and large cell types, ana plastic ,
m a rare form resembling angiOirrmunobaste t-een lym p homa 116301. Use of
sese variants is optional but they call attentoo to the spectrum of ffiO(phoIogical
appearances Some cases exhi bit a
e xeemc pattern of infiltration. with
preservation or dilation of lymph node
souses that contain malignant cells. The
I'Iflammatory background is usually
sparse. although eosinophilia may be
present. The neoplastic lym phoid cells
are typically medium-sized to large. etten
WIth pronounced nuclear pleomorph ism .
The nceer Chromatinis coarsely clumped
with distinct. someti mes promine nt, nucleoli. Blast-like cells with transformed nuclei and dispe rsed ch roma tin are prese nt
11 variable propor tions 12010J. Giant cells
w,th convoluted or po lylobated nucl ear
contours may be p resent. Rare cases
may be composed predomin antly of small
~phocytes, with irreg ula r nucle ar c onlours Cell size does not co rrelate with the
clinical course 11036 ). with the exception
of the chronic and smo lde ring for ms, in
which the lymphocytes have a mo re normal appearance.
Lymph nodes in some patien ts in an ear ly
pease of adult T-cell lymphoma/leukaem ia
may exhibit a Hodgkin-lymphoma-like histology 116321. The lymph nod es have expanded oaraco rt'ca t areas co nta ining a
diffuse infiltrate of small 10 med ium-s ized
tyTnphocytes with mild nuclear irreg ularities, indistinct nuc leoli an d scant c ytoplasm. Epstein Barr vir us (EBV)+ B
tyTnphocytes with HOd gk in -like feat ures
are interspersed in this back g roun d , The
expansion of EBV+ B-ce lis is telt to be
secondary to the underlying ewnuoooenciency seen in patients with ATLL
In the PB. the poIy1obat ed appearance of
ee neoplastic ce lls has led to the term
bier cells. These cells have deeply base~ cytoplasm . mos t readi ly observed
liI'Ilh Giemsa stains of ai r-dried smears.
lrdallOW infiltrates are usually pat chy.
rang ing from sparse to mod erate. Os teoc lastic activity may be prom inent, eve n in
the absence of BM infiltrat ion by neop lastic cells .
Skin lesions are seen in mo re than 50% of
patients with ATlL. Epid ermal infiltration
wit h Pautrier-like rnicroabscesses are
commo n 116301. Dermal infiltr ation is
mainly pe rivas c ular. bu t la rge r tumour
nodu les with exten sion to subcutaneous
fat may be observed .
Diffus e infiltration of many organs is indicative of the systemic nature of the disease, a nd presence 01 circulating
malign ant cells.
Irrmunophenotype
Tumour cells express r-cea-assocretec
ant igens (C 02. CD3. CDS) . but usually
lack CD7. While most cases are CD4 +,
COB-, a few are CD4-, CD8+ or double
posi tive for CD4 and CDa. CD25 is
stron gly expressed in nearly all cases.
The large trans formed cells may be positive for CD3Q, but a re neg ative for AlK
121 49} and Cytotoxic molecules. In ad dition, tumou r celts frequently express the
chemoune receptor CCR4 and FOXP3, a
fea ture of reg ulatory t-eens 11 112},
Fig. 11.22 Neoplastic eels Jlihrale Ihe epidemIis, pr0ducing Pautrier e microabscesses.
Genetics
An tigen receptor genes
T-cell rec e ptor genes are clonatly rearranged 116311.
Oncogenes and other molecular changes
Neoplastic cells show monoclonal integration of HTLV-1. No clonal integration is
present in healthy carriers 122741. Tax, encoded by the HTLV-1 pX reg ion, is a critical nonst ructu rat pro tein that plays a
central role in reukaerrcqenese. and activa tes a variety of c ellular ge nes {17221.
Furthermore, enhanc ement of cyclic AMP
response ele ment b ind ing transc ription
fact or (CREB) phos phorylation by the
Fig. 11.23 Adu~ T-cee ietJkaemiaI1Y!ll1lhoma, A InItlis case, Itle infttlra le coessts of largeeens with anaplasticfealures,
B The cells arestrongJ y C030+, ra i~ng the differential diagnosis ofarlaplasliG large eel ~
Adult T-cellleukaemiaJtymphoma
283
~ (~ )
._....
CI'ftnIc ('52}
L.ymphomll ( 1&11)
. _
Col&5l
(fNl ilf*1l tr_form.w,,)
--...,
..
O'
"
-.....
No<
....ec
"
00
v....
Fig. 11.25 A &r.1vaI cJ paliln5 wiltIlOA T-<:elI~.Acute;nj ~1lluS Iorms I1a'o'8 l1l'i ~ ctilical 00U'Se. whe!'82S longer ~ i'I seen.,
paIIentS..etI ctwnic Of ~ disease. B MA T - a ' ~. HR\Ll proWaI ONA~ a"d cinicaI Sl.tJIype$
virus appears to playa role in leukaemogenesis 111481.

Almost all ATLl cases have clonal chromosome numerical and structural abnormaunes. but none of them is soecitc.

Peripheral CD4+ t -eens. It has been suggested thai the CD4+CD25+FOXP3+
regulatory t-eens are the cl osest normal
coun terpart 111 121. This finding correlates
with the immunodeficiency cha racter istic
of the disease.
284
Mature T and NK-cell neoplasms

Clinical subtypes, age . pertorrerce status, serum ca lcium and LDH levels are
major prog nostic factor s 124641. The survival lime for the acute and lymphomatous variants ranges from two weeks 10
more than one year. Death is often
caused by infectious com plic ations including Pneumocys lis carin ii pneumonia.
Cry ptococcus men ingitis . disseminaled
herpes zoster and hypercalcaemia 120101.
The chronic and smoldering forms have a
more protracted clinical cour se and better
surv ival, but can prog ress 10 an acute
phase with an aggressive course 11633}.
Extranodal NKIT-cell lymphoma,

nasal type
Definition
A predominantly ex tranodal lymphoma
characterized by vascular damage and
destruction, prominent necrosis , cytotoxic
phenotype and association with Ep steinBarr virus (EBV). It is d esig nated N KIT~
(1'lSlead of "NK") , bec ause whi le most
cases appear to be genuine NK-ceU neoplasms, some cases show a cytotoxic

tee! phenotype,
97 19/3
J .K.C. Chan
L Ouintanilfa-Martinez
JA Fer ry
S.-C. Peh
Extranodal NK/T-ce ll lym phom as c an

occur in the selti ng of immunos uppression , includ ing post -transp lant 198 1. 12221.
tissue, g astrointestinal tract and testis,
Some c ases may be accompanied by

secondary lymph node invotveme nt 1381 .
386. 1137, 1220 , 1738,22481. Rare ex-
Sttes of involvement
Extranodal NK/T-ce Ulym phoma almost atways shows an extranodal presentation .
The upper aerodiq estive tract (nasal c avity, nasopharynx , parana sat sinuses ,
palate) is most co mmonly involved. with
the nasal c avity being th e p rototyp ic site
of invo lvement. Preferential sites o f exnanasat involvement incl ude the skin, soft
amples of primary lymph node disease in

the absence 01 extranodaJ mvovereot
have also been reported 1421 , 1082, 10051.
Cli nical featu res
Patients w ith nasal involvem ent present
wi th symp toms of nasal ob struct ion or
epistaxis d ue to p resence of a mass lesion. or with extensive midfacial destructive
Syrooyms
AngiOCentric T-cell lymp homa; malign ant
il'idIlI1e reticulosis; polymorphic renculoSIS: lethal midline g ranuloma: anqlocen rIC immunopro hlerative lesion .
Epidemiology
Extranodal NKfT-c ell lymp homa is mo re
prevalent in Asi an s. and th e n ative Amer-
can population of Mexico, Central America
lrIdSouth Ame rica (55. 104 , 38 1,17951 .

ecccurs most often in ad ults, an d is more
carmon in males than females . A low tre~ of HLAA' 0201 allele has been rellOrted in patients with EBVposihve nasal
NrJT lymphomas 11094AI .
Fig. 11.26 E.x1rcn::ldaI NKIT-<:eI ~. nasattype. A fJparIsionol\tle nasal bIidge, B Cor!lMedlom:lp'n, The
Uncu II \tie nasal caVIty edenCls upwMl no toe ortlil reSIAlrlg II proplosis
EIioIogy
Li~ le is know n ab out the etiology of extram al NK/T-cell lymp homa , However, the
ofJfY strong association wit h EBV, irreeecnve of the et hnic or ig in of the pa llents, suggests a prob able pathogenic
Qeol the virus 170, 386, 389, 639, 1093 ,
'795, 22991 , The EBV is present in a
IXrIaI episomal form 170, 389 , 639 , 944 ,
KOO. 1448, 1795. 2 130,2299J with type II
lalency pattern (EBNA-1 + , EBNA-2-,
IMP1+), and commonly shows a 3O-base
pair deletion in the late nt membrane protein1 gene 1415 , 589 , 639 ,1 205 , 2 143J
Most stud ies sho w that the EBV is almost
l tlays of subtype A 11 48, 639, 1717,
21)), 22481 . The d isease activity c an also
te monitored by measuring Circ ulati ng
EBV DNA; a high titer is furthermore corI!Iated with extensive disease, un'r.Q.jrable response to therapy an d poor
s.tVival l1 OSI.
FIg. 11.21 ExtrarcdaI NKIT<.elI ~ ,nasaI-type . A F'!'ot!wlenI \k.efa1lon and necrosis 1\ ht nasal nu::osa
B Thenasal rru:osa ill dlIMely rihlBd 1nI e~ by.. abnarmaI WlOId irIIinIIt . The rru:usaI gIIilnds ~
showa pecuIar dear eel cNnge . C,D ~ NKIT<eI ~ in Itle IestJS C There is a tifIlJse dense1ymphoid infiltrate. wilhprorrW1enl ooagt*l1rve oeaosis. D TheneopIiIstic eels a~ monoICInOuS and are mediuTl-lIized.
Extranodal NKfT-ce lllymphoma , nasal type
285
lesions (lethal midl ine g ranuloma ). The

lymphoma can extend to adjacent tissues
such as the nasopharynx , paranasal stnuses. orbit, oral cavity, palate and
oropharynx. The disease is often localized
to the upp er aeroo'cesuve tract at presentation. and bone marrow (BM ) involvement is uncommon 124371. The disease
may disseminate rap idly to various sites,
e.g. skin. ga strointeSlinal tract , testis or
cervica l lymph nod es during the clinical
course. Some cases may be complica ted
by a haemophagocytic synd rome 14 13.
12201.
Extranodal NKIT-ceil lym phomas occurring outside the uppe r aerodigestive tract
(often referred to as "extranasal NKIT-ceU
lymphomas ) have variable presentations
depending upon the ma;or site of involvement. Skin lesions are corrvnonly nodular,
often with ulceration . Intestinal lesions
often manifest as perforation. Other in-voIved sites often present as mass lesions.
The patients commonly have high stage
disease at presentation, with involvement
of multiple extranod al sites. Systemic
symp toms suc h as fever, malaise and
we ight loss can b e present 1386. 1137,
24381 . Lymph nodes can be involved as
part of di sseminated disease. Marrow
and periph eral blood (PB) involvement
can occ ur, and such cases may overlap
with aggre ssive Nk-ceure ukaernia.
This disease is to be distinguished from a
Morphology
The histological features 01 extranooar
NKIT-ce ll lymphoma are similar irrespecuve of the site of involvem ent. Mucosal
sites often show extensive ulceration. The
lymphomatous infiltrate is diffuse and permeative . Mucosa l gland s often become
widely spaced or are lost. An anqcceotnc
and ang iode strucli ve growth pattern is
frequently present. and fibrinoid changes
can be seen in the blood vessels even in
the absence of arqtonvasion. Coagulative
Fig. 11.29 Edrilnodal NKIT<el1ymphome in !he sUI.

The ~ inNlrate inotves !he epidlIfrM,
dermrs iI'ld Slb::utaneous tissue.
Fig.11.30 The cylWgic spednm 0I1OOrlwloda1 NKIT<eI

nasal type, A.6,CThisnasal UIIlu is ~
predorrinantIy 01 small eels IfI'Ilh JregINr nudlIi (A). Medium-5ized cel5 1f1'1lh pale cytoplasm (B). large alll51C"'
D Nasal typeextranodal NKIT<eII ~ 01 &kiloW'IIll pleoilOphic largeeels ar:mxed WI\tI smaller C8IS
286
.'~ ' .$.'

Fig. 11.28 ExtranodaI NKIT<eII ~. nasal type A The ~ nNrraIe shows infiltration and destr\I::tIon
01 ananery B In tis case irM:M'lgtleskrl. tie I'fn'4tOfSLus iniIImB has an II Ig1OC8lI1ric ~ quaIrty.
spectrum of EBV-associated t-een or

NK-cell tympropronterative disorders
such as chronic active EBV infection .
systemic EBV+ T-cell lymphop rOliferalive
disease of childhood and hydroa veccsforme-like lymphoma , which occur predominantly in ch ildren 111 49, 16001.
necrosis and admixed apoctonc bodies

are very common findings. These have
been attributed to vascular occlusion by
lymphoma cells . but recent studies have
also imp licated other factors (such as
chemokines. cytok ines) 121851.
The cytological spectrum of extranodal
NKIT-ceillymphoma is very broad Celts
may be small , medium-sized , large or
anaplastic. In most cases , the lymphoma
is composed of medium-sized cells or a
mixture of small and large cells. The celIS
often have irregularly folded nuclei which
can be elongated. The chromatin is gra~
ular. except in the very large cells. which
may have vesicular nuclei . Nucleoli are
generally inconsp icuous or small. Thecytoplasm is moderate in amount and often
pale to cle ar. Mitotic figures are easily
found , even for small cell-predominant
w-ana,
~,
J'
'. I
.'.
" '.
11.31 Tcu::h pte9al'abOn 01 a nasal ~ (Gemsa

1tllIIl~ AzuroI:'oI* granules are eviclent 1"1 IIle pale
qqlasm 1II h I)'!I1lhoma eels.
fig
lesions. In touch preparations stained with

Giemsa. azurophilic granules are commonly detected. Ultrastructurally, eieceoo-oeose membrane-bound granules
are present
ExtrGrlOdal NK/T-celllymphomas, particularly those predominated by small or
mixed cell populations . or those accompanied by a heavy admixture of muammalory cells (small lymphocytes. plasma
cells, bstocvtes and eosinophi ls) may
ll'IlITIiC an innarrmatory p roc ess 1381.
911 1. The lymphoma can some times be
accompanied by florid p seudoep ithe jcn atous hyperplasia of the overlyi ng
epithelium
Irrmunophenotype
The most typical immunophenotype of
emanooat NK/T-ceillymphoma is: CD2+ ,
CD56+. surface CD3- (as demonstrated
on fresh or frozen tissue) and cytoplasmic
CO&+ (as demonstrated on fresh, frozen
or lixed tissues) {381 , 388, 1032, 1037,
22131. CD56, although a highly useful
marker for NKcells, is not specific for exlranodal NK/T-ceil lymphoma and c an be
expressed in peri pheral f -ceu lymphomas. particu larly tho se tha t ex press
the't6 l-cell receptor.
Cytotoxic molecules (such as granzyme
B. TIAl and perforin) are positive {639 1
Dlher T and NK-cell associated antigens
expression 115901. On the other hand.

nasal or other extrancx:iallymphomas that
are CD3+ . CD56-, but negative for EBV
and cytotoxic molecules should be diagnosed as peripheral r-eef! lymphoma. unspecified.
A diagnosis of extranodal NKIT-celilymphoma should be accepted with some
skepticism if EBV is negative {307, 389.
639.1205. 1590.2 1431. fnsiluhybridizahon
for EBV encoded RNA (EBER) is the most
reliable way to demonstrale p resenc e of
EBV. with Virtu ally all lymphoma cells
being labeled. Immunostaining for EBV
LMP1 yields variable and inconsistent results.
Genetics
T-cell recepto r and immunoglobulin genes
are in g erm line configuration in most
cases. In a small proportion of cases. the
T-cell recep tor gen es show clonal rearrangement, p resumab ly c orrespo nding
to the ca se s of cy totox ic T lymphocyte
der ivation (1169, 1590, 21431.
Cytogenetic abnormaNties and oncogenes

A variety of cytogenetic aberrations have
been reported. but so far no specif ic
chromosomal transiocatons have been
identified The cornrnonest cytogenetic
abnormality is del(6)(q21q25) or ~6)(p 10).
but it is currently unclear whether this is a
primary or progression-associated event
{2028. 2029, 2238. 24401. Aberrant
me thylation of promote r CpG regions of
multi ple genes is common. in particular
p73 120 271. Comparative genomic hybridization studies show that the commonest aberrations are: gain of 2Q: and
loss of l p36.23-p36.33. 6q 16.1-q27. 4Q12.
5q34-q35.3, 7Q21.3-q22.1. 11q22.3-q23.3
and 15ql 1.2-Q14 {15671. A p roportion of
cases exhibit partial deletion 01 FAS gene
or mutation in TP53, a-catenln K-RASor
C KIT gene, bu t the signi ficance is still
unclear 1959. 1796, 20021 .
Postulated norm al c ounterpart
Act ivated NK c ells and, less commonly,
c ytotoxic T lymphoc ytes.
are usually negative. including CD4. CDS.

CD8. TCAO, ~F1 . CD16 and CDS? CD43,
C045RO. HLAOR. CD25. FAS (COOS)
and FAS ligandare commonly expressed
11589. 16341. Occasional cases are pesdivefor cm or CD30 {12051.
Lymphomas that demonstrate a CD3&+,
C056- irTYTIunophenotype are also classifed asextranodal NK/T-ceillymphomas if
bcttl cytotoxic molecules and EBV are
IX)Silive. since these cases show a similar
ctncal disease as cases with CD56
Fig.1U3 ExtranodaI NKfT<eI~ , nasall)llI assodaled WIth prOO'Olfll pseudoeprlhelio ~

01 the IT"UCOSaI epllheUn. Thrs can~ be Iilisit""peted as squamous c:ell3'CinlIlIa
Exlranodal NKIT-celllymphoma, nasal type
287
.,.'.
Fig. 11.34 Emnodal NKJT<elI ~phoma, nasa/type A,S The neoplasticcells show strong staining !ofcyloplasmic CD:k (A) and CD56 (B). C The neoplasticcells show s~
granular staining b granzyme B. 0 In situ hybridizabon!of EBV-eocoded RNA(EBER). InthiS rlasallumour, practically alilhe oeopIastic cells show nuclear labeling.
Prognosis and pred ictive lactors

The prognosis of nasal NK{T-cell lymphoma is variable, w ith some patients respo nding well to therapy and othe rs dyi ng
01dissem inated disease desp ite aggressive therapy. Historic ally, the survi va l rate
has been poo r (30-40%), but l he surviva l
has imp roved in recen t years with mo re

intensive therapy inc luding up fron t radio-
therap y 11 48. 4 13. 4 14, 422. 493,1169,
288
Mature T and NK-eell neoplasms
1220, 12931. Significant unfavourable

prcqrostc factors include: advanced stage
d isease (stage III or IV), unfavoura ble International Prognostic Ind ex (2), invasion
of bone or skin, high c ircu lating EBV DNA
leve ls and p resenc e of EBV+ cells in 8 M
141 4,422, 99 1, 1266, 1590 1, The prognostic importanc e of c ytolog ical grade is
unclear; some studies suggest that tumours composed predominant ly of sma ll
cells are less aggressive. but most stoo.

ies have not shown th is fea ture to be ot
significance on mu ltivar iate ana lysis 1148,
413,943 ,12051.
Extrano dal NKIT-ceillymphoma occurring
outsi de the nasal ca vity is highly agg ressive. with short survival times and poor response to therapy 1381, 386}. Exp ression
of multi-drug resis tance genes may contribu te to chemotherapy resistance 16121.
Enteropathy-associated T-cell
lymphoma
Defin~ion
G, all
H. Stein
t-een
Enteropathy-associa ted
lymphoma
(EATl) is an intestinal tumou r of intr aepithelial T lymphocytes , shcwv'ing varying
degrees of transformation but usually presenllng as a tumour composed of la rge
I)rnphOid cells. otten with an inflammatory
background. The adjacent small intestina l
mucosa shows villous atrop hy w ith c rypt
hyperplasia, In 10-20% of cases, the lymphoma is compose d of monom orphic
medium-sized ce lls . This monomorp hic
variant (type II EATl) may occur sooraorcally. without risk factors for coeliac
disease.
ICI}{) cod e
PG Isaa cson
A. Chon
97 1713
Syoonyms
Intestinal I-ceaIvmonoma (with and with-
cot enteropathy), As a variety of Teen

~phoma subtypes c an p resent with inieennerdisease(extrancd at NK/T-eeli lymotona. )'Ii t-een lymphoma . anaplastic
large cell lymphoma), the term Intestinal
tcea lymphoma should be used only in
re setting 01 incomp lete information
regarding the precise diagnosis.
E,>demkllogy
The disease is uncommon in most p arts
al tha world, but is seen with g reater frequency in those areas w ith a high prevalence of coeli ac d isease , in part ic ula r
Northern Europe . However, the monomorphic variant appears to have a b roader
geographic distribution, and is encounin Asia and oth er regions whe re
coeliac disease is rare .
eeo
Etiology
In EATL, the association w ith coeli ac disease is borne out by positive serolog ic al
iests. HLA 002 or Da B ex pression an d
associated clinical findings suc h as d ermalltis herpeutormle an d hyposp len ism
1569. 1921, 23051. In the monomorphic
form cI EATL, an association with coeli ac
c! seese and othe r risk tacto-s is not
prtM!O 15481. suggesting that the I1"lOflOrrorphic variant may represent a oistmct
osease entity,
Fig. 11.35 Enteropathy-associated 1<8 11 lymphoma,

Jejunum showing cill::lJm l~lI y-orien led ulcers.
Sites 01 involvement
The lymphoma occurs most commonly in
the jejunum ()( ileum. Presentation in me
duodenum , stomach, colon or outside the
gastrointesti nal trac t may occur but is
rare ,
Clinical features
In EAll. a small proportion of the patients
have a history of childhood onset coeliac
disease. Most show ad ult onset disease
()( are d iagnosed as having coeliac disease in the same clinical episode in which
the lymphoma is diagnosed . Patients
present with abdominal pain , often assoc iated w ith intestinal perforation In a p roportion of p atients, the re is a prod romal
per iod of refractory coe liac d isease that
is sometimes accompanied by intestinal
ulce ration (ulcerative jej unitis), The clini c al
Fig. 11.36 Enteropathy-associated 1<811 lymphoma,

deeply infillrabngintoad jacent enteropathic rTIUCOSlI,
presentation of the monomorphic variant

is similar. with the exception that most patients do not demonstrate evidence 01
coeliac disease.
Macrosco py
The tumour usually p rese nts as multiple
ulcerating raised mucosal masses. but
may present as one or mor e ulcers or as
a large exophytic mass.
The tumour teems an ulcerating mucosa l

mass mat invades the wall of the euesure.
The tumour cells exhibit a WIde range of
cytological appearances POlS, 24481
Mo st co mmonly. the tumour cells are
relatively monoton ous me di um-sized to
large ce lls with round or angulated vesicular
nuclei. p rom inent nucleoli and moderate
Table 11.03 f eatJns d entelQpalhy-asslXialed __ Ieslillal T<.elI Iymphoma (EAll) and lTl(ll1Ol11Olpl"ic WestrIaI T<eI
lymphoma (Type" EAll~
EATl
Type liEAn
Mostly negative (20%+)

Negatve (>90%)
Positive (>90%)
Mostly positive (80%+)

Positive (>90%)
PosItive (3O-4O'It)"
F""""""
Immuoophenolype (437}
CO,
C056
HLA-OQ2I-D08
GenetICS (543}
+ 9q31.3 or-1 6q12.1
._,
+ l Q322 -q41
+ 8q24
tUYCl
""
""
""'
""
Correspondmg to ee normal frequency 01 HlA.fJ02f.D08 among the Caucasian population.

Ente ropathy-associated T-cell lymphoma
2B9
to abunda nt. pale-sta ining cytoplasm,

Less commonly, the tumour exhib its
marked pleomorphism with multinucleated cells bea ring a resemblance 10
anaplastic large cell lymphoma. Most tumou rs show infiltration by inflammato ry
cells, inclu ding larg e numb ers of histiocytes and eosinopbns and in some cases
these may be so abundant as to ob scure
the relatively small number of tumour cells
present. Infiltration of the epithelium of indiv idual crypts is present in many cases
The intestinal mucosa adjace nt to the tumours, espe cially those in the jejunum,
usually shows enteropathy comprising villous atrophy, cry pt hyperplasia, increased
lamina propria lymphocytes and plasma
cells and intraepithelial lymphocytosis
{437, 4381. The degree 01 enteropathy is
highly variable. however, and may consis t
only of an increase in intraepithelial lymphoc ytes 1124}.
In the monomorphic form of EATL (type II
EATL), the neopla stic cells have med iumsized round, da rkly staining nuclei with a
rim of pale cy toplasm, There is usual ly
florid infiltration of intestinal crypt epithelium. The ad jacen t intestinal mucosa
shows villous atrop hy and cryp t hyperplasia with striking intraepi theliallymphocvtosis involving both cry pt and surface
epithelium. An inflammatory background
is absent. and necrosis is usually less
evident than in classical EATL
Il1YTIunophellOtype
In EATL, the tumour cells are COO+, CDS-,
CD7+ , CDB-/+, CD4-, CD 103+. TCRI1+/-,
and contain cytotoxic gra nule associated
proteins, In almost all cases, a varying
prop ort ion of the tumour cells express
Co30 12064, 2448j The mtraeottbeuat
lymphoc ytes in the adjacent enteroo attuc
mucosa may show an abnormal immunephenotype, usually C03+ , C05-, C08-.
290
C04 -, identical to that of the lymphoma.

The monomorph ic form of EATL has a dig.
uncnve immunophenotype. The tumour
ce lls are C03+ , C04-, C08+ , C056+ and
TCR6+ 14371 and the intraepithelial 1ympnocytes in the adjacent mucosa share
the identica l immunophenotype 11241 .
Genetics
TR8@ and TRG@genes are cionanv rearranged 110 17, 1552J in allrrorpholoqica!
variants, More than 90% of pati ents with
coeliac disease have the HLAOOA 1"0501,
00810201 genotype, also seen in patients with EATL 19841 .
In contrast to primary nodal PTCL. most
EATL cases (58-70%) harbour complex
segmental amplif ications of the 9q31 ,3qter ch romosome region or. alternatively,
show deretcos in 16q 12.1. These features
are prevalent in both forms of EATL and

form a COfTlTlOO genetic link between the
2 types . However, the class ical form 01
EATL frequen tly displays chromosomal
gains in 1q and Sq , while the monomorphic variant is more often character ized
by 8q24 (MYC) amplifications 1548. 2491 ,
2494}
Precursor lesions
As indicated above, EATL may be precede d by refrac tory coe liac d iseases
(RCD) with or without ulceration, In some
cases of RCo , the mtrae otmenat lymphocytes (IEL) are phenotypically aberrant
showing down-regulation of C08 Slmiar
to the IEL in mucosa adjacent to EAlL
These cases of ReO also show ~
clonal T-cell rearrangement 01 the IEl srn.
uar to the clona l rearrangements that may
,
f IJ 11.39 Type II enteropalhy-aSSOCl3led T-<:eI Iym-
>'Una aJII1l(lS8d IXsmaI FWldmoll()fT(llllhc eels.
be found in the enteropatnlc muco sa

,qacent to EATL (1241 . sugges ting that
the irrm unopheno typic ally a berrant IEL
constitute a neoplastic po pulation. In
sese patients with RCD who sub sequently develo p EAlL. the IEl share the
same monoclonal TRGG gene rearrangement as the subsequent t-een lymphoma
189, 358, 359. 5081 . Furthermore, the IEL
in these cases of ReO c arry gains of
Fig. 11.40 A Sma. inlesbnal muoosa from a case of

reIracDy coeiac diseasei'rnu'loslanId seqlllWlllaly lor
C03 (alkaline phosphatase-blue) iW'ld C08 (peroldase~), Most ntraepIheiaII!ynl:tloc)1eS IIr8 COO.., C08-
The monomorphic form of EAll may also

be preceded by RCD in which the im.
munophenotype of the IEl is similar to
that 01 the neoplasti c cell s in the subsequent lymphoma. namely CDa. and
CD56 . This type 01RCD has not been
well characterized
Fig. 11.'1 PCR of D~ extraded from enteropathyassocialed TGlI ~ . M.1I'OlecUa' weio;tIt rn<rter;
p. positive contn:ll; N. negative contn:ll; IMes 1 iWlCI 2.
!ynlIhoma: lanes 3lmd -4, ~ non-Iymphomatlu
"""".

Intraepithelial t -eens 01the mtesnoe.
chromosome 1Q in common with EAIL

123321. Thus, RCO In which the IEL show
these immunophenotypic and genetic
features can be considered as examples
of otraepnheliat T-cell lymphoma or, alternatively, EATL in situ. In a second group of
AGO patients 12332], the IEl express a

normal immunophenotype and are polyclonal. These cases prob ably do not
progress 10 EATL.

The prognos is is usually poor with death
frequentty resulting from abdominal complications in patients already weakened
by uncootrolled malabsorption. Recurrences
are most frequent in the small intestine .
Both cl assic al EATl and the monomerphic form have a similar clinical cou rse.
Entercoamv-assocateo T-cell tympttoma
29 1
Hepatosplenic T-cell lymphoma
P. Gaulard
E.S. JaHe
L Krenacs
WR. Macon
Definition
Etiology
Hepalos plenic l-cal! lym phoma (HSTl) is
Up to 20% of HSTL arise in the seni ng of

chronic immune suppression, most com-
an extrarooat and systemic neoplasm de-
rived from cytotoxic t-eens usually 01 }IS

T-cell receptor type . 11 is usually composed
of medium-sized lym phoi d cells. d emonstrating ma rked sinusoidal infiltration 01
spleen . liver and bone marrow (8 M).
ICD-{) code
971613
Eoi_
HSTl is a rare form ct~. representing < 1% 01 all noo-Hodgkin lymphomas.
Peak incidence occurs in adolescents and
young adults. with a male predominance
(rreoen. -35 """'11176. 4651
monly long term immunosuppressive

therapy for solid organ transplantation or
prolonged antig enic stimulation 1176. 764 .
2322 ,245 11. In this c ontext. HSTL is reg arded as a late-onset post-transplantation iymoroorouteranve cnsoroer of host
orig in. HSTL may also occur in patients,
especially child ren, treated by azathioprine and infli ximab for Cronn'e disease
(1355. 18721.
Patients p resent with marked sprenomeg aly. usually with hepatomegaly. but
with no lymp hadeno pathy [672 1. Bone

marrow is almost constantly involved
1176.465.23211 .
Clinical features
HSTl typically p resents with hepatosp lenomegaly and systemic sympt oms.
Patients usually manifest marked thrombocytopenia. often with anaemia and
leukopenia. Peripheral blood in\l'Qtvemert,
uncommon at presentation . may OCCll"
late in the clin ical cou rse 1176. 465,
232 11. HSTl is easily distinguishable IrtlTl
other ')'6 t-een lymphomas wllich in\lCll\le
extrarooauocanzetons (skin and scrcotaneou s tissue . intestine or the nasal region) 181, 22541.
Fig. " ,43 Hepaklspleric T-eel lymphoma A Cords and sinIsoids ofh! spleenareirlfillra1ed by a ~ plJpl.UtIon of neoplastic ~ eels wrth ITl9liI.rn-size ru:iI
in! a mocIeraIe m.of palecytIplasm. B The neopIas1ic eels ddIuseIy in6IlraIe !he Ile9abc SirluSl::G C The bone marrow is usoaty tlypeft:eWar wilh neopIasbc OllIs inIInIrIJ
5nISOicIs. D NeopIas1ic caIs ~ wilh imrYulOhistx:totl,isty b CD3.
292
""'phoIogyThe spleen is enlarged with diffuse involvement of the red pulp, without any
gross lesions. Diffuse hepatic enlargement is present as well.
Histopathologi cally, the cells of HSTL are
monotooous, with medium-sized nuclei
and a rim of pale cytoplasm 14651. The
nuclear chromatin is loosely condensed
with small inconspic uous nucleoli . They
involve (he cords and sinuses 01 the

splenic red pu lp with atrophy of the white
pulp. The liver shows a predominant
sWlusoidal infiltra tion Neoplastic cells are
amos! constantly present in the lhe 8M
with a predominantly inlrasinusoidal disIJWion. This may be difficult to identify
WI!tloul the aid of immunohi stOChem istry
rx flow cytometry. Cytologic atypia w ith
large cell
Of
blastic changes may be
seen, especially with disease progression
1176. 1414, 232 11
""""""'-
The neoplastic cells are CD3+ and usually

TCRiI +. TCf\4I, C056+'-, C04., CO&/.
and CD S-. Most y6 cases express the VB 1

epitope {176, 17831. A minority of cases
appear to be 01up type , which is considered a variant of the more common yO
form of the d isease {1357, 21171. The
cells express the cytotoxic granule-associated p roteins, TIA 1 and granzyme M,
but are usually negative for granzyme B
and perforin 1465 , 678 , 11911. They etten
show aberrant coincident expression of
multiple killer immunoglobulin-like receptors (KIA) .sotorme along with d im or absent CD94 115221. Therefore, the cells
appear to be mature, non-activated cytow ith phenotypic aberrancy.
toxic
t-eens
Genetics
The cells have rearranged TRGO genes
Cases of .,& origin show a brauetic rearrangement 01 TRGOgenes. TRBOgenes
are rearranged in up cases: however,
non-productive rearrangement of TRBO
genes have been reported in some .,&
cases 17641. Isoc hromosome 7Q is pre sent in most cases, and w ith disease prog ression a va riety of FISH patterns
equivalent to two to five co p ies 01

i(7}(Q1 0) Of numerical and structura l aberrations of the second chromosome 7 have
been detected 127, 24251. Ring chromosome leading to 7Qamplification has also
been reported 121541. Trisomy 8 and loss
of a sex c hromosome may also be present. EBV is generally negative .
Postulated normaJ counterpart
Peripheral.,& (or less commonty o.(J ) cytotoxic memory t-eens of the innate irTYnune
system 11035, 11911.
The c ourse is aggressive . Patients may
respond initially to c hemotherapy, but selapses are see n in the vast ma jority of
c ases . The median surv ival is < 2 years
(1761_ Platinum-eytarabine 11761 and
2'-deoxycoformyc in have been shown to
be act ive agents 1473A I.
Hepatosplemc T-eclllymphoma
I
293
Subcutaneous panniculitis-like
T-cell lymphoma
E,S, Ja ffe
P. Gaulard
E. Ralfkiaer
L. Cerroni
C.J .L.M. Meijer
Definition
Subcutaneou s pannic ulitis-like T-eeillymphoma (SPTeL) is a c ytotoxic t -een lymphoma, wh ich preferentially infiltrates
subcutaneous tissue . It is composed of
atyp ical lymphoid cells of varying size.

typica lly with karyorrhexis of tumour cells
and associated rat necrosis. In contrast to
the third ed ition of the WHO c lassifica tion.
c ases expressing the )'IS
receptor
are excluded. and now reclassified as primary cctareous js T-eelllymphoma.
t-een
ICD-O code
970813
Epidemk>logy
SPTel is a rare lorm of lymphoma, repre senting <1% of alt non-Hodgkin lym-
phomas. II is slightly more common in

females than males and has a broad age
range 11 202/. Approximately 20% of
patients are under the ag e of 20 (median,
35 yea rs) 1240BI . Up to 20% of patien ts
may haveassociated autoimmune disease,

most commo nly systemic lupus erythematosus (SLE) 124081.
Etiology
Aut oimmune d isease may p lay a role in
some pat ien ts, The lesions may show
ove rlap p ing featur e s w ith lup us profundus pann icu litis and in some patients a di agnos is of SLE ha s been documented
ru' A""'...... '<.::::n..
Fig. 11.'4 SlIX:ulaneous panniCulibiHike T-ceII Iymphoma, Infiltrate is conMed 10 ltl& subculaneous bssue
wiltIoul invoIvemenl oI ltl& overlying demli:s orepidermis,
Fig. 1US Immunohistochemical stains highlighth

rimming of individual Iat spaces by tumolJ" cess wrllI
staining few coe lAo) and T1A1 (B).
11 365 , 1412j , In some pat ients, the early

lesions may c losely mim ic lobul ar pannic ulit is. Whet her a benig n lobular pannic ulit is preced es the de velopment of
SPTCl in pa tients w ithout SlE is not clear.
Epste in-Barr virus is abse nt 11 202).
Sites of invo lveme nt

Patie nts present wi th mul tiple subcutaneous nodules, usually in the absence of
other sites of di sease . The most common
sites of localizatio n are the extremities
and trunk. The nod ules range in size from
0,5 em to several cen timetres in diameter,
Tlible 11 .04 Oilfaf&l1tia1 diagoosis of neoplasms expre~ng T<eUandNK<eUmarkers with frequent cutaneous involvement.
CD3,
CD4, COl
CliniCalleatures
Disease
-.-,
T-cell
Uneagt
reee...
R
,....
r....
NK-oelI, somt-
Cytotoxic
' PTCt
T~ . extremities and
Primary Q.l\aneoUs y6 TCl
TUITllUS , plaques. uk::enlted nodules
...-
Extranodal NKIT<:eM
Nodules, tumours
+,',
Primaty aJtaneous Ala.
Superftcial nodules -Md1 epidermali1'o'o1vement
+, +,-
Patches, plaques. tI.ITnn Iale in course
Mycosis IqoiOes
-~
dendnbc eel neoplasm
......."""'"
. ~ pUHssoc:iaIed prolewl,
+,',
-1+
" +. -
CD56
_.
"""""'"
,....
Iines T.-
I;....
- '"
T1A1 itr'ldIorGranzyme Bat'Id1or perbin: SPTa.., subcWnecus~ T<eI~, TCL T<eI~ ; Al.Cl
~Jargeoel~.
294
trunk
EBV
moltculuo
Mature T and Nx-cen neoplasms
Fig.11.46 A SlIbclItaneous panniculitis~ i ke T-cell lymphoma. Turrour cells are associated withabundant histiocytes containing apoplolic debris, B NeopIasticcellssurround fat cells,
~ witl1 some admixed histiocytes, C Neoplasticcells have round to oval hyperchromatic nudei with inconspicuous nucleoli and abundant pale cytOl)lasm.
larger nodules may become necrotic;

towever, ulceration is rare 11202. 24081 .
CfnicaJ teanees
Clinical symptoms are primarily related 10
me subcutaneous nodules. Systemic

symptoms may be seen in up to 50% of
panents. Laboratory abnormalities . including cytooenras and elevated liver
Junction tests are common. and a frank
haernopbaoccvnc synd rome is seen in
15- 20% (8141, Lymphad enopathy is usuallyabsent. Hepatosplenomegaly may be
seen, but almost alw ays not due 10 lymphomatous involveme nt 112021.
The i1I~ trate involves the fat lobules. usu ally WIth sparing 01 septa. The overlying
dermis and epidermis are typically uruo...::ived. The neoplastic cells range in size,
bullfl anygiven case, cell size is relatively
constant. The neop lastic cells have irregular and hyperchroma tic nucle i. The lymphoid cells have a rim of pale -stai ning
cytoplasm , A helpful di agnostic feature is
the rimming 01 the neoplastic ce lls surrounding individual fat ce lls. Adm ixed
reactive histiocytes are Irequently present.

particularly in areas of fat infiltration and
destruction. The hetocvtes are frequently
vacuol ated , due to ingested lipid material.
Other inflarnnatory cells are typically absent, not ably plasma cells. which are
common in lupus panniculitis. Vascular invasion may be seen in some cases. and
necrosis and karyorrhexis are common
114131. The tetter feature is helpful in the
d ifferential diagnosis from other lymphomas involving skin and subcutaneous
tissue[1202} . Cutaneous y8 T-c ell lymp homa s may show p anniculitis-like features. but com mo nly involve the dermis
and epidermis. and may show epidermal
ulceration.
Irrmmophenotype
t-een p henotype . usually COS-positive. with expression of cytotoxic molecules including

granzyme B, pertonn. and t-een intracellular antige n (TlAl) 11202, 19191. The
cells express I3 F1 and are negative for
CD56. helping in the di stincti on from cutaneous 10 f-ceutvmpborna (8 1, 2253 ).
The cells have a mature (I~

Mature cytotoxic a~ r-cea.
Genetics
The neoplastic cells show rearrangement
of t-een recep tor genes. and are negative
for Ep stein-Barr viral sequences. No specific cytogenetic features have been reported.
Prognosi s and predic tive factors
Dissemination to lymph node s and other
org ans is fare 181 4, 1175. 19191, The
5-y ear median survival ove rall is 80%;
however. il a haemophagocytic syndrome
is present, the p rog nosis is poor 11413.
24081 Combination chemotherapy has
traditionally been used, but one study
suggests thaI more conservative irmulosup pressive regimens (cyclosporine,
prednisone, chlorambucil) may be effective {2273BI . A distinction Irom cutaneous
-yO t-een lym phomas is impor tant. since
SPTCL has a much better p rognosis
12254,2408 1.
Subc utaneou s panrncullt is-lill;e T-cefllymphoma

I
295
Mycosis fungoides
Definition
Myco sis lungoides (MF) is an eoioermotrooic. primary cutaneous t-een lymphoma (CreL) cha racterized by infiltrates
E. Ratfkiaer
L. Cerroni
CA sander
8 .R. Smeller
R. Willemze
Table 11.05
CinIcaI stagIIg system lor mycosis UlpIes and S6zary syndrome. asrecenIIy propos.ed by\lle ISCL-EORTC {1642\.
Stage I
Disease conlilecl kl tile skin with pa1dleslpapuleslplaQues <10% (5Iage IA) ex:>10% (stage IBI of
the ski! Sl.dace; no ch:aIy abnom\aIlyn1tJ 1'IlXIe$.
Stage .
Skll'l~ WlltJ pa~BSSOOaIed 'II'lIh early(N1-N2)~ node rwotvemen! (Slage. AI ex skin irrIoOlvemel'll withone ormere un::us (:>l an) (stage 11B~
St.iJge III
Skin ~ witherytIVtlderma. no oreerty (N1-#Q) Ifnlih node IIWCWemenl am absenl: ex IcM

blood Unc:u"bun:len 100G\d CI'OJlalI'lg seza,y eels)
Stage rI
!'to;;! t:bld UTn.r tud8tt (:>1000lt1 ~ SUary oeis l ard'or eXlerlsi'o'e ~ node ifflCIwment (NJ)orvisalrallll'Mllver'nel1 (Ml ).
of sma ll to medium-sized T lymphocytes
with cereontor m nuclei . The term MF

should be used only lor the class ical
cases characterized by Ihe evolution of
patches , plaques and tumours, or for variants showing a similar clinical course ,
lCD-Ocode
970013
Epidemiology
TOIbIe 11.06
MF is the most corrmoo type of CTCL and

accounts lor almost 50% of all primary c utaneous lymphomas 1240n Most patients
are adults/elderly, bullhe disease can be
observed in children and ado lescents.
The mare.temaie ratio is 2: 1 124071.
Sites of involv ement

The disease is. as a rule, limited to the skin,
staging lor dinicaIyabnormaIlyn1tJ nodes (:>1 .5 an)., mycosis!lJ1goides and 5ezary s.,..,.nme
ISCLreORTC (1642)
.,
DutchIystem (195aA)
NO clusifitation {lJ4(lA}
Categy 1, DL, no atypical CM(;
l NO. no atypicaIlymphocy1es
LN l : oa:asionaI, isolated atypK:aIlyn1JIlocyIes
lN2: ~ (3-6 oe1s ) d at)'piCal ~
Categy 2 Dl withearly lIIVOIvemen! with sc.anered atypical cue
.3
trac ted pe riod, Extraculaneous dissemi-
Category 3: parllal effacement 01

architeclll'e withmanyCMC
nation may occur in advanced stages.

mainly to lymph nodes, liver, spleen ,
Calegory 4 wnpleteeflacemen1
of architecture
with widespread distribution. lor a pro-
lung s an d blood 12407). Involvement of

the bone marrow (8 M) is rare 12407J
Clinical features
MF has an indo lent clinica l co urse with slow
p rogression ove r years o r some times
dec ad es, from patc hes to more infi ltrated
p laques and eve ntua lly tumours. Patie nts
with tumo ur stage M F c haracteristically
show a combination of patch es. plaq ues
and tumou rs, which often show ulceration
lN3 iIggI'llQates ofalypicaIlyrnphocyIes, bul
""''''''''-
l~ parllal ex complete eflacemenl 01 a~

lecture with manyatypical lymphocytes
Ol, dermatopathic lymphadenopathy; CMC, cerebriform mononlJdear cells with nllClei :>7.s...m
' N2 is divided into2 categories, N2a withoot donal!)'rearranged T-eellsand N2b with donaUy rearranged T-rels.
124071. Uncommonly. pa tients present with

or develop an erythrcxiem1ic stage of disease
that lack the haem atolog ic criteria of Sezary
syndrome !23421.ln some patients, lymph
node and visceral org ans ma y become
involved in the later stages of the disease.
Fig.11.41 Myoosis blgoides A Early sageW!Ih palches. B DissenWlated plaQlJe stage.
Morpholog y
The histolog y of the skin lesions varies
with the stage of the disease. Early patch
lesions show superficial band-like or
lichenoid infiltrates. ma inly consisting of
lymp hoc yte s and rnstocvtes. Atypical
Fig.1u a Eany MF W11h in6Itrates of CItypiCaI.1\aIoell

~ II the basal layer of epicIem'Is
296
Mature T and NK-cell neoplasms
lmmunophenotype
The typ ical phenotype is CD2+ . CD3+ .
TCRfl+. CDS+, C04 +. Coa- I1809I. Rare
c ases ma y be positive for CDa 118091.
Suc h c ases have the same clinical be-haviour and p rog nosis as CD4+ cases,
and should not be consi dered a separate
entity {24071. ACD8+ phenotype has been
re port ed more commonly in paediatric
MF. A lac k of C07 is freq uent in all stages
of the d isea se 118091. Other alterations in
antigens may be
the expression of
seen , but mainly occur in the advanced
(tumour) stages 118091. Cutaneous lymphocyte anti gen (CLA) associated With
lymphocyte homing to the skin is expressed in most cases. Cytotoxic granuteassociated proteins are only rarely
expressed in the early patch/plaque
lesions, but may be positive in a fraction
of the neoplastic cells in the more advanced lesions 123331_
t-een
cells with small to medium-sized, highly

irdented (cerebriform) nuclei are few, and
rrostty conlined to the epi de rmis wh ere
tt"ey characteristically colonize the basal
layer 01 the epi dermis often as haloed
cells, eithersingly or in a linear distribution
11411J . In typical p laq ues , epi de rmotropism is more prono unced. The p resence of intraepi de rmal collectio ns of
atypical cells (Pautner mic roabscesses)
s a highly c harac te ristic featur e. but is
observed in only a mino rity 01 c ases
114111. With progression to tumour stage,
the dermal infiltrates become more d iffuse
and epidermotrop ism may be lost. The
tumour cells increase in number and size,
showing variable p rop orti on s of small ,
medium-sized to larg e c erebriform cells ,
blast cells with prominent nu clei and
Intermediate forms 12407f. Histologic
transformation. d efined by pr esen ce of
>25% large lymphoid ce lls in the d erma!
infiltrates may occur. ma inly in the tumou r
stages 1361. 567. 23301. These large cells
may be CD30-negative or C D30-positiye.
Entarged lymph nodes from patients with
MF frequently show dermatop athic lymphadenopathy w ith oaracor t'car ex pansion due to the presence of large number
Ii renocvtes and interdigitating cells with
abundant. pale cytoplasm.
The ISCL-EORTC staging system lor cunlCally abnormal lym ph nodes (> 1.S cm) in
tEm Sezarysyndrome 116421integrates
se previous NCI and Dutch lymph node
staging systems I 1940A. 1958AI . There
ow-e 3 categories . essentially reflec ting no
involvement. early involvement (With no

architectural effacement). and overt involvement (with partial or complete arcttectural effacement). Recognition of the
ea rly infiltrates can be d iffic ult and can be
aided by T-ce ll rec eptor analysis 11642 1.
N3 lymph nodes may simulate peri pheral
lymphoma. NOS
Hodgkin Iym.
f-ceu
pr oma.
or
Genetics
T<ell rec eptor genes are clonally rearranged in a variable proportion 01 cases ,
possibly depending upon the number 01
tumour cells and the detection technique
employed 11765. 23981.
Complex karyotypes are p resent in many
patients , in par tic ular in the advanced
stages 11 381 . 2 1901. A vast number of
Fig. 11.50 MF!um()IJf stage (AJ wiltl histological translotmation toa large cellymphoma (8).
Mycosis fungoides
?37
12297f. Due to the deep localization 01 the

neoplastic infiltrate. the d isease is less
accessible to skin-targeted therapies, The
disease-specific 5-ye ar-survival is approximately 70-80%, w hic h is significanny worse than that of p atients with
classical plaque stage MF 1797. 22971 .
Fig. 11.$3 Mycosis l.npdes. A FoIo.*Jtropic myoosis foogoides Wlt!l atypic:al ~ irlfiltrabng a _bide
B Hole O8lebllforrn nudIi , C The alypicaleels areCOJ.potsi\i'we. 0 The irM:llYed loIde shows IIlI.ICinOuS ~lion
WIlh ~ of AIc:ian bkJe-positive matel'ial.
different structural and numerical alterations have been desc ribed . Constitutive
activation of STAT3 and macuvauon of
CDKN2A1p ltr" ... and PTEN have been
identified and may be associated with
d isease progression 11583. 1951,1952,
205 1, 24241. Ge ne ex p ress ion p rofi ling
studies have srown tumour necrosis tactoe
(TNF) antr-acootonc pathway activ ation in
the tumouri ge nesis of MF 1226 11.
in patients with skin tumours andJor extracutaneous d issemination 12298}. Age

above 60 years and eleva ted lactic dehyd rog enase are othe r adverse prognostic
parameters 15681. Histologic transformation wilh increase in blast cells (>25%) is
also an adverse parameter 13611.
Postu lated nor mal counterpart

Mature skin-homing CD 4+ t-een.
Ponloulctroplc MF
Fo lliculotro pic MF is c haracte rized by the
presence of follicular infi ltrates of atypical
(cerebri form) CD4+ T lymphocyt es etten
with spari ng of the ep ide rmis 1797f. Most
c ases sho w muc inous de ge neratio n of
the hair fo llic les (fol licu lar mucinosis) bu t
similar c ases with out fo llicular mucinosis
have bee n reported {2297}. The lesions
p referentially involve the head an d neck
area and often present w ith g rouped follic ular papules associated with alopecia

The sing le most important prognostic fac tor in MF is the extent of c utaneous and
extracu taneous d isease as reflect ed in
the clinical stage. Patients with limited d isease ge nerally have an excellent prognosis with a simi lar survival as the general
population 122981. In the more advanced
stag es. the prog nosis is poor, in pa rticular
298
Variants
Pagetoid reticulosis
Pag etoid reticulosis is characterized by
the presence of patches or plaques with
an intraepidermal proliferation of neoplastic t-eens 1870}. The term should only
be used for the localized type (WoringerKoIopp type) and not for the disseminated
type (Ketron-Goodman type) as cases
corresponding to the latter category woUd
currently most likely be classified as
aggressive epidermotropic C08-positive
CTCl or cutaneous y&-positive T-cell tyrophoma 124071. The atypical cells have
medium-sized or large. sometimes hyperchromatic and cerebriform nuclei, and either have a CD4+, C08- or a CD4- . CD8+
phenotype. CD30 is often expressed. In
contrast to classical MF. extracutaneous
dissemination or disease-related deaths
have never been reported 124071Granuloma tous slack skin
Granulomatous slack skin (GSS) is an extremely rare subtype of CTCl characterized by the slow developme nt of folds 01
lax skin in the major skin fol ds (axillae.
groin) and histologically by a g ranuloma
tous infilt rate with clonal CD4+ T cells.
abundant macrop hages and multinucleated g iant cells 123001, In approximately
one third of the repo rted patients. an assoc iation w ith C HL has be en observed,
An association with c lassical MF has also
been reported (2300 ). Mos t patients have
an indolent clinical c ourse [12611.
Sezary syndrome
Definition
5ezary syndrome (SS) is defined by the
reo ct erythroderma. generalized tym~lhy and the presence of CIOnaJIy
related neoplastic
with cerebriform
ru::lei (5eZ8ry cells) in skin , lymph nodes
and peripheral blood (PB). In addition.
nc. moreof the foiloNing criteria are reIpfed: an absolute 5ezary cell count of
aeasr 10CXJcelis per mm3,an expanded
CD4+ t-een population resulting in a
C04ICD8 ratio 01 more than 10 and/or
t-eens
'oss ol one 01 more t-een antigens.
9701/3
KDOcode
ThIs is a fare disease, which accounts for

less than 5% of all cutaneous t-een Iym-
E. Ralfkiaer
R. Willemze
SJ . Whill aker
immunoperesrs associated with loss 01

normal circulating CD4 cells 19891.
MOrpho logy
The histological features in 55 may be
similar to those in mycosis fungoides
(MF). However, the cellular inliltrates in SS
are more often monotonous, and epidermotropism may sometimes be absent. In
up to one third of biopsies from patients
with otherwise cl assical SS the histologic
picture may be non-specific 122701. Involved lymph nodes cnaractenencanv
show a dense, monotonous infiltrate 01
Sezarv cells with eff acement 01 the roemal lymph node archi tectu re 119591 _Bone
marrow may be involved, but the infiltrates
are oft en sparse and mainly interstitial
12018}.
eeree 124071_ II occurs in adults , char-
eiensncanv presents over the age 0160.
Fig. 11.54 sez.y S)'!Doole. Geoeralzed skin eseee

lIIiltlerylhrOOenna.
M-Auorescence in ssu hybridization (FISH )

and comparative genomic hybridization
(CGH ) tech niq ues have shown a high rate
01 unbalanced nansiccanons and associated deletions often involving chromosomes 1p, 6q , 1Oq, 17p and 19.
suggesting a high rate of genomic msrability 113821. Inactivation of TP53 and
p I(J"I'<'" are frequent 11 440 . 1583, 19511.
Amplifica tion of JUNB, has been icenntied in Sezarv syndrome {13841. Gene express ion profiling stud ies have not
yielded consistent findings 1239 , 871 ,
1110 , 2296 1.
Clinical features
Immunophenotype
Tumo ur cells are CD2+, CD3+ , TC RB+
and CD5+ . Most cases are CD4+ . Exp ression of CDa is rare . Sezery cells express cutaneous lymphocyte antige n (CLA)
and the skin-homin g receptor CCR417031
and characteristically lack CD7 and CD26
1204 , 1571 , 2046}. T p lastin mRNA and
protein have been shown to be enha nced
in Sezary ce lls relativ ely 10 normal he lpe r
t-eens 11110 , 2 1161.
Postu lated normal counte rpart

Mature eoroermotrootc skin
CD4 + T-cells.
Patients present wit h erythrode rma an d

generalized lymphad enopathy. Other features are pruritus , alopecia , ect rop ion,
palmar or planta r hype rkeratoses and
OI1ychodystrophy. An inc reased pr eva e-ce of second ary ma lign anc ies, bo th
cctareous and sys temic, has been
reported in SS and attributed to the
Ge netics
T-ce ll recept or genes are c lonally rearranged {1765 , 239 7, 2398) Recurrent
c hromosomal ab norma lities have not been
detected in SS, b ut com ple x karvotvpes
with numerical and structural alterations are
COTfT'Olandsimilafto MFl 161, 1381, 13821.
Prog nosis and p red ictive fact ors

This is an agg ress ive disease with an
overall survival rate at 5 yea rs of 10 - 20%
12407f. Most patients d ie of op portunis tic
infections. Progn ostic teet er s include the
degree of lymph nod e and PB involvement 11161. 2342 1.
and has a male predominance.
Sites 01 involvement
SS isa leukaemia an d thu s b y definition a
generalized disease. All viscera l organs
may be involved in the te rmi nal stages.
I"owever, there is often a remarkab le
&paring of the bone marrow (8 M),
homing
Ft ll j5
.-1""--
~d
sez.yC8b in Gi8msa ~ bklodIilms IA) arK! by lhastrucUal ellamllalion(B).
FIg. 1t .5& SUI iniItrates in SS wiIh epioermotllC

I'IflIlraIes of aIypl3, ceoeb"'''' ~
Sezarv syndrome
299
Primary cutaneous CD30-positive T-cell

Iymphoprolif erativ e disorders
Primary cutaneousCD30-positive Iymphoproliferative disorders (LPO)are the second

most common group 01 the cutaneous
years . Child ren are sporadically affec ted

{172, 2407} . The M:F ratio is 2-3:1 11721
T-eelilymphomas (CTCL), accounting for

app roximately 30% of the cases. This
group includes primary cutaneous
anaplastic large lymphoma (C-AlCL),
lymphomatoid papulosis (LyP) and borderline cases.
These diseases tom a spectrum that may
show overlap ping histopathologic and
phenotypic featu res 124071. The clinical
The most freq uently affected sites include
trunk . face, extremities and buttoc ks .
appearance and coo-se are therefore critical lor the definite diagnosis. The term
"borderline" refers to cases in which , de.
spite careful clinicopathologic correlation.
a definite distinc tion be tween C-A lCl
and LyP cannot be made. However, clinical examination du ring follow-u p will generally disclose whether such p atien ts
have CALCL or LyP {172 1_From a clinical perspective LyP is not considered a
malignant d isorder , despite oemonstraton of monocionanty in many cases.
Primary cutaneous anaplastic

large eel/lymphoma (C-ALCL)
Definition
C-AlCl is composed of la rge ce lls w ith
an anaplastic, p leomorphic or immunoblastic cytomorphology that express the
C0 30 antigen by the ma jority (> 75%) of
the tumour c ells (2407 1. Patient s with
C-ALCL should not have cl inical evid ence
Of history of myco sis fung oid es (MF ); in
this selling the diagnosis should be considered trans fo rmation of MF to tumour
stage. whic h may be CD30-positive or
negative 124071. The d isease must also
be d istinguished from systemic ALC L with
cutaneous involvement, which is a separate disease wi th different cytogenetics.
clinical fea tures and outcome 16131.
ICD-O code
97 1813
Epidemiology
C-ALCl is the second most common type
01 CTCl 11721. The median age is 60
300
E. Ralfk iaer
R. Willemze
M. Paulli
M.E. Kadin
Cli nical featu res

Most patients present with solitary or
localized nodules or tumou rs. and soretimes pap ules , and otten show ulceration
1172,2407). Mullifoc al lesions are seen in
about 20% of the patients. The skin
les ions may show partial or com ptete
spontaneous regression as in lyP. These
lymphomas freq uently relapse in the skin .
Extracu taneous disseminat ion occurs in
-10% of the pat ients , and mainly involves
the regional lymph nodes 1172, 2407 1.
Morphology
Histology shows diff use , usually noneot cermotropic infiltrates with cohesive
sheets of large CD30-positive tumour
cells. In most cases the tumour cells have
the characteristic morphology of anaplastic
celf s , showin g round, ova l or irreg ula rlyshaped nuc lei, prom inent eosinophilic nuc leoli and abundant cy to p lasm 124071Less commonly (2Q-.-.25% ), they have a
non-a nap lastic (p leomorphic or immuneb lastic) appearance (172 , 17 111. Reac tive lymphoc ytes are often present at the
per ip hery of the lesion s. Ulcerati ng
les ions may show a l y P-like histology
with an abundant inflammatory infiltrate of
reactive T-cells , hlstto c vtes. eosi no phils,
neutrophils and relatively few Co30-posilive
cells. In suc h c ases ep iderma l hyp e rp lasia may be prom inent . The inflammatory background is espec ially p romin ent
in the rare neutrophil-rich (pyogenic) vari ant 12991.
Immunophenoty pe
The neo pl astic cells sho w an activated
C04 + t-een phenotype with variable loss
ot C02, C05 and/or C03 and freq uent exp ression of cytotoxic p roteins (granzyme
B . TlA1 , pe rtonn ) {255 , 1204 . 24071 _
Some cases 5%) have a CD8 +
phenotype_C03J is by defll'\ilionexpressed
t-oea
FIg.11.5a C-ALCl with conAuent sheets 01 large cell

with anaplas tic ~.
by a majority (>7 5%) of the neoplastic

cells 12407 1_Unlike systemic ALCl, most
C-AlCl exp ress the c utaneous lymphocy te antigen (CLA ), but d o not express
EMA or AlK (anaplast ic lymphoma kinase)
(5 16 , 537 , 21821. Unl ike Hodgkin ano
Reed-Sternberg cells. staining for CD15
is g ene rally negative, Coexp ression of
C056 is observed in fare c ases, but does
not appear 10 be assoc iated with a~
unfavoura ble prognosis (15811.
Genetic s
Most cases show c lonal rearrangement ci
the t-een rec eptor (feR) genes 124071
However. TCR p roteins are often not
expresse d 12381.
Stud ies usi ng comparative genomic hyb ridi zation have revea led c hromosomal
imbalances with gains of several puteee
oncogenes 113831. However, specmc and
consistent cytogenetic abnormalities have
as yet not been identified. Unlike svstere
AlCl, C-AlCl does not carry transccetions involving the ALK gene at chromosome 21537. 613 . 2182 1.
Postulated I'lQI"mal couterpart

Transformed/activated skin-homing T IyrnphJcyte.
The prognosis is usually favou rable, with
a l(}.year disease-related survival of approximately 90% 1'72, 13221. Patients
:resenting with mounocarskin lesions and
patents with involvement of regional
tyrrch nodes have a similar prognosis to
patients with only skin lesions 11721. No
dlfl!fence in clinical oresentanon. clinical
oehaviour or prognosis is found between
cases with an anaplastic morphology and
cases WIth a non-anaplastic (pletllTl()(phic
CJ i'Tvnunoblastic) morphology 1172.
1322.17111.
Lymphomatoid papulosis
Defr'lilion
l'lfTlPhomatoid papulo5is (LyP) is a ctvcoc.

recurrent, self-healing skin disease comPlSEld 01 largeatypical anaplastic. irTTnJnoblaslic or Hodgkin-like cells in a marked
lIf4arrmatory background. In some cases
Ole pattern of cu taneous involvement may
resemble MF (type B).
(;[}{) cod.
97 18/1
Epidomdogy
lyP most often occurs in adults (med ian
age, 45 years). but children may also be

affected. The male 10 female ratio is 2-3: 1
1172, 1322, 1996, 2303).
lyP isa skin-limited disease that most freq'Jently affects trunk and extremities
11721. Rarely, oral muc osal lesions may
te present.
tln ical leatures
lyP is characterized by the presence of

papular. papulonecrotic and/or nodular
skin lesions at di fferent stages of oeveropment[1721 . Individual skin lesions disappear within3-12 weeks, and may leave
tlehind superficial scars. The duration of
fie disease may vary Irom several months
klrrore than 40 years. In up to 20% of pa\Ief'I1S. lyP may be preceded by. associaled with. or followed by another type of
malignantlyrnphoma, generally MF, cutaIIlnJS anaplastic large ce ll lymphoma or
ttxigkin lymphoma 1172,10791 .
Fig. 11.59 lYfl'lhomaDd papIbas, l p A..lDlSISling d atypicaIlyrnphoid eels adrriJced \MGl many nftarrmaDyeels
(A). The alypical eels havea cerebriIorm or Hodglc.n-like ~y (B) and are strongty posrtiye forC030(el
-ogy
The histologic picture oflyP is extremely

variable. and in part cor relates with the
age of the biopsied skin lesion. Three histologic subtypes ollyP (types A, B and C)
have been described, which represent a
spectrum with overlapping features 1172.
2407j, In l yP type A lesions. scattered or
small clusters of large, sometimes multinucleated or Reed-Sternberg-like. CD3Q.
positive cells are intermingled with
numerous inflammatory ce lls, such as histrocvtes. smal l lymphocy tes. neutrophi ls
and/or eosinophile. LyP. typ e C lesions
demonstrate a monotonou s popul ation or
large clus ters of larg e CD30- posi tive
T-c ells with relatively few admixed inflammatory c ells. l yP. typ e B is uncommon
10%) and is c haracterized by an eprdermotropic infiltrate of small atypical
cells with ce rebriform nuclei similar to that
observed in MF.
Genetics
Clonally rearranged T-een receptor genes
have been detected in approximately 60%
of lyP lesions 110791. Identical rearrangements have been demonstrated in LyP lesions and associated lymphomas 110791.
No consistent abnormalities have been
described The (2;5)(p 23;q35) translocation is not detected in l yP 1613. 614).
Postulated normal c ou1erpart

Activated skin-homing T lymphocyte,
Prognosis and predi ctive factors
LyP has an exc ellent prognosis, In a
study 01 11BlyP patients, only 2 patients
(2%) died of systemic disease after a median follow-up duration of 77 months
11721, However, since risk factors for the
deve lopment of a systemic lymphoma are
unknown, long-term follow-up is advised.
lmmunophenotype
The large atyp ic al cells in the l yP type A
and type C lesions have the same phenotype as the tumou r cells in C-AlCL
The atypical cells with ce rebriform nuclei
in the l yP. type B lesions have a CD3+.
CD4+ . COB phenotype and do not express CD30 124071. Rare cases of LyP
with COB and NK-cell phenotype have
been reported 1709. 13661.
Primary cutaneous CDJO.-posillVe T-eelllymphoproliferative disorders
301
Primary cutaneous peripheral

T-cell lymphomas, rare subtypes
P. Gaulard
E. Berti
A Willemze
E.S. Jaffe
Perip he ral T-cell lymp hom as (PTeLl not

uncommon ly involve the skin, either as
primary or secon dary manifestation of the
disease. Within this group, three rare provisional entities were delineated in the
WHo-EORle classification lor cutaneous

lymphomas. inc lud ing primary cutaneous
-,fJ t-een lymphoma , primary cutaneous
aggressive epidermotropic COO-positive
cytotoxic r-ceu lymphoma and primary
cutaneous CD4-positive smalVmediuffisized p1OOlTlOfphic t-een lymphoma The
tarter two entnies are sntt c on sidered provtsicoar. It should be emphasized that a
diagnosis of mycosis lungoides (MF)
must be ruled out by complete c linical ex-
arrmanon and an accurate clinical history.
Primary cutaneous gammadelta T-calllymphoma
Fig. 11.60 Primary ~s -yI) T-c:el IympIloma. l esions are dinicaIy diYefse. alld consist 01 plaques. with or....
out lkeration (A,B), ortulTOUrs (C). The lesion may consisl 01 an indlrclled plaque. with subl::ul<wleous i'IMtrcIIicn(DI.
Definition
Primary cutaneous rt'i t-een lymphoma
(PCGD-Tel) is a lymphoma composed of
a clonal proliferation of mature, activated
yS T-eells with a cytoto xic phenot ype . This
group includes c ases p reviousl y know n
as subc utaneous panniculitis-like t-een
lymphoma (SPTCl) with a y() ph enotyp e.
A possibly related co ndition may pres ent
primarily in mucosal sites. Whether cutaneou s and mucosal y(i TCl are all part of
a single disease, i.e. m uco-cutaneous yO
TCl , is not yet clear 11 040 , 24321.
ICD-O code
The provisional code p roposed for the
fourth edition of ICD-O is 9726/3
Epidemiology
PCGD-TCL are rare, representing approximately 1% of all cutaneous T-cell lymp homas 12254. 2407 , 24081. Most cases
occur in adults. Thereis no sex predilection.
Fig. 11 .61 Primarycetaoecos -yI)

epidermis is neaotic.
T~ llymphoma .
The
Impaired immune function associated with

chro nic antig en stimulation may predispose to the developm ent of PCGD -TCL
[81,24321 .
Etiology
Sites of involve ment

PCGD-TCl often p resent with generalized
skin lesions. p referentially affecting the
extremities 12254, 24081.
The d istribution of d isea se reflects the

localization of normal ylJ t-eens. which are
believed 10 p laya role in hos t mucosal
and ep ithelial immune responses 12291.
C linical features
The clinical presentation 01 patients with
PCGD-TCl is variable. The disease may
302
Mature T- and NK-eell neoplasms
Fig. 11 .62 Primary cnaoeccs yO T-cell lymphoma

In ltlis case the iI1filtrate is primarily dermal.
be predominantly eotoermotrootc and

present with oatcnesroraques. Some
patients may present with deep dermal a
subcutaneous tumours. with or without
epidermal necrosis and ulceration lS1
207, 1068,2254,2408,24321. The leeces
are most often p resent on the extremes.
but other sites may be affected as wei
11410.2254.24081. Dissemination tOrTlr
cosar and other extranccar sites is
frequently ob served, but involvement d
lymph nodes, spleen or BM is uncorrm:n.
A haemophagocytic syndrome may 0CCl1

Functionally matu re and act ivated cytotoxic yO T-cells of the innate ITrru'le system.
Prognosis and predic tive factors
PCGD-TCl are resistant to mulliagent

cll emotherapy and/or radiation and have
a poor prognosis with a median survival
of app roximately 15 months 12254, 2408].
Patients with subcutaneous tat involvement
tend to have a more unfavourable prognosis
as c ompared with patients with epidermal
or dermal disease only 122541.
Primary cutaneous CD8-positive

agg ressive epidermotropic cytotoxic
T~1I1ymphoma
Fig. 11.63 Pnmary cutaneous yO T<811 tymphoma. H,slological penems arecverse. and maybe PiWlnicUitJs-like in the
OemIaI lnMration is usualfy present and !tie overlying epiOenTis may be ulcerated.
IticlUIeous fat
in patients with pa nnicu litis-like tumours
12254. 24081. B symptoms, inc luding

fever. night sweats and weight loss are
seenin the majority of patients.
~
rnee ma)or histologic pa tterns of in'ldYement can be present in lhe skin: epillerrrolropic, dermal and subcutaneous.
O'ten more than one histologic pattern is
present in the same patient in different
tiopsy specimens 01' within a single
boosvsoeorren 1207,1 4 10,2254.24081.
Epidermal infiltration may occu r as mild
eccermotrocism to marked pagetoid
reticulosis-like infiltrates 1207. 1540, 18111.
The subcutaneous c ases may show rimmng of tat cells, similar to SPTCL 01 a ll
cngn, but in addition usually show dermal
F, 1161 Plimary cutaneous aggr&SSive epidennolropW;

cytoloxic T-cell lymphoma. te soes are
_1IaemorltIagic, and llffl llSsocialed with ulcefalion
IIItPdem'1a1 necrosis.
~ve
and/or epide rmal involvement (2254,

2408 1. Til e neopl astic c ells are generally
med ium to large in size with coarsely
clumped ch romatin 122541. Larg e blastic
cells with vesicula r nuclei and prominent
nucleoli are infrequent. Apootosts and
necrosis are common. often with angieinvasion 12254. 24081 .
Immunophenotype
The torrocr cells characteristically have a
JiF1-, C03+, C02+. CDS-, C07+/-, CD56+
phenotype with strong expression of cytotoxic proteins 11 040, 1410, 1919. 2254,
2408, 2432} . Most cases lack both CD4
and CD8, although COB may b e expressed in some c ases 12254, 2408) The
cells are strongly positive for TCR6 with
appropriate detection methods. If staining
for TCRO cannot be performed , the absence 0l lJF1 may be used to infer a yO
origin und er appropriate circumstances
(1068 ,1919,2254.2408} .
Genetics
The c ells show clo nal rearrangement of
the TRG@ and TRO@genes. TRB@ may
be rearranged or deleted, but is not expressed. Cases with predominant subc utaneous involvement express Wi2, but this
has not been studied in other PCGD-TCL
117831. Epstein-Barr virus (EBV) is negative
lB1. 1091, 2254,24321.
Definition
This provisional entity is a cutaneous
T-eelllymphoma (CTCll characterized by
ponteraton 01 epioerrroncoc C[)B..positive
cytotoxic t -eens and aggressive cl inical
behaviour. Differentiation from omer types
of CTCL expressing a COBpositive cytotoxic t -een phenotype is based on the
cli nical presentation. clinic al behaviour
and certai n histological features, such as
marked eoioe rrrotroprsm with ep idermal
nec rosis.
IClJ.Ocode
970913
Epidemiology
This d isease is rare accounting for less
than 1% of all CTCL 11 2. 209, 24071 . It
occurs mainly in ad ults. There are no
known predisposing factors.
Most patients present with generalized
skin lesions.
Clinical features
Clinically, these lymphomas are cha racterized by local ized or disseminated
eruptive papules, nodules and tumours
show ing central ulceration and necrosis
or by superfic ial, hyper keratotic patches
and plaques 1209. 19341 _These lymphomas may disseminate to omer visce ral
sites (lung, testis. central nervous system,
oral mucosa), but lymph nodes are often
spared (209, 1404, 17901.
Morp hology
The histolog ical app earance is very
variable ranging from a lichenoid pattern
with marked . pag etoid eproermoeocls m
Primary cutaneous peripheral T-cell lymphomas, rare subtypes
303
Genetics
The neop lastic T-eens show clonal TeR
gene rea rran ge ments. Specific genetic
ab nor mali ties have not b een described.
EBV is nega tive {174, 1410 1.
Postulated norma l counterpart
Skin-h omi ng. COB-positive. Cytotoxic
t-eens of ~ type.
These lymphomas often have an aggressive clinical course with a median survival
of 32 mon ths 12091. There is no difference
in survival between cases with a small or
large cell rTIOfphology 11741.
Pnmary cutaneous CD4-posmve

smaJl/medium T-cell tymphoma
F"IQ. 11.65 PmwyaDlllwsagps:siYe epdeoll()(r<4Jit
C()8...posltive C)1oloxiC ToOIlII lymphoma. The atypical

lymphoid oeRs in~ ltra le in the superficial dermis and
extend into the epiderrris in a pageDd Iashon.
Definition
This p rovis ional entity is a cutaneous
T-cell lym phoma characterized by a pre.
dom inanc e of small to mediu m-sized
CD4-positive pleomorphic t-eens without
evi dence of patc hes and plaques typical
of mycosis fungoi des. A majority of cases
p resent with a solitary skin lesion .
teo-oro
970913
Epidemiology
This is a rare disease, accounting for 2%
of all c utaneous T-cell lymp homas 124071.
Fig. 11 .66 Primary wlarleOUs aggressive epidermotropic
C08-positive cylotox ~ 'l-cell lymphoma, Skin section
stained lor coe, highlighting the marked epdermojrcpism, with the majority of the neoplasticcells kxalized to
the epidermis.
and subepidermal ede ma to deepe r,

mo re nodu lar infiltra tes. The epi de rmis
may be ac anthotic or atrop hic , often with
necrosis, ulceration and blister for mation
[ 12,2091. Invasion and destruc tion of adnexal skin structures are commonly seen.
Angiocentricity and angioinvasion may be
p rese nt 11 4 101. Tumour cells are smanmedium or mediul'T'l-large with p leomorphic
or blastic nuclei 12091.
Immunophenotype
The tumour cell have a I3F1+, CD3+ ,
coa+ , granzyme B+ , pertonn- . TlA l+ ,
CD45AA+f- , CD4SAO-. CD2-f+ , CD4- ,
CDS-. CD7+f- phenotype 112. 174.209.
1410, 19341.
304
There is a predominance of small/mediumsized pleomorph ic t-eens 1174. 177. 734,

209BI. A small proportion 30%) of large
pleomorph ic ce lls may be present {1771.
In some cases a consid erable ad mixture
with small reactive lymphocytes and hisbocvtes may be ob serve d 11 9501.
Eosmoptuls may be numerous in some
cases 1754AI The princi pl e drtterennar
diagnosis is w ith a reactive lymphoid infiltrate in the skin . so-called p seudolymphoma or cutaneous lymphoid hyperplasia
Immunophenotype
By definition these lymphomas have a
CD3+ . CD4+. CD8-. CD30- phenotype.
sometimes with loss of pan T-cell markes
1174. 20981. Cytotoxic proteins are not expressed 11741. Adrrixed poIyclonal plasma
and
may be present, making
distinction from a reactive process difflcUt
in some cases
ceus
a-cens
Gen etics
The TeR genes are cionanv rearranged
1209B. 234 11. Demonstration of an aterant t-een phenotype and clonality are
useful cri teria to differentiate these smaW
medium-sized p leomorp hic CTCL from
pseudo T-cell lymphomas. which also may
present wi th a solita ry p laq ue or nodule
11321 . Specific genetic abnormalities
have not been described. EBV is negative,
These lesions usua lly present w ith a sol itar y plaqu e or nodule, mo st co mmonly on
the fac e, neck or upper trunk 1174, 754A l .
Involveme nt of lower extre mities is rare .
By definition , there shou ld be an abse nce
of pat c he s ty pic al of mycos is fungo ides
{174 , 734 , 2098 , 23411.
Clinical features
Patients are generally asymptomatic , with
the detection of a single skin lesion being
the sole manifestation of d isease {17 4.
754Af. A minority or patients may p resent
wit h lar ge tumours, or multiple skin lesio ns {754AI.
MoqJhology
These lym phomas show dense. diffuse or
nodular infiltrates within the dermis with
tendency to infiltrate the subcutis. Epide rmotropism may be p resent focaUy. but
if conspicuous. consideration should be
given 10 the diagnosis 01 mycosis h.ngoides,
Fig. 11 .67 Typical presenIatlons of IlfIl*Y ausma&'medium ~ T<el 1yrllJIuna
I
I
I
Postula ted normal counterpart
Sc.in homing CD4-positive T-cell.

Prtrgtosis and predictive factors
r-ese lymphomas have a rather
~l'OUI'a ble prognosis with an estimated
).year survival of approximately 80%
1174 177, 706. 734, 825, 2098, 2341,
24071, Partic ular ly, cases p resenting with

a solitary or loc alized skin lesions seem to
have an excellent prognosis 11741. In

such patients surgical excision or radiotherapy is lhe preferred mode 01 treatment. Patients with multiple lesions or
large tumours may have a more aggressive clinical course 1754AI.
Primary cutaneous per ipheral T-cell lymphomas. rare subtypes
305
Peripheral T-cell lymphoma,

SA Pileri
E. Raltkiaer
D' D. Weisenb urger
S, Nakamura
I. Sng
HK MOlier-Hermelink
E.S. Jaffe
Definition
A heterogeneous category of nodal and
extranodal mature T-cell lymphomas. which
do not correspond to any of the apectticeny defined entit les 01 mature T-celilymphoma in the current classification.
ICD-O code
9702/3
Epidemiology
These tumours account to- approximately

30% of "",,_aJ T-eel "'"""""'" (PTCll
in Western countries 118491. Most patients
are adults. These lymphomas are very rare
in children . The male:female ratio is 2:1.

Sites of involvemen t
Mosl patients present wi th peripheral
lymph node involvement, but any site may
be affected. Generalized disease is often
encountered with infilt rates in the bone
marrow (8M), liver, spleen and extranodal
tissues 11849 1. Peripheral blood (PS) is
some times involved, b ut leukaemic presentation is unc omm on. Extranodal presentatio ns may occur, with the skin and
gastrointestinal tract represent ing the
most co mmonly affecte d sites. Und er
these c ircumstances, the diagnosis of periph eral t -een lymphoma , not ot he rwise
spec ified (PTCL, NOS) sho uld be made
only when othe r specific ent it ies have
been excl ude d. Other less frequ ently invol ved sites inc lud e th e lung , sa liva ry
g land an d ce ntral ne rvous system.
Clinical features
Patien ts most often present w ith lymph
node enlargement and a majority have
advanced disease with 8 symptoms {18491.
Paraneo ptastic features such as eosinophilia, pru ritus or rarely haemophagocytic
syndrome may be seen 118491.
Morphology
In the lymp h node, these lymphomas
show paracortical or diffuse infiltrates with
effa cement of the normat architecture.
The c ytolog ic al spectrum is extremely
broad, from highly polymorphous to m0nomorphous. Most cases consist ot numerous medium-sized and/or large cells With
306
Mat ure T- and NK-eel l neoplasms
Fig. 11.69 Periphelill T.e:en lymphoma. NOS. A Diffuse infillrates of large !yrrlIhoid cells WIth pIeomOi phic, ~
nudei and prcminent 1'IJCleoIi. B In between the neopIastlc eels, !here arescaneeed eosinophiIs andI'kJmetOUS vessA
C Nutlei are marke<ly pleomorphic WIth po/)iobaled nuclear features. 0 In some cases. nudei areround and rrall)o
morphic in appaalill'lC8,
irregular, p leomo rp hic , hyperch romatic or

vesicular nuclei, pr ominent nucleoli and
many mitotic fig ures 1898, 10351. C lear
ce lls and Reed-Stern berg (RS)-like ce lls
can also be seen, Rare cases have a pre-
dominance of small lymphoid cells wi!:!

atypical, irregular nuclei. Hig h endothelial
venures may be increased 1898. 10351,A
T zone patt ern may be observed, but is
not specific for a d istinct entity, An inflam-
Table 11.07 Differential diagnosis of nodal penpteral T-Wli lymphoma, not otherwise specified ,
Disease
Immunophanotyplc fsaturlll
Peripheral T-cell "rmphoma.

rot otherwise specified
C04>CD8, arltigen loss frequent (C07, C05, CD4IC08. CD52).

C03(h1+. C056-/+,COlD-,
CLCX1J.. POI-
~fTII1unob1a stic lymphoma
CD4+ or mi ~ed CD4I8. C010+/-, BCl6+1. CXCl13+.P01+, hyperplasia

01
EBV+ C020+8 blasts
AdlAI T-cea IeukaemiaJlymphoma
CD4+, C02So , C07, C03O-l+, COl5-l+, FQxP3+/.
Anaplasticlarge eel lymphoma
C030+. ALK+/. EUA+. CO25+-. cytOtoxic glilnules+, CD4+/-, C03-l+.

CD43+
acre..
roc.
I.ga C020+ bIasls m background of Coo+reactive T-<:e/Is

Mixed awcD8. 1Iltad ard'liIecture. vanable C025andCD3O: scatlerlld
CO... _
+ . nearly a~ posiWe: oJ_.majOnly posrnve, .) +, rrirlOnCy pos.trve, FCC. kJIcuIitI' denlrtlic eees EBY.
Epsleirl-8arT virus.
matory background is often present, lnckKllng small lymphocytes,

plasma cells, la rge s-cene (that may be
dOnal rresoecnve of EBV infection)
123591and clusters of epithelioid tusnoc:ytes. Epithelioid t nenccvtes are particularly numerous in the lymphoepitheliOid
eel variant. The ortterennal diagnosis with
rgoirrrnur"OOlastic T-cell tymphoola (AITL)
may requireextensive im:nunophenotyping,
rl one uncommon va riant, the neoplastic
cellsselectively infiltrate the lym pho id follicles, and the resultant follic ular gr owth
pattern may suggest a B-cell lym phoma
dfollicular origin 15241
Extranodal involvement takes the form of
use infiltrates composed of similar
eels Inee skin, the lymphomatous popJalion lends to infiltrate the dermis and
!LbcuIis. often producing nodules that
-nay undergo central ulceration 117101.
lcoerrceooism. anqccenmotv and adl'e1aI invotvement are at times seen 117101.
In the spleen, the pattern is very variable
fTtm solitary or multiple fleshy nodules to
dl~use white pu lp involvement w ith c olorization of the periart eriolar shealth or in
!tJllEl cases predominant infiltration of the
red pulp13821.
eosmoonus.
the distinction from anaplastic large-eell

ly mphoma (A lCL) and Hod g kin lymphoma 1149. 23901. Aberrant expres sion
of C02Q and/or C079a is occasionally enc ountered 12359, 23901. Unlike AITl.
PTCl, NOS usually lac ks a follicula r T
helper (TFH) phenotype (C01O+, BCL6+,
Po l+ and CXCL13+ ) with the exception
of the follicu lar/perifollicular variant 199,
60S , 852, 2390 ). Prol iferation is usually
high and Ki67 rates exceed ing 70% a re
associated with a worse progn osis
123901.
Genetics
TCR genes are clonally rearranged in
most cases 118491.

These are usually highly aberrant neoplasms with complex karyotypes 118491.
In both conventional and array comparative genomic hybridization (CGH ) studies .
recurrent chr omosomal ga ins have bee n
observed in c hromosomes zq. Sq. 17q
and 22Q. and recurrent losses in chromosomes 4Q, 5Q, 6Q. so. 10Q, 12Qand 13q .
Dele tions in ch romosomes SQ. lOq
and 12q are associated with a better prognosis 12233, 2492 1. The genetic imbalances observed in PTCL, NOS d iffer from
those of other T-cell lym phomas. such as
AlTL and AL CL 12233. 24921.
Gene expression profiling studies have
provided some hints for better understanding PTCl, NOS 1137, 494 . 1451, 1739AI.
In particular, its gene signature d iffers
from those of AlTland AlClI523, 1739A 1.
lmulophiberrant t-een phenotype with frequent
PTCL,NOS is usually char ac terized by an
OC!fI'!Vegulation of COS and CD7 123901.

AC04+,coa- phenotype predominates in
rr:daI cases. CD4/cD8 dOuble-positivity or
lb..OIe-negativity is at times seen, as is
COB. CD56 and cytotoxic gr anule ex[2390 1. T-c ell rec ep tor (TC A)
oeIa-chain (I3F 1) is usually expresse d . aiIC\Img the differenti ation from "to t -een
'l'mphomas and NK -c ell lymphomas .
COO2 is absent in 60% of c ases 1393 ,
'740. 18561. CD30 ca n be expressed, exceptionally with Co lS. but the global
;tl8'lOIypic profile and morphology allow
cesson
Rg. 11.11 Periplleral T~ lymphoma, NOS. A NoIe the marked pleomorphism ollhe neoplasticpopulation. B"
Ki67Iabeling. C ~F l slall'lng.
Peripheral
t-een lymphoma. not orrerwee specified
307
In comparison to normal T lymphocytes,

it is characterized by the rec urrent dereg ulation of genes involved in relevant cell
func tions. e.q . matrix oeposmon. cytoskeleton organization . cell adhesion,
apoprosrs. proliferation. transcription and
sign al transduction 11 739A I The product s of these genes might have therapeutic relevance 1494 , 1739AI.
EBV inte gr atio n has been reporte d in
some cases 1632. 23901.
been developed 1749. 23901. Involvement

of the bone ma rrow (BM) has been proposed as a negative prognostic factor.
b ut this needs furthe r confirmation. EBVpositivity. NF",B pathway d ereg ulation. a
high p roliferation signature by gene expression. and cytotoxic granule expression
have been found to correlate with a poor
p rog nosis 187, 494, 632 , 23901 .
Variants
Postu lated normal counter part
Activated mature T lymphocytes. mostly
CD4+ ce ntral memory type of the ad ap tive immune svtem 1523. 769. 1739AI.
Prognosis and pred ictive factor s
These are hig hly agg ressive lymp homa s,
with a poor resp onse to the rap y, freq uent
relap ses and low 5-yea r ove rall survival
and failure-free survival (20 -30%) 118491 .
The only fac tors c onsistently associate d
with prog nosis are stage and IPI sco re
11 849). New scoring systems have rece ntly
306
Mature T- and NK-eell neoplasms
Lymphoep ithel ioid (Lennert lym phoma)

This variant shows di ffuse or, mo re rarely,
interfollicular gr owth , Cyto logically, it consists p red ominan tly of small ce lls with
slight nuclea r irregularities, confluent clusters of epithelioid histioc yte s and some
targer, more atyp ical , p roliferating blasts,
There can be admixed inflammatory c ells
and sca ttered Reed-Ste rnbe rg-like ce lls
(usually EBV+ ), High -end othelial venues
are not prominent. In the majority of cases,
the neop lastic cells are CD&positive 17701.
Follic ula r
This variant usually c onsists of atypical
dear celts forming intrafollicular aggregates
(mimicking follic ular lymp homa ). small
nod ular aggregates in a ba ckground of
progressive ly-tra nsformed ger minal centres (mi mic kin g nodular Iymphocytepredom inant Hodgkin lymphoma) or
enl arged perifollic ular zoneS/nodular aggreg ates surrounding hyperplastic follicles
(m imic king nod al margina l zone 1ymphoma) 1524. 18941. Despite a FTH phenl>
type, early stage d isea se, parti al lymph
node involvement, lac k of enlarged follic
ctar dendritic celt meshworks and lack cJ
prominent high endothelial veocies distngu ish it from typical angioimrnunoblasllC
T-eelllymphoma. Recently. a 1(5;9) Iranslocation has been reported in a subset cJ
cases with these featu res 121121. Other
terms have been used for this variant, n.
cluding per ifollicu lar. intrafollicular, paracortical nodular and expanded mantle
zone 11002, 13581.
T-zone
The T-zone vari ant is characterized by a
pe rifollic ular growth patte rn throughout
the lymph node 11894 , 23591. The ne0p lastic cells are p redominantly small wlll1
minimal cytological aty pi a, and the
process ma y be mista ken for benign
pa rac orttca t hyperp lasia. The cells express CD3 , CD4, and may show loss 01
CD5 or CD7, Some studi es have sug
ges te d that this variant may be associated with a more indo lent cou rse than
other PTCL, NOS 11894, 2359 1. but data
are limite d. Many PTCL can show focal
residu al tomcures: this histologic al feature
alone does not constitute evidence for the
'l-eone va riant.
Angioimmunoblastic T-cell lymphoma
A. Dog an
P. Gaulard
E.S. Jaffe
E. Halfkiae r
H .K, MuJler,Hermel ink
Definition
Angloimmunoblastic t-een lymphoma
(AITL) is a penpheral t -een lymphoma
Characterized by systemic d isease. a

poIyrnorphouS inlil trate involving lymph
nodes. with a prom inent pr oliferat ion of
high endothelial venules and follicular
deool'llic cells.
970513
~ and historical annotation
AITl was previously tett to be an atypical

reactive process . angioimrnunoblastic
~aclenopathy, with an inc reased risk
fA progression to lymphoma . Cu rrently.
tHerNhelming ev idence sug g ests that
A1TL rises de novo as a peripheral t -een
""""""'" 15971.
-kllogy
"Ill occurs in the middle-aged and elderly, with an eq ual incidenc e in ma les and
females 15971. It is one of the mo re com--
man soecmc subtypes of peripheral t-een

~,
acc ou nting lor approximat e ly
15- 20% of cases, or 1- 2% of a ll nonHodgkin lymphomas 11896).
E!K>kJgy
The nearly constant association with
EpsteinBarrvirus (EBV) has suggested a
possible role for the virus in the etiology,
possibly through antigen-d rive (6231.
fbwever, the neoplast ic T cell s are EBV
regative.
Ft 11.74
Fig. 11.73 Angioimu'IobIasT-<:eI~. A T~ cytJklgy d ~ T-ceI:s wdtl~ rw.dIi

iiW1d copious paieLIdeaf cylopIasm. BThe inNlriIte is CDIlp05ed of medUn " Iafge ~ eels wilh atIln:Ian:dNr
The pr imary site of d isease is Ihe lymp h
node and virtua lly all patie nts present with
general ize d lymp hadenopathy. In ad d ition, sp leen , liver. skin and bone marrow
(BM) are frequenlly involved 15971Cl inical featu res
AlTl ty pic ally pre sent s with advanced
stage disease, generalized lymp hadenopa thy, hepatosp lenom egaly. sys temic
sym ptoms, and poivcionar hypergamm aglobulinemia 1597, 1234A. 1529A, 202 11Skin rash , often with prur itus, is frequ ently
present. Other common find ings are pleural effusion, arthritis and ascites. l aboratory
find ings inc lude c ircu lating immun e co mplexes , cold agg lutinins with haemolytic
anaemia, positive rheumatoid fac tor and
anti -smooth muscle antibod ies,
Patients exhibit immunodefici ency sec ondary to the neoplastic proc e ss. In the
majOrity of the cases (75% ). expansion of

B-cell s po sitive for EBV is seen , though t
10 be a conseq uenc e 01 underlying immune dysfunction 19 71.
Mo rphology
AlTl is c harac terized by pa rtial efface me nt of the lymp h nod e arctateciure.
etten with perinodal infiltration but spar ing
of the pe ripheral co rtic al sinuses . There is
marked proliferation of arbor izing high endothelial venutes (HEV). There is predominantly paracortcat polymorphic infiltrate
co mpose d of small to medium-sized lymph ocyt es, with c lear to pale cyto plasm
and di stinct ce ll membranes and minimal
cytological atypia, The neoplastic cells often
form sma ll c luste rs a round the follicle s
and HEV and are admixed with variabl e
numbers of small reactive lymphocytes,
eo sinoph ils, plasma cells and hatlocvtes.
The polymorph ic infiltrate is frequently
patterns of angioimrru'lobIstic T-cel lymphoma. AAn early case 'lWilh hypefpIastlc IoIidn and paracoI1icaI e~ (Pallem 1). BAcase MIll
JoIdes renWIscenl of cas1Ieman's disease MlI marked pcncorlicaI expMSion (Panem 2). C 0asSICiII1fuphoIogy WIll ~~ of normal ~ aM
IWd ma& "II"""'atIol, assooaIed WI\h aggegateS d 8typicaI ~ eels (Pattern 3)
~
AnglOimmunoblasllc T-cell lymphoma
309
~'h v-lJ . ' .

~.,
pll'u .
...
'**
Fig. 11.75 AngioinYnlSIObIaslic T-ceII!yrr4tlcIna. A M~uclealed cells resermling Reed-Stemberg eels . B low poMf view of C02t imllllOOSlain h91191bng marbd
dendntIc eel pI ~ aIJoI l eUb ilWlllQ tIigtl 8l'lCIOh!iaI wenJIes. C The c::hactenstic pheno(ypeof tumou' eels expressrog CO] {Cl. COtO(D) and CXCl..1] (E). F E8Y~
B-ceI proWerallon in angw:irmw.Jnotlslic T-<:elI !yrr4tlcIna <loutiIe Sl<WIed lor C07'9a
~J and ESV-E8ER
lllue-oocIe).
r...
associated with incr eased follicular d end ritic cell meshworks. Early cases may
contain hyperplastic follic les with illdef ined bord er s an d the ch arac teristic
histology may be lim ited to the perifollicular areas w ith predominance of clear cells
118281. The relationship between AITl
showing limited caraccencar involvement
and the follic ular variant of perip heral
T-cell lymphoma . NOS rema ins to be cla rified . An ex pansion of B fmmunobrests is
usually present in lhe paracort ex. The expa nsion of normal Bccetls and follic ular
dendritic celts in the les ions ha s bee n
linked to the functi ona l properties of the
neoplastic cells as follic ular helper
(TFH) of the normal follicle The expression of CXC l 13 mediates expansion of
and , adh esion of
follicul ar d endritic
B-cell s to HEV with subseq uent entry to
the lymph nodes. EBV-positive Be ene are
nearly always present. They range in cell
size and e xpa nsio n of B lmmunobrasrs
may be prom inent 12377 . 2490J. The EBVpositive B lmrnunobrasuc pro liferati on
may progress. either composite with AITL.
or at relapse to EBV-positive diffuse large
a-cen lymphoma 15, 99 , 24901. EBVpos itive Reed -Sternb erg -like cells of
lineage may be present and may simulate
classical Hodgkin tyrnphoo1a 117941. In advanced cases. the inllarrmatory component is diminished. and the proportion of
c lear cells and large c ells is incr eased .
r...
Immunophenotype
The neoplastic
express most pan
t-een antig ens such as C03. C02 and
CDS and , in vast majo rity of the cases,
C 0 4 a lthough nume rous reactive C08+
t-eens
t-eens
are often p resent. Cha racteristically. the tumour cells show the phenotype
of normal TFH expressing COW, CXCl1J
and PD-1 in 60-11)0% of the cases 196
523. 605 , 85 11. This phenotype is helpfLl
Paracorte x
t-eens
ceus.
a-ces
310
Mature T- and NK -eell neoplasms
't
Gcnninal Center
Flg.1'.16 TheoretiCal model of angioimmunoblastic T ce~ lymphoma patllogenesis. EBYpositive 8-c:eIIs pr&Sel'll EFl
proteins (e.g. EBNA-t) in assodalioo with MHC class II molecules. upregulaleCD28 ligand (BT). and ~ I:Co
stimulatory SlgrWs lor TFH eel adMlllon. TFH cells uPf89Jlate CXCR5 and CXCl.. t 3. CXCl13 promotes 8<111 II'
0'\lItmenl 1O h! I'fr!1ltl flOde 1tlrouo;1l 8lIlefenO!I of !k:::IllIs OIl "'lfl endoltleliaI vetUes (HEV) and ~
gemWIaI centres. h:Jeased 8-ceIsexpand in 1hepar3COI'Iel and ~ adMlled.sere paraa::wticaI Ek:eII bea:ir'ne EBr
translormed. CD21-positive dendri!(; cells expand from ee HEY Figure r&l'fOdtlCed with permission from 1623).
viraj
in distinguishing AITL from atypic al paracortical hyperplasia and other peri pheral
teen lymphomas 1631. 8521 as well as di-
Postulated norma l counterp art

CD4+ follic ular helper t -een.
agnosing extranodal d issem inat io n 198.
Genetics
t-een rece pto r genes show clonal rearrangements in 75-90% of cases 197,
2155,23781_ Clonal immunoglobulin gene
rearrangements may be found in around
25-30% of cases 197. 21551. and correlate with expanded EBV+ Beene . The
most frequent cytogenelic abnormalities
are trisomy 3 , trisomy 5 and an additiona l
X chromosome 1597,19611 and comparative genetic hybrid ization has srcwn
gains of 22q , 19 and 11q 13 and losses of
156. 1656A1. B immunoblasts and plasma

cells are polytypic : however, secondary
EBV-positive a-ceu proliferations includfig diffuse large B-ceillymphoma . classical Hodgkin lymphoma or plasmac ytoma
may be seen. Follicular dendritic cell
'I'leShworks expressing CD21. CD23.
CD35 and CNA42 are expanded , usually
Sl1I'OlXldII'lg the high HEY.
13q in subset 01 cases [2233 1 Gene

expression prof iling studies have shown
that the neoplastic cells show features of
CD4+ TFH [5231.
Prog nosis and predictive factor s
The clinical course is aggressive with a
median survival of less than three years.
Patients ofte n succumb to infec tious
c ompncauons. which makes del ivery of
aggressive c hemotherapy d ifficult 11336 ,
!ynl:lhoma
202 11. Supervening large
(often but not invariably EBV-positlVe)can
occur 15, 99 , 135,24901 .
a-ces
";
Angioirnmunoblastlc
r-cea lymphoma
311
Anaplastic large cell lymphoma (ALCL) ,

ALK-positive
Definit ion
Anaplast ic larg e ce ll lymphoma (ALC L),
anaplastic lymphom a kina se (ALK)-positive
is a T-cell lymp homa consisting of lymp hoid cells that are usually larg e with
abundant cytoplasm and pleomorphic ,
often horseshoe-shaped nuclei, wit h a
translocation involving the ALK gene and
expression 01 AlK protein, and exp ression
of CD30 AlCl withcomparable rrcepbologic and phenotypic features, bul lacking ALK rearrang ement an d the ALK
protein, are considered as a separate
category (ALCL. ALK-). A LCL, ALK + must
also be d istinguished from p rima ry c utaneous AlC L and from other subtypes of
T- Of B-ce ll lymphoma with anapl astic
features ancsor CD30 expression .
ico-o code
A LCL . ALK+ frequ ently involves bo th
lymph nodes and extra noda l site s. The
most commonly involved extranoda l sites
incl ud e skin , bone , soft tissues . lung and
liver 1285 . 668, 20871. Invo lvement of the
g ut and central nervo us syste m (CNS) is
rare . Mediastinal disease is less frequent
than in classical Hodgkin lym phoma. The
inc idence of bone marrow (B M) involvement is approximately 10% lNhenanaJyzed
with H&E . but is inc reased significantly
(30 %) when immunohistochemical stains
are used 17241 . since BM involve ment is
often su btl e. The small cell va riant of
ALCL. AL K+ may have a leukaemic pre sentation with peripheral blood (PB) involvement 1164 , 11521,
C linical features
The majority of patients (70%) present with
advanced stage III-IV disease with peripheral and/or abdom inal lymphadenopathy.
- - --
RD. Gascoyne
H Stein
M C . Kinney
50 .1-- 40
5
'0
j
Male (n : 22 8)
Female (n:158)
30
z 20
10
0."'"
. ..
... " . , . " ,lI _
" -11 M-W _
...
''''''''!-E'''
- IJ~''?"'''P'',
. . II .. ... . ....
,0-"
_
1lI _~.
971 4/3
Epidemiology
ALCL, ALK+ accounts for ap prox imately
3% 01adult non-Hodgkin lymphomas and
10- 20% of childhood lymphomas 12OB71.
ALC L, ALK+ is most frequent in the first
three decades of lile 1188. 6681 and shcJWs
a male pre dom inanc e (M:F ratio 1.5: 1).
312
60 .,--
E.S. Jaffe
G _Delsol
B. Falini
H K MOtier-Hermelink
E. Campo
Fig. 11.77 Dlstnbution 0( anaplastic 1af9El oeIlymphoma (AlCL). ALK. by age (n=386).
often associated w ith extranodal inlilt rates

and invo lvement 01 the BM 1285. 668.
2(9 1). Patients olten have B symp tom s
(75%), espec ially high fever 1285. 668 ,
predominate. Five lTI()(phologiC patterns

can be reccqneec .
The "c ommon pattern" ac counts I()( fi(A;,
of cases 1188, 6601 . The tumour cels
20911.
Morp hology
A LCL, ALK+ show a broad morp holog ic
spectrum 1188, 383 , 55 1, 660, 898, 1033,
1 152, 1746 1. How eve r, all cases c onta in
a variable propo rtion of cells with ecce ntric . horse shoe- or kidney-sha ped nuc lei
often w ith an eos ino philic reg ion near the
nucleus . These ce lls have bee n referred
to as hallmark cells because they are
prese nt in alt lTI()(phologic variants (1881.
Although the hallmark cells are typically
larg e. smaller cells with simi lar cytologica l leatures may be seen and c an g reatly
aid in accurate diagnosis 11881. Depending upon the p lane of sec tion, some cells
may appear 10 co ntain nuclea r inc lusions,
but thes e are not true inclusion s but invagination s of the nuclea r membrane .
Ce lls wit h these fea tu res have been referred to as doughnut cells 11 0331.
Morphologic features of AlCL , ALK +
range Irom small ce ll neoplasms to an oppo site extr eme in whi c h very large cells
Fig. 11.78 GeneralleaturesofALCL,common t)'pt , n.

tynVI node an::Mecture is obliterated by ~ceII
and fltrasinusoicIa eels are obsefwd ,
hiM! ebc-oent cytoplasm that ma y appear

dear, basophilic or eosinophilic. Mu ltip le
'udei may occur in a wreat h-like pattern
and may give rise to cells resembli ng
~Sternberg
cells. The nuclear cbro-
rarely 11881. Hallmark cells are always present and are often conce ntrated around
blood vessels 1188, 11521. This morphologic
varia nt of ALC L is ofte n misdiagnosed as
per ip hera l T-cell lymphoma. NOS by
conven tional examina tion. When the PB is

involved, atypical cells reminiscent of
flower-like cells can be noted in smear
prep arations,
The "Hod g kin-like pattern" (3%) is characterized by morphological features mimicking nodular sclerosis classical Hodgkin
lymphoma (NSCHL) 123161.
More than one pattern may be seen in a
single lymph node biopsy ("composite
pattern") (15%)11881. Relapses may reveal
morphologic features d ifferent from those
seen initially 1188. 9461. Other histological
patterns include tumours shOWing ce lls
with monomorphic. rounded nuclei. either
as the predominant populatioo or mixed
with more pleomorphic cells. cases rich
in multinucleated neoplastic giant cells or
displaying sarcomatoid featu res 13831.
Occasional cases may have a hypocellutar appearance. with a myxoid or edematous background 14101. Spindle cells may
be prominent in such c ases and may simulate sarcoma in cases presenting in soft
tissue 110341. In rare cas es, mali gnant
ce lls are exceedingly scarce. sca ttered in
an otherwise reactive lymph node . Capsula r fibrosis and fibrosis assoc iated with
tumou r nodules may be seen, mimic king
metastatic nonlym phoi d ma lignancy
Wolin is usually finely cl umped or

ueoersed with multiple small, basophilic
nceolt In cases composed of larger

cells, the nucleoli are more prominent , but
eosinophilic. inclus ion-li ke nucleoli are
'ar~y seen. When the lymp h nod e arch itecture is only partially effa c ed, the
wn:our characteristically grows within the
sreses and thus. may resemble a

metastatic tumour,
The "Iymphohisl iocytic pattern " (10%) is
rtaractenzed by tumour ce lls admixed
wm alarge number of reactive t nstccvtes
1188,660, 17461. The histiocytes may
Mask the maligna nt c ells whic h are often
!maIler than in the commo n pattern. The
'l!qlIaslic cells etten cl uster around b lood
I'eSSE!ls and can be hig hlight ed by irnf!ktIOStaining using an tibo dies to C D3Q
~ AlK. Occasion ally. the histiocytes
~ signsof erythrophagocytos is.
"'he "small cell patte rn- (5-10%) shows a
pecmoant po p ulation of small to
medll,m-sized neoplastic ce lls with ineguat' nuclei P88. 660, 1033 . 11521 . In
e-e cases, the majority of the cells have
palecytoplasm and centrally located nuteJs . referred to as "fried eg g cells".
S!gnet ring-like cells may also be seen
Aoaoiasnc large cell lymphoma (ALCL). AlK-positNe
313
I
Fig. 11 .13 Other tistological patterns of ALCl. (althese cases were positive lor ALK prolein). A AlCl shlWItng ~ large eels with round nucIel. B ALa. oonsrsMgd
pIeoi,o.,nc: Prt cells CAla.1I:h n signet rilg eels.
lmmuno phenoty pe
The tumourcells are positive for CD30 on

the cell membrane and in the Goigi region
120911. The strongest immunostaining is
seen in the large cells. Smaller tumour
cells may be ooly weakly positive or even
negative for CD30 11881. In the Iymphohistiocytic and small cell patterns. the
strongest CD30 expression is also present in the larger tumour cells. wtlich etten
cluster around blood vessels 11881. ALK
expression is absent from all postnatal
normal human tissues except rare cells in
the brain 117861. For this reason, immunohistochemistry has largely supplanted
molecular tests for the diagnosis of ALCl,
ALK +. Note that tor AlK staining it is ad visable 10 use monoc lonal antibodies
3 14
(mouse or rab b it ) instead of polyclonal

anti bodies whic h may give false positive
staining. In the ma jority of the cases that
have the t(2;5)/NPM.ALK translocation.
AL K staining of large cells is both cytoplasmic and nuclear l188, 660. 20871- In
the small cell variant. ALK-positiyity is
usually rest ricted to the nucleus of tumour
ceus 1188. 660, 1785 ,20871 . In cases with
va riant transiocenons. the ALK staining
may be membranous or cytoplasmic
1188.660. 1785 .20871. Cases with t(2 ;5)1
NPM-ALK translocation show aberrant
cytoplasmic expression of nocreoohosmin (NPM) , whi le ALCL. AlK+ carrying
variant transiocenons show the expected
nuclear-restric te d expression of NPM
16691.
The majOrity of ALCL , ALK+ are positiyefa

EMA but. in some cases, only a proportioo
of malignant ce lls are positive 1188, 5511
The great majority of ALCL. ALK+ express
one or more t-een antigens [ 1881. HctNever,
due to loss of severer pan
antigens.
some cases may have an apparent "nul
cell" phenotype, but show evidence for a
lineage at the genetic level 17221
Since no other distinctions can be found
in cases With a
versus a nutl-cel
phenotype. T/null ALCl. ALK+ is
ered a single entity {188. 8981_COO, the
most widely used pan
marker. IS
negative In more than 75% of cases 1188.
2381. C02, COS and C04 are more usefu
and are positive in a significant prooonco
of cases (70%). Furthermore. most cases
r-ceu
t-een
t-een
co-so-
t-een
~~~~~~~:~~~~~
: .~ ..
'.'
...
.. ,;,r.';.., '.... .,-
~ . .. . ~. ""'
' . .
~ ..1 '
1,\ \t
,-r ..,.. ... "}.
: ,,:': - \ ... . _ . ,,-;.
,;
. ~'
'
. : , .. . .;",.
_ . . .. . _.... ' ,I, '. i ,.... ,, '{'.,.:,.'.. ,:"_' . , . ,
' ~.olI"'" .I ,. '..
. - ,..:.
y.
. ,.. . . -r-
' ..
. " .- . ... . -j" " .. ~

I
~ ' . ... ..
"
.. , ' --: "
~ ~"l '-:-"
J 7 ",/ 1 ~ "
' . ",
..
'
,.
"
.'
' .1':'
.r;
. ."
II
~
-; -1" ' '; ';
.......
~: ." . ' ," "
.' , ~ 't .. -J' \'" .. " .,l".'
; "'~" . . I t";
I " (,. ' ,~ ; n,
/t ....,>,'
'''-'15
/i'1. t"...<..
~ ..: ~: '.., : .. '.,
" 1 , ," ~ , .
.f ",,;- ,;:. ,
<,
, . 1 .,. , . ", ..
.. ,10'0 '
... -
"
__ ,
" ~
<:
- > 'f~ _
, .
'"
" f,
.....'" I :_.", I " ',
I.
_" ~ :I
..
(.y ,
L~
Fig. 11 .86 A HypocellularALCL B Malignant cells are h~hlighted by ALK staining
exhibit positivity for the cytotoxic associated antigens TIA 1, granzyme B, and/or
perforin 1722. 1192). COB is usually negative. but rare COB-posit ive cases exist.
C043 is expressed in two thir d s of the
cases. but this ant igen lac ks lineage
specificity. Tumour ce lls are variably po sitive for CD45 and CD45RO and strongly
cosisvefor CD25 15511. CD15 expression
IS rarely observed and when present only
asmall proportion of the neoplastic cells

is stained (188 1. Granu la r stain ing for
scre entocoes reactive with CD68, such
as KP1, may be seen, but other ant ibodies
j rected aga inst the macrophagerestricted form of COBB, such as PGM1 ,
eereqative. ALCL , ALK+ are BCL2 nega:r;e 14841. ALCL are also consistently
rapative for EBV (i.e. EBEA and LMP1)
12791,A number of oth er antigens are expressed in ALCL but are not of d iagnost ic
'ialue They include cnetenn (23831. SHP 1
p'osphatase 19621, BCL6. C/EBP 11798 1,
serpinAt l12421and tascm .
,
,
"
>,
II
I
d
~ II
f-
te
is
8,
ul
'"es
Arare distinc t d iffus e large B-cell Iym ptonawith immuno b lastic/plasmablas tic
ezeres expressing the ALK p rote in m ay
ll.perlicially resem ble ALCL, ALK+ d ue to
freq uent sinusoidal g rowth pa ttern. These
ftrl ptlomas exp ress EMA (as do ALCL)
bLot lack C0 30 and sho w a characteristic
Cjtcplasmic-restricted g ranular staining
l:ntJe ALK protein 1553J,
&me non-haematopo ietic neoplasms such
eest oorr wosercom a 1660 , 8981 and in~arrnatory myofibrob lastic tumours 1843}
may be positive fo r ALK but are mo rpho\:Jgically distingu ishable from ALCL and
re recanve for both CD30 and EMA.
lJenetics
Nltigen receptor genes
"wroximalely 90% of ALCl, AL K+ show
ctml rearrangement of the T-cell rec ep tor
ITCR) genes irrespective of wh ether they
exp ress t- een ant igens or not. The remainder sho w no rear rangement of TCR
or IG gen es 1722}.

The gen es fused with ALK in variou s c hrom os omal translocations and the subcerlula r distrib ution of NPM-ALK and X-A LK
ch ime ric p rote ins are shown in Tab le
11.08 . The most freque nt genetic alte ration is a tran sloc at ion , t(2 ;5)(p23 ;q35) ,
be tween the ALK ge ne on ch romosome 2
and the nuc leophosm in (NPM) gene on
ch romosome 5 11244, 1407, 15251, Variant
tr anslocation s involv ing ALK an d other
par t ner genes on chromosomes 1, 2 , 3 ,
17, 19 , 22 and X also occu r (469 , 669 ,
93 1,124 1,1243,1408,1449 , 1868,2087,
2256,2258 , 2268 , 242 7) Th e t(2;5 ) can
be detected by RT-PCR , but cases w ith
va riant translocations w ill be negative by

standard AT-PCR us ing pr imers that are
specific tor the ALK and NPM genes 1660,
17621. A ll these translocatons result in
up reg ulation of A LK, but the subcellular
d istr ibution of the sta ining var ies depending on the tran slocation,
The ALK gen e encodes a tyrosine kinas e
receptor be longing to the insulin recept or
supe rfam ily, wh ich is normally silent in lymphoid cells 11525). In the t(2;5)(p23:q35),
the nuc leophosmin (NPM) gene, a house keeping gene, fuses the ALK gene to pro duce a c him eric p rotein in wh ich the
N-terminal portion of NPM is linked to the
intracytoplasmic portion of ALK (1525j
The particular cytoplasmic , nu clear and
nucleolar stain ing seen in cases assoc iated with the t(2: 5) can be explained by
the fo rmation of heterod imers between
Table 11 .08 Trans iocation s and fusion proteins inl'Ol'ling ALK at 2p23
ALK partner
MWtofALK
hybrid protein
ALKstainIng pattern
% 01
eases
t(2;5)(p23:q35)
NPM
80
Nuclear. diffuse cytoplasmic
84%
t(l ;2){q25:p23)
TPMJ
104
Diffuse cytoplasmicwith
peripheral intensification
13%
Chromosomal
anomaly
Inv(2){p23q35)
ATIC
96
Diffuse cytoplasmic
1%
t(2;3j{p23:q21)
TFG Xiong
TFG long
TFG sholt
113
97
85
Dnfuse cytoplasmic
Diffuse cytoplas mic
Diffuse cytoplasmic
<1%
t(2;17kp23:q23)
cac
250
Granular cytop lasmic
<1%
t(2;X)(p23:q11-12)
MSN
125
Membrane staining
<1%
t(2;19)(p23:p13,1)
TPM4
95
Diffuse cytoplasmic
<1%
t(2;22)(p23;q11.2)
MYH9
220
Diffuse cytoplasmic
<1%
t(2;17kp23:q25)
AL017
NO
Diffuse cytoplasmic
<1%
Nuclear or cytop lasmic
<1 %
Others'
NPM, nucleophosmin gene; TPMJ and TPM4, non-musculartropomyos ingene: TFG. TRK-fused gene, three
different fusion proteins of 85, 97and 113kO(TFG-ALKs , TFGALKl , TFGALKxL) areassociated with the
1{2;3)(p23:q35) which involves theTFG: ATIC, arnoc-terrrwoe of 5-aminolmidazole-4-carboxamide ritlooucleolide
formyltransferasel lMPcyclohydrolase gene:
c1alhrin heavy polypeptide gene; MSN, moesingene: MYH9.
myosinheavy chain 9 gene; AL017, ALK lymphoma oligomerization partner on cororoscre 17,
" unpublished series of 270 cases ofALCL, ALK+
cnc.
Anaplastic large ce ll lymphoma (ALCLj, ALK-pos itive
3 15
wild -type t;.l PM and the fusion NPMALK

protein, On the other hand , the formation
of NPM-ALK homodimers using cnmertseuoo sites at the N-term inus of NPM mimleks ligan d b ind ing and is responsible for
the ac tivation of the AlK catalytic domain
and for the oncogenic properties of the
Al K protein 117851 .
Compa rative genomic hybridiz ation (CGH)
analysis shows that AlCl. AlK+ carry
freq uent secondary c hromosomal imbalance inc ludi ng losses of c hromosome 4.
l 1qand 13q and ga ins of 7. 17pand 17q
11923 1. In addition , th is study demonstrates that Atx-posmve and negative
ALCl have a d ifferent representation of
secondary genetic alterations. supporting
the concept that they are d ifferent biological entities.
1,00
ALK1+
n=215
0,75
0,50
ALK1
n-28
0,25
p= 0,001
125
250
Months
Fig. 11.87 0veraI so.nivaI d AlK-po6ItiYe and negalive petlents.

Supervised analysis by class compa rison
between ALC L. ALK+ and ALCL. ALKtumours p rovided d istinct molecular signatur es 11242 1. Among the 117 ge nes
ove rexp ressec in ALCL . ALK+ . BCL6,
PTPN12 (tyrosine phosphatase) . serplM 1
and QfBP werethe four top genes, bemg
overexp resse d with the most significant
p-value. This ove rexo ress loo wa s also
confirmed at the protein level lo r CIEBP.
BCL6 and serp in A 1,
Postulated normal counter pa rt
Ac tivated matur e c ytotoxic T-cetl.
Prognosi s and predi ctive fact ors
The international prognostic index (lPI)
appears to be of some value in predicting
outcome in AlCl, AlK+ . although less
316
Mature T- and NK-celt neoplasms
significantly than in other variants of 1ymp homa 1668, 7601. No differences have
bee n found betw ee n NPM -AlK-po sitive
tumours and tumours showi ng variant
transiocanons 1658. 66 9 , 760. 20131. II
might be that cases with small ce ll variant
histolog y d o not have the same
fav ourable prognosis as the other Al K
positive tu mour s since these patients
often present with di ssemi nated disease
at d iag nosis. ALCl , AlK+ patients have
a favo urable pr ogn osis compared with
AlCl , AlK-I668, 760 , 20 131. The ove rall
5-year surv ival rate in At.Ct. . AlK+ ap proaches 80% , in c ontrast to o nly 48% in
AlCl, AlK-. In the recent study by Savage
and co- workers {1943AI, the overallS-year
surv ival of AlCl , ALK+ pa tients is slig htly
lower (70%) due to the excicsoo of paed iatric pa tien ts. In the latter study, the
5-year la ilure free survival (FFS) of paIients with ALCL. ALK+ was 60% versus
36% lo r AlCL. Al K-. Relapses are not
uncommon (30% of cases), but often remain sensitive to c hemotherapy ; alkr
geneic BM trans pla nt may be ettecnve in
refract ory cases {13191. Since it is now
cle arly demon strated that AlK is essential for the p roliferati on and survival 01 the
cells of AlCL . ALK+ . it can be expected
that specific ALK inhib itors, c urrently
tested in prec linical models , may be available in the near future for c linical trials
117631
Anaplastic large cell lymphoma,

ALK-negative
DY Mason
N.l. Harris
Definition
mimi c carcinoma Features such as sclerosis or eosinophils may occur, but when
present shou ld raise the susp icion of
CHL. The neoplastic ce lls show a similar
morphologica l spectrum to AlCL, ALK+ .
althOugh a osman ce ll variant" is not recognized. Biopsies typically show large
pleomorphic cells. sometimes conta ining
prom inent nucleoli. Multinucleated, including wreath-like. cel ls may also be
present and mitotic ligures are not infrequent In addition , to a variable degree,
"hall mark" celt s with eccentric . horseshoe- or kidney-shaped nuclei are seen .
The neoplastic cells in ALCL, AlK- tend
to be large r and more p leomorphic than
tho se seen in cl assic al AlCl, ALK+
and /or have a higher nociea rcytootasmc
ratio 1668, 1565 . 1762.20131 . The latter
feature may suggest a diagnosis ot PTCL,
NOS. but in the latter d isorder abnorma l
small to medium-s ized lymphocytes are
often admixed with a morphologically
homogeneous neoplastic cell popu lation.
and the sheet-like or sinus pattern of
infilt ration typical of ALCL is absent.
AlK-negative anaplastic large cell tymjtana (AlCL. ALK-l is included as a proM1aI entity. and is defined as a CD30+
k:eI neoplasm that is not reproducibly disWlgUiShable 00 morphologica l grounds
m AlK-positive AlCL (AlCL, AlK+). but
tacks anaplastic large c ell lymphoma ki-ase (AlKI protein. Most cases express
tcee -assoeateo markers and cytotoxic
J<WlJIe-associated proteins. AlCL. AlK!T\lSI be distingu ished from primary cuta-
-eces AlCl, othe r s ubtypes 01 CD30+

f. cr B-cel1 1ymphcrna WIth anaplastic teaties, and cl assica l Hodgkin lymphoma
ICHl).
roo code
G . Delsol
H . Stein
AlCL. ALK- involves both lymph nodes
and extrarooar nssue . although the latter
sites are less commonly involved than in
AlCL. AlK+ . Extranodal sites include
bone, soft tissues and skin . Cutaneous
cases must be d istinguished from primary
cutaneous AlCl and cases that invol ve
the gastrointestinal tract must be distingu ished from CD30-positive enteropathyassociated T-cell lymphomas.
Clinical featu res
Most patients present with ad vanced
stage til to IV disease. with peripheral
and/or abdom inal lym phadenopa thy, and
B symptoms 121801.
9702/3
",,,,,,hology
,
v
e
d
Y
,-
Is
9p'alyms and historical annotation

"lCL ALK was included in the third ecnlI:rI 01 the WHO crassincauon. together
.1tIALCL. AlK + in the broader entity 01
'areplastic large cell lymp homa " 15541 .
ltJwever, it was also recognized that
ALCL, ALK (mainly because ottneir older
In most cases the nodal or other tissue

architecture is effaced by solid, cohesive
sheets of neoplastic cells . When lymph
node architecture is preserved. the
neoplastic cells typically grow within
sinuses or within T-ce ll areas , commonly
showing a "cohesive" pa ttern that may
E. Campo
M.C. Kinney
E.S. Jaffe
S. Falini
Median ageand more aggressive clinical

course) are felt to be distinct from AlCl,
A.LK+ (5541 . However, there are also valid
arguments for excluding AlCl, AlK- from
Tie category of pe riphe ral t-een Iymptpma (PTel), not otherwise specified
INOS) 1659,1 034 , 2030 , 2431 ). Unforturately, there are few de tailed cl inicopathocqcal studies of AlCl, AlK- 121811 and
'llspecific oncogenic abnormalities (e.g.
croaraoe to ALK gene rearrangement)
rave been identified. Thus, the distinction
beI~n PTCl, NOS, and AlCl, AlK- is
'llt always straightforward. The current
00 Classification considers AlCl, AlKt De a provisional enti ty within the spec11m of mature t-een lymphomas, distinct
itrn both AlCl, AlK+ and PTCl, NOS.
-"Ie peak
incid ence of AlCl, AlK - is in
Wts (40-65 years), un like AlCl. ALK+ .
1tIdl occurs most corrmon ty in c hildren
young adu lts. a lthough c ases c an

1659. 208 71. There is a
'IOies1 male preponderance ( 1.5: 1).
;r(!
:ttiJ' at any age
Fig. 11.88 IrnmunostawlI1g lor COJO in cases of AlCl, AlK shows ee coheSive and inIra$inuSOidaI !Towlh
pattern of!le 1l.JOOU" and Ihe homogellllOUS eqJf9SSioo ofIt'iIIIllWter on 1l.JOOU" eels . Hole !le GoIgi- and ~
assodaled pattern of stanog Asteris.ls mcate ~ ~ lcIicies.
AnaplaS!lC large cetltymPhorna. ALK-negallve
317
although di ffuse cytoplasmic positivity is

also common. Staining should be strong
and of equal intensity in all cells. a feature
that is important in distinguishing ALCL,
ALK- from other PTCl , which can express
CD30 in at least a proportion of the cells.
and usually with variable intensity. AlK
protein is by definition undetectable.
Loss of
markers can occur, with
greater frequency than typically seen in
PTCL , NOS . In this respect . AlCL, ALK
is sim ilar to AlCL, AlK-+ . However, OVel'all more than hatt of all cases express one
or more T-cell markers. C02 and COOare
found more often than CD5 , and COO is
almost always expressed . CD4 is POSitIVe
in a significant proportion of cases
whereas COB-positive cases are rare
Many cases express the cvtotoxcas sociated markers TIA 1, granzyme 8
and/or perforin. A substantial minority ~
cases is positive for EMA (on at least a
proportion 01 malignant cells). a marker
that is almost always seen in AlCL, AlK..
bul on ly occasionally in PTCL, NOS.
In c ase s that lack all T-celVcytotoxic mark
ers. CHL rich in neoplastic cells or another
large cell malignancy (e.g, embryonal
ca rcinoma) should be ruled out, In this
regard. slaining for PAX5 is useful ; CHL
will show weak expression of PAX5 in ee
majority of cases. whe reas it should be
negative in all cases of A LCL, ALK r:I
ALK+. The demonstration of CD 15 sho.tI
raise a suspicion for CHL. However, CD15
may be expre ssed in some cases 01
PTCL NOS, and such cases are ger.eraty
strong ly C030-positive (1491. Whether periphe ral
neop lasms expressing botl1
C030 and CO tS should be c lassified as
ALC L, Al K- or PTCL, NOS, remains to be
determi ned. Notably. these cases havea
very poor prognosis, thus c linically more
closely resembling PTCL, NOS. AlCL, AlJ(.
are consistently neg ative for Epstein-Barr
virus (EBV) (i.e. EBEA and l MP1). and the
expression of these markers shoUd
strongly suggest the possibility of CHL
A single study has reported that AlCL
AlK- and AlCL, ALK+ lack
recece
proteins. and in this respect tend to dille!'
from PTCl , NOS 12381. Ctus terin is also
commooly expressed in AlCL. ALK- and
ALK+. bu t rarely in PTCl, NOS 11235,
1574. 1905 1; this marker has not ceeneamined extensively in CHl, but was neg.
atrve in the cases studied 123831.
t-een
..
Fig. 11.89 ~ laalures of loll' cases d AlCl, ALK-. A Note \tie high nuclear 10 cytIplasmic rallo.
B ~ (lll'I'llWSj ewe present (otten In ~l btA otherlealuresof IiCJ(lgU1 tymptIoma we absenC. C Typical
mrph1ogicai and phenotypic fe.1IlIns of ALCl (a hallmark eel is arrowed) but arose in ee gaslrtllnleslNllrad
(glanlUar 8pI\tleil.ITl is seen WI the upper Ieft.l. 0 Case Wlth more celkJIar ~
Emphasis should be placed on CD30

expression; If a large c ell lymphoma 01
roo-Been phenotype stows strong. forogeneous CD30 expression . especially if
this is strongest in the Gotgi and rnembrane regions. and the ITlOfphologicallealures are consistent with AlCL , it should be
classified as ALCL. AL K , Fortunately the
distinction between AlCL, AlK and

PTCL, NOS currenlly car ries no major
clinical implications.
Immunophenotype
All tumo ur cells are strongly positive for
CD30. usually most strongly at the cell
memb rane and in the Gofgi region.
r-ceu
t-een
Fig. 11.90 ALCl, ALK s/lowing a IIigh nudear 10cytIplasmic ratio. A Some featlJ'es suggest periphefaI T<.eI
1')'rr4lIlomI. NOS Horweotef. eOlnsiw CDJOellPes5lOl'l in eYefy c:eI is ctIariK::teI.sticol ALQ..ALK. (8). C l)'lT'9lOma
eels exp!e$S COO (e l and (;Of {D). tJle a \IeSSel SI.I'IOI.I'Ided by normal. smaI C03+ T<8k
318
Mature T- and N K-cell neoplasms
r,~
a_
FiJ. 1U1 EJ+ression oflhe t)'t*lxiC TGI m.1I ef1 TlAt (A) and perfom (8) II
OOterantial dlagnosis
The principle dlfferenllal diagnosis of
Al Q.,ALK.
arid phenotype are very close to those of

ALK-positive cases. with the only cnsnnc-
Genetics
The malOrity of cases shOw clonal rearrangement of the T-cell receptor (TCR)
genes, whe ther or not they express t-een
antigens.
No recurrent primary cytoqenenc abnormalities occur with any fre quency. Two
studies indicate a tendenc y of ALCl, AlKto differ (e.q. in terms of chromosome
losses or gai ns) both from PTCl, NOS
and from AlCl, ALK+, althoug h overlappin g fea tures can also be foun d 11923,
24921. Similarly, pu blished gene expression studies suggest that ALCL, ALK- has
a distinct p rofile but these results do not
p rov ide definitive evidence as to whether
the d iseas e is more closely related to
A LCL , A LK- o r to PTCl, NOS 11 37,1 24 2,
tal being the presence or a bse nce of
223 11
ALa... AlK is with PTCL. NOS. and CHL.

HiSloncalty. many cases referred 10 as
HOOgkin-like AlCl have now been recassneo as tumour cells rich forms 01
CHL With complete immunophenotypic
a'Id genetic studies. AlCl. AlK can be
distinguished from CHL in virtually all
cases, Bycontrast , the d istincti on between
PTCL, NOS and ALCL, ALK- is nOI always
cear-cu.and even experts may disagree
CI'Ithis subject. In general, the WHO Clas-
sIlica!lOl"l advocates a conservative approach. recomme nding the d iagnosis of

ALCl, ALK, only if both the morp hology
ALK. ALCl, AlK- must also be di stin guished from primary c utaneous AL C L,
;{1~h can have a similar phenotype and
rrPholog y, Clinical co rrelation with stagr,g ISot paramount importance in this d iflerenlial Primary cutaneous Al Cl has a
rruch better prognosis than AlCl, AlK-,
Postulated normal co unterpart

Ac t ivated mature c ytotoxic T-cell.
than that 01 ALCL. ALK+ 1668, 760, 21801,

There is some suggestion that there is a
plateau 01 long-term survivors (not seen III
PTCL, NOS), but this remains to be confirmed . In a recent report by the Internahonal Peripheral
Lymphoma Project
{1943A} , the clinical features of the ALCL ,
ALK+ and ALCl, AL K- have been com pa red wi th each other and wi th PTCl,
NOS. The results of this study further
highlight the outcome differences between PTCL, NOS and ALCL, ALK-. The
5-year FFS (36% vs 20%) and OS (49%
vs 32%) were supe rior in ALCL, ALKcompared to PTCL, NOS, Furt hermore ,
confining the analysis of cases of PTCl,
NOS with high CD30 exp ression (>80% of
cells), a g roup that can be d ifficult to d ifferentiate histologically from ALCL. A LK-,
mag nified the d ifferenc e in 5-y ear FFS
and 5-yea r OS ( 19% ) com pared to ALCL,
ALK-.
t-een
Progn osis and predictive factors

The cl inica l outcome of ALCL, ALK with
convent io nal therapy is c lea rly poo rer
Anaplastic large celt lymphoma. ALK-negatlve
319
Introduction
Definition
Hod gkin lymphomas (HL) share the torlowing cha racteristics: (1) they usually
arise in lymph nodes, preferentially in the
c ervica l reg ion; (2) the majority 01 them
manifest clinically in young adults ; (3)
neopl astic tissues usu ally con tain a small
number 01 scattered large rroroouciesl ed and multinucleated tumour cells
(designated Hcx:Igkin and Reed-Sternberg
celts or HA S celts) residing in an abun dant heterogeneous admi xture of non neoplastic inflamma tory an d accessory
cell s ; (4) lhe tumour cells are often ringed
by T lymphocytes in a rosette-like manner,
Hodgkin lymp homa s account lor -30% of
all lymp homas. Their absolute inci dence
has not apparen tly chan g ed . in contrast
with non -Hodqkln lymp hom as where
there has been a steady increase in incidence.
H . Stein
Subclassificati on
Biological and clinic al studies in the last
30 years have shown that Hod gKin lymphomas are c omprised of two disease
entities 133 , 573 , 1406A. 16031: nodular
lym phocyte predominant HodgKin lymp homa (NL PHL) and classical Hod gkin
lym phoma (CHL ), These two entities drtfer in their clinical features and behaviour
as well as in the composition of the ir ce rlular backqrouoo and -diagnostically
most important- in the morphology. immunophenotype and the preservation or
extinction of B-eell gene expression program. Within classical HL, four subtypes
have been distinguished: nodular sclerosis, mixed cellularity, lymp hocyte-rich and
lym phocyte-d eple ted , These subtypes
differ in their sites of involvement. clinical
features, growth pattern, presenc e of

fibrosis, composition of cellul ar background, numbe r and/or degree of atypia
of the tumour cells and freq uenc y of
Epstein-Barr virus (EBV) infection, but not
in the immunophenotype of the tumour
cells, which is the same in all four vanants A oetauec account of the historical
evdJtioo at the suOClassification at Hodgki'l
lymphoma is provided b y Mauch et al
114321 and by Anagnostopoulos et al. I331
Staging
Treatment of HL is bas ed on clinical, and
occasionally on pathological staging 01
the disease. The mod ified Ann Arbor
slaging system {132OB} is used (Table
12.01).
r. ble 12.01 Cotswold revision (l 320B) oI1he Ann Afbor stagingdasslblion (337AI.
Synonyms and hist orical annotation

This neopl asm was recog nized in the first
half of the 19th century by Thomas
Hod gkin 19471 and Samuel Wilks 12404 ,
24051. The latter named it Hodgk in disease.
The di sease was also c alled lymphog ranulomatosis, a term that is no longe r in use.
Since the orig in 01 the Reed -Sternberg
cell is known to be a lymph oid cell -most
often 01 a-ce! typ e- the term Hodg kin
lymp homa is pr eferred over Hodgkin's
disease. The mod ern classifica tion of
Hodgk in lymphoma is based on the
Lukes-Butler scheme \1344, 13451
322
HodgKin lymphOma
Stage Deflnllion
In'o'Olvemenl of a single ~ rooe regoo or IynllIloid structure (e,g. spleen, thymus, Wakleyerling).
It
Involvement of two orrrorelymph rooe regiol'ls 0fI1he same Side of the diaphragm (the med~slinum is
a sing~ site;hilar lymph nodes areIateraHzed): the number of anatomic sites shouldbe indiCatedby
suffix (e. g. I!:y,
III
Involliernent of ~h IXIde r&gion s or strllCtlJres0fI both sides of the diaphragm,
111 1 With or withoUt splenic, hilar, celiacor portal nodes
111 2 With paraaortic , iliac or mesentericnodes.
IV
Involvement of extraoodal site(s)beyond thesedesignatedE.
E, involvement01a single extranodal site,or contigOO!Js or proximal 10 known nodal site of disease.
Nodular lymphocyte predominant

Hodgkin lymphoma
S, Poppema
G,oelsol
SA Pileri
H. Stein
S,H. Swerdlow
R,A, Warnke
E,S. Jaffe
DefirWon
'b:luIar lymphOCyte predominant Hodgkin
~phoma (Nl PHL) is a monoclonal
B-ceI neoplasm c harac terized by a nodu1M, Of a nodular and diffuse proliferation
rj scat tered large neoplastic ceus known
!S poocom or lymphocyte predominant
eels (lP cells) - formerly called l&H

eels for lymphocytiC andfor histiocytic
Ud-Sternberg cell variants, These cells
esoe in large spherical meshworks 01101k;.Jar
j
dendritic cell processes thaI are
eo with roo-neoprasnc lymphocytes

01"(1 tastocv tes. One third of the cases
of
:lagnosed in the past has an NLPHl
<
.ere lymphocyte-ric h classic al HL. It is
QlITently not clear whether a purely dit-
use form of NLPHL exists. Most lesions

dagnosed in the past as diffuse LPHL
were probably r-ceu-ncn large B-eeillymecee (Te ASe l ). At present an overlap
teween NLPHL and TeRSeL cannot be
ecaoeo.
roo code
9659/3
Fig. 12.01 Nodoor lymphocyte predorrln8rI4 Hodgkin IymJtlorna (NlPHL). A Thenodules are usually 1arger1hin 1tYJse
present in follicular lymphoma andfollicular hyperplaSIa. and are closely packed and lack mantle zones. B Three
popcorn cells(ai'TOWS) with !tie typically lobated nudei areviSlbIe in a background 01 smail lymph(id eels anda lew
histiotytes. C TheCDlO staining revea ~ Itlalltle nodules oIltllsIymp/Ioma predomioarllty consisl of B-celIs, DAI hIifoer
magnilicabon. the strong membrane slllilling oIlhe popcorn cellslor COlO is visib~ ,
-~k>gy
~lPHL represen ts appro ximately 5% of
iiiKodgkin lymph oma s. Patients are prem inantly male and most freq uentl y in
te30-50 year age g roup.
~L
usually involves c ervical, axi llary

inguinal lymph nod es. Med iastinal.
sjenic and bone marrow (8 M) invo lve 1TBl! are rare,
Cl
CfricaI features
\\:lsI patientspresent with loc alized peri.
~"lefal lymphad enop athy (staqe I or II).
5-25\ of patients p resen t with advanced
iQe disease 133. 20091.
~
-~ lymph
node architecture is totally or
I3"JaIy replaced by a nodular or a nodulr and diffuse infiltrate, predominantly

IXI'lSISlII'lQ of small lymphoCytes, histio:yleS. epithelioid nlsuccvtes and interted LP cells. The latte r cells are large
I'd usually have one large nucleus and
sc ant cytoplasm . The nuclei are often

fold ed or mul tilo bated , often to such an
extreme that the y have also been termed
' popc orn" cells. The nucleoli are usually
mul ti ple. basophilic and smaller than
tho se seen in cl assical Hodgkin and
Reed- Stern berg (HRS) cells How ever,
some LP cells may con tain one prominent
nucleolus andior have more than one nucleus, and thus ma y be indistinguishable
from classical HAS cells on purely rroprological gr ounds . The d ill use areas are
main ly composed of small lymphocytes
with ad mixed henccvtes which are either
single or in clusters. The proc ess is (arely
totally diffuse . According to current criteria
the oetecnon of one nodule showing
the typicalleatures of NLPHL in an otherwise diffuse growth pattern is sufficient 10
exclude the diagnosis of a primary
Nodular lymphocyte predominant Hodgkin lymphoma
323
T-cell/hist ioeyte-rich large B-cell lymphoma (THRLBCl). Hetocvtes and some

poly clonal plasma c ells can be found at
the margin of the nodules . Neutrophils
and eosinophils are seldom seen in either
the nodular and diffuse regions. Occasionally, there is reactive follicular hyperplasia
with progressive trans formation of ge rmina l centres (PTGC) adiacent to the lesion
or it may proceed or follo'N a diagnosis of
NlPHll33, 8981. It is uncertain whether
these lesions are preneoplastic . The vast
majority of patients with reac tive hyperp lasia and PTGC do not develop Hod g kin
Fig. 12.04 Nodular ~ predominant Hodgki1Iy1f4lhoma (Nl PHl). A C~smc positMIy of the popcom
eels lor J.<:haIn is seen, B Membrane and dot./ike stairWlg in the Go9region lor epdheIiaImembrane antigen (EMA)
is .mtlle li the popcorn eels
lymphoma 1700. 16571.

Sclerosis is infrequently present in prj.
mary biopsies (7%), but can be found
more frequently in recurrences (44%).
Remnants of small germinal centres are
infrequently present in the nodules 01
NlPHl, a finding more typical of Iymphc>cyte-nch c lass ical Hod g kin lymphoma
(LACHL) 133. 6711
Immun ophenotype
lP cells are posi tive for C020 1457, 1752,
17531. C079a, C075, BC l 6 and CD45 in
nea rly all cases. J chai n 11771, 20891 is
p rese nt in the majority of cases, and
epithelial membrane antigen (EMA) in
more than 5O'lb of cases 133. 4271 (Table
12.02) , In coonast to HRSceils from classical HL, QCT2 , BOB .1 and acnvetcoinduced diaminase (AID) are coosistentty
coex oressed in NlPHl. l abeling lor ~
munoglobulin lig ht and/or heavy chains is
frequently strong 11 964 , 1965 , 20901. In
9-27% of c ases the l P ce lls are Igo.
positive 1837A, 1777,20901. Tbe exoressco
of IgD is more commo n in youn g males
(17771, l P cel ls lac k CD 15 and CD30 in
nearly all instances. However, CD3Q.
positive large c ells may be seen : these
are in most instances reactive immunoblasts unrela ted 10 the lP cells 1331. In.
frequent ly, the lP ce lls show weal;
expression 01 CD30. As revealed by thei
nuclear positi vity for Ki67 . most LP cells
are in cycle. Most of the LP cells are
ringed by CD3 -+ T cells, and 10 a lesser
extent by CDS7 + T cells.
The arc hitec tural background in NlPHL is
co mposed of large sp herical meshworks
of follic ular dendritic cells, which are predominantly filled with small B ce lls, and
nume rous C04+/C057-+ T cells /17721.
These T-cells express markers like c-MAF,
PO-1, BCL6 , IRF4/MUM 1 and CD134, <II
consistent with a subset of germ'
centre T cells. but they do not produce
TIA1. and CD4ll.
Il 2 and ll41951.
positive cells are absent, whereas
CD4 -+ICD8+ cells are relatively frequert
11804/. Immu nosl aining lor CD20 is helpful in d etec ting nodules in lesions that appear to be totally d iffuse in H&E stains.
T c ells are nume rous in the d iffuse areas
and tend to incr ease over time 1331.
A number of immunoarch itect ural pat.
tern s have b een des c ribed, including
cl assic (B-cell-rich ) nodular, serpiginious
nodular, nod ular with prominent extranodular l P cells , t-een-non nodular,
TCRBCl-like and diffuse Bcea-nch 167l)
coa.
...
Fig, 12.05 NOOuIar ~e predominant Hodgkin lymphoma (NlPHl). A Non-oeoplaslicbyslander~ b1aslS

stain lor C030 whereas the neoplastic popcorn teH(arrow) remains unlabeled. B Many non-oeopIastic bystander
T-c::eIs are labeled lorCOS7. TheseCD57+ eels may be ifNolved II !he roselle-like bilding 10the popcorn eens wtIidl
is pal'tIoAarIy pronounced in the case Iustraled here.
324
Hodgkin lymphoma
Afollicular dend ritic cell marker, such as

CD21 , is esse ntial for recognizing these
~erent patterns. A prominence of ext ranodular lP cells is associated Wi th a
propenSIty to develop a diffuse p attern
resembling T-cellJllistiOCyte -ric h large
B-cellym phoma (THRLBCL-like) . This is
seen more frequently in patients with
recurrence 167 11 . It is prob ably good
practice to labe l cases 01 NLPHL that
pattern as
pcqress to a diffuse
NLPHL, THAL BCL-like, an d d istinguish
sesefrom primar y THALBCL.
In me differential d iag nosis . p resence of
small Beene and C0 4 +/CD57+ T c ells
favours NLPHL. whereas absence of small
scets. and presence of CDB+ c ells and
TlAl + cells favours pr imary THALBCL
of ongoing mutations. The rearrangements

are usually functional and IG mANA transc ripts a re detect ab le in the LP cells 01
most ca ses 113871. Latent Epstein-Barr
virus (EBV) infection is consistently absent
from LP c ells, but may be present in bystan de r lym phocytes 1331. IGH@-BCL6
translocations have been fou nd in 5/2 4
NLPHL cases as well as in the NLPHL ce ll
line DEY 194,1 838 1and BCL6rearranga-ments (involving IG, lKA ROS, ABR etc)
(48%) 12426 1 are frequent in NLPHL
Abe rrant somatic hypermutat ions were
found in 80% of NLPHL cases. most Irequently in PAX5, but also in PIM"
RhoHITTFand MYC11 318 1.
t-een-ncb
of cas es (572, 573. 1603}. It is not clear

yet whether immed iate therapy is nec essary to ach ieve this favou rable prognosis.
There fore in some cou ntries (e.q. Franc e)
stage I d isease is not treated , especially
in c hil d ren, atte r the resectio n of the affected lym ph node {17201. Adv anc ed
sta ges have an unfa vourable prog nosis
{5731 Progression to large B-cell lymphoma-like lesions has be en reported in
ap proximately 3 -5% of cases {425. 884 ,
14761 . In some c ases OLBCL was found
to precede NLPHL {67 11. The large Been
lymphomas associated w ith NLPHL, if
kx;alized. generally have a good prognosis
18841. A donal relationship between NLPHl
and the associated OLBC L has been
demonstrated 1838, 23991. Bone marrow
invotvement is rare in NLPHL and raises
the possibility of THRLBCL in particular if
there are only C057-negative T cells and
no small B cells in the bac kground. Cases
of NLPHL with BM involvement were
found to show ag g ressive clinical benaviour1 11411.

Germinal centre B cell at the centrob laslic
stage of differentiation
Genetics
LPeells have cio nauy rearranged immunoglobulin (IG) genes 1262 , 1387 , 1627l.
The clonal rearrangemen ts a re usually
ret delectable in who le tissue DNA
but only in the DNA of isolated single LP
cells, The variab le reg ion of the IG heavy
chain genes (VH) c arry a high load of
SO'llatic mutations , and also show signs
Prognosis and predi ctive fact ors

This d iseas e develops slowly, with fairly
freq uent relap ses. It usual ly rema ins respo nsive to the rapy and thus is rarely
fatal. The progn osis of patients w ith stage
I and stage II disease is very good ; with
10 year overall survival in mo re than 80 %
~O.6
J'le 0 ,4
Q.
0.2
~o..........-
Nodular lymphocyte predominant Hodgkin lymphoma
325
Classical Hodgkin lymphoma,

introduction
Definition
Classical Hodg kin lymphoma (CHL) is a
monoclonal lymphoid neoplasm (in most
instances derived from B cells) composed
of mononuclear Hodgkin cells and multi-
nucleated Reed-Sternberg (HAS) cells reo

sid ing in an infiltrate containing a va riable
mixture of non-neoplastic small lym phocytes. eosinophils. neutrophils, tastocvtes .

plasma cells, fib roblasts and collagen
hbfes. Based on the characteristics of the
reactive infiltrate and to a certain extent
on the morphology of the HRS cells [i.e .
lacunar cells). tou r histological subtypes
have been dlshnguished : Iymphocyterich CHL (lRCHL) , nodular sclerosis CH L
"arIl~
COJO
CO"
004'
COlO
CO,"
'AX'
J chair!
I,
OCT-2
608 ,1
CO,
NlJ>Hl
-'
..,-,S
TeRBCl
-'
.,.,-
Perforin/Granzyme B
CO"
EMA
ALK
l MP1
.,-
.,-
SA Pile ri
LM . Weiss
S, Poppema
E.S. JaHe
(NSCHL) . m ixe d cellula rity CHL (MeeHL)

and lymphocyte- depleted CHL (LDCHl ).
The immunophenotypic and genetic

featu res of the mononuclear and multinu cle ate d cells are iden tical in these histological su b ty pes. whereas their clinical
featu res and association with Epstein-Barr
virus (EBV) show differences.
96SOI3
ICD-O code
Fig. 12.08 Classical HoclgkfI~ , Spleen.
E,>demJology
Classical HL accounts for 95% of all
Hodgkin lymphomas. with a bimodal age
curve in resource-rich countries , showing
a peak at 15-35 years of age and a second
CHl
.,,.,,.'
.
-'
,.'
"
-'
-'
CD'
H. Stein
G. Delsol
-'
.,-
DlSC l
ALCl,
AlCl,
AlKt
AlK-
.,
>
>
.,-
-,
.,
n.a.
n.a.
1'1&.
.,.,-
.'
.,.,-
,.-,.
,..,-
n.a.
NlPHl. nodular IympilocyIe predominant Hodgkin lymphoma: TCRBCl, T~kid11arge 6-ee11 lymphoma:CHl,
classical Hodgkin lymphoma: DlBCl, (li1l1JSe large B<eIlIymp!loma;ALCl, aflaplaslic large T-oeII lymphoma,
+an cases are posihve. +1 majOrity of cases positive, -1+ minoOty creases positive. - allcases arenegative, S
strong elpression.
' Positive in rare cases,
PnJrninenI e~ III anaplaslic variant and variable expression in mediastmallargefk:8II subtype.
s0lxaSl0I'IaI cases may show local positMIy.
Present in up1040% 01 ee cases but usuaIy expressed 01\ a rninonIyofturnourceis WIlh variable 111eoso1y,
~ Up 10 10'li.lT1lI1lt be negab...e
' The COfTVTJJIl posiIMlyb IgG and boIhIg IighI chalf1s reIIects upta ke oflhese proIeins by !he hJrnoIJ"ceIs
rather ItIan S)flthe$i$
' Slmng e.q)rMSion bJnd in - 10'J1, of tIWI cases.
' Rarecases (- 10'Ji,) may shaw scatIered 'lW8iI/I posIbvily.
, any II minOrIty is negative
II; W8ak e.qnssion may be seen in VnOur eels in 51. 01 !he cases.
" Most ~ seen in DL.BCl wiII'I anapIask IfIOIllI'Dogy
peak in late hfe. Persons with a history d

infectious mononucleosis have a higher
inc idence of CHL 115351. Both familia l and
geographical cl ustering have been desc ribed 115351.
Etiology
EBV has been postulated to p laya rote in
the pathogenesis of C HL EBV is found in
only a proportion of cases, pa rticula rly in
MCCHl and lDCHL, but a sea rch for
other viruses has been unsuccessful,
loss of immune surveillance in mmu-cd efic iency states such as HIV infection
m ay pr edispos e to the d ev elop ment 01
EBV-associated CHL. In tropical reg ions,
up to 100% of CHl cases are EBV-positi~e
!64 A, 1277A , 2369 , 2370 1. It is possible
that EBV infection of a B cell replaces one
of the gen eti c alterat ions ne cessary lor
the d ev elopment of CHL.
Classical Hodg kin lym phom a most often
involves lymph no d es of the cerv ical
regio n (75% of c as es) followed b y the
mediastinal, axillary and paraaotc regictls
Non-axia l lym p h nod e groups such as
mesenteric o r epitrochlear lym ph nodes
are rarely involved Primary extranooet
involvemen t is rar e . More than 60% ci
patient s have localize d d isea se (stage I
and II). Approx im ately 60% of patients.
Ihe m ajority of them with NSCHl, have
mediastinal involvement. Sp len ic involvem ent is not uncommon (20 % ) and IS
associated with an inc reased risk 01 extranodal d issemination. Bone marrow (8M)
involvement is much less corrmon (5'\)
_~r.
12.09 Classical Hodgkfl ~ A Mononuclear Hodgkrl eels (awws) and a rnbu:I8ated Reed-S1etlWg eel (lW1CI'tI!lead) areseee in a c:etiiIr
~ and tor\IaIIWIg hiStiocyIe$ and some eosirophis. B Onerrumified Hodgkil OlIIlamJw) rod w VItal Hodgkn eels can be seen.
As !tie 8M lacks lymphatics. 8M infiltration

ooc ates vascular dissemination of the
disease (stage IV). The anatomic distei:Moo varies among the histological sub~s of HL
120091.
ClircaI features
Patients usually present with pe ripheral
~thy, localized to 1 or 2 lymph
~e-bearing
areas. Med iastinal involve-
ment is most freq ue ntly seen in the nodular

sclerosis subtype, while abdominal and
splenic involvement are more common in
mxedcell ularity. B symptoms co nsistin g
c tever. drenc hing night sweats, and signkant body weight loss are present in
up1040% of patients.
Macroscopy
Lymph nod es are enla rged , encapsulated
and on cut section show a fish flesh

tumour, In NSCH L there is p rom inent
l'JOdularily, d ense f ibroti c bands and a
thickened ca ps ule. Splenic invo lvement
usually shows scatte red nodules within
tile wt1i te pulp . Sometimes ve ry larg e
Masses are seen, these can demonstrate
fibrous bands in the nodular sclerosis

subtype. Classical HL in the thymus can
be associated with cystic degeneration
and epithelial hyperplasia 113131. Aare
cases can be confined to the thymus.
-logy
The lymph node architecture is eHaced by
variable numbers of HRS cells admixed
with a rich in"arrvnalory background. Classical diagnostic Reed-Sternberg (AS) cells
are large. have abundant slightly basophilic cytoplasm and have at least two nuclear lobes or nuclei . The nuclei are large
and often rounded in contour with a prom inent, often irregular nuclear membrane,
pale c hromatin and usua lly one prom inent
eosinophilic nucleolus , w ith perinucle ar
clearing (halo), resemb ling a viral inclusion.
Diagnostic AS ce lls must have at least two
nuc leoli in two sep arate nuc lear lobes.
Mononucl ear variants are termed Hodgkin
ce lls. Some HA S cells may have conde nsed cyto plasm and pyknotic red dish
nuclei. These variants are known as mummifie d cells. Many of the neop lastic cel ls
are no t proto typic HRS cells. The lacunar
rid! n
AS variant is characteristic 01 nodular sclerosisHL.

The reccasrc cells typically represent only
a minority of the cellular infiltrate With a frequency ranging from 0.1- 10%. The c0mposition of the reactive cellular infiltrate
varies according to the histok:lgical subtype.
Involvement of secondary sites (8M and
liver) is based on the identification of atypical mononuclear (CD3J-pos;live Hodgkin
cells with or without CD15 expression in the
appropriate inflam matory bac kground );
thus diag nostic multinuclear AS cells are
not required in a patient with classical HL
diagnosed at anothe r site 11 8 19AI.
Irrvnunophenotype
H AS cells are positive for CD30 in nea rly
a ll cases 11 97BA, 2088, 209 1/, and for
CD 15 1987, 209 1, 2092] in the ma jor ity
(75-85%) of cas es and are usually neg ative fo r CD 45 and co nsistently negative
fo r J c hain, CD 75 and macroph age spec ific ma rkers suc h as the PG-M 1-epi lop e
of the COB8 molec ule 1427. 662A ) (Table
12.02). Both CD3Q and C01 5 are typ ic ally
present in a mem brane pattern with
Classical Hodgkin lymphoma. introductlOl1
327
accentuation in me GoIgi area 011he cytoplasm; C0 15may be expressed by only a

minority 01 the neoplastic cells and may
be restricted only 10 the Golg i area. In
30- 40% of cases. C020 may be detectable but is usually of varied intensity
and usually present only on a minonty of
the neoplastic cells 11964. 25071 . The
8 -cell-associated antigen C079a is less
often expressed. The B-cell nature of HAS
cells is further demonstrable in approximately 95% of cases by their expression
of the s-een specific activ ator protein
PAX5!BSAP 17231 - The immunostaining of
HRS cells for PAX5 is usually weaker than
thai of reactive B cells . a feature that
makes the PAX5-positive HAS cells easily
identifiable. The plasma cell specific transcription factor IAF4/MUM1 is consrstenny
positive in HAS cells, usually at high intensity, In one study, BLiMP1, the key regulator of plasma ce ll differentiatio n, was
expressed in on ly a small proportion of
HRS cells in 25% of CHl 12941 . The
plasma -cell -assoc iated adhesion molecule CD 138 is consistently absent 12941,
EBV-infected HRS ce lls exp ress lMP1
and EBNA-1 without EBNA-2, a patt ern
characteri stic of latency typ e II EBV
328
HodgkIn lymphoma
infection 15521. EBV-encoded LMPl pos sesses strong transforming and annapootonc potential.
Expression (usually weak membranous or
sometimes globular cytoplasmic) 01 one
or more t-een antigens by a minority of
HRS cells may be encountered in some
cases 1504 /. This is, however. often difficult to assess because of the T cells that
usually surround the HRS cells . Most of
the T-cell antigen-po sitive classical HL
cases have IG gene rearrangement in the
HAS cells instead of t-een receptor gene
rearrangement. so that the expression of
t-een antigens is either aberra nt or artfactual \19871. Expression of epithelial
memb rane antigen (EMA) is rare and usually weak if present. A further characteristic finding is the absen ce of the
transcription factor OCT-2 in - 90% of
cases and absen ce of its coactivator
BOB,1 in the same frequency. Cases in
which both OCT-2 and BOB.l are ccexpressed are rare 113281, The transcr iption factor PU,1 is consis tently absent
from HRS ce lls 11328, 2250A). Most HRS
cells express the proliferation-associated
nuclear antigen Ki67 1775Cl.
CHl cases rich in neoplastic cells may
resemble anaplastic large cell lymphoma

(ALCL), a T-cell neoplasm. Their identJlication as classical HL is facilitated by
demonstrating positivity for PAX5 and absence 01 EMA and ALK protein 1723,
20871. The detection 0 1 EBV-encodea
RNA (EBER) or LMPl is indicative of classical HL 1992AI_The most difficult dillerenter diagnosis is with large B-cel
lymphoma displaying anaplastic morphology and expressing CD3O. There may be
a true biologic overlap between such
cases and CHL (See Chapter 10).
Cytokines and chemokines
CHL is associated with overexpresson
and an abnormal pattern of cytokines and
chemokines and/or their receptors in HAS
cells 1919, 962A. 1080, 1081, 11 08. 2293).
which likely explain the abundant admixture of inflammatory cells P067, 21861.
fibrosis 110801. and the predominance at
Th2 ce lls in the infiltrating t-een population 122931.
Genetics
HRS cel ls contain clonal immunoglobulin
(IG) gene rearrangeme nts in more than
98% of cases. and clonal r-ceu receptor

gene rearrangements in rare cases 11105,
1388.1553. 1987,20861 The clonal rearrangements are usually detectable only
in the DNA of isolated single HRS cells.
and not in wh ole tissue DNA. The rearranged IG genes of the tumour cells
harbour a high load of somatic hypereuatcos in the vanaore region of the fG
teavy chain genes (IGHVtI), usually wuhC'JI signs of ongoing mu ta tions. These
tr1dings. in conjunction wi th the study of
CO"TllQSIte lymphomas c on sisting of etasseal Hl and loIli cular non -Hodgkin lym:tuna . support the view that HAS cells of
B-cel lineage are derived from a germinal
cenlre BceU 1261A. 1387AI.
AL:notmaI gens expression

Oespte their derivation from germinal
centre B cells. HAS c ells have lost much
j eeB-eett speci fic expression program
and have acquired B-cell inappropriate
gene produc ts [636A . 1205A . 1388A.
14 1M. 1977A. 2090 . 1047AI. ln addition .
oeregulated transcription fac tors in CH L
P"OITIOte pro nteranon and abrogate apopese in the neoplas tic cells. The nanscnoton fac tor NF"B is constitutively
activated in HRS cells. and there is el\ered activity of the NFKB targ et genes.
which regulate proliferation and survival
1938A. 9388 . 962Al. the AP-1 complex
11416A. 1416B) and the Janus kina se/SIgnal transducers and activators 01 transcrption (JAK/STAD signaling pathway
12030Aj. Mutati ons of the JA K reg ulator
SOC- l are assoc iated with nuclear STAT5
accumulation in HRS cells . indicati ng a
bockage of the neg ativ e feed bac k loo p
cHheJAK!STAT5 pathw ay 11 070A, 1459A .
fig. 12.13 0assicaI HodgkIn ~ A EBV infected HRSceIs suongIy eapress!tle EBv~ 1alenI~
proIein 1fLMP1). B EBV4lf8ded HRS cells consistently ihow a 5trr6lg e~ of EBER il \llei' ~ as revealed
by l'lOIHadio<lcti il situ hybimalion.
observed in HRS cells in 17% of CHl
Genetic abnormalrlies and oncogenes

Despite the frequent overexoreeecn of
p53, mutations of TP53 are rare or absent
in primary CHL tissue . although they have
been observed in Hodgkin cen lines 1700A.
1504 1. Conventional cytogenetic and Al.Il>
rescence in situ hybridization (FISH) stud ies show aneuploidy and hypertetraploidy.
consistent w ith the multinucleation 01 the
neoplastic cells; however. these techniques fail to demonstrate recurrent and
specific chromosomal changes in classical HL 11935,19601 . Comparalivegenomic
hybridisation, however, reveals recu rrent
gains of the chromosomal sub-regions on
ch romosomal arms zp. so. and 12q and
d istinct hig h-level amplifications on ch romosomal bands 4p1 6 . 4q23-q 24 and
9p23-p24 11071]. Thetranslocalions t(14;t 8)
an d t(2;5 ) are abse nt from HRS cells
1831. 12441 but 1(14; 18) may occur in CHL
arisi ng in follicular lymp hom a 11561AI. In
a recent study using interphase cytogenetics
breakpoints in the IGH@ loc us were
cesesttaatzq.
In more than 98% of CH L. the neoplastic
c ells are derived from mature B cells at
the germinal c entre stage of differentiation { 1105. 13881. In rare cases. they are
derived from peripheral (post-thymic ) T
cells 1514.1553. 1987 1.
Prognosis and predicti ve factors
Modern rad iation and chemotherapy
have made CH L curable in more than
85% of cases 1462A. 571AI Staging determ ines the mode of therapy. and both
clinical and laboratory pa rameters are relevant to prognosis 19041. The response
after two courses of ABVD as seen on
FOG -PET imaging is an important prognostic ind ica tor 1748A] Histo log ic subtype is less important as a p redictive
fact or 125. 10761.
23881
Epstein-Barr virus infection
-he prevalence of EBV in HRS ce lls var ies
according to the his tological subtype and
epidemiologic factors . The highest fre~iJency {.75 %) is found in MCCH L. and
ee cwest incidenc e ( 10-40%) in NSCH L
1992AI. In resou rce-poor reg ions and in
pa:ients infec ted with the human immune
delIClency virus. EBV infection is more
p-evaIenl approaching 100% 164A, 1277A,
2369.23701. The type of EBV strain also
enes among geographical areas. In resarce-rich cou ntries strain 1 p revails ,
i'ld in resourc e-poor countries strain 2.
~ 0081 infection by both strains is more
c:onmn in resource-poor countries 1280.
00.23701.
100
BEACOPP
80
COPP.ABVD
60 t - ---y-- ' < - - --
- - - -f I QQQ Q3)
onlyalkylating
(IQiS)
40
20
no treatment
(1940)
5 years
Fig. 12.1 4 HoclgIoo tymp/loma. Progress oflhe natrnent of advarad Slages since 1940.
ClassiCal HodgkIn lymphoma. in troduction
329
Nodular sclerosis classical

Hodgkin lymphoma
H . Stein
A. von Wasiele wski
S. Pop pema
KA Mac l ennan
M. Guenova
Definition
Nodular sclerosis classical Hod gkin lymphoma (NSCHL) is a subtype of CHL
Characterized by collagen bands that surround at least one nodu le, and HOdgkin
and Reed-Sternberg (HRS) cells with
lacunar type morphology
ICD-Ocode
966313
Epidemkllogy
NSCHL accounts for apprOl(imately 70%
of CHL in EuroPe and USA ; rcwever. the
rate varies greatty among other geographiCal reg ions: II is more common in
resource-rich than in resccrce-occe areas .
and the risk is highest amon g those with
high socioeconomic status 14451. The incidence of NSCH L is similar in males an d
females and peaks at ages 15-34 years
11 01 . 1525A I.
r'lJ. 12.15 Nol1JIa' sdetosis dassicaI Hodgkll ~ ACTscan shcM$ a Ia'ge<Illeri:Jr mEdastlnaI mass. B0lIll
X-ray d ltle samepatient shows mecIia$bnal massel ceedKlg CJIl&oltwd of!he chest diameter.
Med iastinal involvement occurs in 80% of
cases, bulky disease in 54%, splenic
and/or lung involvement in 8-10%. bone
involvement in 5%, bone marrow (BM)
involvement in 3% and liver invol vement
in 2% 1456. 20091.
Clinica l fea tures
Most pat ient s p resent with Ann Arbo r
stage II d isease. B symptoms are encounte red in approxima te ly 40 % ot c ases
120091
Morp ho logy
lymph nodes have a nodular g rowth pat tern , with nod ules surrounde d by collagen bands (nodul ar sclerosis). The broad
fibroblas t-poor coll agen ban d s surroun d
at least one nodule . This fibrosing process
is usually associated wi th a thick en ed
lymph node capsule. The lymphoma contains a highly variable number of HRS
cells . sma ll lym phoc ytes and othe r nonneoplastic inflammatory cells. The HRS
cells tend 10 have more lob ated nuclei
with smaller lobes. less prominent nucleoli. and a larger amount of c ytop lasm than
in other types of CHL In formalin-tilled
tissues the cytoplasm of the HAS cells Ire330
HodgkIn lymphoma
fig . 12.16 Nodularsclerosisdassical Hodgkin lymphoma

B 5everal lacunar cells (arrowed) are present.
quently shows retraction ot the cyto plasmic me mbra ne so that the cells see m to
be silting in lacunae. These ce lls hav e
the refore been de signa ted lacunar ce lls.
lacunar c ells may for m ce llular ag gregates . whi ch ma y be associ ated with
necrosi s and a histioc yt ic reaction. resembl ing nec rot izing g ranuloma s. When
agg reg ates are very prominent. the term
"syncyti al variant" has bee n used . Eosinephils, htsnoc vres. and to a lesse r exten t
neutroph ils, are often numerous 117431
Gra d ing ac c ord ing to the proportion of
HRS c ells or the characteristics 01 the
back groun d infiltrate (such as the number
of eosmo pbns) may predict prognosis in
some settings. b ut is not req uired for routine c linical p urpo ses 1936. 1356,2307.
2341AI: it may serve a research purpose
in protocol studies.
Immun op henotype
The mal ignant cells exhib it the CHL
ph enotype (see Introduction ): however.
associ ation with Epstein-Barr virus (EBV)
as demonstrated by EBEA or the EBV encoded lMP1 is less frequ ent (10-40%)
than in m ixed c ellul arity CHl 1918A.
919A, 237 4A. 23 77AI.
Prognosis and predicti ve factors
NSCHl has a better prog nosis overej
than that 01othe r types of CHl1251. Massive med iast inal disease is an adverse
p rog noshc fact or 120621.
Mixed cellularity classical

Hodgkin lymphoma
L.M . Weiss
R. von Wasielewski
G Detsol
S. Poppema
H. Stein
Definition
.,heel cellularity classical Hodgkin Iymecre (Me e HL) is a sub type of c lassic al
Hodgkin lymphoma (C HL) w ith scattered
classical Hodgkin-Read-Sternberg (HRS)
cells in a diffuse Of vaguely nodular mixed
~tOfY bac kground without nod ular
sclerosing fibrosis. C ases wh ic h d o not III
Ino !he other subty pes are pu t in this cal"PY.
965213
iology
The mixed ce llularity subtype comprises

approximalely 20-25% of CHL. MeeHL
is more freq uent in pat ients with HIV in'ecton and in developing co untries. A
bimodal age distribution is not seen. The
reoen age is 38 years and approxi'Mlety 70% are male 120091.
Siles 01 involvement
Peripheral lymph nodes are frequently
evolved and mediastinal involvement is
uncommon. The spleen is involved in
m . 8M in 10%. liver in 3% and other
opens in 1- 3% 14561.
Clir'l ical features

Bsymptoms are frequ ent.
Morphology
The lymph node architec tu re is us ually
Dbliterated although an inte rfol licular
growth pattern may be seen . Inte rstitial
".
Fig. 12.17 Milled celkllanly subtype of dassical Hodgklll~ . COJO.negatiYe ~, wrlh a prtIIIJUIICed
epithelioid dilrerenbatlon forming cilsters. predominate. The CD30 imrTlJl'lOSlaifIing ~ ee presence d a large
Reed-Slemberg cell and a sma. Hodgkin eel.
fibrosis may be present , but the lym ph

node capsule is usua lly not thickened and
there are no broad bands of fib rosis as
seen in nodular sc lerosis Hod g kin l ymphoma. The HAS cells are typical in appearance. The bac kg rou nd cells consist
of a mixture of cell types, the composition
of whic h varies greatly. Eosinophils, neutrop hils, histioc yte s and p lasma c ells are
us ually p resent. O ne of these cell ty pe s
may predominate. The t ustrocvtes may
show pronounc ed ep ithe lioid featur es
pa rticu larly in Eps tein- Bar r virus (EBV)associate d cases 15521 and may for m
g ranuloma- like clus ters or g ranulomas.
Immunophenotype
The ma lignant cell s exh ibit the CHL immunoobenotyoe : however, the EBVencoded lMP1 and EBEA are expres sed
muc h more frequently (approx imately
75% of cases) than in nodular scleros is
and lymphocyte-rich CHL 133).
Prog nosis and pred ictive factors
Before the introduct ion of mod ern therapy,
MCC HL had a worse p rog nosis than
nod ular sc lerosis and a better prognosis
than lymphoc yte-de pleted CHL. With current reg imens, these d ifferenc es have
targely vanished although rot entirely [251.
F'i- 12.1. lobed ~ MtItype of dassicalliIldgUl ~_ AThe nixed teUJr I'llitrate does nolconlaIn fIbrotIC bends.
IIIIIlld ceII.Mr rilltrate wiCI'I ~. IJIilO'OI)hageS and ~ is 'tiSibie
Mixed cellularity ciasscat Hodgkin lymphoma
331
Lymphocyte-rich classical Hodgkin

lymphoma
Definition
lymphocyte-rich classical Hodgkin lymphoma (LRCHl) is a subtype 01 classical

Hodgkin lymphoma (CHL) with scattered
Hodgkin and Reed-Stenberg (HAS) cells
and a roouiar or less common diffuse cellular background consisting of small
lymphocytes and with an absence of
neutrophils and eosinophils.
Epidemiology
l RC Hl comprises approximately 5% of
all CHL. in similar frequency to nodular
lymphocyte predominant Hodgkin lymphoma (NLPHl). The median age is similar to NlPHL and signJlicantty higher than
in other subtypes of CHL 15731. There is a
male predominance (70%) 120091.
ICD-Ocode
332
9651/3
Hodgkin lymphoma
Peripheral lymph nodes are typically involved . Mediastinal involvement and

bulky disease are uncorrvnon 1573, 20091 .
I. Anagnostopoulos
PG, Isaacson
H . Stein
Clinical'eatures
Most patients present with stage I Of II
disease. B symptoms are rare. The clinical features are similar to those of NlPHL
with the exception that multiple relapses
seem to occur less frequently 15731.
Morphology
There are two growth patterns: a corrmon
nodular one 133. 901 and a rare diffuse
one 1331. The nodules of the nodular vanant encompass most of the involved
tissue so that the T-zone is attenuated
The nodules are composed of smail lymctocyl:es and may harbour germinal ceores that are usually ecc entrically located
m relatively small or regressed . The HAS
cells are predomina ntty found within the
nodules but consrstennv outside of the
germinal centres. A proporti on of the HAS
cells may resemble l P ce lls or mononudear lacunar cells. This subtype can easily
be ccofuseo with the NlPHL. In the past.
approximately 30% of cases initially diagnosed as Nl PHl were lound to be
LRCHL j33l. The demonstration of an immunophenotype typical lor classical HAS
cellsisessential in making this distinction ,
Icsnopbus and/or neutrophils are absent
from the nodules and if present they are
located in the Inteetoutcurer zones and
are low in number, In rare instances , the
lRCHl-typicaI nodules may be SlJJOlXlded

by fibrous ba nds assoc iated with randomly distributed HRS cells in
zones, Typ ing of these cases as nod ular
sclerosis cla ssical Hod gk in lymphoma
(NSCHl) mig ht be more appropriate. In
some cases, seque ntial biop sies have
shown NSCHl imp lying a possible relationship between the two subtypes 01
CHl and this is further inferred by the
finding of HRS cells within expanded follicular mantle zones in some cases 01
NSCHl jl 01 1AI. A coe xistence oflRCHl
and mixed ce llularity classical Hodgkin
lymphoma (MeCHl ) occurs but is rare. In
diffuse l RCHl ca ses the small lympho c ytes of the cellular background may be
admi xed with histiocytes with or without
epithelioid features.
t-een-nett
,.
1~100)
U'H.
00
..
~r 1W2 ."'~ )
00
..
..
00
r,
-----
NSMCA.O (12$12....7)
J ..
00-
00-
1IlCK.1~100)
1.51
1~
The distinction 01 l ACHl Irom NLPHl is

possible by immunophenotyping in all i~
stances 1331. The atypical cells in LRCHl
stlCM' the sameirrYrulophenoty (CD30+.
CD15+/ , CD20-/+ , CD75- , J cnein-) as
the HAS cells in the other subtypes of
CHL. The small lymp hocyt es present in
the nodules display the features of mantle
cells (l gM+D+). Thus the nodules predominantly represent expanded mantle
zones . At least some of them cont ain
eccentrically located . usually small, germinal cen tres which are highlighted by a
dense meshwork of CD21+ follicular dendr itic cells, As intact germinal centres are
infreq uent in NLPHl, this feature is helpful in differential diagnosis . CD15+ granulocytes are abse nt from the expanded
mantle zones but may be present in low
numbers within the otertoncuar zones. In
the rare diffuse subtype the lymphocytes
are nearly all of t -een type with CD15+
granul ocyt es and eosinophils being absent. These features fac ilitate the differentia tion of l RCHl from MCCHl. EBV
lMP1 expression is seen more frequently
than in NSCHl bul less frequently than in
MCCHl j33 l.
With modern risk-adjusted treatment, survival and prog ression free survival are
slightly better than in the other subtypes
of CHL and similar to that of NlPHl exce pt thai relapses are more common in
NlPHl than in l RCHll33, 573, 20091.
1121 A 0eraI suMYaI byMldogIc SIbyplt. B 0YeraI evenl-Iree SU'\'MI by Ii:skllogic ~ {2OO9}.1..RCHL.
~dassblHodgkrI~ :l.PH.,~~~ ,MC ,nued~ ,
\'S.1IXUar sdIllrosi$; LD, ~ depletion.
lymphocyte-rich classical Hodgkin lymphoma
333
Lymphocyte-depleted classical
Hodgkin lymphoma
D. Benharroch
H . Stein
S.-C. Peh
Definition
If a nodular sclerosin g fibrosis is present,

the disease should be assigned to nodular
sclerosis Hodgkin lymphoma.
lymphocyte-depleled classical Hod gkin

lymphoma (LDC HL) is a diffuse subtype
of classical Hodgkin lymphoma (CHL) rich
in Hodgkin and Reed-Stenberg (HRS)
cells andlor depleted in non-neoplastic
lymphocytes. The deflnitiorl 01LDCHL has
undergone several changes in the past

few decades with the result mattre body
01 reliable clinical data on this SUbtype is
limited , Since a proportion ollhese c ases
have been reclassified into differen t 1ymphoma entities , the previously described
clin icopathological coretatioos are 001
necessarily tenab le ,
ICD-O code
965313
Epidemiology
This is the rarest CHL subtype 1% of
cases in Western countries). 60-75% of
patients are male and the me dian age
ranges from 30-37 years 125, 20091 . This
subtype is often assoc iated wi th HIV infectio n and is seen mo re often in developin g countries {80S, 23 171.
Siles of involvement
LDCHL has a pred ilec tion for retroperitone al lymph nodes, abdominal organs,
and bone marrow.
Clinical features
l DCH L pr esents at a mo re advanced
stage (Ill-IV) and with B symptoms than
the other subtypes (1585, 2OO9}.
Mo<phology
Although the appearance of lDCHl is
highly variable. a unifying feature is the
relative predominance of HAS cells in
relation to the background lymphocytes.
One pattern may resemb le mixed cellularity but com pa red with increased numbe rs of prototypic HAS cell s. In some
cases, pleomorphic HAS cells may pred ominate, producing a sarcomatous appearance. These c ases may be ditticult to
differentiate from anaplastic forms of
large cell non-Hodgkin lymp homa
Anot her patter n is ch aracterized by diffuse fibrosis with or without a p roliferation
of fibroblasts an d only a few HA S cells.
Immunophenotype
The HAS cells show the same immunephenotype as in the other subtypes 01
c lassica l HL Most HIV + cases are EBV
infected and stain positively lor lMPl
1932.2020.22761. Coexpression 01 CD30
and PAX5 is very helpful in differentia ting
lDCHl from AlCl, ALK- .
Prior to modern therapy, the course 01
lDCHl was aggressive and it has remained so in some parts of Europe 125,
17821 and in developing countries . In the
US and UK, the course is comparable 10
other CHl subtypes of similar stage , Poeprognosis is seen in Hrv-rerateo lDCHL
patients.
Lymphoproliferative diseases associated

with primary immune disorders
De finition
Lymphoprouterauve diseases (LPD) associ ated with prima ry immune d isord ers
(PID) are lymphoid proliferatiOns that arise
as a result of illYTlune deficiency due to a
pr imary immunodeficiency or immunoregulatory c nsoroer. Because the pathology and pathogenesis of the more than
60 PIOare hete rogeneous. the manifestations of the Iymphoproliferalive diseases
are Ijghly variable. The PlD most frequently
assoc iated with LPD are ataxia telangiectasia (AT), WISkOll:-AIdrdl syndrome (W~),
oomr<Jnvariable_(CV1D),
severe ccrooec rrm.n:xJeficiency (SClD),

X-linked Iymphoproliferatrve disorder (XLP),
Nijmegen breakage synd rome (NBS) ,

hyper-19M synd rome and autoimmune
Iymphoprohleralive syndrome (ALPSl
Epidemiology
Age -sp ecific mo rtality rates for all neoplasms in patients WIth P1D are 10-200 limes
the expec ted rates lor the general po p utenon. Howev er, g ive n that PIO are rare
disorders . the overall occurrence of PID
associated LPD is low With the exception
of CVID . these di seases present primaril y
in the paediatric ag e group . They are
more common in male s than fema les, primarily because severa l of the primary
genetic ab normalities are X-linked, e .g
XLP, SCIO and hyper-lgM synd rome 110631,
Etiology
The c ause of the LPO is related to the underlying primary immune oetectl tsoa].
Epstein-Bar r viru s (EBV) is involved in the
majority of PIO-associated lymp hoi d proliferations [23021, In these cases, defective
T-ce ll immune surveill ance to EBV is believed to be the pr imary mechan ism 1935,
17881. The absence 01 T-cell control may be
complete. resulting in fatal infectious m0nonocieosrs. or partial. resulting in other LPD
in the g ene for C040 or CD40 ligand .

which affect inte ractions between
and B-cells. and impair effective differenti ation of B-cefls into class-switched
p lasma c ells 110081
In autoimmune iym onoprouteranve syndrome (ALPS). mutations in the FAS or
FASL gene (and rarely other abnormalities)
may contribute d irectly to lymphoid prolif.
erations through the accumulation of lymphoid cells tha t fait to undergo aocotosrs.
resulting in the accumulation of CD4 and
COB dou ble negative cells in the penphefal
blood (PS) and lym phoid tissues 11300.
20421. In AlPS, tile severity of the apoptotic d efect correlates directly with the risk
01 d eve lo pment of LPD 1104 11. The importance of FA$ mu tations in ca using
LPO is supported by the tact that sporad ic FAS mutation s are associated with
lymphomas in the absence of immune
abnormali ties 16551.
In AT. an abnorma l DNA repair mechanism due to mutatio ns of the ATM gene
ca n co ntribute to the d evelopment of lymphoma . leukaemia an d other neoplasms
16381. In these patients, nonleukaemic
t -een clones c an be d etected in the PB
that have lranslocations involving the TeR
genes similar to those seen in ove rt
leukae mias.
NBS also resul ts from defects in DNA
repair du e to muta tions in the NBS 1 gene ,
resulting in many chromosomal breaks and
transrocatrons. includ ing tho se in antigen
receptor genes. In pa tients with NBS, LPD is
J,H. Van Krieke n

M. Onciu
K S.J . Erenrtcoa-Jormson
E.S. Jaffe
t-eens
the mostcommonneoplasm 154,339, 23141.
hyperplas ia may occur in the lung and

gastrointestinal trac t \1929\. a setting In
which more aggressive LPD or overt 1ymp hom a may develop 15591.
Presentation is dependent on the underlying d isease. More often. LPD present in
extranodat sites. most commonl y the gastrointestinal tract. lung and central nervous system (CNS).
Clinica l features
Patients often present w ith symptoms resem bl ing those of infectio n or neoplasia
{i.e. fever. fatigue, infectious mononucleosislike synd romes), In some d iseases. such
as ALPS and XLP, the lymphoid proliferation is the first sig n of the underlying immune d efect. but in most patient s, the
d iag nosis of PIO has already been establish ed becau se of other manifestatioos.
In patients with CV IO. marked lym phoid
11042/
WAS is a complex immune d isord er. w ilh
defects in function of tceas. Beene. neutrophils and macrophages. T-cell dysfunclion
is significant . and tends to increas e in
severity d uring the course of the di sease.
Hypef-lgM syndrome results fran rTUtations
336
Fig. 13.B2 DiltLJse largeB-alIIymphoma II a pabenI WIth Ionp-slaodIng carmon ariabIe InrTulOdefiOelq ~
A l~ eels ant seetl ll asates IUd nt show marked pleoITuptlisnl. B L~ eels are EB'V---poslIM t,
EBER'" situ hybrWaticwl.
Irrmunodefic iencyassociated Iymphoproliferative disorders
C Pa-ar::or1lCal T eels show
~
.I.s In other immune deficiency slates.
n
,.
,.
~d prolifera tions in patents with pri-
rr.ary immunodeficiency inc lude reactive

~rplasias.
ia
polymorphous lymphoid
(M/alessimilar to those seen in Ihe post1arsplant setting, and frank lym phom as
tat do not differ from those in immunoerroeient hosts, The type and frequency
eech lesion differ among the PIO (Table
s-
1301),
,.
,h
a-
,e
b
/lori-neoplastic lesions
Crmary EBV infection in PIO may result in
fatal infectious mon onuc leosis (FIM) ,
curacterized by a high ty polymorphous
~,iferation of lymphoid ce lls showin g
ecerce of plasmac ytoid and immunetesc ditlerentiation . Reed-Sternberg-like
::etslllay be seen. This cond ition is prirrarly seen in patients with XlP (Duncan
~rome) [BOOI and SCID 11 7881. The
noma! a.cell pr onteranon is systemic,
'ldYi"g both lymphoid and non-iymphoid
~. most corrmor"lly the terminal ileum,
rlaer"cphagocytic syndrome is frequent,
Rl 'SlT'OSt readily identified in bone ma r(BM) aspirates. In CV IO, waxing an d
IymphoprOliferations ma y occur in
rcoes and extranocar sites, with
morphology including follicula r
IflerpIasia, and paraco-ncat expansion
wi th m any EBV-positive cells. often

including la rge atypical cells . that may
res em bl e Reed-Stern berg cells. CV IO is
c haracteriz ed b y nodular lymphoid
hy per pl asia in the gastr ointestion al tra c t;
VJ- PCR may detect clonal B-c ell populations tha t ar e self-lim ited 11 256 . 19291,
In AL PS. expansions of double-negative
(CD4-/CDB-) a lph a beta CD 45 RA +.
CD45RO- T cel ls in PB . lymph no des.
spleen and othe r ti ssues are the hallmark
of t he d isease. T-cell expan sion can be
ve ry ma rked, and the T-cel ls may hav e
slig htly immatu re ch romat in, wh ich ca n
lead to a m istaken diagnosis of T-c eil lym phoma especially when , as is usual , lhe
patient does not c arry a pre exi sting d iag no sis of A LPS (13001. Follicular hy perplasia is often prcrn inent, and prog ressivel y
transform ed g erm in al centres may be
seen 113001.
Hyper-lgM syndrome is c har ac terized b y
c irc ulating PB B-cells that bear only Ig M
an d IgO. G erm inal centres are absent in
lymph rooes . Ig M-producing plasma cells
often accumulate , most commonly in extranodal sites , such as the gastrointestinal
tract, liver and gallb lad der. These lesions
ma y be so exten sive as to be fatal, withoul
p rog ression to clonal LPD.
Lymphomas
Lymphomas occurring in patients with
PIO do not genera lly d iffer in their morpholo gy from those occurrin g in immunocompetent hosts.
Lym phom atoid g ranulomatosis (LYG). an
EBV-driven proliferation of B-cells assoc iateo with a ma rke d t-een mtntratlon. is
inc rea sed in fre q ue nc y in patients with
WAS { 1003) (See Chap ter 10), The most
com mo n si tes of involvem ent ar e lung,
skin, brain and kid ney,
Diffuse la rge B-ceillymphoma (DLBCL) is
the mo st com m on type of lym phom a seen
in PIO in general; Hodgkin and Bur kitt
lymp ho mas 1224 11 an d peripheral r-celt
lym p homas also occur [ 17291, In AT, and
10 a lesser ex tent in NB S,
lymphomas an d leukaemias are mo re common than B-cell neoplasms 121641. Rare
cases of lru e pe rip he ral T-een lymphoma
have been se en in patients with ALPS
11729 . 21 08 1. Both T lymphoblastic Iymp homaaeukaerma (T AllJlBl) and T-cell
p rolym phocyt ic leukaemi a (T-PLl) have
been reported in PID.
t-een
Hodgkin lymphoma
Hodgkin lymphoma-like Iymphoproliferalions resembling those seen in the setting
01 methotrexate therap y as well as LPO
wilh all morphological and phenotypic
Lymphoproliferative diseases assocetec With pnmary immune disorders
337
fig. 13.05 Reactive ~ node from a pabenl with ALPS. A There is prominent parac:ortlcal expansion. B ALPS tynllh node. Reaclive geminaI centres eve present and tle
C The ceb are slqllIy Ia'gerthanIIOITIIaI smallyrnphocyte$. wilh dispersed dYoma\Jl.
parac:or1eX is expMded.
features of classical Hodgkin lymphoma

has been reported in patients with WAS,
and AT 1638. 19091. In ALPS , nodular 1ymphocyte predominant Hodgkin lymphOma,
classical Hodgkin lymphoma and t-eenrich large Bccel! lymphomas have been
described 113001.
In cases showing evidence of plasmacytoid differentiation, monotypic cyloplasmic

irrmunoglobulin (Ig) may be identified
The immunophenotypes of the specnc
B-and Teen lymphomas in PID do not differ from those of the same lymphomas in
immunocompetent patients
Precursor lesions
The underlying primary immune disorder
is the principal precursor lesion leading to
the development of LPO. This morphological spectrum is accompanied by an increasing dominanl ccoar poputanoo: from
clearly poivcionel. to oligoclonal to mono-
Genetics
Since lPD in PID is a spectrum from reactive to aggressive Iymphoproliferalloos lhey
can be polyclonal, oIigoclonal or m0noclonal. FIM is generally poivcionai: overt
lymphomas such as OlBCl or Bunott 1ymphoma have clonal immunoglobulin heavy
and light-chain gene rearrangement 1638,
1256 . 19291. Presently there is only limited
expe rience with
clonality tests in the
selling of PID.
clonal. However, monoclonal expansions,

particularly if they are minor clones. do not
necessarily progress 10 major persistent
clonal lesions 112561.
t-een
tmmunophenotype
Non-neoplastic proliferations
In ALPS. there is expans ion of a d istinc tive
CD 3 + CD4- CDB- CD45R A+ C045 ROnatve t-een pop ulation in the PB and BM,
The T cells ma y exp ress C05? but not
C025 Inc reased nu mbe rs of CD5+ polyc lonal B cells may also be seen ( 1300)
Hyper-lgM syndrome is cha racterized by
PB B cells tha t bear only Ig M and IgO.

Genet ic alte rations may b e di rectly related to the p rima ry immune defect. suc h
as FAS gene m utation in patients w ith
ALPS , mu tations of the gene encod ing for
SAP/SLAM in XLP, and ma ny c hromosomal b reaks in NBS {799 , 2t581 , Ot her abnormalities ma y occur in the course of
LPO , In AT, in addition to mu tations of the
Neoplasms
Most of the lymphomas in patients with
PIO are of B-ceillineage, and thus express
B-cell antigens co rresponding to their differentiation stage. EBY infection of B cells
often leads to down-regulation of s-een
antigens. Thus, C020. C0 19 an d C079a
may be negative or expressed on only
some of the neoplastic cells in EBY-positive
LPD . Sim ilarly, EBY leads 10 the expression of C030 in most cases . In patients
with EBY-positlve lPD resulting from defective immune surveillance, the latency
genes including LMPl may be expressed.
Ftg. 13.06 Hypef-IgM syndrome. ", l ymph notle cootalns

B C020 stan Iigt"ighIs oortIcaI areas
338
ImmunodeflClencyassoclated Iymphoprolileratlve disorders
ATMgene. inversions and nenccatcose

the
t-een receptor genes on cbrcro-
somes 7 and 14 are common. Theseollen

show breakpoints at 14qt 1-12. 7Q32-J5
and 7p15 , These nansiocanoos may
involve the TeL I gene, leading to T-eel
Iymphoproliferative diseases. inclUdIl'll;
tom pre T-ALl./lBL as well as T-cell PLL
Other chromosomal rearranoerrerse
franslocations include inv(7)(pt3q35~
1(7;7)(p13q3S), t(7; 14)(p13;q1 t), and
1( 14 .14)(q 11;q32 ). The immunoglobUin
gene loci also may be involved 12t64).

The prognosis is related 10 both the underlying primary immune disorder and ltE
type of LPO. The immunological status d
the host is an important risk factor {33tl
The lymphoid p rolif erations in ALPS are
often self-limiti ng , Lymphoid hyperplasas
in CYIO may be indolent, Most 01 the ather
LPO in patients w ith PIO are aggressive,
However, g ive n the wide variety of uocely ing co nditions and ensuing lympboproliferative disorders , the prognosis rras
be eval ua ted in each case ind ivid ually I
pa tients with EBV-driven infectious rrceonucleosis. a hae mophagoc ytic syndrome
ma y be the primary cause of dea th, usuatj
ro1e ~
wilh pnmary foldes, but Iacts gemWIaI ants.
,a
associated with ma rked pan cyt openia ,

liver dysfunction, co agulopa thy and fureer infectious com plications.
Treatment is based both on the nature of
the neoplastic process and the underlying genetic de tect. In gen era l. less ag gressive therapy than in pat ients without
PIO is need ed , Allog eneic BM transp lantation has bee n used in patients with WAS,
SC IO and hyper-Ig M sy nd rome 1629,
8681, Since the EBV-d riven B-cell expansion in LYG is often not aut onomou s, it
may resp o nd to immu no regulatory the rapy using inte rferon u -2b 124201
TillIt13.01 ClinIcaI leatures 01 the pnmary inrnunoOefJoenc (PIO).

Frequency
I"""'"
GIn.{.) or protein!.)
MOIl common abnonnal;ties
Mosl commonISsOCiated
Iymphoprolilerlliv. disortl~ {"loy
impkaled
dPlO"j
CorOled T.
9-1 6'Ji,
. . 1koI
-..nodefic:ienc:itt
....
1-5%
~1C)'
,sao,
VdlamofL2R.Il.J.R. tl-1R,
1l-9ft1L15R, tl-21R, JAK3
lunase: Il l R, C045,C036 or
C03t . RAGll2. Al'tems. NJA
1-'"
C040 1ga1'ld (C04Ol. C0154J

~ C040
Reo.mntsevere bactefJai. fIIngai
EB'I-assooated lesions. fatalrnedIous
aM will t!fedions, ir'lcb)ng

opptJrtunlSlic i1feclians, SU1ra:st1.
/l'lOI'lCI\UCie (!'l8al1y 100%)
--
EBV--astOOated lesions.
(DlBCl. HodgloJn 'nphoma)
granular ~e 1etJkaer!ia
haemolylic anaema. biliary tact

andtver disease. oppor\Ilfll5lic
larve
i11ecbOns
Pndonlinantty
IfIIJbody PIOJ
CcrrIIOlwnabit
21-3 1%
Badenal infecbons (king. GI).

autoimmuf"ll cytopenlas.
granOOmalOlJS dlSNSI (lung.liver)
..,..,lldeblrq
iClDl
EBV--assoaated lesions (Ol.BCl. HodgIlll'l

lymphoma). exlJaoodal marginal zone
tympOOma. SII1a11 'nphocylJc lym~.

lyrnphoplasmacybc lymphoma, peripheralT-Gel
lymphoma (l'afe~ 2-1%1
0lI' welklefil'lfld
5--22%
iIIlmlmodtliciency
11l1 dro mes
WiskottAAjricl1
13%
Thrombocykl~ , small platelets.

eczema, aLttoimmune disease,
bacterialinfections
EBV-asSOCiatlld lesions (OLBCl, Hodgkin

Iymphoma. lympnomatoid granulornatosis)
ATM
Ataxia, telallgiectasias, increased

AFP, increa sed sens ili~ity to
ionizingradi ation
Nonleukaemic clonal 'r-eef proliferations.

DLBCL, Burkitl lymp/loma, TPLL, T-ALl.
Hodgkinlymphoma (10--30'4)
NBSflNibrin)
Microcephaly, progressi ~e m&ntal

retardation,sensitvity to ioniZing
radiation. predispositiOn to cancer
OLBCl.peripheral T-<:eIllymphoma, T-lBLlALl,

Hodgkin lymphoma (28-36%)
WASP
Ij"'O'oole (WASI
Ataxialslangieeta sia
2-{l%
:AT)
NffJe9E!" tlreakage
l~ome (NBS)
OlMaMloflmmun.
1- 3%
<1%
SH2D1A
<1%
FAS {lype 1a). FASL (type
,-
1b). CASP10(caspase 10)

(type 2a) or CASPS (caspase
aulOIlTlmune cytopenias. f8CII[8[lI
~ulatjon
WlO\Ji...liYe
tfOtrne (XlP)
-~
.,........abve
"'-iAU'S.
CnI!--SrMh Syrd'ome)
8) (type 2b)
(3-9%)
EBV-triggered abnormalities (fatal

1M, twlpalibs. aplastiC anaemia),
EBV-asscOaIed lesions (Burtoll lymphoma,

DlBCl) (nearly 100%)
Defective IynlII'loc)1e apop\OSis.

splenomegaly. adenopatlly.
Nodulaf LPHodglurl lymphcma. Classical

Hodgkin lymphoma , OlBCL BOOUII IyrnpIona.
peripheral T<el lymphoma (rare}~CHl. 0l.6Cl
and Bl may be EBV+ or) (3-10%)
"'-.
repol1s 01 severalnalional and i1teInational registnes TCR. T-(eII anligen receplor; NI. normal; ADA. aOenosIfIe deamioase: B. B~,
I T ~. !g, serum irmu'logIObI*l: AFP, e. fetoproleln. " "it where provicled n:licates appfOlUtTl8Ie %rJ pabenls II wtlom LPOdevelops.
' :W ~ !rom
tvmonopronteranve diseases associated With
primary IfTlmunedisorders
339
Lymphomas associated with

HIV infection
M. Raphael
J . Said
B. Bensch
E. Cesa rma n
NL Harr is
Definition
lymphomas tha t develop in HI V-posil ive

pat ients are predominantly agg ressive
B-eell lymphomas. In a proport ion 01
c ases they are con sid ered ac quired
immunodeficiency syndrome (AIDS)defining conditions and are the initial
mannestanoo of AIDS. These d isorders
are heterogeneous and include lymphomas usually diagnosed in immunocompetent pa tients. as wett as those seen
much more often in the selting of HIV
infection. The most common HIV-associatec lymphomas include Burkitt lymphoma
(Bl), diffuse large a-cen lymphoma

(DLBCL) (often involving the central nervous system). p rimary effusion lym phoma
(PEL), and plasmab lastic lymphoma.
Hod gk in lymphoma (HL) is also increased
in the setting 01 HIV
Epidemiology
The incidence of all subtypes of nonHodgkin lymp homa (NHL) is increased
60-200 times in HIV-positive patients. In
partic ular, be fore highly act ive antiretroviral
therapy (HAART) was availab le , pr imar y
central nervous system (CN S) lym phoma
and BL w ere increa sed approximately
1000 times in co m parison with the general population 1193, 1283). Since the introduction of HAART. the risk of NH L
declined dramatically (from 53 to 23 standardized incidence ratio): the risk dec reased cons id erab ly in 1996 and has
remained sta ble ther eafter (646! Moreover. the d ecr eased incid en ce of most
Fig. 13.07 RadiaogicaI firdngs in HIV-assOOaled~ . A Nuc:le magnetICresonance (NMRj lnagilg $I2lfll
tile brain shows a Iiwge tl.molJ" mass in !he basal gangb. BMlIbple*'9 defects n seen in iYer
AIDS-associated NHl after HAA RT introduction is consistent with improved C0 4

cou nts 1211,2171. HAA RT is also associated wi th enhanced survival with a 75%
decr ea se in mort alit y. although lym p homa s now contrib ute to a greater percentage of first A IDS-defin ing illness 1570,
6461. There has been an unexpected
increase in the inci dence of HL since the
advent of HAART therapy 1451! , Since HL
incid ence is lower among pa tien ts wi th
severe imm unos upp ress ion than among
those w ith moderate immu ne d efect , the
recen t increase of HL incid enc e co uld be
possi bly related to improvements in CD4
coun ts (218!.
Etiology and pathogenesis
Lym phomas in HIV-patients a re heterogeneous. reflecting several pathog eneti c
mechanism s: chron ic antig en stimulation,
Fig. 13.08 Dilfuse Ia'ge Ik$I "JnlIhoma. HI'..associaIed.

AIiwge tun'lOls nvotves ee basal g<lngia
340
Immunodeficiency-associated Iym phoproliferative disorders
genetic abnormalities. cytokine deregulation , and the role of Epstein-Barr virus (EBV)
and Human Herpes Virus 8 (HHV8) 1336
3371. However, EBV-positive lymphomas
decreased in the HAA RT era 19411. HIVrelated lymphomas are consistently rroocclonal and are ch aract erized by a numbel
of common ge net ic abnormalities of MYC
and BCL6 genes, as well as tumour suppressor genes 1743, 22821. The recognition of a porv cionat or ono ocionar newe
of some f-nv-retatec lymphoid proliferations
suq qests a multistep lymphomaqeness
B--cell stimulation, hypergarnmaglobulinema
and persistent generalized lvmoreoercpa thy preced ing the development oi
these lymphomas probably reflect the roe
of chronic antigenic stimulation. Denotco
of the c ytokine network leading to hign
serum levels 01lL6 and IL 10 is a featured
Hrv-rerateo lym p homas assoc iated wltn
EBV or HHV8 . EBV is id entified in the reoplastic cells ot approx imately 40% of HIlirelated lymphomas , but the detectce d
EBV varies consi d erably with the site ct
presentation and histo log ical subtype
EBV infec tion occurs in 80--100% 01 pi"
mary CNS lymphomas 13251 and PEL
80% of DlBCl w ith fmm uoobtastc teatures and 30-50% of BL 1877!. Nearly <II
Hl cases in the settinq of HIV inlectlOll
are associated with EBV 1107, 2068
HHV8 is specifically associated with PEl,
which usu ally occurs in the late stagesIi
the disease, in the settmq of prof
immunosuppression 13721.
~.
:.8 0;
t.g. 13.10 Ii &r1utt lymphoma. eel ~ is urVIoon. B In arw;Jlher case of Burkill tymp/'lOma, eels show mud! great vanaIion in size and shape. C BI.rtillIynllhoma'"
pliI5trIaq'loid dItI8rentlation. eels have an ec:c:enbic rim rJ deepty stained cylopIasm
na.
11 11 Ii Prmary CNS lymphoma. dassIIied as liIfuse largeEk:eIIymphoma i'I an HIV-posiIiYe pabent. B Diffuse largeEk:eIIymphoma. irnrTulobIaslic variant. presenlIng in
.. a:nnI nervous system. Thecellshaveprominentcentral nucleoli. C Cells extllbit marked pIasrnar;ybd ddIenlnIiabOn.
These lymphomas display a marked
,e
,
,f
::ropensity to invo lve extranooat sites, in

particular the gastrointestinal tract. e NS
(less frequent since HAAAT ), liver and bone
na rrow The peripheral blood is rarely incveo except in occ asional cases of BL
presenting as acute leukaemia. Unusual
eessuch as the oral cavity, jaw and body
cavities are often involved . Many other exrenooal sites. e.q . lung. skin, testis, heart
!rid breast, can be involved , lymph nodes
are involved in abo ut one third of patients
.t presentation (2131. but since the
AAART era , nod al involvement account s
\:Jr half of the cases 194 11.
,-
,-
,f
,f
,-
,-
,"
.n
1 .
L.
of
.d
Clinical features
\tIs1 patients present with advanced clincal sta qe: bu lky d isea se with a hig h
urccr burden is frequent. LDH is usually

mar\(edly e levated There is a sig nificant
'8ationship betw een the subty pe of Iymrtoma and the HIV d isease status .
llBCl more often occurs in the selli ng of
b'lg-stand ing AIDS and is associate d
MU'I a trend towa rds a hig her rate 01 opXlrtunistic infec tions and lowe r CD4 +
kell counts wi th a me an below
1JJx1()5/L In con trast , Bl occurs in less
tmJOOdeficient patien ts, with a shorter
lean interval be tween the d iag nosis of
HIV seropositivity and lymphoma and signilicanlty higher CD4 + f-cen counts (more
than 200x 1CJ61l) 121 1, 3351.
Morp hology
In HIV-positive pat ients, d ifferent ty pe s of
lymp homa can occur. Some are the same
ag g ressi ve B-c ell lym pho mas that develo p sporadically in the abse nce of HIV
infection, wh ile others co rrespond ing to
poly morph ic lymp hoid proliferations and
unu sual lymphoma bistotvpes occur more
spec ifically in AIDS patients,
Lymph omas also occurring
in immunocompetent patients
Burkitt lymphoma : Burkilllymphoma accounts for 30% of all HIV-assoc iated lymph omas, One third of cases displ ay the
spectrum of mo rp hologic fea tures descri be d in the Bl chapte r, with EBV be ing
positiv e in 30 % of cases 11 8 191. Two
thirds of cases show p lasmacytoid d ifferentiation, which is relatively unique to
AIDS pa tients. They are ch aracterized by
medium-sized ce lls with ab und ant basoph ilic cytoplasm, a nd an eccentric nucl eus , often with one c entrally loc ated
p rom inent nuc feolus. The ce lls often cootain cytoplasmic immu nog lobulin. EBV is
posi tive in 50-70% 01 cases 15 111
Diffuse large 8-cell lymphoma: The maJOl"Ity of these lymphomas contai n numerous
centroblasts , vari ably ad mixed with immuno btasts. This type acc ounts for
25-30% of HIV-assoc iated lymphomas ;
EBV is present in 30% of cas es, DlBCl
containing more than 90% immunoblasts
and usual ly exhi b iting p lasmacytoid tealures are cl assified as the immunoblastic
va riant. They account for about 10% of
HIV-assoc iated lymphomas, contain EBV
in 90% 01 cases, and allen occur fate in
the co urse of H IV disease. Primary ce ntral
nervous system lymphomas are usually of
the imm unob lastic type {325 f,
Hodg kin lymphoma. Most cases co rrespond to either the mixed ce llularity or
lymp hocyte dep leted forms 01 c lassical
HL Some c ases of nod ular scle rosis Hl
are also seen . HIV-re lated HL is associateo with EBV in nearly all cases: the cells
express Ihe latent mem brane protein 1
(LMP 1) and are EBER-po sitive. Atypical
forms with Hodgkin-like features may be
observed in such con text 11 9091.
Other lymphomas: Rare c ases of MALT
lymphoma have been described in both
paed iatric and ad ult pa tients with HIV
infection 11436 , 2 1871. Rare cases of
pe ripheral t-een and natu ral killer ce ll
Lymphc:WnaS associated WIth HIV Infection
341
Lymphomas associated with

HIV infection
M. RaphaAI
J. said
B. Bofisch
E. Cesarman
N L Harris
Definition
Lymphomas that d evelop in HIV-p ositive
pa tients are p redominan tly agg ressive
Bccef lym phomas. In a proportion of
c ases they are conside red acquired

immunod eficiency syndro me (AIDS)defining conomons and are the initial
mani fest ation 01 AIDS. Thes e disorders
are heterogeneous and include lymphomas usually diagnosed in immunocompeten t patients. as welt as those seen
much more often in the setting 01 HIV
inlec lion. The most common j-nv-assooateo lymphomas include: Burkitt lymphoma
(BL), diffu se large a-ces lymphoma
(DlBCL) (often involving the ce ntral nervous sys tem), primary effusion lymph oma
(PEL), and p lasmablastic lymphoma.
Hodgki n lymphoma (HL) is also incr eased
in the setting of HIV.
Epidemiology
The incidence of all subtypes of nonHodg kin lymphoma (NH L) is inc reased
60-2fXl times in HIV-positive patients, In
particular. before highly active antiretrovirar
the rapy (HAA RT) was available , primary
central nervou s system (CNS) lymphoma
and BL we re inc reased approximately
1(XX) times in compa rison with the q enere! po pulatio n 11 93 , 1283 ). Sinc e the introd uct ion of HAART, the risk of NHL
declined d ramati cally (from 53 to 23 sta ndardized incidence rati o ): the risk d ec reas ed c on sider ably in 1996 an d has
rema ined sta ble therea fter (6461. Mo reove r, the decreased inci denc e of most
Fig., 3.08 DilIuse I<wge Ik:eI ~, HlV-associated.

A largeUnour irrYeIIves Itle basal gangia.
Fig. 13.07 RadIOlogical findings in HIV-associaled lymphoma, It Nuclear ~ rescoeece (NMR) imag'ng scan d
ee bra,n shows a large tumour mass in 1Ile basal ganglia B Mufliple filling defects areseen in Mr,
AIDS-as soc iated NHL alte r HAART introd uction is consistent with improved CD4
co unts 1211, 2171 HAART is also associated with enhanced survival with a 75%
d ec rease in mo rta lity. although lymphomas now contri b ute to a greater percentage of first AID5-defining illness 1570.
6461. There has been an unexpected
increase in the incidence of HL since the
advent of HAART therapy /4511. Since HL
incidence is lowe r among patients with
severe immunosuppression than among
those with moderate immune defect, the
recent inc rease of HL incidence co uld be
po ssib ly related to imp rovements in CD4
counts 12181.
Etiology and pa thoge nesis
Lym phomas in HIV-pa tients a re hete rogeneou s, reflecting sev eral pathogenetic
mech anisms: ch ronic antigen stimulation,
gene tic abnormalities, cytokine deregulation , and the role of Epstein-Barr virus (EBV)
and Human Herpes Virus 8 (HHV8) (336,
33 7}, Howe ver, EBV-positive lymphomas
decreased in the HAA RT era /9411. HIV
related lymphomas are consistently rro-oclonal and are characterized by a number
of common genetic abnormalities of MYC
and BCL6 genes. as well as tumour ~
p ressor genes 1743, 22821. The recogrtton 01 a polyclonar or otigoclonal nature
of some HIV-reIated lymphoid proIiferam
suggests a multistep Iymphomagenesis
B-cell stirn,J1ation. hypergammagloblJlinemia
and persistent ge neralized lymphadenopa thy pre c ed ing the develop ment 01
these lymphomas probably reflect the role
of chronic antigenic stimulation , DisrupliOO
of me c ytokine netw ork leading 10 high
serum levels of IL6 and lL 10 is a reatoree
Hrv- rerated lymphomas associated with
EBV or HHVB. EBV is identified in the reoplastic cells of approximately 40% ot HIV
related lymphomas. but the detection ci
EBV varies considerably with the site ci
presenta tion an d histological subtype
EBV infection occurs in 80-100% of prmary CNS lymphom as /3251 and PEL
80% of DLBCL with imm unob lastic teatu res and 30--50% of BL /87 7). Nearly a~
HL c ases in the setting ot HIV infection
are associated with EBV P 07 , 20681,
HHV8 is specifically assoc iated with PEL
whic h usually OCCUfS in the late stagesof
the disease. in the selling of profound
immunosuppression 13721.
:. ~
l.
r,. 13,10 ABurtitl~ . tel Jl(lIdabon is t.IlIform.

~ lkIIereotiabon. CeIs
B In anothercase 01 &rtitl~ , eels show muctll1N1er variabon in size aid shape .

haw an ecoenlric rimof deeply stained cytoplasm.
ens
Fig. 1111 A Pnrnaty

lymphoma. dassifled as ddluse large8-cel1ymphoma in anHIViJosrtive patient . 8 Odfuse large 1k:eI
IIIcenIraIlllIIVOUS s)'5lem. Thecells haw prominentcentral nucleoli. C Cells e d ubll. marked pIasITIacylllId dlflerentJalion.
These lymphomas display a marked
eropensrty to involve extranod at sites, in
carncurar the ga stroin testinal tract, e NS
(less frequent since HAART).liver and bone
matrow. The periph eral blood is rarely in-
\'O wed except in occasional cases of Bl

presenting as acut e leukaemia . Unu sual
saes such as the oral cavity, jaw and body
cavities are often involved. Many other 8Xtranodal siles, e .g. lung, skin, testis, heart
and breast, can be involved. Lymph nodes
are involved in abo ut one third of pal ients
at presentation [2 131. but since the
HAART era, nodal involvement accounts

tx half of the cases 19411.
Clinical feature s
Yost patients present with ad vanced clincal stag e; bulky di sease with a high
unour burden is frequent. lDH is usua lly
markedly elevated . There is a significant
relationship between the sub type of lymphoma and the HIV di sease status.
DLBCL more etten occurs in the setting 0 1
l:lng-standing AIDS and is associated
NI!h a trend toward s a higher rate of OJ)cctomsuc infec tions and lower CD4 +
T-re11 c ounts with a mean be low
lCKb: l lJ1lL. In con trast. BL occurs in less
.rrmunod efic ient patients. with a short er
mean interval between the d iag nosi s of
HIV seropos itivity and lymphoma and significantly higher CD4+ T-cell counts (more
than 200x 1()6!L) 12 11, 335 1.
Morphology
In Hrv-oosmve patients. different type s of
lymp hom a can occur. Some are the same
ag gressive B-een lymphomas that d evelop sporad ically in the ab sence of HIV
infec tion, wh ile others correspo nding to
polymorph ic lymphoid prol iferation s and
unusual lymphoma histotypes occur more
specifically in AIDS patients,
Lymphomas also occurring

in immunoco mpetent patients
Burkitt lymphoma: Burkitt lymphoma ac counts for 30% of an HIV-associated lymph omas . One third of c ases di splay the
spec trum of morphologic feature s d escribed in the BL cha pter, with EBV be ing
positive in 30% of c ases 118191. Two
third s of cases show plasmacytoid outerennarron. which is relatively un ique 10
AIDS pa tients. They are cha racterized by
medium-sized c ells with abundant ba soph ilic cytoplasm. and an ec cent ric nucleus. often with one centrall y located
p rominent nucleolu s. The cells often c0ntam c ytoplasmic immunoglobulin. EBV is
positive in 50-70% of cases 15111.
~.
irm'UlotIlastic vananl. preseobng 1\
Diffuse targe B-eelt lymphoma: The ma jority of Ihese lymphomas contain numerous
centrobl asts, variably admixed with immu nobtasts . This type accounts for
25-30% of j- nv-assoctateo lymphomas;
EBV is p resent in 30% of cases. DLBCL
containing more than 90% immunoblasts
and usually exhibiting plasmacytoid features are classified as the immunoblastic
variant. They ac count for about 10% of
HIV-associated lymphomas , conta in EBV
in 90% of case s, and often occur late in
the course of HIV disease. Primary cen tral
nervous system lymphomas are usually of
the immunoblastic type 13251.
Hodgkin lym phoma: Most cases correspond to either the mixe d c ellularity or
lym p hocyte d epleted forms of cl assical
HL. Some cases of nodular sclerosis HL
are also seen , HIV-relaled HL is associ ated with EBV in nearly all ca ses: the cells
express the latent memb rane p rotein 1
(LM P1) and are EBER-pos itive . Atypical
forms with Hodgkin-like features may be
observed in suc h con text 119091.
Other lym phomaS: Rare cases of MALT

lymphoma have been de scribed in both
pa ed iatr ic and ad ult patents With HIV
infec tion 11 436, 21871. Rare cas es of
pe ripheral T-cell and natural killer cell
Lymphomas associated WIth Hrv infection
341
Iymphoma.can also occur 186. 213. 300.

330.801.863,956. 10571.
Lymphomas occurring more specifically in
HfV-positive pa tient s
Primary effusion lymphoma (PEL). Plasmablastic lymphoma. lymphoma arising in
HHV8-associat ed multicentric Castleman
Disease (See Chapter 10).
Lymph omas occurring in other
immunodeficient states
Polymorphic lymphoid proliferations resembling post -transplant associated Iympbo prouteranve disease (PTlD) may be
seen in adults and also in children, but
are much less common than in the posttransplant setting, representing less than
5% of Hrv-essocrateo lymphomas. These
con form to the c riteria of polymorph ic
342
B-eell PTlO. The infiltrates contain a range

of lymphoid cells from small cells. often
with plasmacytoid features, to immunoblasts, with scattered large bizarre cells
expressing CD30. EBV is oflen present,
but some cases are EBV-negalive 111 51,
1399,1556 ,2160)
Prognosis and predictive teeters
Before the HAART era, the rate of complete remissions was abou t 50% for most
of histological subtypes. The z-vear survival was sign ificantly lower for Dl BCl
than Bl in univariate analysis. The International Prognostic Index (lPI) appeared
to be a reliab le indicator. The degree of
immunodeficiency also co rrelated positively with the IPI score 118741 . Some other
adve rse prognostic factors were ident ified . such as age >35 years. intravenous
Immunodeficiency-associated lymphoproliferative disorde rs
drug use , stage IIlIIV and CD4 counts

less than 100)(1CY'/L Despite dose adjustment, the outcome of patients with lymphoma and HIV infection was clos ely
related to the severity of immunodeficien cy {2531 .
Since the introduction of HAART. the overall survival of patients with DlBCl has
improved. and outcomes are approaching those of patients with de novo
lymphoma 113011. The achievement of
complete remission is the most important
prognostic teeter with respeclto the time
of survival 124341. l ong -term survival can
be achieved in approxima tely one third of
patients with favourable prognostic characteristics. PEL usually has a very poor
prognos is with a low comp lete remission
rate,
Post-transplant Iymphoproliferative
disorders
Definition
Post-transplant IyrrVloproIrferative osooes
(PTLD) are lymphoid or plasmacytic oroIiferatoo s that develop as a consequence

01 immunosuppression in a recipient of a
!did organ, bone marrow(BM) Of stem cel l
:lIIograft. PTLD compr ise a spectrum rang-
SH Swerdlow
SA Webber
A . Chad burn
J A Ferry
lymphomas in allograft recipients are designated as they are in the normal host and
not considered a type of PTLO. Detection
of rare EBV-positive cells in the absence
01 an appropriate Iym phoi dlplasm ac ytic
proliferation is also not considered diagnost ic 01a PTLD
ng from usually Epste in-Barr virus (EBV)driven mtecucus mononucleosis-type
Ep idem iology
pelyclonal proliferations 10EBV-positive or

uN-negative proliferations indistinguish-
The characteristic s of PTLO appear to

differ somewhat from one institution to
another, probably as a result 01 different
patient populations, a llograft types and
immunosuppressive regimens. A var iety
01 risk teeters have been id entified 1308.
309. 164 6 1. but the most important risk
rector lor EBV-driven PTLO is EBV seronegativity at the time of transplanta tion
1309. 23661. Among adult sol id organ
rec ip ients, the frequency of PTLO c orrelates. in part, with the intensity of the
immunosuppressive regimen; patients
rec eiv ing renal allografts have the lowest
frequency of PTLO 1%), those with
hepatic and ca rdiac allografts have an
intermediate risk ( 1-2%), and those receiving heart-Iungll ung or intestinal allog rafts
have the high est frequ ency (5% or g reater)
1133, 308, 309, 1646). In ch ild ren, the
inc idences are very much high er 1562,
2367} , w ith the major ity of cases being
associated with post-transplantation primary
EBV infection 12367}.
Per ipheral blood (PS), ste m ce ll and 8 M
allog raft rec ipients in g eneral have a low
risk of PTLO (- 1%) with the fis k of earlyonset PTLO 1 yea r) highest w ith unrelated or HLA mismatched related donors,
selec tive t-een depletion of donor BM, and
use of antithymocyte globulin (ATG) or
anti-C03 monoclonal anti bodies . The risk
of PTLO in Ihese patients increases up to
22% for thos e with two or mo re of these
risk factors 1499} . An unexpectedly high incidence of EBVassociated PTLO (17%)
has been recently observed in patients undergoing unrelated umbilical cord blOOd
transplants with a non -mveioabtanve
preparative regimen containing ATG 12911 .
PTLO -ljk e le sions are rare after autologous BMT; they may be associated with
additional high-dose imnunosuppressNe
ilbIe from a subset of B-cell or less often

teen lymphomas thai occ ur in irrvnunocorceteot individuals. The monomorphic
m Hodgkin-type PTlO are further cate~ed as in non-immunosuppressed pasents. according the lymphoma they
resemble. Indolent B-cell lymphomas

such as follicular lymphomas and MALT
, . 13.02 CategaJeS d
POSl-tran~ Iymphopolifer-
1M esease (PTlD).
e.ty Itsi0fll1
9971/1
P1asm<lCytic hyperpl as~

Infectious mooonudeosis-like ~
PolymorphicPYlO
9971/3
llQrIOIllorphic PTL01
(classifyaccording to I)'mplloma lIMy membIt)
&t6# neoplasms
Diffuselarge B-celilymphoma
Burkilllymphorna
Plasma cell myeloma
Plasmacytomalikelesioo
"'"'"
T<eI fI60PIasms
Peo:'iptoeral T-cet lymphoma, NOS
HepatOSlllenic T-<;ell ~phoma
"*'
Clinical Hodgkin Iymphomatype PTLD'
rnass-ll~& leslQr1S in the posHransplan1

may h&ve the morphok)glC appearance of
Icn:I klIaAar hyptfpIasia orotherll'\8l1<.ed but
lIlfI-I,I.lle Iy!npl'loId hyperplasias.
Jm.o ccdts b' 1IlMelesions we the samt as
tee b' IllIIeSI)8drve IyrnptIoId or p1asmacybc
1
-..
~ ~ IkeII ~.-.sMlg in trans. . ~ in not ~ among the PTlD.
regimen s and are best cons idered iatrogenic, rather than post-transplant, irTYn.Jno..
oencercy-associated LPO 115761.
Etiology
The ma;ority of PTLO are associated with
EBV infec tion (usually type A), and appear
to represent EBV-ioduced monoclonal or.
les s often, poIyclonaJ B-cell or monoclonal
proliferations that occur in a setting
of decreased
immune surveillance
1376,450,699. 730. 1166. 1569. 21331. Up
to 30% ot PTLO are EBV-nega tive with
some series reporting an even higher proportion of ca ses and with about 213 of
T-PTLO EBV-negative 1224 . 699. 1260.
1586.2 133 1. Furthermore. the proportion
of EBV-negative PTLO appears to be
inc reasi ng /15861 . EBV-negative PTLO
are more common in adults. tend to occur
later than EBV,poSit ive cases and are
more likely to be of monomorphic type
1791. 1586 J. Human herpes virus 8
(HHV8)-associated PTLO are reported including post-transplant primary effusion
lymphoma [606, 1106, 142 11; however,
the etiology of the vas t majority of EBVnegative PTLO is unkno wn . Some may be
due to ESV that is no lon ger detectable
[2073J, some d ue to other unknown
viruses and some due to chronic antigenic stimulation, includ ing by the transpl ant itself 1224) The EBV-negative cases
are still co nsidered to repre sent PTLO and
some may respond to decreased immunosuppression {15861.
The majority (>90%) of PTLO in solid organ
rec ip ients are of host origin and only a
minori ty of donor origin . Donor origin PTLO
appear to be most common in liver and
lung allograft rec ipients. and frequently
involve the allograft 178, 378 , 1255,2069,
23801. In contrast, the majority of PTLO in
BM allograft reci pients are of donor origin,
as would be expected. since successful
engraftment results in an imm une system
that is nearly exclusively of donor origin
t-een
t-een
125101.
Involvement of lymph node, gastrointestinal
tract. lungs and liver are common in all
Post-transplantlymphoproliterallve d soroers
343
allog raft types, whereas ce ntral nervous

system (eNS) invo lvement is rare 1699,
1569, 1723, 23671. The e NS may be the
only sile 01d isease or may be associa ted
with multiorgan involvement 13431. In solid
organ recipients, PTLO frequently
involves the allograft and this may cause
diagnostic con fusion since rejection and
infection may result in a similar clinical
picture. Allog raft involvement appears
more common in earty-onset. EBV-positive
disease 1133. 7911 The heart is the only
organ in which allograft involvement is
very rare. "Early lesions ' often present
with tonsil and/Of adenoid involvement
but may also occur at other sites. Overt
BM involvement by polymorphiC aOO
monomorphic PTLO is not comoon. and
PB is rarely involved . Bone marrow auograft recipients tend to present with widespread disease involving nodal and
extranccat sttes. including liver, spleen.
ga strointestinal tract and lungs 11723.
1998. 2510 1.
Fig. 13.12 Intecbws rrDU'lUdeosis-ie(lM)Iesionfla D"ISiI ofan 11--year-<*l renal aIograftredpiert. lhefe ispesel
vatlon of cwertying epIlt1eiI.m and crypts. 1M normal tildes iJfI!I absenl and hire is a li1tuse ~ p1 oifelalo'L
Cflnical features
The clinical features 01 PTLO are high ly
variab le and correlate With the type of
allog raft, and to some extent, with the
morphologically de fined ca tegories. Almost all solid organ transplant recipients
are currently managed with a carcmeunn
inhibitor (cyc losporine or tacrolimus). With
Ihese agents. PTLO frequently presents in
the first year after transpl antation. earlier
than tended to be obser ved in the
pre-cyclosporine era 11 569. 1723}. EBVnegative PTLO and TINK-cell PTLO tend to
present later (med ian time to occ urrence
4- 5 years and 6.5 years, respe ctively)
11260. 1586. 21331. The majority of PTLD
in 8M allograft rec ipients dev elop within
the first six months 14991. PTLO presentation may be non-specific with features
such as malaise. lethargy, weight loss and
Table 13.03 PathologicevaluallOn ofspecimens for !hediagnosis of PM.
Method of tvalualion
Necessity
-...._- .........
Histopathology
EBER in situ h)tlrWalion
EBV <blaIily
PUrpoIie
Evaluate arthit6cture and cytologic features, requued lordaS$llicaboo

il11t chatn classres\nCtlOl'l' and basic ~ subsets, requiredlor cIassofK:aIioo
Uost senSltiYe method lor assessing ~ PTlD is EBV1J05Ilive, aidsII dIagnosrs and possobly
prognostication. useful in dtIlerenbaI dl~ \WlIh f'eJlldIOn i1 aIografI (If positive)
Detema ~,Iineage of clonal popuIation(s). d\I'or"nOSOOIaI and oncogene abnom'Ia\ItJes,
may be needed klr dassificaboo
IdellIJfIcation of minor c:Iones
Assess possible
"Pnllin section i1vru~ ddlen fall k1demr.f1Slrale ~ 8-<;eIpopuIaIions, eY8I'1lf jn'SeI'C, Lriess 1henl1S pIasmacytit~.
~1f!he less senWo'e EBV-lMP1 ~ is posiIie. EBER in SlftsIlybrOZaIiOn is not rllQI,lO:l.
344
ImmunodefICiency-asSOCIated tymphoprolilerative disorders
.s
lever. Lymp ha denopathy and or gandysfunction are also common

ceseotatcos. Obstructive symptoms such
as enlarged tonsils are another type 01
presentation. Pres enta tion with disseminateddiseaseseems to be less COITIlTlOlI in
'he ccreot era. perhaps due to increasing
aeeeress 01 the diagnosis and due to rooWle EBV viral load monitoring 01 seronegatve recipients in many transplant centres.
scecmc
Prognosis and predictive tactors

Tne "early' lesions tend to reg ress with
reduction in immune suppression. and if
ns can be accomplished w ithou t g ralt
eectoo . the prognosis is excellent , partie.Jarty in children {133O.2486 1. Polymor phic
end less often monomorphic PTLD may
aso regress wit h reduction in immune
aocresstcn 12080, 236 71. Howeve r, reOOUnd acu te and chronic reject ion may
be observed and c an lead to gr aft loss
a"l{\ death 1236 71. A proporti on of poly -rrxphic and even mo re numerous mon oroorphic PTLD fail to regress, and require
additional therapies suc h as monoclonal
e acooes directed ag ainst B-cell antigens
(roost commonly anti-CD20) 1435 , 6431.
chemotherapy (436, 643 , 8561 o r co mbiretone of both . Several cen tres are also
pe'forming phase I clinical trials of cellular
nmunotherapy to restore EBVspec ific
cytotolCic T-cell immunity in EBV-driven
'l!lractory disease {46 1. 889, 1946 }. The
~tous lesions usually do not regress
fllIh decreased immunosup pression , and
T!NK-eell PTLD are also considered to be
aggressive with the exception of those of
rarge granular lymphocyte type {2 133} .
'eermerese. some T-PTLD do respond
l:l reccosntu ton of the pa tients' imm une
esen The plasmacytoma-like lesions
Vt'8 a variable outcome {1074 1. EBV
~tivity in PTLD and even among the
- K-eell PTLD, is also considered an
adverse prognostic inchcator, although not

a ll studies document a survival difference
1435.21331
A number of additional prognostic factors
associated with an adverse outcome
include multiple sites of disease and
advanced stage, older ag e at diagnosis.
late onset d isease. high Internat ion al
Prognostic Ind ex and elevated lactate
dehydrogenase 1309, 435, 643, 792.22691.
However. risk factors for adverse outcome
vary g reatly between stud ies . Multi-site
d ise ase may not be a risk fact or lor
adverse outcome in paediatric patients
12367}. Overall , the mortality of PTLD is
g reate r in BM allog raft reci p ients than
solid organ allograft reci pients and may
be lowe r in c hildren than adults.
Early lesions: plasmacytic hyperplasia (PH) and inf9ctious

mononucleosis (IM)-/ike PTLD
Definition
The early lesions are defined as lymphoid
proliferations in an allog raft rec ipient,
characterized by arch itectural p reservation
of the involved tissue , with preservation of
the nod al sinuses or tonsillar c rypts. and
residual or sometimes florid ly reactive fol

tcies in some cases. In most cases. they
form mass lesions . These lesions should
be distinguished from lymphoid proliferation s with other known explanat ions or
other non-specific c hron ic inflammat ory
processes. Cases that have florid follicular hyperplasia but which do not fil into the
PH or 1M-like c ategories have been sepa rately designated by some author s.
Clinical featu res
PH and 1M-like lesions occur at a younger
age tha n the other PTLD and are often
seen in c hild ren or in adult solid organ
rec ip ients wh o have not had prior EBV
infec tion {376, 1330 1. Case s described as
post-transplant florid follicular hyperplasia
also occur most c ommonly in children
12284 } The early lesions involve lymph
nodes o r tonsils and adenoi ds more often
than true extranodal sites 113301_ They often
regress spon taneously or with reduction in
immunos upp ression: however, 1M-like
lesions ca n be falal. In some case s, polymorphi c or monomorphic PTlD may follow
early lesions 11569 , 2453).
Morphology
Plasmacyte hyperplasia is characterized
by numerous plasma cells, small
Post-transplantlymphOproliferatlYe disorders
345
lymphocytes and g ene rally infrequent

bland-appearing immunoblasts, white the
1M-like lesion has the typi ca l morphologic
features of 1M. with paraconcat expa nsion
and numerous immunoblasts in a bac kground of T cells and plasma ce lls. Oth er
non -de stru ct ive lymphoid hyperp lasias
that either show fewe r immunoblasts or
more prominent follicu lar hyperp lasia than
typ ical c ases of 1M may also occur in the
post-trans plan t setti ng and c ause ma ss
lesions 122841. Criteria for the dis tinc tion
of these ea rly. non-d estruc tive PTlD from
othe r react ive lym phoid infiltrates are not
well-defined and rest on the extent of the
proliferation. clin ical correlations and the
presence or absence of EBV
Genet ics
Clonally rearranged immunoglobulin genes
are not expected in PH. although small
clonal pop ulations may be demonstrated
with Southern b lot analysis using probes
to the term inal rep eat regi on of the EBV.
Some 1M-like PTlD may have small monocl onal or oligoclonal pop ulations, The siq nificance of oligoclonality or a small c lonal
b and in these cases is unkno wn [ 1166,
24531. Flor id follicu lar hype rplasia (FFH)
does not usually demonstrate clonal B
cells b ut. as also repo rted in 1M-like
cases. rarely demonstrates simple clonal
cytogenetic abnormalities 122841.
PbIymorphic PTLD
Immunophenotype
Immunophenotypic studies shOw an admixture 01 pOIyclona/ B cells, p lasma cells
and T cells WithOut phenotypic aberrancy
EBV is present in many bu t not all of the
cases of nodal PH and cases describe d
as florid follicular hyperplasia 11 166, 22841.
1M-li ke cases are typic ally EBV-po sil ive
with EBV-l MP1+ immunoblasts 113301.
346
Definition
Polymorphic (P) PTlD are morphologically
po/yrTk)rphiclesions composed of immuneblasts. p lasma ce lls and small and intermediate-sized lymphoid cells that efface
the architecture of lymph nodes or form
destru ct ive extrano dal masses and that
Immunodeficiency-associated Iymphop roliferative disorders
do not lulfill the c riteria for any of the recognized types of lymphoma described fl
immunocompetent hosts. Distinction ci
some P-PTlD from more -monorrorohc'
(i.e. lymphom a-like) lesions that show pasmac ytic di fferentiation is not well-defined,
Clinical features
The frequ ency of P-PTlD var ies from en!
institution to another, rang ing from 20%10
over 80% of the cas es 1450, 699, 735
110 7,1 166 ,1 569 ,1 586 1. ln c hildren ltlis
is the most common type 01 PTl O 123671
and frequently follows p rimary EBV intec
lion. The cl inic al p resentation of lhese
cases is not distinguishable from PTLO
general. Reduction in renuooeuooessian leads to regression in a variable po
portion 01 cases ; others may progress.rd
require neenreot for lymphoma 11t 6f.
1569,2080,23671 .
Morphol ogy
In con trast to early PTlO lesions. P-PTlO
show effacement of the underlying tssce
architecture 1735. 8871, Unlike most tyrn.
phomas. however, they show the lull fange
of a-cea meunauon . from immunoblasts

to plasma cells, with small and mediumsized lymphocytes and
with irregular
nuclear contours. There may be areas of
geographic necrosis and scartereo large,
bizarrecells that not infrequently resemble
Reed-Ste rnberg cells (atypical immunooIasts ); numerous mitoses may be present .
Some cases have areas that appear more
rronomorp hic in the same or other tissues ;
eos. there may be a cconnoous spectrum
between the se lesio ns and the moool"'O'J)hic PTLD. Other P-PTLO have features
nat more c losel y resemble Hodgkin lymphoma. Some of these cases have been
referred to as "Hodg kin-like" in the past.
Variably sized . but usually small . lymphoid
aggregates wi th or wit hout p lasma cell
ekJslers are seen in the 8M in some
patients with P-PTLD (and occasionally in
\WTl O) 111731. They are more com mon
nmldren than in adults . The c linical sig wcance of these aggregates, that are
n:x always EBV+ , is uncertain .
cens
mnunophenotype
mmunop henoty pic studi es demonstrate
cells with or without lig ht c ha in c lass
restriction and a variable proportion at
'eieroceneous T cell s that sometimes
ceoonoete 1625. 1569J. light c ha in
class restrict ion , when present , may be
ttal. and some cases may demonstrate
OOIerent clona l populations in the same or
dferent sites 115691. Cases with cleercut
911 chain class restriction are recog ~IOO but this observation mus t be noted
fl the diagnos tic rep ort, as some of these
cases could also be cl ass ified as a
rrooornorp hic OLBCL-like PTLO w ith
resmecvttc d ifferentiation, a DLBC L-like
P'lDwith significa nt polym orph ism or as
I plasma ce ll neop lasm w ith inc reased
rsstormeo cells . Aeed-Stern be rg-Ii ke
:~I s when p resent a re often C030+,
[120. but C 0 15-{4061. Most cases of
~.pTLD contain numerous EBERpositive
:ellS. Detec tion of EBV by EBER in situ
~dization is a uselul tool in the differr.a l diagnosis of PTlO versus reject ion
allografts.
n
,I
,j
,e
10
5.
lis
i7 1
ecse
in
3S.,0-
,od
66.
""""
;JlllD are expected to demonstrate

etralty rearranged irTYnunoglobulingenes
,LD
sue
ymnge
'IOJgh the c lones are less predominant

l8'Inrra 1Q1IOphic PTlD 1449 , 1107, 1166.
WI . EBV terminal repeat analysis is the
sensitive method lor demonstrating
inaI population s in the EBV-positive
cases. In some repo rted c ases , tumou rs

at d ifferent sites in the same pat ient may
b e clonalty distinct 13 75 1. Seventy-five
percent at P-PTLO are reported to have
mut ated immu nog lo bulin gene va riable
regions (lGVj wit ho ut ongoing muta tions
and the rema ind er are unmutated 1334J.
Sign ificant I -cell clones are not expected.
Clonal cytogenetic abnormalities may be
present although less commonly detected
than in monomorph ic B-ce ll PTLO (593,
22841 . Comp arative g enomic hyb rid izat ion studies also demo nstrate abno rmaut ies in some P-PTLD incl ud ing some
rec urrent abnorm alities also seen in
monomorphic PTlO (17641. BeL6 soma tic
hype rmutations may be present as well as
aberrant promoter methylation, but other
oncogene abnormalities are not detected
1334,37 11 .
Monomorphic PTLD
The group of monomorphic (M) PTLO
fulfill the criteria tor o ne of the B-cell or
TIN K-<:e ll neoplasms that are recognized
in the immunoc om petent host and
scr ibed elsewhere in this monograph. The
only exception to this is that the small
B-<:elllymphoid neoplasms such as follicular lymphomas or MALT lymphomas are
not designated as PTLD even though
oe-
anention has been drawn to the occurrence

of MALT lymphom as arising in the posttran sp lant setting 1986 1. The M-PTLO
should be des ignated as Ptl.D in the diagnostic line of the pathology report. and
then further categorized based on the
clas sification of lymphomas arising in the
immunocompetent host. Although the term
M-PTLO reflects the fact that most cases
are composed of a monotonous proliferation of transformed lymphoid ce lls or plasmacytic cel ls , the re may b e sig nificant
p leomo rphism and va riab ility 01 ce ll size
within a g iven ca se. In addition, because
polymorph ic and monomorphic PTLD of
B-cell orig in for m a spec trum , their dis tinc tion can become b lurred . Currently,
their distinction in problematic cases is
usually based on a subjective assessment of whether there is a predominance
of large transformed ceusnrrmurobrasts.
The presence of abnormalities in oncogenes and tumour suppressor genes may
also favour the diagnos is of M-PTLO {11661.
Monomorphic B-cell PTlD
Definition
The monomorphic Been PTLD are fT'IOr'Il)clonal transformect B lymphocytic or ptasmacyt ic prol iferations that fulfill the criteria
for a diffuse large Been lymphoma. less
Post-transplant Iymphoprollferative disorders
347
even thoug h only a minority are CDl38

positive, whereas the EBV negative
cases are more likely to hav e a germinal
ce ntre type phenotype (C OlO, BCl 6t .
IRF4/MUM1 -, C0 138-: 60% of ca ses in
o ne stu dy) 1106 11. The myelomatous or
plasm acytoma-like lesion s, which may be
EBV-pos itive 01 negative, are phenoIypicaty'
simi lar to those in immunocompetent
patients {2 1651_
often a Burkitt lymphoma or a p lasma cell

neoplasm. The latte r may have alt the fea-
monomorphic PTLO - some cells may be

bizarre and multmucleated and even
tures of plasma cell myeloma or of an
resemble Reed-S ternberg-like cetls- and

there may be plasmacytoid or plasmacyte
differentiation. Thus. the term. m:)l')()ITl()I'ic,
does not mean com plete cellular mono tony,
only that most of the c ells appear to be
transformed or more uniformly p1asmacytic.
ext ramedullary plasmacytoma with involvement of the g astro intes tina l tract . lym ph
nodes or other extranodat sites .

Clinical features
The c linical presentation of patients with
monomorphic B-PTLD is not distinctive

and is, in genefaJ . smilar to the presentation
of the IympOOmas or plasma een neoplasms
that the y resem ble.
Morph ology
Monomorphic B-PTLD fu lfill the co nve ntional criteria for DLBCL Bu rkitt lymphoma,
plasmacytoma or myeloma 18961. This is

in contrast to the full range 01maturation
seen in polymOrphic PTLO. II is important
10 recognize , however, that me re ma y be
p leomorphism of the transform ed c ells in
Table 13.04
Cr ~eria
Immunopheno type
The oon-p1asmacytic lesions show B-cellassociated antig en expression (C0 19 ,

C020, C079a), with demon str ab le monotypic immunoglobulin (of ten w ith expression of g amma or alp ha heav y c hain) in
about half of the c ases. Many cas es are
CD30 + , with or without anaplasfic mor phology. Mo st M-PTLO are of non-GC type
based on irrmunohistochemistry 1332,
10611. The EBV-p:)SitIvecases usually have
a late germinal centre/post germinal centre
phenotype (C0 1O, BC l6, IRF4/MU M 1+)
used in the categorization of PTLD.
'"""'"
Hisl~thoIogy
.........
""""""'"
......
,oty . . . .
Pdymorphic PTLD
MollQl,lOIptic PTlO
Present
"""" .....
Hodgkn IymptIoma
"''''''
type PTLO
Genetics
"""_
.....
._Major findings
eels, :l irJm.IlDblasts,
Immu~
In sifu hybriciution
Pd B ails & a:lmiled
T eels: often EBVt
...
fu~ spectrumof
lymphoid maturation
Pel (l( mel B cells &

admixedT ~Is:
often EBV+
FtAs aRenaIcf a NtI.
(OUlef than one of the jn.

doIefII !kelt neoplasms)
(I" lMsma eel neclsrn
Varjes based ontype01

neoplasm they resetmle.
EBV lOO"e vaRable than
n other&ategories
FuffiRs l7itefialor CHl
Similar tootherCHL;
19tt wiD not be eaSily
EBV+
der'nonslraled.
=
=
Pd, polycIooal; Md, mnc1onai: NK. nalufalkiller OIly: TeR,T-wl anbgen recepIor.
~
348
Genetics
Clona l IG gene rearrangement is present
in virtually all ca ses, and the major ity conta in EBV genome s, which, if pre sent. are
in clonal episomal form 1449, 450 , 11071.
Most cases hav e somatically mutated
IGV with a minority showing ongoing
mutations 13341. However, some cases
have IGV loci inactivation related 10cripp ling mutations as seen in Hl l333 l . Asio
non-PTlO DlBCL, on cogene abnormal~
ties (RAS or TP53 mut ati ons and MYC
rearran gements) may be found , and
BCL6 gene somatic hypermulation IS
c ommon; however, BCL6 trensiocatcos
are uncorrmon 1371, 11661. Cytogenetic
abnormalities are cornrnon, and are mere
freq uent than in the early or polymorphic
lesions 122841_ While some recurrent
abno rm alities are reported in PTlD such
as breaks involving lq ll -q21 region,
8q24.1, 3q27, 16p1 3, 14q32, l 1q23-24
and trisomies 9, 11, 7, X, 2 and 12, differert
studies find different conrnon abnorTnalles
1593.22841 . Comparative genomic hytnd ization studies demonstrate additional
gains and losses, althou gh no ind iviCUI
Irrvnunodeflciency-asSOC18ted Iymphoprolileralive disorders
Md Bcells, norK:IonalT
celts
Some have BCl 6

soeatc hypefmutalions
!\ ~.
-:r ~~c:.::c'~_~~:iZ~
Fig. 13.19 HodgkJHype PTLD 1l52-yearl male(post renal transpIanl). The Read-5tentlerg eels _
lJClSIq:Ns, ~ 0Ih WIlh C03O+ ellpfflSSion (B) n Golgi-Iype C01S expression Ie).
aboofmality is very common; some are

shared with DLBCL in immunocompetent
tosrs 11764. 18471 EBVnegatlve mononnphic PTlO frequentty lack expression
of the cyclin dependent kinase inhibitor
CDKN2A (pltJ'"1.-) 11397/. Abe rrant
promoter hypermethylalion and aberrant
somatic hypermutation also occur in
EBV+, AReed-Stemberg eel WfCU'ldedbysmaI~ and some
Clinical fea tures

Clinical presentation depends on the type
of T/NK-celloeoplasm. Most cases present
at extranodal sites, sometimes with associ ated lym phadenopathy 12133I.The more
COlTV1lOO sites of involvement include the
PB or BM, spleen, skin, liver, gastrointestinal tract and lung
M-PTLD 13341.
Mo"","_
Moncmorphic
TIN K~ I
PTL.D
Definition
Monomorphic PilO of l IN K-ceil type
IT/NK-PTLD) include PTLO that fulfill the
criteria lor any of the T- or natural killer
(NK) cell lymphomas. They include almost
!he entire spectrum of T- or NK -eell neoplasms, with the larges t group being
oeripheral T-eeillymphoma, not otherwise
specified type. followed by bep atoeolenlc
Icelllymphoma. Other typ es of liNK-ceil
PTLD include T-cell large granular
~phoc yl8
leukaemia.
adult
T-cell
leukaemia/lymphoma, extranod al NKIT-cell

~phoma , nasal type, mycosis fungoide sl
sszarv synd rome, primary c uta neo us
e-epiastc large cell lymphoma and other
anaplastic large ce ll lymp homas. In North
America and Western Europe, they ma ke
Jp no more than 15% of PTLO. In some
rserces
PTLD have occurre d with,
e soosequentto, ot her types of PTLD,
t-een
The morphologic features of T/NK PTLD

do not di ffe r from those of the same
T/N K-cell lymphomaSin irTYT1llOCXXllT1petent
hosts.
fmmunophenotype
T/NKPT LD show express ion of panand sometimes NK -associated antigens.
Depending on the specific type, they may
express CD 4 or COB, CD30, AL K an d
either ali orto T-cell rec eptors. A bout 1/3
of cases are EBV-positive .
t-een
Genetics
Cases of
or igi n hav e c lonal T-ce ll
recep tor ge ne rearrang ement. Chromosomal ab normalities are commo n and
similarto those seen in TIf\JK-cell neoplasms
in the immunocomp etent host suc h as
i(7)(q1 0 ) and +8 in mo st of the neoatosplenic
lymphomas 1593, 21331.
TP53 and othe r oncogene mu tations are
also reported in a high p rop ort ion of
T/NK - PTLD 19801.
r-ceu
r-ceu
ClassicalHodgldn lymphoma
IypePTLD
Classical Hodgkin lymphoma (CHL), the
least COlTlTlOl1 ma,or form of PTLO, occurs
in the post-transplant setting . roost often
in renal transplant patients, is almost
always EBV-positive and should fulfill the
criteria for CHL as described (See Chapter
12) . Because ReedSternberg-like celts
may be seen in early, polymorphic and
some monomorphic PTLD, the diagnosis
of HL must be based on both classical
morphologic and immunophenotypic features, preferably inclu ding both CD15 and
CD30 expression 11 570 , 18871. Although
CD15-negative cases occur. caution is
advised in maki ng the d iagnosis of CHLtype PTLD as these cases must be disting uished from Hodqkin-Hke lesions, in
which the EBV+ Aeed -Sternberg-like ceas
areCD45 +. CD 15-, CD20 + and where one
may find small and intermedi ate-sized
EBV+ lym phoi d ce lls as well 1406, 609,
823, 1570 , 1759 , 18171, Rare c ases may
fo llow other typ es of PTLO. Although the
d istincti on of Hodgkin-l ike PPTLD from
true HOdgkin type PTLD may be d iffic ult
in some cas es, the former are bett er characterized as eithe r a polymorph ic or
monomorphic PTLD. depending on their
overall morphologic features 11759,18171,
Post-transplant lymphoprolilerative disorders
349
Other iatrogenic immunodeficiencyassociated Iymphoproliferative

disorders
P. Gaulard
SH Swerdlow
N.l. Harris
E.S. Jaffe
G. SundstrOm
Definition
The other iatrogenic Iympho prolile rative
d isorders (L PD) are lympho id prolifera tion s
or lymphomas that arise in patients

treated with immunosuppressive drugs
for au toimmune diseases or conditions
other than in the euoqran/auroqratt transplant setting. They comprise a spectrum

rang ing from polymorphic proliferations
resembling polymorphic post-transplant
Iymphoprolilerative disorders (PTLDl to
cases that fulfill the criteria for diffuse
large Be e nlymphoma (DLBCL) or other
s-een lymphomas. periphe ral l INK-ceil
lymphomas or classical Hod gkin lymphoma (CH L). Iatrogenically-related lymphomas supe rvening on naematoiogncat
malig nancies are not co vered here l4]
Epidemiology
The freque ncy of these disorders is not
well known, and it is dlfhcult to determine
how many are directly related to the iatrogenic immunosuppression rather than the
underlying disorder, Of to chance alone . It
is likely that the risk and type of LPO that
develop in this setting varies depending on
the type of irrmunosuppressive agent and
on the nature of the unde rlying disorder
being treated (e,g rheumatoid arth ritis
(RAJ. inflammatory bowel disease (IBO].
psoriasis and psortasc arthritis or other
autoimmune disorders) 13171, Methotrexate was the first reported immunosuppressive agent associated with LPD in this
rug
~ule
setting 11089. 1709, 1920). predominantly

in patients being treated for RA. In one survey. 479 lymphoma cases were recorded
among 101,589 patie nts treated with
methotrexate and/or anti-TNF therapy for
RA {24351. Many 01 these patients received
a combination of several immunomod ulators. complicating interpretation of the role
01 any specific agent. Among the TNFu antagon ists (inlliximab , ada hmumab and
etanercept), patients with Grahn's disease
treated with infliximab have been reported
to have a lymphoma prevalence higher
than in a healthy age-ma tched population
{ 1355}. A striking associ ation between
nepatosplenic t- een lymphoma (HSTL)
and young patients with Crotm's disease
receiving infliximab in combination with
azathioprin and/or e-mercaotoounne has
U~ng di$Ofdel
ThefaJ1Y duratiOn
Type of LPD
~ diseases,
3 year.i (0.5-5 ~l
OLBCL. If.
PoIymorptIIC LPO. PTCL
6 weeb (2-44 weeks)

1- 56 rronth$
OLBCl. ottlerlype$
HSn.olIlertwes
psor1aSlS
Antagonists 01 TNFo:
InfIIIlITI3b (MAll)
~d lseases
CtdIn's disease (young
patients)
Adalimuf1lilb (MAll)
Autoimmune diseases
NA
Altftype
Etarercept (fusion
protem with p75)
Autoimmune diseases
8 weeks (2-52 wee ks)
AJly type
NA, rv>l available: MAll. monoclonal antibody: TNF. tlll'llOtlr necrosis faclol': DLBCL. dlfllt$lliarge B-ce~ 'Ym~.
HL.1"lodgUl tymphorna; LPO, /yf1'lpI'qlroIOOrabYe disoI'def', PTCL, peripheral T<ellyn1lnoma: HSTl, hepatospl&ric
T<ellymphoma (reported only in pabenls eeeteo WIIh InlWnab. not with other drugs)
350
Immunodeficiency-associated Iymphoproliferahve disorders
been reported 11355. 18721, Cases eX

large B-ce ll lymphoma and Hodgkin
lymphoma have been reported in RA patients treated with TNF inhibitors. although
it is not clear whether there is a signdicart
increase in incidence 1284, 24351.
Etiology
Although some of these other iatroger.:;
LPD are associated with EBV. like rr'\iI1y
PTLD, the frequency of EBV intectot IS
very variable 1982, 19201 Overall. atxxA
40% 01 lPD in RA patients treated W1Il
methotrexate are EBV+, with EBVdetected
more frequently in Hodgkin lymphcrna
(-80%) than in OLBCL (-25%) or olhe!
a-ces lymphoma types, It is almost con
stantly found in polymorphic lPD and In
lPD with Hodgkin-like features in this se.
ting {982, 19201. EBV is not seen in Hsn.
The deg ree and duration of i~
suppression likely plays a role in ee
development of EBV-positive lPD. H0wever, the presence of inflarTrnation anQia
chronic antigenic stimulation as well as ee
patient's genetic background may be
important determinants of the risk and type
ol lPO 11221. For example, oanents we
RA are estima ted to have a 2- to 2O-Idd
increased risk of lymphoma even in the
absen ce of methotrexate therapy (122,
2230). and may have an altered EpslenBarr virus (EBV)-host balance 13161.lnaddition, HSTL -a lymphoma that tvoce
affects young men in the non-lnmcrcecpressed popu latioo- is common in)'OUl"\l
men receiving inlliximab for lBO, but not in

older patients or in patents with RA receiving this agent.
Cl inical featu res

These do not appear to differ from those
of imm unocompe tent patients with similar
appearing lymphomas.
Sites rJ involvement
M10ng the cases reported in patients receiVIlg methotrexate, 40 - 50% have been
enrercoat. inclUding the gastrointestinal
sect, skin, liver and spleen, lung, kidney,
Ilyroid gland , bone marrow (BM) and soft
tssoe 1982, 19201, As with HSTL in other
sermqs. spleen. liver and BM are the
COOII'TIOIl sites of involvement of HSTL in
Crohn's disease pa tients receiving inflixrreb 11355. 18721
Histopathology
The d istr ibution of histologic types of
iatrog enic Iymphoprohferation s in nontransplantation sett ings appears to d iffer
from that seen in other immunod eficienc y
settings, with a probable increase in the
frequency of Hodgkin lymphoma and lymphoid proliferations with Hodgkin-like
features. Among patients treated with
methotrex ate . the reported cases are
most commonly OLBCL (35- 60%) and
CH L ( 12-25%). commonly of mixed
TJbIt 13.06 Charactensbcs of melholrexate-assoeiatedIymplloprolileralive disorOers (135 cases withdetailsfeported).

Tolat
jpt
EBVt
EilfanOdal
Rtgr . n "
rsse
15/27
.,
7141
'"
keff Iymphoprolif.raliv. disordersllymphomas
.,
~BCL
64
Ptl/ymorphicl1 ymphoplasmacytic LPD
11
FoIIbJlar lymphoma
'18
' /5
&r'o.itt lymphoma
1/3
0/1
!,IlL/MALT lymphoma
0!3
"
Lrmp'loplasmacytic lymphoma
casu
.,
012
Tail lymphoprolil. rallv, dlsordtrsllymphomas
.,
.,
3/5
0/3
1/1
a.
01
EOlodaI NKIT lymphoma. nasal type
1/1
1/1
1/1
etrw R PO
1/1
1/1
1/1
10/12
2119
5118
PTCL
lbtgUI lymphornato
1Iod{I k~i
tI:GI
lnlons M
28
3IS
515
214
515
135
4011 06
32169
2&'90
r IlW. hal oIlhestCil9M. fle t1.rabCrl oIl1!lT1SS1CJ'1 was short 11- 10 mcnlhs) and c:hendherapy washfl reqlIIlld.
-n:ludes PTa.. notOlherwise s.pealiedand ~ T<eI ~.
1I.n. dIIIuse Iargt Ek:eIIymphoma; MZl.IUALlll'lill'glnal zone ~rnlCOS3-associated nphoid!issue
~ CLlISU.. d1roIic/yll'lphlXyliCleukaemaIsmaII ~~: PTa.. ~T-<dlyrrVona.
JD, ~oIlftlalrYe clIsorOer.
cellularity type. with less frequent cases

of follicular lymphoma (5-10%), Burkitt
lymphoma, extranooat marginal zone lymphoma of muc osa-associated lympho id
tissue and PTCL [982. 1086, 1392, 19201.
Polymorphic or Iymphoplasmacytic mfiltrates resembling polymorphic PTLD have
been described in up to 15% of the cases
in this setting. Lesions conta ining ReedSternberg-like cells but not fulfilling lhe
c riteria for Hodgkin lymphoma. that in the
past were referred to as Hodgkin-like
lesions . have bee n repor ted in all these
settings {10901. The HSTL in patients who
have been treated WIthinlliximab is indistUlQuishable from HSTL arising in irTYn..o:lcompetent or post -transplant patients.
Immunopl1eoolype
The irrmunophenotype of the LPO does
not appear to d iffer from those of similar
histologica l types of lymphoma in ronirmlunosup pressed hosts, I~
type is a usefu l tool in the d istinct ion
between LPO with HL-like features - that
should 001 be considered to representHLand CHL . the large cells being C02O+!
CD30+iC 0 15- and C020-iCD30+! CD15+
respectively, EBV is variably positive.
Genetics
The genotype of these immunodeficiencyassociated LPD does not appear to differ
from lymp homas of similar histological
types n01 associated with immunosuppression.
A significant p roportion of pat ients with
methotrexate-assoc iated LPO have shown
at least pa rtial regr ession in respo nse to
d rug withd rawal (Table 13.06): the majority of responses have occurred in EBVpositive cases 1982, 19201 A variab le
proportion of OlBCl (up to 40%) and
CHl (up to 30%) have reg ressed. while
most require cytotoxic the rapy: overall
survival of OLBCL is approximately 50%
[982 . 1088 . 1089, 10901. Some pa tients
whose LPO may initially regress after discon tinuation of MTX. regrow at a later
date and require chemotherapy {9821.
Regression after discontinuation of drug
seldom occurs in patients who develop
LPO following the administration of TNFn
blockers. Like in other ind ividuals without
overt immunodeficiency. cases of HSTLin
pat ients treated with infliximab appear to
be fatal 11355. 18721.
Omer Iatrogenic lrrenorooetcencv-aseoceteo tymphoprohferative o.soeoers
35 1
Histiocytic and dendritic cell neoplasms,

Introduction
R. Jaffe
SA Pileri
F, Faccberu
O.M , Jone s
E.S Jaffe
Hetlocync neopl asms are derived from

mononuclear p hagocytes (macrophages
and dendritic cells) or tnsuccvtes. Dend ritic cell tumours are related 10 seve ral
d ifferent linea ges of accessory antigenpresenting cells (dendritic cens) that have
a role in phagocytosis. processing and
presentation 01 antigen to lymphoid cells.
Peucuiohis tocv tos is and Rosai -Dorfman
disease. which are covered in the WHO
Classification of TlJT1QUrs 01 the Skin, will
not be included in this chapter.
Epidemiology
Tumour s of tusuocvtes are amon g the
rarest of tumours affecting lym phoid tis sue s, p robabl y repr esenting less than 1%
of tumours presenting in lymph nodes or
soft tissues 1673. 17451. As several of
these tumou r types were poorly recognized until recently, their true inci dence
remains to be determined. Historic ally,
some large cell lym phomas of Been or
were though t to be histioc ytic or
reticulum cell sarcomas on p urely mo rphologi cal grounds, but only a sm all num ber
r-cenrspe
prov e to be of true macrophage or dendritic ce ll o rigin, Some of the reg ulator y

disorders such as macrophage activation
or haernophagocytic syndromes may have
large numbers of hetocytes but the se are
roo-recotastc. No sex. race or geographic
predilection has ye t been described
Histogenesis
The cellular counterparts of this group of
neoplasms consist 01 myeloid-derived
macrophages, rnyeloid-derived oeodnnc
cells and stromal-derived dendritic cells ,
The myeloid-derived macrophages and
dendritic cells constitute divergent lines
01 d ifferentiation from bone mar row (B M)
precursors, althoug h traneortterennauon
or hyb rid di fferenti ation states likely occur.
Monocytes. macrophages. his tiocytes

Me tch nikoff is consi dered me father 01 the
macrop hage and in 1883 coined the term
phagocytosis, postulating a central role
for the process in the bodys innate defense
against infe ction 1821A, 146 7AI . The
histiocytes/m ac rophages are derived from
~LT3L
OIll~5f
._~- -
<p
n_
..
-- . -- -----
","
'.
OM-esl'
c::::;co,..
. ,
.' !.~
,
...~...... ,,
.J.L(~
""'"
Fig.14.01 Sdlemabc diagram d!he 0f9II- Bolh maaopllages and dendritic eens (Mligen presenIilg eels) are ~
from a canmon bone marrow preanor. In contrast tokuIar deOO1IJc cells are Ihougt'4 m be d ~
origtn. - . rrost 4 I'lOl: III oeII poSItMt: ., aI eels negabve: ~+, a rrinorily of cells pos4Mt, 'I. vanabIe 1Jl18nsity,
354
Histiocytic and oeoonn c cell neoplasms
BM-derived monocytes and ton

migration/maturation in tissues participate
in the innate response with pro- and SI1Iinflammatory cytokine effects as weN as
particulate removal and tissuerecoosaen
1821A. 82 1BI . They are derived large!'{
from the circulating peripheral blood (PS
monocyte pool that migrales thfOl.9l
blood vessel walls to reach their SIte ~
action. but local p roli feration also cootributes 118161. Histiocyt ic tumours are
closely related to the roonocytic tUI'l'M:U5
from which their precu rso rs are derIVed
The distinction between a ieusaenc ilti
trate of monocytic ori gin and nrstocrtc
sarcoma can sometimes be difficult (II
morphologic grounds alone.
Mac rophages display phagocytosis lnler
some conditions 01 activation and. at ths
stage, there is hei gh tene d exp ression ~
lysosomal enzymes that can be demonstrated by netocnemlstry including ~
specific esterases and acid phosphatase
Phagocytic activity is not a prominent
feature 01 histiocytic mali gnancy but is a
cardinal feature of the haemophagocybc
synd romes, The naemopbaqocvnc macroph age activa tion syndromes are an in-;.
potent group of ron-neoplastic prolileratrve
di sorders tha t need 10 be dilterenliated
from true histiocytic neoplasms, and are
far more co mmo n, The haemophagocytic
sy nd romes are the result of genetic or
ac q uired di sorders in the regulation of
macrophag e activa tion. The primary familia
tvmonobienocvnc d isorders are due to
genet ically dete rmined inab ility to regulate
ma crophage killing by NK and /or T ces
becau se of mu tatio ns in perform, Its
pa c kag ing , export or release. AcquiredlX
seconda ry causes of the naemoonacccvtrc ma c rophag e ac tivati on syndromes
follow c ertain infections, most nola
Epstein-Ba rr virus (EBV) and a wide varl8':Y
of other infectiou s agen ts, as well assere
malignancies. rheLmatic disorders and mJ.
npie organ failure 11 04 51. The characteristic cvtopentas of the haemophagocyoc
syndromes are most like ly du e to BM ~
pression by the cytoone storm since t"le
BM is often twperceuoiar at the outset
Tlblt 14.01 Trufl histiocytic malignancy, a vanishingdiagnosis.
Original diagnosis
Currently considered
HisIr::q1ic lymphoma, nodular anddofl1Jse
Diffuse largelX:e1l lymphoma

Folicularlymphoma, grade 3
PenpheraI T-cee lymphoma
HrstJocyte-rich variants 01 B-oeI. T-cell and Hodgkin lymphoma

Anaplastic largecellympIloma (ALCl)
--
AtCL
RegressIlg aIypical hrsliocytosis
Pmwyeutaneous COJO.posilrye
...... ~ hisIJoc)1osfs
Enleropathy-type T-cel ~
~ ~!tlIc ~s
Subcutaneous ~ T-<:eII~wilh
....
TZIIt t4.02
HCIefTlCI/IQOCYIic s~s
Haemophagocytic syndromes
~ I!Wkers01 ~Iic
~ .
F"""""
CO"
""
lC
'DC
-c
..
. 1-
' 1-
CO2'
COJ5
ClJ68
CDl63
F_
'-""
''''''''''
5100
TCll
..
..
. /.
..
..
..
macrophages and dendntJccels.
FDC
....
com
Facb' nna
T_
Pot
DiDC
.,-
-t,
..
..
+/++
,.
. /-
./ -
' 1_
. 1_
FCR, Fe IgG receptors (include C016, C032, C064 onsome cells); LC, la ngerh ans cell; IOC, interdigitating
dendriticcell; FOC, follicu lar dendritic cell: POC, plasmacytoid dendritic cell: Mia, macrophage: DIOC, dermal/interstitial dendriticcall: c. cytoplasmic: e. surface.
Expression is semiquanlitatlvelygraded 0 thrOlJQh H , + present, ++ high, +/-Iow or varies wilh cell activity.
Myeloid-derived dendritic cells

Dendritic c ells or antigen presenting cells
are found in various sites and at different
Slatesof act ivation , and no single marker
foil identify all de ndri tic cell subse ts {138,
1816,2094/. Langerhans cells (LC) a re
soecanzeo dendritic cells in mucosal
Sfe!:Jskil that upon ac tivation become specialized for antigen presentation to T cells,
and then migrate to the lym ph node
nrough lym ph atics. Lymph nodes also
conta in a paracort ical d end ritic ce ll type,

the interd igita ting cell (lOG) wh ic h may be
de rived in part from LC 17711. This classical
dendritic cell lineage is believed to give rise
to Langerha ns cell t sstccv tosrszsarcoma
and to IDC sarcoma. A third, poorly-defined
DC subset, de rmaVinterstilial dendritic cells,
are found in the soft nssue . d ermis and in
most or gans, and can be inc reased in
some inflammatory states 11381.
Plasmacytoid cencrtnc cells (POC) (also
known as p lasmacytoid mooccvtes) are a

distinct lineage of dend ritic cells, which
are be lieved to give rise to the blasticplasmacytoid dendritic cell neoplasm
(See Chapter 6) 19201. The histogenetic
origins of POC are controversial but are
likely 01 myelomonocvtic lineage. Interferon-a-producing PDC prec ursors, which
are not strikingly dendritic in appearance,
circulate in the PB and have the capacity to
enter lymph nodes and tissue through
high endothelial veouies 113251.
Stromal-derlved dend ritic ref! types

Follicular dendritic cells (FOe), which are
resident within primary and secondary
B-cell follicles, lIap and present antigen to
B cells FOe can store antigen on the cell
surface as IITrnune complexes for long periods of time 123041. FOC appear to be
closely related to BM stromal progenitors
with features of myofibroblasts 113601.
They are a non-migrating population that
forms a stable meshwork within the follicle
via cell-to-cell attachments and oesrrosomes .
Fibroblastic reticular cells (FAG) are invotved
in maintenance 01 lymphoid integrity, production and transport of cytokines and other
mediators. In lymph nodes, they ensheath
the pos t-capillary venuies {1 115. 23201.
They are of mesenchymal origin and express smoo th muscle acti n Hyper plasia of
FRC (i.e. stromal overgrowth) may be seen
in Castleman's d isease (1028, 1309 1. and
tumours of FRC arise in lymph nodes and
have features of myofibroblastic tumours
and closely related neop lasm s 144).
Because there are few phenotypic markers
uniq ue tor the dend ritic or macrop hage
tusuocvtes. the investig ator should use a
panel appropriate to the ce ll in qu estio n
and rigorously exclud e other cell lineages
(T cell, B cell. NK cell but also stromal,
meranocvuc and epith elial) by immunophenotypic and molecular means. It is also
worth mentioning that some reueaemtas
and anaplastic large cell lymphoma can
be ac com panied in lymph nodes by an
exuberant histiocytic response that may
obscure the neoplastic cells.
Introduction
1
355
Histiocytic sarcoma
1M. Grogan
SA Pileri
J ,K ,C . Chan
L.M , Weiss
C.D .M. Retche r
Definition
HistiOCytic sarcoma is a malignant pronteration of cells showing morphologic and
immunophenotypic features of mature

tissue histiocytes. NeoplastiC prOliferations
associated with acute monocytic Ieuka~
are excluded
ICD-O code
9755/3
Epidemiology
Histioc ytic sarcoma is a rare neoplasm
with cxty limited runbefs of reported series
of bona fide cases 1473. 886. 964.1087,
1745, 23451 . There is a wide age range.

from infancy to elderly; howeve r. most
cases occur in adu lts (median age , 52
years) 1964. 1745 . 234S1. Ma le predilection
is found in some studies 11745. 2345} b ut
not in others 19641.
..
Etiology
Fig. 14.02 Histiocytic sarcoma. Ditluse etlacem&nl 01 arctlitectln is seen by a large eel prokIeraboo N iI
irdsmgiWlable from a diffuse latge Ek:eII lymphoma by c:onvenlionalllistopalhology
The etiology is unknown. A subset of cases

occurs in patients wi th mediastinal ge rm
cell tumour, most co mmonly malignant
teratoma, with Of without yol k sac tumour
intestinal tract, skin and soft tissues . Othe rs
component 15551. Since teratocarcinoma
present with I;-mphadenopathy. Rare patients
cells may differentiate along haernatopoietic

line s in vitro 14951. histiocytic neoplasms
have a systemic presentation , with multiple

sites of involvement , some times referred
to as "malig nant histiocytosis" 1347, 1745 ,
24 19).
lesions to innumerabl e tumours on the

trunk and extremities. Patients with intesllnal
lesions often present with intestinal ocsnucnon. Hep atosplenom egaly and associa ted panc ytope nia may occur. The tooe
ma y show lyti c lesions (964, 1745,23451,
Clini cal feature s

Patients may present with a solitary ma ss,
bu t sys temi c symptoms are relatively
com mon, e.p. fever and weig ht loss 1964,
1745, 2345 1. Skin manifestations may range
from a benig n-ap pearing rash to soli tary
Morphology
The tum ou r co mp rises a diffu se roocohesi ve pro lifera tion of large cells (>20
IJm), but a sinuso idal distribution may be
seen in tymph node, liver and spleen. The
prolife ratin g cells may be monomorphic
may arise from plurip otential ge rm cells,

Other cases may be assoc iated with
malignant lymphoma , either pre ceding or
subseq uent. o r with my elodysp lasia and
leukaemia 1677 . 964 ,1745, 2345 1.
The majority of cases present in extrarodal
sites {964, 1745 , 23451, most co mmonly
356
HistiOCytIC and
cenontc cell neoplasms
or. more commonly, pleomorphic. The individual neoplastic cells are usually large
and round to oval in shape; however. local

erees or spindling (sarcomatoid areas) may
be observed The cytoplasm is usually
abundant and eosinophilic, often with some
Ire vacuoles. Haemophagocytosis occurs
occasionally in the neoplastic cells The
nuclei are generally large, round to oval
or rregularty folded, and often eccentrically
placed; large multinucleated forms are
corrmonly seen . The chromatin pattern is
usually vesicular, and atypia varies from
rrjd to marked . Irrmunostaining is essentia l
lor distinction from other large cell neoplasms, such as large cell lymphoma,
melanoma and carcinoma.
A variable number of reactive cells may
be seen, including small lymphocytes,
plasma cells, benign ntsuccvtes and
eosi"Klphils. SometimeS the neoplastic cells
are obscured by a heavy inflammatory
rilltr ate including many reueoonns, mimdUng an inflarrmalorylesion; this feature is
partICUlarly corrmon in histiocytic sarcoma
IrlYOIVing the central nervous system 1411}.
Ultrastructure
The neoplastic cells show abundant cvtoplasmwith numerous Iysosomes. Birbeck
granules and cellular junctions are not seen.
Irrrnunophenotype
lir
Fig. 14.1)4 HIstiocytic sattOI\"Ia, AHIstiocytic satO:llNI iNCM'lg tie bowlt B Nole tle al::u'ldarC cyt;)pIasm. wI'ich stans
stn:lf9Y b' C068 (e) and tysozyme (Dl
expression of CD 15 occurs 11745 1. In addition , CD45, CD45RO and HLADR are

usually positive. There may be expression
of $. 100 protein, but this is usually weak
or focal 117451, There is no positivity for
specific B-eell an d
markers . CD4 is
often positive. These tumou rs are devoid
of HM B45, epithelial memb rane antigen
or keratin. The Ki67 index is variable 117451.
t-een
By definition, there is expression of one or

rrore histiocytic markers, including CD163,
CD68 (KP1 and PGM1 ) and lysozyme
WIth typical absence of Langerhans cell
(C01a, langerin) , follic ular dend ritic ce ll
(C021 , CD35) a nd myeloid cell (CD33 ,
CD13, myeloperox id ase ) markers 1964,
1745, 2345 ) Both C D68 and lysozym e
show granular cytop lasmic staining. The
~zyme staining is accentuated in the
Goigi region. CD 163 staining is in the ce ll
membrane and/or cyto plasm. Rarely. weak
Genetic s
Histiocytic sarcomas usually lack clonal
Ig H or TCR rear rang ement s 1473), bu t
rare cases have been reported to show
ant ig en receptor ge ne rearrangements.
most likely repr es enti ng exa mp les of
transd ifferentiation 1886. 1810,23451.The
rare c ases a rising in med iast inal ger m
ce ll tumou r show isoc hromosome 12p .
id entic al to the gene tic c hange in the
germ cell tumour 115941.
Postulated mormal counterpart

Mature tissue histiocyte.

Histiocytic sarcora is usuaJly an aggressive
neoplasm, with a poor response to therapy.
although some exceptions have been reported 19641. Most patients (60 -60%) die
of progressive disease reflecting the high
clinical stage at presentation (stage III/IV)
in the majority (70%) of patients 11745 ,
2345). Patients w ith clinically localized disease and small p rima ry tumou rs have a
more favourable long-term outcome (964,
1745).
HISllocytlC sarcoma
357
Tumours derived from Langerhans cells
A. Ja ffe
L.M , Weiss
F. Faccnetn
The tumours discussed in this section

originate from Langerhans cells of which
they maintain the phenotypic p rofile and
ultrastructural features. According to the
degree of cytolog ic atypia and clinical

aggressiveness. they are divided into two
main subgroups: Langerhans cell histio-
cytosis and Langemans eel sarcoma. There

may be rare cases that can be difficult to
assign to one or the other category; these
cases need further clmicopathologic
studies to clarify their nature.
LangarfJans cell histiocytosis

Definition
Langerhans cell histiocytosis (lCH) is a
clonal neoplastic proIiferaticrl of Langerhanstype cells thaI express COla. Iangerin and
S 100 protein , and stowe Bubeck granules
by ultrastructural examination.
ICD-O code
975 113
Synonyms
Histioc ytosis X, eosinophilic granulo ma (if
solitary lesion). Hano-Scnuner-Chnsnan
d isease (if multiple lesions), Lette rer-Siwe
d isease (if d isseminated o r viscera l involveme nt).
Epidemiolog y
The inc idence is about 5 per m illion po pulation pe r yea r, with most cases occurring
in child hood. There is a pred ilection for
males (M:F ratio 3.7:1) 117451 . The d isease
is more common in whites of northern
B
f ig. 14.05 I..angemat1s celllIstJotyklsls, A Radioo;1aph from a paten! WIth eosrIOptilic ~ cl bone .....
a discrete ~ lesion. B Agalun SC8l1 sI'lOWS high uptakei'llytic bone lesion.
European descent and rare in blacks.

Fam ilial clustering has shown a high concordance rate for identical twins but not
dizygous pairs and no vertical inheritance
{761. Primary Langerhans cell hetocvtoers
of the lung is almost always a disease of
smokers, usually non-clonaf and thought to
represent a reactive process 1502, 24791.

The disease can be localized to a single
site. multip le sites within a single system,
usu ally bone, or more disseminated and
multisystem 11480, 22421. The dominant
sites of involvement in the solitary for m
are bone and adjacent soft tissue (skull .
fem ur, ve rte bra, pelvic bones and ribs )
and, less co mmonly, lymph node, skin
and lung . The mu ltifoc al lesion s are
large ly c onfined to b one and adjace nt
soft t issue. In mu ltisystem d isease , the
skin, bon e, liver, sp leen and bone marrow
(8 M) are the preferential sites of involvemen t. The gonads and kidney appear to
be spared eve n in disseminated forms ,
Cl inical features
Patients with unifocal disease are LlSI.latf
older childrenor adults wOO rmsl: lXlrTJTUtf
present with a lytic bone lesion , eroong III
cortex. Solitary lesions at other sites peset
as mass lesions or enlarged lymph nodes.
Patients With unevstem momtocar disease
are usually young chil dren who presem
with mulliple or sequential destructive 00'Ie
lesions often associated with acaceot sdt
tissue masses. Skull and mandibular involvement is common. Diabetes insipidus
follows cranial involvement. Patients witt';
multisystem involvement are infants whJ
present with fever, c vtooenras. skin and
bone les ions and bepatcsplenomeqav
175, 14821 Pulmonary disease in childl'cj
is c linica lly variab le {16 19l.
There is an associatio n between lCH
and T lymphob last ic leukaemia, with the
leukaem ia-associ ated T-cell receptor gef1l!
rearrangement p resen t in the LCH cells:
this has been considered a transd ifferentiation phenomenon (6761.
Fig. 14.06 Langemans celMIiOC)1O$IS. A Numerous lange!t\arJS eeas are seen. wiItI scattered eosinophiIs and smallymphocy1es. S Ni*ll'oe typical cytlIocjit leau.d
I.Mgernans eel$. WIfl many nudei contaIIWIg IneargtOOYe$ CEosI'lophic microabscess.
358
HistIOCytIC and dendritic cell neoplasms
1
Fl;. lUI langertIans eel ~...-aslruclln
A typical BII'bect granule is seen.
~
Tne key feature is the identification of the
l CH cells. These are oval, about 10 - 15
.m, recognized by me grooved. folded.
tdenled or lobulated nuclei with line
ctvomatin, inconspicuous nucleoli and thin
can be confirmed by tangerin expression.

The Birbeck granule has a tennis racquet
shape. and is 200-400 nanometers long
and 33 wide. with a zipper-like appearance.
Immunophenotype
lCH consistently expressesCDla, langem

and 51 00 protein 1418. 1191AI . In add ition . the c ells are positive lor wreren.
C068 and HLA-DR. CD45expressonand
lysozyme con tent is low. B- and
t-een
ncear membranes. Nuclear atypia is

rwlimal, but mitotic activity is variable and
,
j
I
j
e
e
."
can be high without atypical forms The

cytoplasm is moderately abundant and
s~ghtly eosinophilic . Unlike epidermal
Langerhans cells or dermal pe rivascular
eens. l CH cells are ova l in shape and de\'Old ofdenonnccell processes. Thecharectensncmilieu includes a variable number
of eoslnopnns . hrsnocvtes (both multinuceeieo l CH forms and osteoclast-type
cells especially in bone). neu uoonns and
small lymphocytes. Plasma cells are usually
sparse Occasionally, eosinophilic abscesses with central necrosis, rich in

Oarcot-tevoen c rystals , may be found . In
early lesions, the l CH ce ll p redo minates
along with eosinophils and neutroobus. In
Ia'.e lesions, the lCH cells are dec reased
n number. with inc reased foamy mac rop'lages and fib rosis,
Il'MlIved lymph nodes have a sinus patte rn
Mtt1 secondary infiltration of the paracortex.
~ showsnodular red pulp involvement.
liver involvement has strong pre ference
'cf intrahep atic biliary involvement with
~ressi ve scle rosing cholangitis . Bone
lI'arrow biopsy is prefe rred to aspi rate for
c crrentatlon of BM involvement [14811.
-arge clusters or sheets ollCH cells ac::cmpanied by eosmoprnrs can be found
other lesions , lymphomas and sarmas. It remains to be clarified whether

rese represent a local reactive phenomeroo 01 a trenscntterentlaton process 14401.
lIJastructure
-"IE! ultrastructural hallmark is the cyt o:mmic Birbeck granules whose presence
A
~
Fig.1U9 langerhans C&l1 hist~os~ . A,B This lymph node biopsy ~ extensive inwlvementof !he sinuses and
paracoucal regions.
...
Fig. 14.10 la'lge!tIar<s rei histloI:pJsis. A Connst!he bland I'IUl::lN' mor~wifl lhatol1he sarcoma (Seef ig
14.11 and 14.12). B ~ is !loCh I'IJderar and cytopIasnic W'IIh 5100. C COtastai'WIg is lA'lIofrnly SU'1ac:e WIlll a
~ dOC 0 L.angenn slaInilg is rrwn grarWr and cytlJlla$rTiC.
Tumours oeovec from langerhans cells
359
lineage mqrkers (except for CD4 ). CD30

and follicular dendritic cell markers are
absent. Ki67 is high ly variable 11745 1.
Genetics
LCH ha s been shown to be clonal by
x-unkeo an drogen rece ptor gene assay
(HUMARA), except in saneadult pulmonary
lesions 12418. 2479 . 24801. No consisten t
molecular genetic defect has bee n identified 115421
Postul ated normal counterpart
Mature Langerhans c ells.
The clinical course is related to staging of
the d isease at presentation, with 99% or
g reater survival for wutocat disease and
66% mortality lor young Children with m...iltisystem involvement whO do not res pon d
promptly to therapy 1740. 1480. 22421
Involvement 01 8M . liver and lung are regarded as high risk fac tors 11480 . 22421.
Prog ression from inilial focal disease to
multisys tem involveme nt can occur. most
usually in infants. Age. per 58. is less important an indicator than extent of disease
/1480,2242 1, System ic and (rarely) multifocal disease can be complicated by
haemophagocyt ic synd rome 16741.
Clinica l features
Most instances are extra noda l involving
skin and bone an d muttltoc al. hig h-sla g e
d isease (III-IV) is seen in 44 %. Only 22%
are primarily nodal. Hep atosp lenomeg aly
is noted in 22% and pancytopenia in 11%.
Morphology
The most pro minent feature is the overtly
malignant cytology of a pIeom::lrphic turour.
and ooIy the phenotype and/or ultrastructure
w ill revea l the Langerhans cell de rivation .
Ch romatin is clumped and nucleoli are
conspicuous. Some cells may have the
COfT'4)Iex grt:lCNeS of the LGH cell. a key due
to the d iagnosi s. The mitot ic rate is high.
usually more than 50 per 10 high power
fields. Rare eosinophils may be admixed
Langertrans cell sarcoma

Definition
Langerhans ce ll sa rcoma (LCS) is a highg rade neoplasm wi th ove rtly mal ignant
cytologic featu res and th e Lang erhans
ce ll p henotype.
ICDO code
9756/3
Synonyms
Dendritic/histiocyti c sarcom a , Lanqernans
cell type . malignant histiocytosis X.
Epidemiology
La ngerhans cell sarcoma is rare 1183,
232 . 1745 1. and almost all repo rted cases
are in adul ts. The median age is 39 years
(range. 10 - 72 years). A female p redominance is described (M:F ratio 2:1) 117451.
Skin and underlying soft tiss ue are the
most conrnon. with rrultiorgan involvement
that includes lymph nodes. lung . liver.
spleen and bone 1232. 696 . 1745 1.
360
HistIOCytiC and oenonuc cell neoplasms
Ultrastructure
Birbeck granules are present, ~ile
d esmosom es/j unc tion al specializations
are absent 117451.
Immunophenotype
The immunophenotype is identical to thai
of Langerhans ce ll histioc ytosis. amJough
the staining for the indivi dual markers can
be focal and pa tchy.
Mature langerhans cell.
Langer'hans cell sarcoma is an~,
tigh-grade malignancy with > 50% rrortaIti'
from progressive disease
Interdigitating dendritic cell sarcoma
L.M. Weiss
T. M. Grogan
J .K.C. Chan
Definitioo
power fields) . Necrosis is usually not present. There are often numerous admixed
lymphocytes, and less commonly, plasma
cells. The histological appearance is soretimes indistinguishable from a follicular
dendntic cell sarcoma and phenotyping is
necessary for precise d iagnosis.
Interdigitating dendritic cell (IDC) sarcoma

is a neoplastic proliferation of spindle to
ovoid cells with phenotypic features similar
to those of inte rdigitating dendritic cells.
roo coda
The nuclei also appear spindled to ovoid ,

and may show indentations; occasional
multinucleate cells may be seen . The Chromatin is often vesicular, with small to
large, distinct nucleoli . Cytologic atypia
varies from case to case. although the mitotic rate is usually low 5 per 10 high
Inlerdigitaling dendritic
cell sarcoma
975713
E,;demOOgy
nterdig itating dendnlic cell sarcoma is an
extremelyrare neoplasm. With most Studies
representing single case reports or very
small series 144. 68 1, 1343. 1475, 1563,

1564,1745. 1881 .23751. The largest series
IO date have consisted of four cases 1741,
\745, 17481. The repo rted cases have
occurred p redominantly in adults, although
paedia tric series has been repo rted

117481. There is a slight male predomi-
CI'Ie
nance Occasional cases have been associated with low-grade B-ceillymphoma
and rare cases have been associa ted

lIIith t-een lymphoma 174 11,
Fig. 14.13 Interdigitating dendriticcell serccna Tumour is YilQuetylobulatedin fymph node, and firm in con SiSterq
The presentation has shown wide variation.

Solitary lymph nod e invo lveme nt is most
common, but extranodal p rese nta tio ns.
oarticularly the skin and soft tissue , have
been report ed,
Clinical feature s
Pa'ients usua lly present with an asvrr otosere mass. although sys temic symptoms.
SlJ:h as fatigue, lever and night sweats,
have been reported. Rarely. there may be
generalized lymphadenopathy, splenomegaly or hepa tomegaly,
-y
TN! iesonar tissue in lymph nodes is

eesent in a paracorticar distribution
lIIlh residual follicles . The neoplastic prolif.
eexn usually forms fascicles. a storilorm
estern. and who rls 01 spindled 10 ovoid
Sheets of round cells are occasionay 1cLnd. The Cytoplasm of the neoplastic
eels is usually abundant, slightly eosine . and often has an indistinct border.
InterdigItatIng dendntlC cell sarcoma
361
Ultrastructure
The neoplastic cells show comple x interdigi tating cell processes, but well-formed
desmosomes are not present. Scattered
lysosomes may be present , but Birbeck
granules are not seen.
Immunophenotype
The neoplastic cells consistently express
S100 protein and vimentin with CO1a and
langenn being negative . They are usually
positive l or fascin and variab ly. weakly
positive for CD68 . lysozyme and C045.
Strong nuc lear staining for p53 may be
present. They are negative 104' markers 01
follicular dendritic ce lls (C021 . C023 and
COOS). nwecoeroxoase. COO4. specific
B-cell and T-cell associated antigens.
C030. epi thelial memb rane antigen and
cvtosereuns. The Ki67 index usually
ranges between 10 and 20% (med ian
11%) 1681). The admixed small lymphOcytes are almost always of T-cell lineage,
with near absence of B cells
Genetics
The irrvnunoglobulin heavy chain gene and
the beta. delta and gamma chain genes of
the T-cell recep tor are in a germline con-figuration 123751.
Interdigitahng dendritic cell .
Prog nosis and pred ict ive factor s
Theclinical course is generally agg ressive.
with ab out one half of pat ients dy ing of
their disea se, Viscer al organs that are
commonly attected includ e the liver,
spleen , kid ney and lung . Stage may be
an impo rtant prognostic factor, however
histologic features have not been correlated with clinical outcome.
362
:D:' ~ .
~
. ~
Fig. 1.4.16 Inlerd~ ilaling dendritic cell sarcoma. A Nole ttle paraooctical pattern of tulTlOUf growth in the ~m ~ root
B There are scattered sma~ Iympllocytes througlloullhe lesion, CThe CD21stain is negalive on !he lurT'lOlX cek tu:
labels follicular dendritic cells in residual follicles. 0 In contrast. the slain for 5100 protein is strongly posili'le J\!tII
tulTlOO r cells.
HIstIocytIC and oeocnnc cell neoplasms
Follicular dendritic cell sarcoma
J .K ,C . Chan
SA Pileri
G. Delsol
C.D .M, Fletcher
LM , Weiss
K L Grogg
Definition
Follicular dendritic cell (FDC) sarcoma is
a neoplastic proliferation of spindled to
ovoid cells showing morphologic and
immunop henoty p ic features of foll icular
dendritic cells.
975813
EpOdemdogy
Follicular dendrrtic cell sarcoma is a rare
144.385. 1501. 1591, 1724 , 1745,
23751. There is a wide age range, with an
ao:1Jt predominance (meanage, 44 years)
reooasn
11591, 17451. The sex orstntxnon is about

even, but there is marked female preoneclIOn for the inflammatory pseuoorurrourke variant 1409. 1745.23131 . Follicular
dendritic cell sarcoma occurs in associebon with Castleman disease in a small

proportion 01 cases, usually the hyaline-
vascular type \3871. In these cases, either

ee Castleman disease precedes the follicular den dritic celt sarcoma or the two
esoos occur simultaneously,

Ebology
tnere is no known etiology lor most
cases, The inflammatory pseudo- tumourI I~e variant of follic ular dendritic cel l sarcoma is consiste ntly associated with
Epstein-Barr vir us (EBV) (7 1), wit h EBVencoded RNA (EBER) being d emonstra ble in virtually all the neop lastic sp ind le
cells, and Southern blot stud ies ha ve
::Iemonstrated the virus to be p resent in a
rooccronar episomal form 11991)
Ft.l.1, FoicUar ~eeI

~locaIlon.
sartlCII'l'I3.
Precursor les ions

In rare c ases of Castleman disease, there
is a proliferation of fol licular oenontc celts
outside of the foll ic les form ing clusters
and small sheets {1893 1 Follicular dendrit ic
c ell sarcoma may evolve in this setting of
foll icular dendritic cell hyperplasia eoc
overgrowth.
Follicular dendritic cell sarcoma presents
as lymphadenopathy in one half to two
thirds of cases, w ith one of the ce rvical
lymph nodes be ing most often affected
The tumour can also present in a wide
variety of extranodal sites, such as the
tonsil, oral cavity, gastrointestinal tract.
soft tissue, skin, mecnastmom. liver and
spleen 1957). Comnon sites for metastasis
include lymph nodes, lung and liver 14341.
Clinical featu res
Patients most often present with a slow grO'Ning, painless mass, although patients
with ab dominal disease may present with
abdominal pain . The tumou rs are often
large, with a median size of 5 ern. Systemic
symptoms are uncommon in conventional
follicular den dritic ce ll sarcoma, but are
common in the inflammatory pseooo-tcrroclike variant I409 }. Rare patients have paraneoplas tic pemph igus 11 265,1 405. 23571.
Morphology
The neoplasm com prises sp ind led to ovoid
ce lls formi ng fascicles, storifo rm arrays,
who rls (at times reminiscent of the 360 0
pattern o bserved in mening ioma ), d iffuse
Fig, 14.17 FokUaf llerO'CiC eel satCOTI3. This mass

oco.ned n the soft bssues . <n:I has the appeaTC8 cI
'"""'"
sheets or vague nodules. The individual

neoplastic cells generally show ind istinc t
cell borders and a moderate amount of
eosinophilic cytoplasm. The nuclei are oval
or elongated, with vesicular or granular
finely dispersed chromatin, small but distinct
nucleoli , and a delicate nuclear membrane .
The nuc lei l end to be unevenly spaced,
with areas showing clustering. Nuc lear
pseudo-inclusions are common. Binucle ated and multinucleated tumou r cells are
often seen . A lthough the cytologic features are usually relatively bland. significant
cytologic atypia may be found in some
cases. The mitotic rate is usually between
o and 10 per 10 high-power field s, althoug h the more pleomorphic c ases can
show muc h higher mitotic rates (>30 per
10 high-power field s). easily found atypical
mitoses and co ag ulative necrosis,
The tumour is typically light ly infiltrated by
small lymphocytes, which can sometimes
be aggregated around the blood vessels
ASprde eel proWer.lliOn.
Fol lic ular oenccuc cell sarcoma
363
. '1'
'6a,'tof'
,..(.:,,.'
\ . , ...:;, . . ..
. ...
.
~ .
~ . "'~
' ...
.. A I
>"'~1'W "" 1fl
" A
Fig. 14.20 Fojlicular dendriticcej l sarcoma This&lectron

miCrograph shoo.Ys nOOlel'OUS cytoplasmic processes. do
one weI-formed desmosome presenl lnee Cflfltre
as well (3841, Less common morphologic
features include: epi thelioid tumour cells
with hyaline C')1OpIasn, clear cells. oncocytic
cells. myxoid stroma, fluid-filled cystic
spaces, prominent fib rov asc ular septa
and admixed oeteoctastc giant cells 1384,
385, 1724 , 17251. In rare cases, the large
neo plastic ce lls are scattered singly in a
bac kg round of small lymphocytes, mimic king Hodg kin lymphoma. Rare cases
may also show jig saw puzzle-like lob ulation and perivascu lar spac es , mimi c kin g
thymoma or ca rcinoma show ing thymu slike element (CASTLE) 14341.
The inllammatory pseudo-tumour-like variant of follicular dendritic ce ll sarcomas occurs exclusively as primary tumours in the
liver or spleen 171. 409, 19911. The reoplastic spindled cells are dispersed within
a prom inent lym phoplasma cyt ic infiltrate.
Theruclei usually show vesicular chrornallO
patten and disflnct nucleoli. Nuclear atypia
is hig hly var iable: usually many cells are
bland-looking. but sere cells with enlarged.
irreg ularly-fo lded or hyperchromatic nuc lei are always found. Some tumour ce lls
may even resembl e Reed -Sternberg c ells
1199 11. Necrosis and haemorrhage are often
present. The b loo d ves sels frequently
show fibr inoid deposits in the walls .
364
Ultrastructure
The neoplastic cells have elongated nuclei .
often with cytoplasmic invaginations. If-ere
are characteristically numerous long,
slender cytoplasmic proc esses , often
con nected by scattered , mature desmosomes. Birbeck g ranules an d numerous
Iysosome s are no t seen.
Immuno phenoty pe
Follic ular dendritic cell sarcoma is positive
lor o ne o r mor e of the follic ular dendritic
marke rs, suc h as C02 1, C D35, C023,
KiM4p and CNA .42 1159 11. Clus terin is almost always strongly positive, while this
marker is usually neg ativ e or only weakly
positive in other dendritic cell tumours
lB53. 8541. In addition, thel1.mour is usually
positive for desmoplakin, vimenbn, tascn,
epidermal growth factor rec e ptor and
HLA -OR 1384, 21221. It is variably positive
for epithelial membrane antige n, S l00
protein and C068. Exce ptionally. cytokeratin, CD 45 or C020 c an be expressed .
Staining for C0 1a. lysozyme, myeloperoxid ase, C034, C03 , CD79a. C030 and
HMB 45 are neg ative. Ki67 labeling range s
from t to 25% (mean, 13%).
The ad mixed small lymphocytes are
pr edominantly B cells in some cases.
HisllOCytlC and dendritic cell neoplasms
predominantly T cells in some , and mixed

Band T cells in others 1385,17451.
Genetics
The immunoglobulin and
t-een receptor
genes are in a germline conligJ'ation 123751

Data on genetic changes are c urrently
very limited 119271,
Postulated normal cou nterpa rt
Fo llic ular dend ritic cell of th e lymphoid
follic le .
The behaviour is usually indolent. much
like a low or intermediate-grade soft tissue
sarcoma 13851. Most patients are neater
by complete surgical excision . with Of
without adjuvant radiotherapy or
therapy. Local recurrences occur in rTli7l!
than 50% of cases, and metastases OCCU'
in about 25% of pa tients: SLJCh occurrences
may be delayed after many years 1384
1725 , 2054 , 23131. At least 10-20% 01
patient s ultimately d ie of the d isease. often
after a long period of time Cases showing
high -g rade features (significant cvtoccc
atypia. ex tensive coa gulative necrosis
and a high oroseranve inde x), large turro.I
size (greater than 6 em) or intraabdooll'lal
location can pursue a rap id ly fatal course
1365.17451 .
crerc-
Other rare dendritic cell tumours
L.M . Weiss
J.K.C , Chan
C.D.M. Fletche r
There are rare types of dend ritic cell

tumour other than the better-delineated
entities covered in the previous chapters.
These may be derived either from
myeloid-derived dendritic cells, such as
ooetermmate dendritic cell tumour ; or
from stroma-oenveo dendritic cells, such
as fibroblastic retic ular cell tumour. Some
dendritic c ell tumours may rema in unclessifiabledesp ite extensive work-up or show
hybrid features, and such cases may be
tentatively designated "dendritic cell
tumur, not otherwise specified".
the alleged precursor cells of Langerhans

cells . These neoplasms are extraordinarily
rare 144, 203, 236. 391. 11n, 1859. 1865.
2019,2315.2325,2441 .24501 . There may
be an association with low-grade a-cen
lymphoma 12315 1.
Patients typically present with one or, more
commonly, multiple generalized papules,
nodules or plaques, Systemic symptoms
are usually not present.
The lesions are usually based in the dermis,
but may extend into the subcutaneous fat.
The infiltrate is diffuse, comprising cells
resembling Langerhans cells, with irregular
nuc lear groove s and clefts. Cytopla sm is
typica lly abundant and usually eosinophilic. Multinucleated giant cells may be
present. In some cases, there may be
spindling of the cells, The mitotic rate
varies widely from case to case . An accompan ying eosinophilic infiltrate is usually
not present. By defin ition, these cells lack
Bsbeck granules on ultrast ructural examination . There can be complex interdig itating cell processes. but desmosomes
are lacking.
The proliferating cells consistently express
atco protein and COla. Langerin has
been negative in one studied case . They
are negative for sp ecific B- and t-een
markers. CD30 , the histiocytic marker
C0 163, and the follic ular dendritic cell
markers C02 1, C023 and CD35, They
are varia bly positive for C045 , C068,
lysozyme and CD4 . The Ki67 index is
highly variable. One case has been shcM'n
to be clona l by human androgen receptor
gene assay
The dinical coese has been tvgtVy variable ,
ranging from spontaneous regression to
rapid progression. There are no known
prognostic factors. One case has been
associated with the deve lopment of acute
myeloid leukaemia 12325},
RbrobIastic reticular cell tumour

ICQ.{)
code
The tumour is histologically similar to follicular dendritic cell sarcoma or interdigitating dendritic cell sarcoma, but lacks
the irrmunophenotypic profile of these
tlXT1ClU'" types. There are often interspersed
delicate collagen hbres . Ultrastructu rally,
the spindle cells shaw delicate cytoplasmic
extensions and featu res reminiscent of
myofib roblasts (filaments with occasional
fusiform densities, well-developed oesmosomal attachments, rough endoplasmic
reticulu m and basal lamina-like material),
The tumour cells show variable immunoreactivity lor smooth muscle actin, desmin,
cvtoeeratm ( in a dendritic pattern) and
CD68
975913
Indetermina te dendritic ce ll tumour

Fibroblastic retic ular ce ll tumour is very
rare, and the entity reported as 'cytokeratinpositive interstitial reticulum ce ll tumour"
probably rep resent s the same entity 144,
3001. Thistumour can occur in lymph node,
spleen or soft tissue {44, 380, 822 , 10651.
The clinical outcome is variable, with some
patients dying 01 the disease.
ICD-Ocode
9757/3
Indeterminate dend ritic ce ll tumour, also

known as indeterminate cell histiocytosis,
is a neoplastic prolifera tion of spindled to
ovo id cells with phenotypic features similar 10 those of norma l indeterminate cells ,
Other fare dendritic ceutcmours
365
Disseminated juvenile
xanthogranuloma
Def inition
(JXG) is characterized by a proliferation
of histiocytes similar to those of the dermal
JXG . commonly having a loamy (xemromatous) component with Touton-type
giant cells. There is evidence 1Q( clonality
in some instances.
Synonyms
Deep JXG (if soft tissue involvement).
Benign cephalic histiocytosis. progressive
nodular histiocytosis or generalized (nonlipidemic) eruptive histiocytosis (cutaneous
disorders wi th multiple JXG but withou t
systemic mvotverrenn .
Xanthoma disseminaturn (if skin and
mucosal lesions).
Erdhesn-Chester disease (possible adult
form with bone and lung involvement)
12488A.238 1AI.
Epidemiolog y
Solitary dermal JXG is vastly more common than other forms and does not
progr ess to more d isseminated forms
1538Al. The majority 01deep, viscera l an d
d isseminated forms occ ur by age 10 years,
ha lf within the first yea r of life, except for
the adult Erobem-Cbester form 110458 1,
Etiology
There is a know n association with neurofibr oma tosis typ e 1 (NF l); pa tient s with
both are at slig htly high er risk of juvenile
myelomo nocytic
leu kaemia
(J MML)
125 1OAI. Patient s with bot h Langerhans
cell d isease (LCH ) and JXG are encountered.
Sites of Involvemen t
Skin an d soft tissues are most common,
and, in disseminated terms. mucosal surfaces es pecially upper aerocnoesuve
tract . The central nervous system, dura
and p ituitary stalk can be affec ted as well
as eye , liver, lung , lym ph node and bo ne
marrow (8 M). Retroperitoneal and pe riaortic involveme nt is noted in ErdheimChester d isease 1538A, 733A . 104581.
366
A, Jaffe
C.o.M . Fletcher
W. Burgdorf
Cl inical features
Skin lesions other than the common papular solitary fo rm are small (1-2 mm) and
multiple. Soft tissue lesions can be large.
and the lesions present as mass effect.
Optic lesion s can cause g laucoma , CNS
and pituitary lesions, like LCH. can c ause
diabetes I1sipidus, seizures, hydrocephalus
and mental status changes 1538A, 733A .
104S8 1. In contrast to LCH . liver involvemen t does not target the b iliary system Of
lead to sclerosing cI1oIar'Qrtls 11042A1. There
is some ca pacity lor lesions to slowly
regress. While JXG appears to be benign,
a concomitant macrophage activation
syndrome can lead to cytocentas. liver
damage and death in the system ic forms .
Morphology
The JXG cell is small and oval , sometimes
slightly spin dled with a bland round -toov al nucleus without g rooves and pink
cytopl asm. Touton cells are less common
at no n-derm al sites. The cells become
progressively lipid ized (xanthomatous) . A
mixed inflam matory component is invariable, Varia nts include epithelioid cells
with g lassy cy topla sm , The ultrastruct ural
feat ures a re histiocytic without otstlngu ish ing features 124BBAI.
lmmunophenotype
ln co mmon with macrophages, ce lls express vimentin, surface C0 14, C0 6B
(PG M 1) in a co ars e gr anu lar patt ern ,
C01 63 in surfac e and cytoplasmic pa ttern and Staoiun- t (MS- l antige n). Fac tor
Xnta stain ing is common but not unive rsal. Fascin stai ns the cell cytoplasm and
8 100 is variab ly pos itive in less than 20%
of the ca ses; however, none of these
ma rkers is specific lor JXG. C0 1a and
Langerin are negative 1392A, 118BA,
193 1A,24B8AI .
Genetics
No consistent cytogenetic or molecular
genetic change has been identified.
B and 't-een receptor gene rearrangement
are qe rtruire. An association with NFl is
known in some. There is evidence for
clonality in some instances 11045AI.
HIShoc yhC and oenontc cell neoplasms
Fig.14.24 A Radiograph ofa case of Erdheim-ehesler

disease showing a lytic and sclerotic lesion in the ~
femur and theproximal tibia, There is destrudioo ti the
antttrior femoralcortex, with an impactedpatllolo:9c fracture through the lesion and an aote~ateral s.oII--tissue
mass extending from the destroyed femur (arrow)
Reprinted from {187lA}. Courtesy of Or SuS! ~
ram, B Abdomioal CT from a patient with ErcIlet1IChester disease showmg a soft tissue infflm!
SUrroundll'lll lhe aortaand kidoeys (wtVte arrows),
is a sclerotic lesion in the veteea (blaet. arrow),
Reprinted from {1479A}. Courtesy 01 Dr. RGdbE!l1O Gl:JI.
n-
mo..
Fig. tUS Systeri: JXG inYoMng Mr. A The nfiltrate is portal in natJSe but spares ee bi& duct. FewToulon cells
n p-esenl. 8 Faco Xilla There is d1ltuse stailing of the portal hJStJocy1eS.

The celt of origin is debated , In spite of
macrophage prerotvoe. it has been sa id
10 be a defmaVinterstitial dendritic cell on
eebasis of shared Factor Xllla and tascn
immunostaining. but these have limi ted
specificity 11 188A1.

All clinical forms are benign. though multiple lesions in brain , dura. or pituitary c an
cause local consequences and even
death. Systemic teems tha t involve liver
and 8 M have been treated with lCH-type
therapy
Dtsserranated juvenile xanthogranuloma
367
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Sli1\ll1 AmJ$YrgPaI!lQI29 166,-166ol

Adii mP, I(a!zllrlbtfy&r T, S6eber1J'8" H,
GalteniolVler S, Wolf J. S\einIIIin C, Sctrnod 1.1
1,Uet-liefmejOl HK. Ott G(2003). A cnfI d a
~ *VI B-oeI ~ oI~
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147).1476
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823-832.
A1cali1, M, T,aca E. BargotrlllS R,
K _ Ill. 5l-e JC. So:nr~

Arrdd W (t999). ExIr<wnIKl.Aa'y plasmacy-
toma tumor oeeurrem;:e ana Ihe<IpelJtie ~

ceplS cencee 65 ] 3052314
23.
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saoo ~ Fo.>u L MarWI8l P Campo E
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lor ~ cornmdh!KI mveIocl progerotr
origin of cf'ItI:lrllC myek:lrnonQc) .....
and IlJve. . clYonic m\'$kl!(l illuk _'
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EIIIOP"'\TiSkFcn:e 011 L\'fTlII'IOmI ptqII;l

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. . - pro/i'ng ""*- olG3. 503-511
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Marcos-Grill/ara R COOb&rgh JW (2OCI61
Hodg ~in d t _ &.ul'/;"'al In E\IIope aoo the
U S progrnsl>c llgnillC8l'1a1 01 morphologic
9'0I4'S Car<:e< 101 35236(1
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HoJema!OI107 121131
27,
Aiona=m EL, Stamberg J, Kumar D
Jaffa ES, ~ W, Frtlnll C. SChiffer CA
o'Connell eA K~ S. SIaq SA.. "'bruuo
LV (19971 ~ 1q the pnmr,
~ IbnornoaIIy 1'1~ gaon...... T ... ~ L........ 1113157-
A.des lor IhlI
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21,
AIWleIl R 8ryne& Rl<. Si'w'ak loll
Mler 01< (1997}. Ac.uIe myR:T..-emoa .....
1(69) (p23:q341 1tSSOOiIbOn ..... ~
Sti . basophil,i . nd initial C034 nag al'\1I
imm ~ til>e Am J Ciln Patl'ltj 107: 430-
:lIA
AIsabeh R Meaeorlls U GIICUl C
W-SlJ,lT~oI~""'"
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~~""""""J~PaIlDI
1991 21'528-536
2t
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cyl>C 1ymph0m8 \Il'lltl ron-i'1oOgl.n 1ymp'Iom&
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HemalopaltlQlogy lnd E(iDonKoowIes,[)

(ell). Lijlptlloolt WiltamS& Wi!l<ln!
36.
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N SchMIVfll S. Jhelo__ SC.

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flOfl-Hodg'Il" lymphomas d~ rI
major &.ubtypn diIIef by g80Vr~
Nonl1oIlgkln I Lyrnpnoma C
Prqec:t AnnlAW 9. mno
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su",,,,,i" .'pression in di1'l'1,>S\I latglI S-al 1ymp/\otIIQ 1lb:ld 96 1921HI2S.
II.
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D. Bernard L. TlUOIli L VoIoOO S,LUl'i
L, CoiorTtlo E Lo Coco F, IAecoo:i C. FiMli S
Ptk:o f'G (2005) ~ ~ .... I.emis
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N ~ A.. I.d:lI K. ....., CT Ilryder 0

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39.
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Hasl R (2002) FkJor~ i1 \$.; nytwIl
11oo for the Jlujy 01 CfIllIileella ~
myelodyIpIask s~ ..." d1tln<
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ME (1i19Q) Cu!aneout T cet 1ynV.oma W1lh
~(C08)~ dIn!lf>.
Alcindor T
Bndge~
KR (2002)
ar>aemillll B! J liaematol 116
IIIpioty ~ ...:I dwtnIC Ilb~ J""'Aall~22 5fl9.-sn
733743
21 .
'-"')[(InOer 1<. Ani(,to ( Bu.blu m J
(1968) GMlma heavy ~ifl ~ '" man
GIntwnic li8Qt..-.aI ....us t100 IVICOlIigl.OJS
. . . . . n . . . . . QWIe JCIn~82
12J.. AgnIIo V CIlurlg RT,
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22.
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C. Kal RJ. Oriotdeb.". H.
and other r1flOP!asm$, leukan'Oll 1~ 2342.
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Zherog J KoIon>ottl E, 1'1"'11 C (20071
bIn9' ~
IIIOI'IOdonal 8-011 ~ Nrl J Or!

PItrD 128 333-338
31
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c....
~ T BloW AA. '

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Y!lInJ RC (lVT7) Co'rtJnabI
"noMiodgUII~fIl!ollboi
1lIlni'tam IIH, Bower M, M~ 0, KanflllrE,

N ~r~ K~ i200lj. Absence of cyd;11D2 Inc!
1ld-2 e. l.'" ~ wilI'lin If',e germmaI (;ftI'l\r8
type 01,jj!'ule lwge 8<ell ~ ~
I -.ery gooclllft9"O'llC ~ 0/ pa:.tts
bbwt.c e- Treolt Rep61 10:571006

41.
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nonHodVlun I tympl\oma 1M
Non-Hodg n', Lymphom.

Faclors ProjIc1 N Engl J Mtd 329
It kt;II 1'9951 PoIyeyll'lemia 1'e<lI: till

IInI MIllrY 011213 patter'"/oIowtd for 20
Grvppo 11aliaro Studio PoIc:i1l11111a Ann
1lIa11t3 S56-664
dirMclII avlllulTion of
Lymp/'(lma SlIJdyGroup cI.iI"
01 r1<)(I.Hodgkin. lymphoma. ThlI
Lymphomli Claqjfieall(lll
kt;II, 11997). A
,,~
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I'od Elb:ld Ml :ll109-J918
ll. .l.norI (H1911 P!unary tI'I1I1\OIlOder.c-.

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Aeport 01 a WOO """tific ~
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Pror*)' body ~~ ~ Iym-PflOmaI ...... J CIa! P.ro 105' 221-229,
59,
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Ko1lIIlMl H ' ..... Iii ..... Iii. TajofIlI ",
~ 1,1 11991 ~!P:n lor
pIaonI ~ pMiIntI ..?lJ c...Qna;; 21
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.... ci$IaM "Mlh re;r~s of ee
pia .' t d,liwed growIh l3da' rec&pIor beta N
EIlQI J Ued JolT 431..t81
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'OIllo EM Mendonl;a N FossHO.H"""""Iel 1.4,
S\tin H ~20061 Tr.e "9' Irllqll!lr>Cy 01 EBV
inlolclion " pedlalrlc HodgkIn Iymphana It
rtilnd 10 I\e dimaI lype '" BahI3, Br3.l'
Virt:Ilowt fvrJ\ -449:315-319
U
Arll8r DA. CarIer NH. Ik.. D. Slovak Ml.
120031 Value fA combirIed morpllOlogic, cyIOclwT1K;al. afId imrr<Jnophenolypic features ill
pradldi"9 recurrent cytog&nebl; abnormalities
in l!CuT. myelood leul\mnia, Hum Pathol J.l
II ... -utIlp tIIId WI
II
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01l1li j)'llNl't ...,

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la.
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(19B4). L~1lie dO-. 01 donor
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ClaSlolfication Projoct J Clm Oncoi t8 27802795,
80,
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Sillo9ml8l1 LB, Slam AW Clan Boer~ .. f>Jeters
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Til. Griff", JO Kll<smeyer SJ (:?OO3) Irr.<botion
ol fL 13 .., MLl VllidlIbon 01 ~lie lar
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As'IIon-KfIy Lt, Diu TC. PM L lllllAO
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ftcaborl.e-Cfl3 m-la3
~.
at
W-..mz.R, SIetry W(:10081 C056 ~

~ ~ 01 lrII skin A mtJllic::enIer
Hldy rJ lhe Culiw>IIoos Lym&:ilomI P.ajlocl
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io'r-=t0I1ICUII m,relodIeut_ c1:rs' ,
~ ol doolacP1 01 'llOJImlI ~.
Ie iJllnorInIIies and ~ ~ (WI
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~ T~ 1ympIIOmI. Iliblll 01 cf/OlO>:OC
~ lO1\tIlfIlOO$Il or"'" ~
1504~1551
U.
s..
~_~ ""'J5t.J'Q~,.,.,.
lllood91 1123-1131
B2.
MJns E SoItlara L R-..cIM. 9IIll..-.
~'*lIl 1.4
SM. ue-Iw- OJ
s.orwv
PI!OnI 1(....... RJ(2OOEIl ~

01 ! <.ell repetlDore
'-Y 011
paIlo!onIt. bIIIn..,
,,,,,,,,,,too... tmv'O\l)dl 8112 ~
e - ImInwnol
IrmlunDIlar 5'i 11(lO.1110
n
AIuns E Sl.Ilat*Ia J s...- T
*"'_
" - - ru
12!XlBJ
s.-.c
...,VHl/!l"'I .... II'-Yoaa . . . . . . 8J ~ t33 !iOI.~12
Kerl K. Bekkenk I,l
Kempf W. Mei,.. C,
oIBCL2~iI'l~~
Am J PalhoI1SO:. 159-763
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~ I( K~
J. Bc8;jlI A.
BE yin d V. lllc*lt T. HannI G

0a00alM" l s.ol.-.Raddatt B ~
"'" aen
.. SIJiI* R
S ... dli'I SA{1006
8Cl6 ....... ~ regiorI
~ IF'(!
Ilorr!olvglu llIIl*In 01 '7Q24 ... 8'e IliJltM'

~ ~.Q !'/PI 01 Hodgb!'
tyIl~ ctII lint OEV ...... PII\OI
31 61s.683
t5
".,., C, ~ S ..,..,. L "'"
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101. Aul C. ao.- OT YOIhiclI Y (1M).
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111. ...~ H. All" t.l I.lorMJ P,
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~ IlI'lI'I'lIII -...:l prtlj:Olion rJ"..
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~ l"l-.nIl'I aaII rn,oaIoll
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123. e- loR
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Iher1 If'hIlISIlIIl dufeIicrI II'I:l !UfVlYlII I'l acuIe

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115. 8oIcao.." M. R.m.o O. R..... G
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~......
~.
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..,s
dIrf<;al pre$eI1latJ01l
. . . ... I'OmilI~
W DeIIrIgIR F R..m S. T-..anl P,

8IotalII R (2001. C~ ~ w
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lie ItJIIrVnluPI FIWlQ:lPhone <1i IoIytIomtn
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lIlId
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OC B1ft! JC. 0-,-
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~,
s..t
0,
S<Mer CA.
~COtl99T).E~ot . . ntI.nIl
OIIl1Ches1on rrdlcuII CO!J6 II aa<X:>IIed.....,
Mal
L.U
t~
46. )51-)613
Ill . 8IalIl (),l Y. Ii OISI Te . ~
C. j(~ B ~ RP lid*.- AI
FiIlT)' J Ou Me Dogan A ;2(07) P!Wwy ~
laJlIr~ot .... _aro:I~"
dIllS Am J s..g PlIIhoI 31' lO5G-l058
1211. ~ FK. ItensCIn C. CIlan
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we
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121. BlIdIr-Moo rlHl r e, Tct>em.ii G, Mialol F,
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1'1 ~....
IIfvI lkeI
IympI'lotlIas
Re& 21: 234So2352

lZ7. IlaonB(2006. ~1detobIasls .....
lIlrofnlloxyIos
~
l.O\tOrIIfOOIl
m.. 1d
~
~oilIra'we . - - "
(lIdIr8dult:s. BrJ~13ol
J,lo-J.tl
Ba,n BJ i l996).
EOSlnophohc
leukaemias and thl l(Il(lplIlhic hyp.ere
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' 29, sen BJ 11 9!f9), TlMI 'Ilations/lip
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ee mV$kxiyaplastic syndromes and
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U II, 6lJjn BJ (2004) RllII/l<;mtljp betNflll
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131.
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flld""~.
.... wwiInI rJ roe ~llIV*~,

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V. V., ~ JW VaFI dIr

Puma SC t.IIOJIf CJ, MIIma R (1997)
132.
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8-.:1115
UI, .... .lJ
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131.
8;JIMlw8,~O,~C
G. Lui L, lono<l e, 8erILCO F

R. Devllard E Ctft>uccil N
~ UJ, Biml;)8 ~ 0, BraAIoIl p,
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~ ider1tlftlSlllOIecI.ola' sullgtllufls lrI'(III
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0lM:0At J. lebIcqo.e S l.iJ YJ F\Mnl 8.
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llII5 NnJ Rev ~ 18 767..,11
13t. e-a PW Chan J a.ry ....
G ~ C. ~ II GID\JIrl :"II
Hams N.. - - - . PG. . . E5 1
..... ell ~ A lJlIPOIII b"
Dton d .o~"'*""" irmvlolt9C. ""
IIrdlta Am J 5Iit9 PaIlrlI16 r.J1-601O
CIc>\.qI
Booab<da~eh
ea.. c
13M 8ardIIV.Co:s1aLD E.C......, S.

0emuI C. Tamtun J ~ PC, Nfl.F
llo\I'I 8, Jouf<llrl E.
It. hl N,. .
M Orey1ul F, M.yeu' P, l.aocomoI

~G nsceli A, Bemwd OA. 8cl.Iu'I
D, RllCIltr C (2006), ~ ....
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novo .oJte m)'lloid IelP.ernoa IIIlh
OI\ollIlfoI:.ema20'16oU-1646
1010. Bar\oglI e, EpstIi'l J ~
P.,..... . . R\I969i ~0IIIl~
normal ""
~ ~
lIlIIlIJI& a'ld 8IMIaI1l
py 8Iood 13' 1l6&-819

loll . e.oC SaIIdoY.~A.
I CQIonlo l SerT8ro S, SolI F
T,a>'IIOtalO' 1{9,14l(plJll32) II _
~
lOl'II
~ 9 1 \289-1:191
1012. BerQIi G (1999) ~
splIn<
~ lIlMdI. . . . . CIIWlI tJ ~
. . bIIween a.GneouI T<:III ~ an:!
lIlytIoo:l ........ ~ ~
~T-<:eI ~
~ ~
Am J P3IhoI 150
19411!l49
133, Bai<klll" w.., ~.. Imhoff GW,
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Jlft9J)IIC ~ b ctneIlI . . .
''''
1013.
J On CInoll 17
Baro5l G, Hollman R {2Oll5i
myIllOIibrol;os Semn HemalOl 42 246-258.

143A, B. rosi G, Mesa RA , ThoIII
CelVantet F, CampheH PJ, VeolO,,* S.
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327334,
134. Bai<tvs MH, HIirrnIol C. V.. R. I. V.n
Cao-4l s. n - - I K (1991/ E.YIdeooII1lll
~ myIIomI I; "-Y d\IlIl VDJ glnI5
...b" _ _ 0 1 ~ ' .'"
QOnIIlI'l
l
II ' l d ~
h_
~
blI8I.
_
--.c lIlIA*I'lS !loA ...... no .....
lDlil . . - . 8Iood 110. 2326-2335

135 ~ 0 ~ It. C4IoMo l
RoMIo E. Ga'N A "'-""IZ-8en\iI W
RMly JT.Van"-lCCto AJ,i, HarlSO/1 CA

LA Orllll A. Tellilri A, ~
Group
UyelofilltOlll; Rf5IIItlI
(IWG-MRTI (2OOB) ~
I(lI
T~
Wo!llr9 Goo.'ll b'
~ftlT......... ~22U1
P-..A,FuK ~ D Cob'!wD
Bullli JS. W..... AA. Campo E (2001)
EpsIIirt-Ba<r _ ~ ~ plaisma c:eI
1401. e.o. G. AoIIi \', " ' - II.

Gl. P:o A. NIa:h V. ~.
~an:l~
Spleen --.googe<lfM
.. ~ l
OII~a~""'~
donioopa!llolllglo; ~ Nn J s..g Pallol
31 13'll-1J22.
13SA. B!lld..s CO, T.rI'lIf SM. Ruwert ,\S ,
WllIIman SP, Archlll ll.J, MMcI!OO C, Caligiun
MA, Carrol! AJ, VardoniWl JW. PowI.!I BL. N len
.,1M, ~I
JP 1'1<97). OCW'fenCI
al
St. Moore JO, L.Y5On RA. lIoIilI JE, de Is

~ltl A, BMxwnfIeld CO 120(3). BAALC
m ~lIb~
dllO<der ., pallenls "'Ilh
alprnwn p<eclicts donal 0I.0me of OIl 110"'0
NoorIafl I~ J Pldialr 13lJ 885-889

lZ2. 8aec:llUlcI E. Sur>dsIrom C, ~liilom A.
can.eAl.,~P flle'oJS N ~ l
....... Jan ()w;a" 790-19/
. . . '"Yf*lod .....-- PII*1IS

~
IMIh l'KllTIlII
a Cencerand ~ GIoJp 8
*"'J' 8iood 102 161.3-1618
..
R.~ M~I.l.""",U
n~_
1'1
pIlJenIs
'iO'd I'IlIlIPIMII- "
HMTIIIlI I2. 618-625

145, BatoIoG,VIill"lr9OG "-:oA,Roa
P!aWo G, Marchei\I Y , F _ F 12111

DIagnostIC and dir>ICaI 'M\rllllC8 c( itlI rurar
01 circuletlrtg C 0 3ol(~) celIII ., m
W11h rnyelood metapIasia . 1liood 98' 324g.~
s.t. "
Barranl; Sl , FenlOn .lA

RG,.Iad<. ,l,S 12(04). ~
rJ FOXPl ~ a doAnd:
d
lIfge lkell ~ lOUlQ.I . . .
pool' CWllmI 8Iood 104 2933--~
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t. loog P, Murphy KM, Gnmn CA
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R., tfIr A. F~z JM, Seoent l. eer.era J,
Mo&cardo F. 5w """ Cross NC (2002) T~
1(4"22)1Ql2;1l11/ i1 afVpoI.:aI cImlne m~
_ ........ __ OCR e POGfAA Hum IAoI
lAnII n 13811:57.
1U s.-..- EJ. ScOII Uol CamPleI PJ Ed

e, FOIIIlUdas N SwaokII 5 Vas1illou GS.
Bn:h 1lJ. Bov<l E;M, o.nn N. scceMA, Ert>er
WN Gfeoo AR (200S) ~tre(I n1\Jtalroo rJ
lhlllyOSillekNst JAKl :n homBll rnyeloprold
.iII... dIsoIIlln l.ioal 365 1054-1061
184. ~C,~I<.~E.
.... ....... PagM; '-5', Ra.t I<. L..-. L
~ hi. lld-.a 'I. Dip,od F. E...
~ D. ~ l o.l8OI G (1999).
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s.
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~'
report 01 fuur
ca... Br J HaernaIDl1()4 6ollO-6Bl!

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111 monllli e&il lymphoma Bre ~ted wim
bla5ICId...- Illood 93 436S..tJ/4
1M. 8e.a S. TOIl F, PII'I\'Ol M Puig X
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lo/uzIwI N. ClllcwrW D.~ E i2001) Il'ao
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2412
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Te w--tuve<DO.Nn"JO.~
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SJ rnoo R. PoweI J, Wilson WH, Wte ES
Mootserral E. loUBrliermoloIIlk HK SlaWllM
CImpo E. RoeeollflKj A (2005) 0Ilt..- IIrge
B--eeII I)mllIlonlI ~ 110M! ~
IJ8'18IIC pro6iIs IlIl ~ lImDr bo:*:lgy
.-w;l lIftPIO'I9 ~esMlIl-!Ill5ed
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11~.
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tc fl<:lOn 11 ' QI'OIIp rJ 62 PIltieots, e!ood 102'
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Blood 93 364l-3653
176. BetlRdj K, Reyes F, Farcet JP. Tity H,
Ila&lard C, ArI\IOO"' R, Deroonck E, Charioll.
F LellkIId V. UiJouyne E. leder\Il P EmiB
~ DeIrr\III'-- S. 1<IrUI B. z,n" ES
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rJ 21
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171,
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PO
(1994' Pr.,.-ya.ar.u T-oll
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pqroIltc ~ 01 3S ~ . . . . . .
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L(2003) PatiIoIogl<: IJ6l)eCtIofAIDS~
0tI 00c0gI0B 22, ~
119.
C I.a.!zI 5.11eFilco G NJ'O"IIO
A GOl1PlI>,.LeootIOiL(2003jllur>"',,,,,,,"
lftm;l"- ""'lII*" ~ ~
... J Cloo PaIloI: 56 lM-I92.
Bellan C, lau, 5, Hummel M.

Palurnmo N, de Saob 1.1, Amato t , Ny~ J,
Sahall.". E Lazure T, Pilen SA. Raphael M,
S/lllI'l H loti P lerJI\QIII l (20061 lPM'UIo180.
~ ~ ~ rt'4Il$ 2 d$In(:t 0lIl rJ
OOV'" Iof EeVilOSihe _ EBY'-fl8Iljill/we

1lurILlI~ 8IJOd 106'10311006
181. ~llf3OI G, CaneI'mo OA (1966)
I T.ngll!ctaal~
mawlaris erup~'Ill pers\am

With mastocyt<is) Mi10erwa 0e-n-MlcM 41: 436-
Ileo AI"ld F IiIIpIlen M .... 1
eo--.e H
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fl. AI"d K. BeoI AAeIM H
(1989; T~ rJ Iiphe d\eIIl ~
~ N .....
preddon. Blooll I06 3183-31!1O
~d8~lIudylll21 T.......
168. 8elll'lTlin RM, PHngalis GA, RawaPOrt

H (1979) Acule ("maligrlanl") m ~.
cancer 4J 27!lo-293
169. IleeIyt.ffl Kumar S. $OIIlMa l .....
K. R.1IIItll( JIIe E5 (19991 A bqJI.o:typc;
TlIfli.. an-F rertctl l ~t8sboal

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183. Ileo E61I J. l3aIIf'f A. Aam N DelsCIl
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PI!taILVS S, Raltll1d M, Witaoo WH Jaffe ES
(2001) ~~!1i1'1Uklmlllo
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01 dIIK:aI iIInd tIio.ll<Igo; /eomQs.
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5.,.st1me ~ 1!'JJDCt""ll :ntamrnMory
Ilowej dMaie, A case Iepor1 aod chcusIion rI.
gurrot nte!;tlnal ptlthOk:llJy in ~y stllrTlle n\astr><:y.
totiI. Nn J SII'9 Pll1hol 30 1~7&- 14112
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Lymptlorna GIWP 00 !he !or9te<m fcM ll;rroo ~
data 01 219 patierml and guidelirlel; fof dIIIgoosil80d ~ Blood 95,:l(;5J.-3661
171 8elAeok tIW. - - . ~ ..... CJ
111.
v-z. R i2004)
CD5&+ lWllet::IlllgaI __
pal.ents
b~
th~
~R
ShlooDirJK RappeporIH(1991J
X. A dIIIn;:j cn;o.
~8I"IlIIY
1050-1Q80
184. !leo Ezra J. Ilurte J5 S-u WG
llrowoeII "ID Brynes RK,I1IlI LR,tialwwan SN
OIoan MM. W~ f Be, Woodruff R (HIM ) Small
~ ~
e-:.r68
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d",~lhologoc
" s r J 268tll'leS BIoocl73 579-587

l IS.
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Pllox" M VIOlleniel 9 .Imlb loIC. ~ F

f*lSiI JC
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~ ~ lIeIldr*: QItI PlIl1llm rJ
e-
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mqmlc)"y ~ . leukllmill l S 1~"'1 1498.

1". Seo& Me, 8emoer Lt. easasro- RO
CUIOIdi G. DoeIo_ 0,
ller liB Knipp
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lIf'lal)'SlS H'1 24t palJents, Br J fillfMl'lalOl 113
731Wi.
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\.Wllog 'M), MiUM E. 0rfI0 A _lV_MIl
I ~ C"-~
lor lilt
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of
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t..oombtMJ ~~ E ~ K, PlIen
S Mon-. SW MaIoo DY. DeIIol G (1ggB)
ALKpoMlle lymphoma. a singledi!lellS8 With i
t)r(l;ll(j IPf(;lNm of "lOrpilology BkloO 91
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169 IIerollIll IN ~, 0 DineI lIT
FIInITon G GIIon 00A ~ H. S<AIn e,
ec..C(llli9ot\ Thedl'ln:rno,ebd~
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myelomoooc)obC 1el!iulemi8. f>foposals b)i lhe

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45145/l
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FIInIm G GaIloo DA.. \nlrri I1R su. e
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~~.9rJ""""'51
189-lllQ
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Flaodnn G, Gallon DA. Gram HR, Su!\ar1 C
(1989). Proposall lor the tlIIWficaIoOO III
~ 1/I'IIUlI)
T 1yo\'Ih:ICI .........
an
F~(FA8)~
JOIn P.-.ol42' 561.58(.

BBrfl TF BruoerIeoro S. Iloc1
D. sa- llIJ, SaldiI M. JooI S, Vadol A.
~
192.
s.nu"
fM AC,
Uulle<~l
HK. lidlt.- P.
DOOner H, Moler P (200 1). Gall' of dltomoIIOII'e ..... gp is et1i1f8tleris1c III pnmery ~
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Jalte H (1\191 1 AID!HtIIocliIIed nonl-1odlIkm
~
Lan<:oilt 337805-809
~ 1.1 lulY1l R. ~ H. Elley

E (20)1) Flf3 ~ ..., IMIl(II'I8e Ill. . .
InA.
~,
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(1 9951 Proposafl tor lhe OTlrl\lJl'lOlogici
fQl/i;ln 01 &C\lle lll\lkerTll8llJ. ElI"Op8ilIl Group
"'
.., II
J'WI'I1 ...
rid'"
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SaSl'oo Y, Bryon PIo., Co<"'otr e lt 9941,
NonIoIiclJ* smallk>II ~ . a fINro.
~ goup 01 peIBJIs w.et ~ dIIaI
. . . . . ..., out:oIne- Blood &3 283-2835
ItS.
F F...... p. ~ C.
Pr.-. 1. I!aoIell!Jio L, Bryon PA,
G,
~ E Co&r B (2000) Noo-MALl
IIIlW'lI'nalzone B~ ~. a~
rJ cbnal presentation and ouk:o"ne ill 124
peti@<rts Blood 95' 15l5().1 ~
196. 8ergUld M. ltultlelQ U AIrIn RM.
Booo '" Roos G, ErIin&on M ~ J.
Oiaor "
... c.wllllo-~ E
Sl.rM'om C. ~ S. I*:IdrI C,
Hlogblltg 1-1, ~ R. E~ G 120051
E~alUllOOn rJ ~~Pl':n drI!vse litV"
a.vw
s-.
B-celI ~1"IlJ'IOII'Ia and ~s 1m.p9Cl 00 prognos.ia

Mod PalhoI Ia 111l-1120
Itl. 8etglu'ld S
0 (1992)
ft:Idera rJ ~ _ II i dft.POPUIIIIllIl N J ~ 48 20-2'6
191. Iler9fta'1 R 119!l91 11r:M ......... T
ce4l1$OII(IlOl" gene ,_~. Ilu:lIas ll!I . .
z-.....
adluocl 10 \tle tllSlOpIthOOgfC dI!Igr>osli III

m,'CQSili f~? Nrr J Oerll'lillJ901lho1 21
.,.""
1911.
PL "uefII Wt.I (2001)
ow-on- 5.................. ...,..

References 383
rna ()lc:oQenelO ~115622

200. a..~ . Pl.. Kuenl WM 120051
~
Pill!Ioge_ end conMqUeI1t
*", of mtiIIflI' myeloml J cw. 0n0lI

n201,"""'"
~ PI. KileN IW zr..., f
s.,w
J BftIQot 8, ~ J .If
Cydin 0 ~ .. .-Iy lIOO
~~ ..... on~...,..,...
~2OO!l1,
8Iood 106 298-303
Ilemard A M"t;IIIy SB Metvin S

eo..rr... WP.CIIIIulIJ Lerr.-II J IloI.r!-.IIIl
1!llI2)Nm-1 ,.",..e~ . . . . . on
chillIhood IIld MIlll:l-.l ..11'I ~
unor 9looCI511 ~~
202.
211
IliIrnntorI NL en.; N ~
A (2003) A _for TaMo. ra:epIn on IClJftll
.......,. ~ o f nR9l7y ElCf'l hjjgW.
"llrl_ B,*IIld~loor-on
"'III'IOfV B CIIi I!Jlood 101 '5Q)..lSl)l
2M. ~llIG"""'M~p
Luf Oe ..... lt.S--p ~ N
f _ IOIT /2001 ThI.....-..:. of . . C()(.
C02&- ..... rI ... dIl4lll:Mo, 01~

S8zr;'-' Ilr J o.n... 144 125-1)5
205..
e.won J
a.-.
AA ..... L ~
L-o C MIm O.
HWb:llIJ
PwW J l
~1,lP
~C
~H.
v.-
B AllOon CI.4 SIooIi 1.1

f
f2OOOI........ _ of .... , 22llPI3ql1)
..
_ ~
~of
Heftlll' LG. flll<1ks TJ. Sabnis SO. TraViS WD

(2007). POOIoiIIry Iigh! chain depo6itia> d&_
report ollivt! _
and fllVleW ofllle 101I<IU't Am J$ufg f'3lI'Ioj 31' 261216
215. Biagi.IJ. ~ Jf (200"l1 lnsI!1'tS
inlll 'hi moIIcUBr ~ III lo:*:l.iar
IyfnphcmI ..-.g fmm II'lliysis 01 Q8CI'JI'ap/lic
.....-on BloOO 99: (265--(]15
215. e.u- N. ludwig III ~ EO
IAleIer BU, RIIschlIer 0, ~ /.I f~
/.If. PIlbsl T (2005) Ri5l< ~l m
ptl\IIfllI .... ICUliI myeIudleo.QrniI ...", a nor
........ ~ ClinC.lII'lCllI'Res 11 1(16-1(2'
211. 8Igp RJ ~ AI( Goa<1 JJ.
~ fA 12001) AIOS...-eo:l t3U< IIld
-.ryof~onpnore"'"
AIDS J ..... c..c:. Q;i99 962-9n

2". IlogooIr RJ. Jalle ES. ~ JJ
~ A. F'leIIIer R Ef9!lII EA f2OO6l
Hoclglan I\OIIlPl'lIlIIl IIld ........1OOeideI1Cy on
~ .... l-iI\I AIJS 8loocl lUll. 3786-J791
21', Ilogcft R Ctreo A...... R e-zzn
f 8IRi A. Rmn l.lG AgiJslA p. deIIt FlU
~ 0 R9*' Gloi Ca$IClI-3ll1
IlopnC V. ~ T. AtlIlIaz L
\IIIII'lI J, CoDw>a M TodleIo A. Gnllloo!i A

II. 0 . , . B. RIJer N. ~ E
s..-
(2003
WonodonII T-uI . ~ '"

IIdoiIdulIIs ;rill on . . . . . . . .
~
(D'lSISl rJ ...,-,.,e
~1Ild.""'0I38~
1109'
NPG'IfrI:rII ':22l~PJP L. . . . ,.
216-218
201. IlIr1I E A-. E C'PI*J R Giwloe R.
IIIedot T 011I e';Jfl!I!iI"'lg tile X1IvSttn!l

<l* NlCG2CtE tnd NK020 I<JIer c8lI r~
b1 8Iood 101 319&-3204
:tt1. Borwl:.A. ~ A 0Ig'-O G
Cl*'-'9C.f'9*H.~J V-.goerG
G, COlON Fl. 0berI0'lQ f Thomas M
o.IiI 0 VIZlIOfII I' ( I . ~

qbrlA 01. . cIorIo.m JAm Ac.d ~ 19
".zn
201. Ber!I E eem A CIYoa:tln S DIIe 0

SOIigo 0 .....- E, CIpuIo R (1991) ~
~ ~ 1<e111yr1lOl'oT11 ~
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Wi
Berti E 10"'''lI'Ii 0 V.._
UH,
.... CJ AlltAd:, WIem.1IR 119l!9) Pnmao"'/
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211 . IlttoIon C, Goutw A Gabat<1 J,
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o RIprIIII M {2(01) C/WIgII. on ~
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212. 811I-.I KJ. S/IttptI RW (2003)
~ of n.ry-otI ........ a.t Prad
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B ".......
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....
EJ
""*""
TctIemoa G.
.llIo::qI.OllaI C
lNIIA Ul Uorcondul III
fhyin I'
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lelily C
S GrMIy
F(I9611 A _ ~ ~ 0 1
dwmic ~ IIuIterrIlI ~ tun .......
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m.
BN1Jl,~FCa1~
0, e.t..:Jn B 0aYisT. Dqliefll G WIner H

I-WlAI< M, HiImen 1', Kea6ng M Mor\Iserf3I E.
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225. Binet MA, NeoIl~ ME, La Blla" MM
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~l!IuI<f!/I1'" 8O:lod66: 1:l6213711
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_
ab\lI'TIIIl:lnS OIl hoIllllenkelaled
~ durabon elIer 119'-00. ~

inIer1si/iei1llo<1ltl IICIIlI myelOId *,1;..".. \'will
by cylQgIrI8Ile IIJ)Iyp& CIrlOIt' Res
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sa
4179
:m
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$ptrlrlg AI (1995) TCR ~ dIlII 011I
IfIIQIlm:l T-011I sm.I on the ~ ~
11Im Amu Rf\' CII 0... BioI 11 Xl7-53 Xl7.
'"
80ennI 6 YII'lIrrlloll 0 ....., "* 1M
1(004
GenIMr..-:l
ncI.
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.-."'"' ThI ~ .... J
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s.u- J. s-o...sc. s l2OO1I 'lIPO'l

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_01......... "J . . . . . 85 116-120
m . BaII6fl N AldIR: . . l/WJfW V

P<erIl y- nv.. x lIbIInC l !bIIMIIlI I'
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LIbIInc 1 1m- K- HerIRIII 0
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dilllJse largeB-celIyn\plloff'il or JoibJI
pt-o;>ma? Hum P~1t>ol31. 528-533
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van den Berg A. de Jo;'lg B, Kr.IIlM V, PI!
Me. Coullleod R Kluln PM, van !leo 810;
PoppemII S (2003) FollIcuIaf ~
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Stwas\lMl G (1!lW). OJrnparl\Ml
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420. CMOII M DogIIor'j C MIg, hni A,
"'l1W(II'I'II G, Kramperl M, ~ G, RIIheI D,
Plldron S ElenedeI!j A, Scardor' M MIen E,
l eslitl, M. Mentsrlt1a F, f'iuolo G, ~'P' A
11996)
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Me, 0l<8Il ~, Blood E. ~ K.
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1.10 DI'Pfi"1lll1M A, GfflW PR, ~00nIIIC8 R
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lIlI"al. the h)'lllllll lpiold IIld nonh ~
dIdIolomy" "'GUS Blood 106' 21562161
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phase
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SY. CooY KIm YK. Kim YH Kim JS /2004 1
ENicat::y ol In\lltirlW m' l!ylale /STI511)111 chroo
it r>eI.O lroI*>k ltIJlWT1ia wittl 1(15:19) calle
recct Am J Hemakll 11 366-369
434. Choi PC, ToKF, ~ ~M. Lee TW, Vim
I-i' Ch8n JK (2000) FoklAaf dendI*; 0IlI
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SlaudI LM. kUtti LT (2007) 7~
of tolIic\II..- ~ 1Q diffuse large lkeII
lymphornB proc:eeds by dlslJnct 00C0l/IM:
mechIr1lsms S, J f'iJem;ill:Jll3&: 286-293
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R IlalI< SP. K8!IiIl ME (1 992) HodgI<I ~ s c&_ 1~~,ar'Id~
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References 389
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C*"PO
UcMoN T NoI1on A..

HlllTII'lll S. IAlef A.
~J ~RD.S8IIIsG
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1111I ~ 0I"e.-.,.:~"
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8-CIII blIIl a-. d tllkUlr ~

ll'-*9 CIOnClOIIIt lymjtlomI N Engl J
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t.Ied 1 _ 314 131351 . DI~I<.~ P.CoolI

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_
e . .7 Nri J S<sg Pathol 25. 12H1282
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522. de L...-al L, IiJms: NL LQI'I9lirle J, f Wl)'
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lIIJ8 01 Bd-6. COlO Bd-2. .-.cl am "dIlIef
. . . ~ . . . , ~ ...... JSurg
PIih)I
25 132-7"1
os
n- C
YL D*lI G ~ L
Leroy I< "*- J. /oIcJIlnI T 8efg8r F
~ C. w.n L GUIrd P (2OOn Tl-.
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523.
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. , . . . . . . - ~ 0I1lOCl1l
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(:81 ~ 0Im0i . . . . ~
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AIll IIOd IaIiaiIIl' ...... TITFHI
'* ElIood
lit ...... L SMa E I..algDreJ ~

Nt (2001 ~ T-d
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K_ ng IIIJ (1998) ChronIc; Iym~
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0rl00I23 7060-T06ll
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533.
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lllerature MedK:roe (!IaIlrnoce) 68: 321-335

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ll'iII E F~ 1,1 ~ H SdlooIecler G11'1 CorrelaIilII of ~ l"rdn;jI
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~
.-.:1-..._
(lowols
~ gene!-
~ an:! rnKhamms of.,1IerrO~ Cenoa Ga1etCIog1<lel1S 56-16
717, F~ Il Baley RJ, ~ GJ

Rejk_ SII, Hoye' JO lusl JA K'f'Ie RA
Geortz MA. Greopp PR 0ewaIIl (;oN I2OO2'l
Genomo.: ~ ... "'CJ'Odonal gamrr'ql6Illy of urocIela<mined 1llPfIcance IltIOd
100' 14171424
711. Fonseca R Bamgi& e, 8alaoIle R,
BBs1llfd C, BergsageI Pl.. C'- M. 03VItS FE,
D.-ad1 J GrllIPI' PR Kirsl:!1 III Kue/lI 1'11.1,
~ rllllndel JM Minvieile S, PiI~_ , Lid,
Shaug hness~ JO, Jr" Siewarl AK. "Ill.
loise8ll H l2004l Genelics and eyIoglwlBlic1 ol
multiple myeklm8 II wo<Uhop report C Res 64 1546-1558
719. Ford 1\1,1, Fasct1ing K, Panze<
Gi\lrnayef ER KOOf'Iig 1,1, Haas OA, Grell"fl
MF (2001j, Origins of,..Ie rnla~ in c~
tClJte lymohoblutiC levi<smia "",In TH-AUl.1
!\ISIOII gentlS Blood 98 558564
720 , Ford " M, Pomlxl-de.Qlr.-eifll "'S
IIlcCertl1y KP, MacLtllf1 JM Cameo KC
V..-.cenr RF, GreavesM(1997) MorooclonaI 00
gin 01 COflCXIflIn T-eel fIlllI9Iarq " ~liQIj
'""'" Elb:ld 69 2812135
721 . .0flKbIf E. ~m S. ~~lIOw E,
Borgstrom G, Holmgren G ~ K,
~ J If.~ G, A/lClefBl MK
LUI"lIin C, Nmlgfltfl A. RosenquISl R S""*' B
.loNrsof1 8 (2003) Cy\o\IllreIic atII'Ior<nlillI
.. d*Ilood ICl* IllyIIIoI:l *"'- Nordh.
. . . ~ II dlMnr1 emJIed tfl . .
NQPHO.93-No1. NI blI\IIlrIlM't 1993_ 2001
Br J HeemlJlOl121 56&-Sn
122. Foss MD AoiqlcIsqloUI05 ~
, . . C o.r.I G If.urrwnef JA .......... 1,1
SIe n H (1996, A.IIIpIaslIC Iarge-ceI ..,....
phOfIIaI oj T-alii 8Ad rU-oaI l)IlItloIypt
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....".
Blood 88. . . .
Ra ~ ReusdI R. 0fl0n8l G lAnZG

1 ~M SIl*Ill 1_
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References 393
ValOrprolein il RMO-SIBmt>erg tell ~ d8Itical l-lodgkr1's ......' llI'QVI08s ......,. .....

dfw;e b' ,ts 6-aIII 0l19"". Blood 94 31Qll.31 13
724. Fffg.ll lIf. Bruuue l P, Schlaofel D,
Payeo C. Robetl A. Rublt H, Hugutt RIvIl r
Delsa G (1995) kq fI*1OW ~ on
......tic IafVe ctlI Iympho!'ll<l 1..........I'VdIilT'lC:al0IlIdI0n Q/IlDfIWIl~ end
i1s~~ M1JCinPIhlI
103 &2-a9.
n s.
Frag. .... s..chRVerdt L. fOl1lU J

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Glin.-R_
P", MA (2002l T.
c:ei~ ~
lk>II
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Hodg~"\
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1........"*"th.1 21&.229
126.
G t1995) MolIcuIIr
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, . . 01 tunan 1-011I ...... .,.,~...""""

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m.
.,..co V
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Fu.. "Ill
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73M, FroNing S, Sr:toienk RF. B.-ooiINdo; J.

Benne< A t(~ S 100s K. Donner Ii.
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.a.villng Flf31l'l1ta1oo!11'l ~~(16
kl 60 ~l ",til aculII m)elood ilYl.Pmll an;
ncrlIIII~ . ""'" of the AlAL S100y
Group um. Blood 100: 43n-4JilQ
737. Flllhh"'il S. ScI>len ~ RF, Slotte I,
8it*rIIr J B.YIlIl' A, Kr~ S Tobi!> K.
00ttlIr H Clo:Jrr.- K (2004; CE6PA muIiIJonS
II'l 'fOIo"'VIf idIAl5 IfII'IIl aculIlTJl'llbd ........
1IICl1l(ll'lllll~,progn;lSIIc 'e<e.-a
In:l ...,.. of CllOlIOlf*'lI ....1aIIOll$ J CIrt
0nc0I22 112~3
738. Fu It ~ 00. Go:wolo" rc.
c... S. W"Jhl G RoserrwIk! A, CI'IOaUI M.
IqbIl J G.k S, s.ber1 R De Jcrtg D .11III
ES WIIon M; tleGIbII J. 011 G, Daoe 8J
.s.rtgeo- WG Srrd'I Uol RM!sa L, 6rnDIII RU
................. >it< Campo E Gasl:l:lI RD
we
Sload LM 0....
(2005), C)o::Ir1 D1""ll1P"
MI . . . . DIll ~ & lil~
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... ~ Qwil bid J m1V'1C115 62J.Q7.
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lypt AIIld110I ~ B ~ _
Blood
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!tie generalion 01 ..,bbodV ~ &ler.oIl
244115211 57.
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ff( ~ T (2006) .~ ~ T-cII
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S l19fIC C03_ C056 . . of
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. . . . . ~ ....... BIoDa
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m . GoIorgI TI. w.-.IE ~ CO
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IJIdt B-{AI
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-....on IIIJ; PAA5Q11l1_. .' J

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mB. Georvo A ~ I\F !ktIr T Out!

11. Clcl'W U ~ V w.m.r '" \1990
\IIonIIl$ lfl bonI
fIWIV* r.a-. ~ All P!Kt I . 3-21
mo. ~ It IiIr'I*II l#woIfl
It RjU F ~ ItG ... lIrrik J.W
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c::r.on.: .."... ......_
l~L...:IIl2~
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GIrdeI J V.. _ _ J PIIIn S.

~ R V., ~ JA SlIIl H jl1I61l
TII'IIOI CII growl! ~ lfl HoO\JUl" dit_
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___
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1()8
m.
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Gerrnn;j U, Gal\etrrIarIn N Mm.ng H,

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calion rJ CMML---d'\'SllIIslIe _
pro5lerabVi
tvPe LeuI< R8522' 811-878
III Gem-ong U, GlJIlIrmIWVI N ~ C,
Aiv8clo 1.1, AuI C 12\X(l) VaidelQ'I rJ lhI WHO
proposa+s for a IlIW daWficabon of pmlllry
",yelod\'"Plalllc ~ a re!rOll>pr;ll"'l
lIr'lIiysas of 1600 patillnlt. LIl\ll< Rea24 983--992
71'9, Germing U t<ur'ldgen A. Gatlltl"ffiilnn N
Risk
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allots........nt
in
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L vmphoma ~ 5 1311 1316
7a11 . Gem1ing U, Strupp C. K.rI'pp S,
~ .... ~ .... HiOet:tllndl B. AJA
C. HMs R. GallIrmnl 1-4 , ilemlIll oM (]\Xl7),
ctwtnc ~ .......... rlhI 101'" of

hi WHO prtJflCllIII .... owtJb,p::IlI2: 974-977
Ill .
GwnllI
A;vaoo M
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SlrI.w C. KuendgIIl A,
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782. Gennn;JU SW\4lPC ~ A III

S Knc>PS,~ B ~A.~
C GaIlern8"rI N . . . R (2006) ~
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AroJOnf'ahll 94 313311.
785, Gertzw.. K~ RA {2003/. Am)'bdo$is
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0rlC0I30 -"'5-3<a
1M, Gertz 1M.. KyI& IlA. Noej P (19931
Pmwy l~anl'jloidosIs8 ..... ~ .
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me J CIon 0rlC0I t t : g'4-92ll
7117. Ge<tz lolA. Lacy MCl. ~ "-
GreclP PR lJIzow WI. IierderSOII KJ. V..

""'" SA Arvn,nn GJ For-::a R 1200S
CllnocaI IlIlfIlicalionI of til11JHq130321
l(~1 '(p163q32).'" 17p1J Iill'lylliorna
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6alIIti N ...... 0, ~ W. ~
s..o .I.
p~
R Steber! R (2005,
Al. K~_~EkeI~'"
.t,lJ(.QII'ril ....... bIlorgs 10. .
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_ _ '9 18)9..18'0
GeII 5 IGippe< W. wn->-Su/;ler(l ~
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lr1Qd ~.-- 0,- *'IlyM
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of SI.AM~ PlOiIrI e~
lImuloI30' 16911697
lftlIUiIln.nc.lQe(l 0 ~. Am J K.OlIy
Eur J
800. Gilmour KC Gaspar HB (2003)

f'lllIiO(IIl"" ..:l <loIgAotif of )(4r'lkll(I I',mpt..,...... ablOl.-- E>fllII1 Reo. MolDlIl1'
3 S4!l--561
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Bow F
aoo5' HIV'
MALT ~ . . - Illduc:IKI by Il9r

lCtI.e ....tWownI ~ ~ E... J
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....... ....,... JH KO"M PM ....1 V. . U 0-
JOlIO 0 (2005 GIrlIe.- ~ lfl b-
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_8I'lllDgo.dt ... cll<liCIId .......

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1ooJ:s.!Iload loe 110&-IUO

7'9t. GIll p. GudI G SleIa 5 e..-OO 0
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..... , ~ subs1ltold'lMic~
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~ ~abvll tlGCfdon 1'1
Idld organ nnspl8nl paltt"lts
are lhe1' \IIWO olf
1I!l/wII~? T,~
19 244--241
GhobriIl 1M. Habermam TM. """-MJ Geyer SM, fbA:Jw KM. la"lOO is, W_
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~ S~ ard del(Sq) inck.!d
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EplIteirHlalf '''''S-p<lSitl'le 00MrIderrltc Burkitt
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Pal!'vJl 28, 37938~
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Be l~ J. "'len A GoIc2sDlt All
FrriIn lid o..n.Il J. ....-- U (201)1)
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for ........ _ i l l "' 11'0 3 lI:A:vlllr .,.....
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2007
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U.
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c;o.'.cD56-
References 397
l:I.n5ol~ewIq
., and ll5 ~ 10
clIn1r'*c C*b Nn J CIIn P.lhci 127, 68J.T00

921. IiPlg M IO'loo.Ir/ JO WaIlIgIOnLT
!AA'Ic M ......-.g MJ Jores 0 (200011 A ~
....t1t
to ~ oI.....ue T~
. . . - - ....... I_""""oeoty arro:ng 'MiD
~ llb:Io3 t()I 33335
'21 ~ y, P.-l KA. 1'1$1 EO a..g
KC ~ GZ. FOfd R .lane$ 0 (2001)
Ta., .. fl.OIIII VrCq
IU'llIII b-aII
~ d ~
PTWI1<fr olllillr
_ _ . . Ale J ~ PaIlOl 31 1123-
"""'*"
*'
""
m.
Htrllrlg M P_ KA. T""-I MA..

~ r.A R....u F. KcDyashI R. Jores
o (2OOll) . . TCL' e>;l'll6llOll ;nl flIKI T
<:til ~..,...ong defnI
a~
Iie ~ of T-ul ~ lIIu~e<niL

8bod 111 32S-3J7
924. Htrtnq M. T.,11IlI MA, $hen RR,
MedNcs U .u.., 0 (2003) Tel l expressiorl

.. pIill;tIlaeyloid clencI"l>C cells lDC2s ) aroj the
~ttd CD4. C056' blastic tumors of !.ktn
Blood 101 5007-5009
925. Hamlin, 0, Haioun C, L9P!"}Il E,d'Agay
MF, 8r1fltIl J. l.IvIgnao; C, File! G. Sliles G,
MarollNIl jP 0klb0Id J, R<iras F. Ga<Aard P
119961 ~ ~ of bd-2 prolei'1
.~ 11
~in~
191-
n-
pIJJma Groupe dt:1Jde des l~ ~

rAlllAll (GELAI 8klod III 265-212
t N . ~ 0, le'ln f, Iln:lnoooUJ JP
ManD II ./o'l(iNu k. ~ V
o.t.I B VlIIInIi f e.::at. p ilnlchoI C,
B T~ )( (2002) ~ of
v_
.-.us
splD: ~ ....
. . ........: oll"olpllk C _
n..tUI
~Ju.d)l7 . .~
W . IWnIniIz s.r- AA Alvfo t "-w
RJ o..oJ\l988) ~d~_'"
1r;o' ............ ~ ~ J ME1ll
p.,.~SoIlllII32"2612 2fi1-2'62
t2I
~ M dII c..z.o we c.....
A a-o. Jl GoAJerrel NC GonlaIe.l Iol.
~ G s... ~ S (2000) 0irIc8I.
~""'~Q'\oI"''''
of
MyPQI o:IworIil; "'Y'bd 1lIuk_ Ann
0nc0I11 44' .......
'21. ~.IM ~ ..... GIAlIlnW

NC. MoIele '" l.WlInel~ JA, FbrfJS T.
Gooalezl.lll, Pins Mot.. SiIrt MIg'" JF 12001),
N<mI ~ om/llllil1US in B-ceI spIe<"oC
~ lone IyrllpI\QrnaI rweaiold by GO!llll3I"
~ hybrMtton lllld cyloge"llticl
awe
M1 jPallIoI158, 11)43I BSQ

930 , H8m1Mez t, Ilea S, I'ioyol M, OU G
Kallllllber9'Jr T, RQHnwakl A, Bo&Ch F,

l CJl)llZ-Gvtenno A. DeIabiol J, (;olom.e( D.
MonliWl'aI E, C.fnllO E (20051 CDK4 a'>d
I.IDW2 ';l8Ile elteraklos m.11y I)CQK ~ I>9'IY
P'll*'aIMI n ~ m..... eel lymo
IO'IIh Irid-Iype INK4ai"RF locus
phom n
(l99ll) t.IonodonaI
oAnG3f~
hIwf d>aon (~
__
~otl_
Am J IOdney 0.. 2S 12$-131
u s. HIIa:lp HE {2OO!>J
"*'"
d
n.
Bdogy and
_~
MfI.
Xl (1. lb1I_ .......... Illlrgl-
~lCln ~
~ AI'l
Soc:
~ E60c ~
~ A.. 80CIIS
eel ~ PI!lgooIlIc"'- 0I1JiIco'

0ilnI:"... ..... J Ci'I P1hll1O ! 3O!>311
141i. ~ lUI. CaIins RO ~ JP
.ll
loIil.dI P (I"
...,
2ti).26!>
Pri~
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01
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tiodgm s Iiie8se Yd< 01
~~..,
25oI-P1$laged
e - 7 4 7Q$.1l4
'37. HIlIIG o.lDtH.a.-.sM~"
Sogau:o F ~ B Stem MM (20001
RlCUlTerd moIIoJIa' ~ cI IN 12p13
"'JOfI '**"'-Ie III ET\'MR. .. TuI.,....
~
I1ImeIIoI J 1. 42--47
U1A "*- hi. 8euI8I G I(rau\e< J, [))hrw
I( lUI f\lItIlollli. ~ B
~2OOfJ) High llIII!'IffIgic)a I (UN1) ~.~
a predk:lor for poor 0Y\c0rTIe in aWIll
myoloid illJkemla 'NIlh narmill cytogenetics
Blood 11ll! 38ga.3905
_oma
Ga.---"
138.
Htgglnl JP.
W~ rnI\e
RA (1999). CD30
eXpr'lIl 1lkin il common In mediasti"" l large B

eel lymphotrIIi , Am J o;~ " .thol 11 2 241247
'W, Hlnl M lemke P AAag~ I.
~ .. C lVappmam 0 Matl1as 5, DonenB.
Zinke M, 5t.on H 5eheide-re~ C {20(2)
Nudearlactor kappa8-depeodeot gene e>:+i<_
""" ~ ol Hods/kiI'I" diMase Umr . . .

~ . ~ and ~ kl constrtu_1IgnIIl hlrtIcU:ef and ~ ol t:'ansaip1Dn!lll ~ J ~ Ued 196:6OS-611
9318. HiU'" lOMt P !.bh'S, K/applrWV'I
o OMen B ~ C (2001) CcrlsliIL*""
NF.....- -.lIonS !'Iif1I tY pn!lI9Iorl ol I
cNo'*'* Il'Ifl' ntfWCI't I1du3o'lg C040
ctlll6 ..., III ol OII~ gar-. II
~.SIetnce-g ClII!I Elk:o'l97 21te-
2."
SI9"
~ Y ...... Y
~ A'l:';~ .....,
939.
...... ~ I
In5O<n'f 8
E"JHamRII68 112-116
9040.
t-ts.loda U
cn.n 8f
5 l2OOl1
Ieporl d
jdoo
ES
II
ltv
T~
LB (2001) Stcor>d "ncar IlItIdence and

eause--speak IIUIiiIy ....:>rog 3100l pIller'Ib
.... '*'Y c.I 1tul<errIlo. a llOPUlIIIIorKli_
."..m
. ).C.
liern~tltrg AM
398 References
l+en J. MagIl All
_ _ F'lo!
H_ _,," C 'MIeml:1 R
T. . . , CP, 1/..--.1-,11112005) Oisllnd'nol primary em-ous llove &.<;oil ~

'OenIrfIId b<y ~ elpfMSlDl'l ~. 8Iood
lOS'3611-3678
9019. ~ JJ. V~ MH J&fl5'!I'I
PM, FIo>uref\ GJ, Melie' CJ MIemze R 12(03),
BeI2, Bd-6 8ndCOlO ftYpressicM'1 '" wtaneous
BoCIll ~phomII fLJtthl)r 'llJpport IOf a l[)il1de
~~'
..
Reos 58: 1105-1101
HoroliI GIl. ~ CR 'W LN, lu SJ

llll ET 11*) .Arfenie IIlylllolnalllXjl
MI ,
)...,
~~
_ _ bill . . . . . . . Am J Mfm*
58.67,11
162. HoroII S Ra9ab" ~ c.
G. ~TIonas J r.!OO6 SHP1 t*
~01
~ I'IIgIIM!ly . . . . . . ~ K
."
u-
QIinI
Blood 101 4'
ue
II2A ~
F<lIS It) ...,.. 0 i'W
... lIdIr K,S/IeIl H Lopp U ~2002) ~
tond .... ~I1iQIl:Il<lrCCR7rl
r.-tlUllIDl,"~~
. . . . ~.wieIdislOO:~
lIIIOPi** cells on IynIplloid twgans Bklod'11(18.1116
K3. ~ MG . NaIlor RG CMItuII
A, HyjIll EU mghi" "" G, 1 ( - " Ot.l
Cesarm:tn E (1997) Epgtll!l'l-8011T .wi iIIa'lt
gtne elprnl.lOf1 in pMmary ~ffuSlOll ~
phomueoot.iinir>g Ka!lOS"S ~
td hllfpel.'ftI$IOOmaIl hetpesYirus-8 Bk:lod 90'
otn tr& C811origI~ and dlffHmnti!ll diagnostic Slg'
1186-1191
OIficaoce. Br J
1&4. fiomick Jl Jaffe ES, Filltd\er CO

12004\ E.<\rlVIOdaI hisllocylic sart:(l!TIR. cfD:.
patl1oloc9: llfI8lysIa 0114 cases rJ Brn III"hlioid tnIlqIIncy Am J S<;rg PaI'o:JI26 11JJ.
De-rmatol149: 111>31191,
950 HoeInageI JJ, Vermee< ""' Jan""

PM, Fleo.Jren GJ ~ CJ 'MIIrnze R (2003\
Bcl-2.Bd-6""C010e~in~
EktII~ ~r\llef ~!of ,lolIde
oenlrlt cell 0I1gI1 a'ld dIenlr1Iilll doIgnosIc-sI"
I1Ir::Irce Br J Deo:maloI 149 1183-1191

951. ~ MI\ (2l)OF)J. CIi'IICIll ~
IO'lI a'ld COII~1S ollWy 0III11uk111li1i
~ Orm ClinNort> Am 2(t 10r6-1073
9$2. ~ T Dollblro G Cdcmt III,
~.ae-cz
"-'eg J F_ G,
"-
GrINoalIA. TIt\'lIIIA(2OOOl
~liItr~
I8OfIPIOrI b' MI.A c-. 1....... _
dI:Nty
., lyiiVlCO\lll<AIIlo-...e ~ 01
..... loIIrft T-<:elI~ BrJ .........
11~~536
.........
WJ r.brtiurg F. l.Ic*r P
(19M)
~
~ B
/yi'Il(JI'l(ley Il'I6gIIM. HI.J'I'I P3I'd I 9- I 2l!l).
nr,n.;
...
".,
""
t64.4, IiorTwIg SJ, Roserberg 5" (1984' ' "

I'lIUIl I'IIsD'y ol iroIiIIy lI'4fMlI(I ~
Mfl.Ho:IO./kil' ~ Ii EngI J ..... 31'
_. -
14711415
965 HOrny HP KlI MlI'ling E I
l~""IIllI""_llIIIsol
_~"~II_'-I
IOlDgaI ..., ir!'IYUiJI-..:y:::llI ..". &-
l-bn HP. ~ E
1M
P " " " " l.lR l.-..rl K /1.1 lNer Iod
ft ~ ~lfl*I
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c..c. 63 S32-538
M7. Ibl'Iy t-t> I<aiIolrW1g E ~

R RID p F...... 0 WJet R JadIorek I(G
'N*I-() (1~) EwlenCe lor I ~
,.,. or Qn.:>JIIIi'Ig pl;asmIcylOId ~
lIndirqs !rom I case 01 CD56' d\roI
~ 1lIu_ Ell' J HIIIflIIlOI54
Tachik ~
ellnCtlr~9' 1~13 1~17
(?OOJ)
'56.
" SystemIC mastoottosis' rnclJWl ly~

5'1 Of ma.1igna nt Iymphorl\<l? ImmUl\O~ lind II'I(lIecuIBr 1indirI;llln n1IlIf'olIly proc-ed bonll mam:>III boopsy apeo.
N, Ajisawa A, Negishi M, N"Kanva

T, Iwamoto A, Hayash' Y. Motsul>ara D, Sa'liO
y, KifflJl'll 5 I(ikudli Y, T8flJya K. Y3:'>UOta A
()Q 5. 5alIo K, Mori 5, F\I!1RliI N, Sal<l T
~ H (20061 De<nase in El)llMir\-I*!
_~ ~ Iy"lpt'ool.illl thlI
1'loI11"\lsworth He . 5tetler5te llel'iOI1

Gagoet8l' 0 l<iI1g!TIR OW, Raff9ld M,.laflfI
E5 (19'J04) I mmu~odeli<:ttneyauocia(ed
~
~l lyrTV'olM
Three caYI slloomg
d 16 <:ases HwI'l
gerot,pc ~ d boIlI T_ ard 8-oIlI_

_
An> J Sur; F'aD'Iol18: 1ll921101
951. HoIlJMIod K, ~ G m.rm. 1
fllld'er CD (19851 Etlranodll ~.
'*IIic cell WIXI"II d hi gaPoIol\l101lllll Pet
~ """""lOIisbJ...... "'" ....
If1lI:UlII II'IIIyIlS ol two CISIllI Ani J Cin
PIhi 103 90-91
t5f, HaIm LE BlorngetI H ~ T
(1llll5 c..:.1lN on ~ .,;ftdWo;rC lyMo
!'I'Y:lqtIc fOil* N &9 J YlIcl312 801_
'51. I1clrwI T ta/YOi Y
5
Syalfl.dn M Korta 5 Yang Wl
YH t:::t.I
H Kim 0'1 Haral:Io.d'o Y HII\'II T InuyIrriI loll
944
1'aIlDI21 l00l11050
Ho Fe Srim.tM G l.Dke SL Fu lUi
lIl.rIgBP LqR.ChoyO(l99:ll Pn:tswIator
If1d bIlf.caIIr*l gent ~ .., ~

NI<JT -e.II ~ II KorflOl NI(I . . . .' ClncllI
E~_ow.ll MSliI ~orB
RIlIl13 265-211
and T DIll rype HImIIol Oro::d 8' 271281

944A. I-iocI<tnDery OM, luIIer M. Hdey W.
Nnn M, KonrroI1yer SJ (1991) BC12prolein.
960, t-Ic:I1qyo.l T. I(l'OOklI loll T.....,.m E

1..:hI K, NakaIIfI'Ia Y. Aomloa I( ~ T
(1998) F~ p53 mulaIior<S .. d(lynmdnl
- . . - 01 Down.,.oorre. IlIood 101'4l)1

.".
M1 ~ ~C Oq- 0 u*. SL P\dIg IT Fu
0-- yy w-tLM 11m) t19' ~d

E~W\II ...... ~ClIII
01 HN..--t Hado;PTIs cIee850III Am J
P3IIl'O 142 1073-1019
,13. Her\III C8 Zhoo.I XG ~
SJ ..... 5 12002 u.. d 8 0II1l1enlity aIf
......
loa 018 OII-speok ~
hlctlr!I in Hodgk"'~ cek 01
lsIic8I Hao:lykWl IymphllmI ~ 21
It;:IdgIotl T (1832l On _
!TOtIill
oJClP'IIlOllQS 01 ee Ibsoftlenl glIfllls IIIlI
IPI80In lAId Ow SocTr 17' 68.... ~ JJ DiJ"""'" It e..o 1(.
9017.
ttlOIIII
$II>dy JNllllCa'l<:erIns19!l,21S-m
iMO.... Hlsada 1.4, Okayama A. 5hiotri 5,
~ 01., St\Mll'SO Mueller NE{19gel
Ris~ /aclcn !of ~~ T-<:ell leukefT'a ~moog
carnel1 01 human T~ mos type 1
BlOOd 92 3557-6 '
941. H,shlnlB T. Oyaizu N Fuji; T,
(1999 mKf\Md9'l"lt/Tf'Gl"'_i*WW
rJ .....K .. ...-..: _ ClII ~ 1"0"
~ """ *'oc:lInlly ~ TF-GA!.K
.011-...:.0.. 1lloool9ol ~32'68
t12 , MIrIldiII' 8G ~ I< Ching Kl.
HIrnIMN l P,flI M. H!Ima'ldez 5

Nlanl K ~ A l..a'rwlI l
Fain B 011 G ~ OY 0eI!a G. Campo E
ch;:Ilre.u- """ J SlIg PaIIoI23 49-58
...... ear.::.- ...

........ ........
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Gacoyne Ro, s..be<1 R SaIl T ~ F
MorsmIfl DE (2004) ldriIicabon 01 t)'I09IfIeIll: lo<bJrol.Ips and kar/OfypiC pIIlToolyll ol
cIonIIIlNOIutlOn Illoloruar tympi'IornaI Gero8lI
ChmrTlOlOfTlM Cancer 39 ' 95-204,
'55 . I-toiIIH'Id J. Tren'ner OA WasSltfmar1
TH, Fn' ebe!"<.l 8 (1992), PI~smacylom a
Tr .,.tme~l .e-sul's and corWOfSIOfl lDm)'l'lOml
a.. S.
931.
"-'" ME I(n.,- UC f199!J) T'.lSba....,
or III IIIlII OIl .,.... K>-1 * ~ III

. . . . . I:lIII~~n
era of t.jIIy KlJ..... an\!lYlVtJWal therapy.

MiaOOIIlnftcf 8 13011307
tu. .... JK.a.-.g J b V Sctlerer SW,
ZIpLnty A (20031 GATA1 ~ II ran-
ca-.eer,*8521992206
~ leAicted in b _ dIar. . .
Ifecl D'I' apopIOIic DIlldNIh Pmc. IiIlI .IQd Sci
U5 A 88 6961-6965
9015. ~ G' lerNdl T1.l ~
...... ~.-.cI . . . ~
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O(M lllflll R Todd 0
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end
Aoau K Nomur.J T 410051 pS3
1(. . . c;U
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168. Iiorn)o HP, Kat5erl1flQ E, F'erwareIdI
MR, l.ameft I( (1992) lYIJ"illh
1~
nooe
~ailed
rM$IOCytoSia. Hisloplltnology 21
.39-4-46 ,
16' .
i10m y HP, l ange K. SOtlarK.Valettt P

lnl;r9I$e 01 booe m1lfT'()W l~m phoc'\<eS
au-
P8lhcJj 56 57;...s18
In , Holrny HP F'OIIWll/tISCh MR !<aurin;
E ........ It CltlermPl'" uaon- I( Lw*
l<rt9ll6) Mafl 0lIl~ ort111Wyru: J
........ J
-"...."
111.
fbny HP Panorinsdl t.lR l ....... I(
(1985)
8tnI_~1I'Y*"1e
~ ~
P.-u 16 8OU14
.n. .,.".". HP, Rudo: '"

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lot
E 119llO1 IlIood Nr'9' II ......
IZICI ~ MlInt:e 01 ~ .......

lInIlM lJCCI,rf...,;e ol '"J'OI*lp'oMM_ . . .
on
BrJ~76
11&193
Homy HP AUCI< " T K-""OJ E
(1992) Sp6Mn ~ on ~ ~
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Hom., liP. SolII>llIr C NlnK' 0

E WiIf'on'IwIn r.l 5~ B
Cf'!otIA l.Idoner 1(, lenrertl(, I/~ F'11998
DiognoAc YilUI 01~ lot IryptMt
914.
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221132"40
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can
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and o::W\icIj ro'lo<ts Alc/1 Oennatoj 1~3 . 5-50
990. IW'lg 0 C1Illl'lg IQ, GaaI KK W9<l1
LM (2005) I\n ~_ ell!'llnOo1ll! NK-call
Iympnomlo ......,.. fnJm 'ro:IOllwll NI(-call no
p/'Il~""" dis<'J"\1ftr /vrl J S\lfg PidIVJI ]9
'54().ISo13
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t.IE, Ooya ll,(1\198) Her!ItI-.iru9 I~ 6. . . .
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PN( f> iI"'t _.~'l a->d .~hI C

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976. Homy li P ~ k ~ F.
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~~~
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ecl"**~'/I'l:tII:IwINth"'97UT,
1003. .".,. NT Flignaf Cl 0chI MO
Bnc:la:fIk 8. HndiI S ..-s.IE. PunIIo or
WedgloocxlIlJ (1.) ~ qoM wit!
1083-10il9
992. ~ SO ~ J8. "-sen Al:
(20011 ~ IlOIlJIar ~
~ Hadg
drso:lase il'>:l ~
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a/ . . . . . . .. 14dl P~ Lab ""'" 12$' !lO3-
AIdnr:tI ~ poIIIlbIt '. . . . . . . 01....

~ ~ ee EBV I'ilIclian
0.. m.UI(lI ~ .1 ~19-t&I
10M. Irnanv1I N. ~ V ~ k.
VlIlUII k. HQ J 0dI I( ~ Il. DotIy H.
v*"
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~ 01 IIlMge fIP'(IIe rnn,r"

P1lI'ogI!jt- 2llll-J02.
tn.
...
J Cir1
v.... P (2001) o.ur-
Horny HP
01.~
.
. . '10
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Y.-..: P
1OO2l
MP
aIf*U a/ ~ Inl M::II AIIfg,

~ 127 115-111
m ~ Of ~ AD CoupIInll
RW ~ .u Adolt* SA (1995
1'1.......
t92A
IJ
AnagIlo6loclouI
F, l\.oItIiLM P
~C
S6eorlI-!
EBV~padl!I'nSiIl~,.doi
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oefnea ~ _
E.. J ........ 65 132-139
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GuI:ZiiI JM, WIf1lllf1 Gl. Flaid'er J, Sc:acIOe!1 OT,
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ant N EngI J Med 33g, 444-449,
1067, Jon... 0, O'H"ri C Kr_ MD, PltAiz
Atayde AR, Shahsati!trl A, Wul, Oorlman DM
(2000) , bpraellior1 pll ltMn of T-eelI'iaIOCIated
d1emoI:lIl\I receplor1; aM<l!heOr d>tmokines cct
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1ubb8 RR SOollo CO WtJlj 01 SlnOI J.
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fIaII8IlI5 ...... dYoroc E~ W\I8 m.e.
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A, s.nw..eIs A- WlWIl E. f _ EJ 1'hun MJ
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CIon 54 8-29
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De.aid G't'J (1999) I\cuIeIe<Jl.fInlia_atlfO'.
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or T~ ir*9'. A ~ of two CIMlIII18I'lg
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Med1\ers/Wmer G, Bentz M, 1hir)nlon P
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LR, ~ SR(1990) Imm~~
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ong HocJgl<lIl'S d1'iE!aoo, Am J Pathol 136 f209-
121 4.
1080A, Ka<J;n ME, Berard CW, N""ba K,
'NaI<asa H (1963) L\'TfIPhoIlr(ljo/erali"" difI.
eases in Jilj)iIn and Western COUI1_
Proceedillgli of the Ul'1Ilad StatesJIi*'
September 6 llfld 7, 1!<82 ., SNIIt.
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ML W _ RA I I . T". "*'ty!IC .,....
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Cdby TV I( II'Igm;1i OW Jaffe ES 1996)
IiDdqIatIs
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~ I-ioOllions dIeloMlI 11'I ~
-.ng ~ 1ow-1lole mdloIrelMl
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1091. " - - P dI 9n.tll PC 8nert J.
MlijerCJ GUwll P(I9ll6}. E~'fIrus
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1092. K......- P GNIrd P, ~ ~
l.taIIJI\ N Ouo:ls C l.tbe:zu U Malon [)Y
(199S) DIIcordiflle.qll'....",olom~
Irl llnd irs _ ';OQiI\lld fIlOiIQ.Ila mbo-l/C07llj It
!reQt.oanI!y lound I'Il'I'IIIdillillinlj ltrge B c.I 1ymphomas Am J Pl IhoII46 13~74 1
H193. KanaY3r05 P, Lasca Me. Britr1I J
DMna M, Gal.alftau F, Jnth I Botq J, FlIf'aIl
JP, Reyes F, Gau'atd P 11 993) Nasal T~
lymphomc1, a cIinioopalllologlc anlllyI S&OGiat<l(l
witl1 pllCIIl;,r pIlan<>typa lItld wiltl Epslain-Ilart
"'us Blood Bl 2882695
bon wilI'l
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M. Has/lima1O M,
lid'; 1(. Nebjima V. A.=osa K (1999! HLA-.I,
...... at pIlIentS 1Mll1 P'fO\I>onl<a~
lymphoma _--llI*I>-BIrr WlJS (fBV) to)SI
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EiW iaIIInI ~ ~ h J
Cancaf Bl' fo3O.634
11)98. K8noo H Vasunq V luchl K
VII'IMt+o$ T - - . T. ~H Aouu
l< (1996] IAIerlIu'r n.6--"'E'd,all gl'l:Mlh
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Uod PllhOl19 2$-33,
1105, ~ M, I(upp<n R, Hansrrr<lln ML
RajlWSky K (1996) Hodgi.t~ 8IId RM(!
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the OtIIgrowth of a dotntnanl tumor clone
damed from (criWItid) garmilsl cent&r B ~Is
J hp Med 184' 149f>.1505

1106. KapelushrliK J, Ari;Jd 5, Be......rroch D,
Landau D. M068l A. 0els0I G, BfW~$IlI P
(2001). ~t rtIIIl'I tra~ :;.pl<t~tation Ill,,,,,,,, her~vitus 8asoociall!d lymphoprollfetat"5 dO>Otdtr IJrtd Kaposi's sarcoma B< J Haemalol
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~&'ldell'loc;ll~d~
~ tbls~5 <RalIge J Cin ~
1107. Ks!>,an MA, Ferry JA. Hani. Nl ,

Jawbson JO 119!l4). Clonal analysts ,j post.
S,
V....... S ~ H TIII:eIhllI ~ KlIo:.m

M NatalllUra N TaI:.IIu 0 ............ f
T89i""'8 H Sftl I.4. ()hVIinIa I( (1Ol)n COlO.
MlNI . k*:uW lymphomlIllJcb IlCL1 Qll'li
~ and I/loWli ~ 00I0gc
1099 Kant JA, H...tWrll SU LOfl9O DI.

SrncII'I ~. OeWol VT ~ ES ll 9ll6 ~
"_75 167
JaI~~.lab
Kanada H, WI(\B T, Vad\Ill ... Sei 11 Nil T

~add;,m
K:;1e R$ (2003), Moooc:lorlaI ~ Ioghl ctIIinB IfI

S51ii!rotn tI8iIlIt' indiOOuals f LC MGUS. a.n
Ch8m49 pAJ4
1US, Kaufmann H. Acketmanrl J Ilaldia C
~ T W_ R Sad S SagaslII V
1112. ICarI.tla I( CJlalwna I( TIllChlya T

V~ T Kawano R Sulunrfa J
~ A.. Harada M I(qd'o M (21)>11
hptBMIOII 01 FotP3 ~'Y
In
C04CD'<'5 ~ T oak 1'1
T-<ltI
....... \yrftph)mI ~ Br J
126
1094, Kanegl nll H. Bhatia K, Gubllrrez M
Klglmoto
dIclion ct ~ ......III PlIliantri ~ \hi! !eJl;amoC

phaw d cutaneous T eel 1ymptIotna J E.~
Mad197' 1471-1488
1111. ~ba K G..to V ~ J Sugu
V. Nomunl V Vama/l1OtCl K. S/wrnIzu I(
m""
hIllgas T,ends lIrlmInlI27 169-115

1121. Ka-ano S. r _ E. VllM:II N
v...-gadv N Go;J ~ H . . . T , . . . " M
ClIranv.II A.. ~ 0 (19951 """"'-.......:
~...,~~
__ slIgiI d ,..,.
~
~ ~ !iImIlll Drecl lJ ' 11
un KI</ i'iE O'8neM Sl.I PwIIIa All:
~ 5 (lOOT' ThIIIVIe of IJIll1Il*
ImIn II - . g ~ ~ of
P*nII "'" cmnc ~ !IIlllroii
Ll!UlI_ 21 1~18l11
mo. KelIIIIfIg IoU Cam e Col.h S ~
.....
'*" \ -.
It ~ T L...,...- W lIIblIf B t.lao4*'

T "" K T~ G. B8batiIo iii IklNIo t.l
t1nilPf2OO2'l
~lti
~ ..........,.......,.. III
dT41
PIIIt* lot lIllh:lma
"'lltlIprUa.,iClII'.-3P1~_~
J C1I'I 0rclII2O' 2r6-213

1131, I(eaIl; JJ. ror-:a It a.. t.l SdqI
R. e....- A.. CIIlg 'l'fJ .... W. $ TIIld8rlwIn
R SI'Ii Cx s.:.g M Braoo E. ......., T Zhu
U RlgIif H f'ncao. TrosI<a T ...,."."., G
loWlcI'Ii C 8rfts LA. 1(. - $ Gte.pp P
~ ..., Bry..: e, ~ G Iln.fIM L
~ M, "akIP-l 1'1, TitII1I J, $"'-'I AI(
CarpIsn J, ~ PI. (2001) ~
mul..uons aclMl1ll Il>e noncanonocal w: .
kappee ~ II ~ rnyaIDmI c......Cell12 131144
1132, I(N" JJ. Reiman T, lotatlOSll CA.,
Ta)'lor BJ, Lamltt l M ld.lnl MJ, Elek::t1 "'R,
Pilar~~ 1
LM (2003). In
mu~ ipIa
myeloma,
U4:14}!p16;Q:l21i!; .., adwr$8ptOgnlJ$Iic flClOr

II'I'KpIICti>5 of FGf R3 e.prassion, Blood 101'
1520-1529
113l , l(aegM ,"" , GI8.W 5L Clari<ll CA,
G1J ll8y ML,C' aig fE, DtGilMppa JA, DorImIIn
RF t.Ian~ RB, ~, Rf 12005). EpslHlBarr WlJ$ as a marl<e' of "'NN,I Bfler

Hodgk in's Iymplloma: a ~puIalionba sed
study J Clit1 0nccM 23 76(147613
113>4, 1(_
P, Mendel<loo B, Pff110 MI'I
Elazwoo.t W. MscOoogalI L, FlIil.lon G,R.ll1lP.
~ R 1196n AbnotmakIles d dwofTo.
IOm8 1~ll n
Il'IIIlignatlI proIiferllliof1 of
~ notWIfIClo"l lI5SOCiMIon Bt J
HMrMIoI67 25-31
IUS . KaIy'" fbchIrlls SJ ~ M
Stqd, C Se-t AD RobMi BE ScoI CS
(199(\ 00nal0Iy d CDl ~ laoga pl!
~ ~ daWmlrw:l
!It'
POl ~ lr.........., AJCia5 J Oro PIlhol
" ""'"
113S1.. ~L.U. GiIilnl 00 (2002 GsneIcs

~ 18Uf<_ .w.. ~ Geroncs
fJ
Muma.-ll7tl--lllll
11)6. ~ Go' I(ay Ttl -'*-' O'to
I1awIllyCM
56 IIblIi NI.I . . . . P
CorJ"cII l't GI 0 C<II G I2l102l
~ ct. . . . 'wd ~i1i~'
Hull II'IDnIIIy occurno'l9 ... _
""""'4JI
ancl~ . . . .
ng
,
aflll'Y'irl"'_
ean.ua
Reference s 40 1
Pall1oklgv)4.2b32fj6
1m. Kern Wf' S\llIf C~ ~ EH,
Moler TP, r.lIllnIf M, GI'IlQ*1 I'M il~),
Ne'nIC8ll~~,. ~
. . 1<*1 ~ 8'''' _11Mlt1.

propemoly lor ............ 01 ~
Blood 19 2432 2437
mao KIIIIodl HS. IlrY"* ~K t.lIdIMoI U.
0Iq KL SlDva Ul ~ OS. MItr OA
119llB) ne ~ III bItsl ~
f<lr1.-on 01 dWur'f<. ~ 1Iu_, I
tIgh ~ 01 ", ,8(llI*lIf ~ II
~. bIIlIli.., A ~ oIlJlG'p1lOlogic. ~ IllCl ~ Ind. . UOOP-.alll 1211-1221
M MeMo T. YoI<ot.1 S, T~ S. Vachle A

lnIIsIIIII<u S, " ...... K Wai<qJctl< H !1OO)1
~ factoo. b dl<0IllC acWe Ejl'Jlea-
101 4660-4666
1163. Kion -'0. Robl'l J. AAi~ C. Noel P
Brown M, Law t.l, ~ 00, OYrttilI C
NuttrlJn Ttl (mol) ~ _
ancl
flMIISIl0/ myWJlboM WI feIpIJ'llle kl ~
"'"I'W ~ In PI\IIIU wII\
SOOlirlI LR. Wood tv. 1<.&1.0, RafIeId '" .lII1fll

ES (1WIll, l-Vade lTI()n(lI;;iona ~
drwolI1llooll103 473-478.
IIW. Kbn-NelWnInIHC.IludlG
~1yrIIp/'oCIp~~oI
S~Se...nooH8.F ~JH
l.1IIewood T ...... p. 8erelorll 0 "M'l dar LH

Grefn AR. Rooundul K.J M.... AE
........l<JpOIIIlIc ~em cell ~
o.rq~~
ct'*I ..... aar.-d ~
~
...
syn
Art:n PIII'loI UO hIW 123' 8J.tlT
CI\apm8rl
(S.
(2(lO6l
~ ~
01 ~.
~~~II-.
1152A. ~ 1J (19llS) Tre C05 e-.a.I Mol
~aI""l'fIIOO"'~1llCl
Yryol)C1lC IbIl(l111'" II 210 ~ n
-...0147 1171~
1153. i<JPllI TJ (2003).
11~_
AlIIJClnP-.ollll
Kh:uy H 0IIIl
eom..tr
EI. ...... TJ
DE 8aIllIll ....,
JO loa Cl.
~ Ii.)
fA.
"1~1fi
OE
Stj 120031
AwIt ~
~"'.8~1,......"""'oIlll.ol
~
oc_lllCII""'...... l ...
l~
...
171).1718
1141. KJooour, JO _
0 V-.:l ~
UarPIg JT Jt AIIn.LI:lo LV. ~ Fa
MedwoI W (200( 8DnI_ ~
1152. I\n'Iey Me CoIrIs R!) Gr.- jP

WIllock .II\. SwIos N I(aQn UE j1!193) ~
1 1iS
" essese
em.-
rJ
_~
_ CUll" Opon
........-olIO" 31.-318
1154. ~ AE
~-MMdou
do .............,... ~ ms.1 III 35 cmes
HIst:ll HIsIoPaitooI n ~5J9.

1155. I(iIlIlt NI!Iio.aee !<.. MPwa H l.Ia5"J'8 l.!
It uma N TaAaoUl1ll N 0tsW '"
S~ S. IJed;l T '" Ii (1992)
PIlenotroJiC* eM....
rJ ilCl*' ~
..
~ t'(IWIIIC ~
IN*l " IIl')'lIloIro'l lIuI<emiII ~
942401-2106
1143. K.... O ~A. KItlenDIIrgIIl T,011

G ~ E ~TF ...... P,&enntrA,
~A.""~HK.IlenaI.l,
lichIlll' P 000- 11, ~ S (20031 ..,.,
~
slalla IIIld VOJ 1!lilIllII~~ WI.c-
lin III ~
~
* lympno;:.m,
CQrIWIoon 'MIn
aberrallorl5 clIno;8I ch8rllCllt/lt1leS
tlnll~,
BOllj 102 3OOl-3009

1144. KiIu.Jlj 11, $akryamll V. Matsumol<> S.
O!I-tlillo T, NMaoo T, ~ma T, Ok, T.
Hil'mRk8 T, ""81 K j19'l:i1 f Ataj E~...,.1lan'
virus.a~ttd ~mop Mooc yl";
syndrome
8Iood 82: 3259-3264

1145. Killl,k S, M31Utlll E Powln RL.
Hamblin hi. Swanr;(l\H')' J, rrn lf8v~n JG.
lunas A, Alra A, Coloogj.,y D (1m ) OuluJmt
ol bo(lhenoIypic "CUlt iI<J <tmla, Maematologica
&4. 69l<- 7()f;

1146. Kim BIt Sur;, lJ. PlIrld;o. A, Cohen J
RIIl",~
"' S, Sw..-OIow SH 120051.
ChnK:op.tiIoklgJc. Ill'>/lIIJnophtrIotyplt, In(I
moiewIIr CytogeneliC IIuofeIce!lc. III "Iu
~ybncIIl.alIon"""olp"",,1I)'" MlCCl'Wy
~ ~
-"...,
ly'lnOhomn fvIo J
U47 . KIllY weilILN.CtltnYV
Sur9
~IV
(20071 o.ln:l ~ 0"llIIftlI olsrt'*!'C ......

~ Itlll INOIlId IkaI ~
l"'R4II~l 174~17~
114. KIm Vt.l R-. JA. ~.IE G*llat

HA.V.. )P. NyI;Ior; JI( (2007 hIolaaA!J" d\II'.
acIflrlUJllOn ol 1ht 1.'~1IlIllll HflY.l
eoIWlCeI" CO'IllIe< -ala. ptlIIIIIWt fQla /or
CREB~ .. T.. ~ J
BooIa.n282. 187:;0.18751
114. . .......... Ii HoIlII'Cl Y ~ H
TSOIgtJ ~T ~I( ~T
(2001 QrIQI.-.o W!lI(Vl: ~
01
ctrvnoc _ ... EPSlBot>-Ban
IIlIadIon
6Iood!lll 280-2t!16
402 References
~ N,
C t-.a R a..-g U 1200R ~ 01

~ Ill-. III rwhcby _
and
.............
~~
~
poaOo;ls . . ~ CIAl:aN. lfIl# Res
32: 13-37
11M, Kr..- OU e-..... E a.run
A.. fnawa G
JR.-fA. !oIIo;tIW RE
119!15) ~~_~
c:n.
....'o.1lH __
dIsarcl
~ol~."",,,,,,,~
poIiarII"" aIYflICIIl mroooe myeloid . . . .
Ilc:q ~ T ~ 34 1047-1050
1179, KoIMl$u H YfJIIIloOI tl SeIO t.l Il:iI
......... 1. ueda R
C (1
Oriwxpieswn 01 ~1 II
lIN
tyqtonI j)iIlIInI . . . a q1122~1l13.1l1
.~erJ~86.4'1 "'2'iI
11nA. i'D'llo T Kinl H ~ N Yt*IGII

R. To*i Ii. ~) .... W R:lut H
~A
'*_..
F..-T.IUI(l989}.Aga-_
.... am.-..
olATUb
HTl.Y-larrton" JC8n:er4J 101il1~
1110. ~R.~J O".uH m,.N,~E ~E.u
GiIaInII- H. ~ s. ~ R ~ K
,... H. Qrar:tl J (2lXlI3~ o.aaa ~ cno...
_
1Jq II "OllXb'lII1JIlI" ......., ol ........
~ ~ lA*emiI U 1915-1i"l
1111. KorIgstlerg R. za,. N ""-"-'"
J(ror,. E KlIW H FnIz E ~ ~
~TRieI:IL~H
SInOlIIdI I HeN R. J.utMg H. ...... K
~ J (2lXXll PnKkM ... ol ...",..
KJ)'OUQ K (19961 EosnophII13 a!o!OOal8O

..,'" proliIIrnlIoool C0l3- i't.(ll-) aIQIla bela' T
c.eIs willi c/ImmOsOme 16 anomiileS 8, J
Genes Qlromosomllii Cara< & 11~213

1169. Ko YH RflI HJ, K-n WS. Choi WH
~92
~NS
hi If'ft-loIIt:<jo Ulo call ~ ....
p"ewr' IympI'lot'n<l
11M . Koltaridrs PO, Gale- RE, LII'dl DC

(<003) flU ITl<IIabCII5 and iI<J~ Ilr J
~8.2 1j(q22.q22J~ ~
(II"
~ e
H El'nuglIdi All (:2004 0I*una oj
IMI't ~ 01 Il'IllII!kI!tI B-o:8I llllIlglrl

CD19 ~ """ .... oeII rigIn COl'
Illood 80 47~n
1156. KlWlo K ld1I<_ No MaIlIkb 8 ueoo
t.l ~ 1. SfliIllOOil/il S Kodlwa H. ~ F,
Kd;JayWI H S8IlD H QluJ:)O Y Enoi<IIaIll H
"*"
IIa'II t1tllIgIIoIn
I loU. KholIy.lO. ~ LJ. ~ JT.

So*k LE e.-HlaInDI C ~ 0 12002)
Cl>!J6<.) TdT('1 t*Ut ...... ~ OiIIIlumor
K"ll(l S
~B SchaIn"'~A..1d
BIoocI86!iS2-5E6
1167. Klll.M6II [It.l , . . . . . G. I..lbt*XJ A.
CMla-f-. R \1989 ~ geneDc
....,. ol It-. ~ II8(llllIIIN
rJ _
~ den............. e.-e.lI
<iIlnvJIol .-.0 .... poIICIIt fIIltD</Ii
rolf ol
fie ~ VfW 8Iood 73 792799
1168, KikdII S. ,IJOIo R ~ T (11183
~ ollha MAC jlh(llllllology-Wllbody-dwo"'*'"-) ~ II ~ rMcM
o(! donIlI ~I:s JtPOIl 01 ~ ".., .....
'"
....."
~,
~ VA.. ~""inlo R RI.ol~ R 12lIl7) ~ II dIo1rdnln
II pIIInlS ...... ~ ~ ~
AmJ s...g PIfloI28
the /:Qn ~ as r>Jman ~
lOO:~15
aduI~
Un. KoIClIr G. Bnxl<er E8 (1986).
Am kad 0erm.II1ol 15, 591-597,

1178. KoloahoII t.l,IleeIenDW T~~
S~" f'iK, Peceny R. Dilsd*"""', N
lie-
~~olpnmaryl(,.l
s..-...,
~""' .... ~ansong...'"
no::etlIlflg CI'Jloo Mod PdIoI12: 739-743
sUlll,oml)"'$ol~cebllanIll1ll.J
(COX)}> 1<11I ~ Am J S<r,j P;lIIhoI
ltut_
TfOI\illIInl:ZO 111173
1116, ~M.N.aWnu<aS.ltohH ,OhnoY,
Ma_ N, JorihllaT, Suc:t>1 T (199Qi 1.lasl0lli
prdlferaM .I&'lI ol h~ $)\'I.
lhe rnyeb-
liS CIWIg KL ~ u
Ilrtr- RK so.-. "" ~ JL
ArtIer OA 1999~ Al::vIe ~
~
wlolis. Bone M_
llwt'''''''''''ff.o:lion JirlIllcl0is181 521-533

1151. I\XIgmI D".... I.iueIer BU. f*1:o I(
olloooo-dOlt ...~ ~ II dYmic: Ill'JI'bCI

lIu_ll"OIllICM .............,ol3,.. WI. . 0, ... loIRe nl HOVOH IJOI4lI 9Iood
1131.
1, 5Il, KlITl\lla H, I.4onsilIlTl8 T, Kaoegaroe Ii,

CA'lga S HoshIIlo y. M8ed8 A lma S, Ql..ano
1157.
.... ,,~
W'lh
lhe
floe.
315-311
~S,Husl.>yG,SlblIenKi2006)
T"- anwlO aad !IIlQU8fICE <rla~ Al prOl8lll, AlKH i&oiaIed from It>e heart of a pa111l1l1 WIlh
_~
'*
~ - . - ~ . and ~S. !41
KIm Sf< (200) ~

and ~ SlUC!y ol e>:tranodal naUlfypI:t
ro>hJIlIIlUIlII,'T.qI ~ Me! natuIJI .....
.-rDIQ
K OflII:trlS
c..nc.
WIlIl:Ienslroms macrogIObulinerria Itlll llffl\'1Oidosi&, Amyloid , 3 260-262

1158. KWIg~ U, ~an I, Magnussorl KP,
W,~ M, llml P, Wiman KG 11995)
p16ilNK4a and p15ilNK4P gene rnet~l y!>l lion
lIn<1 l1ll18nct of p15JINK4a mRNA and proIeIn
e~ p!ssion in Burkltt s Iympt.oma, Biood 91
1680-1 687
1159. Killin U, GllJIl hinl A, GaidallO G,
CIl8<lI>um A, Cf&armll~ E. DallaFa\'ela R,
C8ttlone ~ (20031 Gene expr!lS>ion plollie
89' 2106-2116
anaIyM 01 AIDS-flllillOiC1 P"'N' IY effuSlQl\ Iympfloma IPEl ) Wgo:)I!M~ a p1alffi3l>las!ic deIi , atioIl and lCl8nlrileS PElspeclfic IIll11~c~pts
fiodo;Jk,ns I,mphon" Blood 90 4075-4091,
lIood101.4115--(121
1160. KleIl U, Tu V. SIlJIo\.1tz+:y GA. Matlicll
M. Cattoretu G Husson H F'WCIlllao A,
~ G, CIO l 8aIdi"o L NenA. ~
A.. O~aY8llI R \20011 Gena el<;lll'SSlOO
profiln;l 018 tel d"ro1C ~ Ie;.r '~
Ill'iMls ~ phenOtype >elated to
1!lIIIlOIY8011lla J E..,1dea 194 162>1638
1161. KJemq CO ~ U. PolIMl N.
~ E GoerdI S (2005) PfOIJ'lOSbC fKtDrs
and jQOIdlOII of ll'ogroo5I5 by It>e eTU
Sf.,..,., InGex
myw'lfS iunQoi<!n ancl

SotDrt tyndIome lit J Detmatli 153 l1So124
1161 Klal AD Noel P fwrJ C..... MA.
~ DC Coob J. UeuIe 00, N>.- T8
Nl
<003 Elfv_ _
a-. IiermI't
....... ol ~ YIIfl a ilIJlIk4JoIlIlo_

.....,. 01 ~ nl"peIleoili!Ol"'* 'l'"llrtwr'e ~
ior:JsIs
poor
_ """ IISoSUe_
_ Illood
~,ano
Chon~,
Metze
D, Ker!Ii, CIJrrorj L 1<0(5), ~ cular.eous

elirucrJpMtllOlogoc fee
tLKl:t5, d88!1ltlCaliclll , and progII05tlC f8Cl()tl ill a
~ge Bo(lIlII fyl r~ :
l1l ,qe lIe1"iIS of p!l [Illi\Ia, Blood 106 .4 912497,

1171. KOduru Pk, Raju K v eomal V,
~ZIl5 G. Shah S, SU5ir1 M. Koiitz J, B,OOIIllI
JD 11997). Correiation belween I'lIUlalion ffl
P53 p5J e,pr_
. c;1og&rlt1tic1, hlllologie
typa. &00 s<uvlvlll " pallenl!l will'l ~
nor>-
1172. Kpel'il<ll HP. l81'ir1t AM, Sf>arI:.IlS M,

Spa rkl:tS RS 11960) ChronIC ",yelocybc
lIJyl;em.a ~ II1volw<l '0 lhf malig<18f'l1
done 8lood55 10631005
1173. Koeppeo H N8lO'Ill K, a-.odl OA
VlIJll<..... JW 119'981 t.Iotp/'lOlOgoe!lollll .....
lOW <:fl8n\le$ ... piIIleflI$ ...ch ~
lim ~.... disotOln Am J SuI;
P~lId <2' 208-214
1174. KoI1a H. SlIlUlIlIya J. Ohst".... K,
lal.elltvll:t 1,4 , ~. N Kiklllh t.l, KoCIIo ...
( 1991)l~~~
I'\all.QI . . . eel ~
~...,
oII~. J
CIn 0nc0I 15 80112
l In KoI5 ....
wer..n 'M).
~ L I # 9 *....
AA IiKtIoII PW 1
lJillPloll.bd ~ . ~
lo!IIC sU11 ol42P'*fIII. ~ 18 283-2lIlI
1113. KoeIer A. 1A:lflt1!'lA, RasniI:tlIn M
BorIn Gf. Hebeda K. ~ w.., .....
KrlMnJHl<OO7I ~1l"J!.IOOSk~d
~~.~92IS4-\iO.
KMm"1oI ' 22.52:J..5J8
1110. !<.CldrIIK, t.la!lSOllt C
I'l8
~bw-..val()i~""
NSIl
IfIIIhII'WOIIteftlenl ol
~ Am J Sur;
Pdloll1 .41-248
1175. J'.oa""" K s...-. K ......, t.l
!<.IIl9" E f ....... J F1AIda 'I T....... 1
"*lofa A. S/wIIzu T AOI' R:. ~ H
1185, Kooldes PA. BI~ne~ JM 119961

Morphology and c:laGsif~lion ol tIEl myekxiy5pIa!!>c lyndr0trJe5 and !heirIl'lthologic ~
$eII\I1 Ii8matol 33 95-1 10.
1186, Kralol/lCS R, Pasaamonb F, Buw ,l,$
T&O SS, Tiedt R, O'!lSsW!!g JR. Td>eIi ~,
Cau ole M. S~oda RC (2005), A ga<n.<lf.flJr>;.
bon mulalion of JAK2 ill m~eloproliflll8~~ dl
OldaM JH. De.loogD, KiIA'
PM119961, Cncal Slgrtlicanc:e oIlld2 and p53
proleIn IIXpm$Sl(IIl '" difluse Iar\II B-QIII1jolIphoma aPQllY~slIn;
JClwI~
14 213121311
1188, K . - MH, Henn;ons; J. W'lli<"9 E.
PllIlWo K. Geelen E VI'iIl Kr8.en JH Da.klll
o. Maar1I:tnrie E. ScIv.Jmg E, 10ooPl.4 (1 9lJII
CIrlIcIj _ vance of BCU, IlCL6 anc Ill'C
l_lgllfIl8ll1s In
(io/IuSII
largII B-QIII 'll""
Illood 92 31523162.
118lA. KrousW , Haley JC RrMR ~L
Mor!In Co\. FItIl:M'CO 12001~ ".llMnla" ...
pIloma
..
~aq
"'IlI'l.~d-.._A'tl
~23
104-111
1189. ~ A.. Butt. G GI*l:lIilrIli

T F~ T.~ CJ (20051 The
d!InoI ol ....,........,. II _
II'!'
KooklIT(1!l97 E~~~
~ lly .......,. ~ DlOoC:I
_
Q!III . . . . ._
1I.I*oINMIl",
~~_tn:I
aw--.nol~~~
101 ol
~~a ",'''''''''
~
tooI:t - - . . . . . .lda
f1aerlI3tOj
mo.
11) 1311.3
K_
M, S(lI!m" M, ~Web S.
S _ K, SChmidt e, Hohr H. OI.-ltan&t/dlWli'ltl' t. F.,.;l r (2Q)31 0iI00rdanI _
lIWTO'* tnWIvelTllWll III ~ lIfge II-oIIIym;YIomI' 03I'IllIQM
l~lJtlI.4IrJ~ l...Wl""'-t
moMQ.llIf"""".......
83101-114
1" ' . l<.rtI\ICS l. S<nl'lh UJ.
E.
KnlrIac:f; T p(oppetl. ~ T.ltII A...........
HIImelr* HI( JIfle ES. RiflIId '" (2003) Tile
_
Il"*- lJ'I'IZY"'t M if
~ ~ NK<:eI, gMlIfllI'- ToQII.1IllI
II'lllI*IIII ToQII ~ .....,.,.rJ otI\JIl'l
m ~ 1IMlMd . . . . . --.....,
Blood 101 358ll-35ll3
11" "- ~ t. TIIlJhoo::l L ~ T
pl""'''.
12112. Kvmaf S, Kr&f\3CS, l , Mlldllir05 J,

ElenI!I:JbrJoIvo KS, G _ tc. SoriJara t.
K'ngtI\II DW, Raneld M, ;aile ES (1996)
~ pamiMllC T..::eIl'f!'1Phoo1.i ISa
32: 362311
121'. Kv.SI'1<"'" HI>I. Tnie~ J (2001)
Cias$thC/IlIan 01ph.negalr.ie ~ m~
tlJmor 01C'f1ol':'.<lC T!'fm~ H~ Patt>:M

29 397..((lJ
1203. I(I>'!\If S Kreoacs L. 0Isukl T. Kcrnif
O. Han" CA. W\lIlmiwIn A.Jaffe S. ~ M
(1996) Ddl f$lmongeme<lllllld cycIi'I 01 pro_ t\P'8SSlOl'l on fRllIIl* ~ PI7rIDlI AAI J 011 P-.oI10~. 7J1_143.
121M. K\I'MIer JA Ver11lllel' ...... Duo.ers 0
...... CJ ~ R (1997). UosIIII'fT"QrI
I/l<;llrl~ P~ ~74 .63-71
dIIIl;liaIrJ(Xl1AIllIQIII'l in~-.d..cl
CloUtlIIOuI CD~ ~
clIlUders _ I ~ ~ ToQII
pr.not~ J InelIl DerrnalI 109 636-040.
1205 " - rr. $IlIl tv. TSlI'Ig NY (2llOoI)
lQNI ~ llII~ in Ta'0N3n.'dnic:o(:IIIlDIDgIc: !Ilucty rJ 22 ta!I8S ,.." ~ rJ
llIIiIfIl ~ ....
IaI1lIIogoC
~lI19931~
..::tooftI"_
~ ~ WIJS
CbWIIl'Mlod1010 J PIhI111 "'001

lIn. K.reo8s l. w.Irnnl A. ~ l
lJ,lP.l
~-.ociak:Il.IIllI~~If1l
J Surg PIhII12 37So387
. . . . - III
. . . . . . . - W - r J T. fd.
0IIl rw- IIllI ~ . . . . . . .....,.. b"
120SA ~R.KiIwlU.~( DIsI.V ~ A C8IlcnCI G,Tv V, SIolov!lzO:,

GA.
HIrJ!imaM \I., Dall-l'MJr'II<
l2OO3i 1Oar"*'*>o, 01 ~ .nl ~
,_. . .IIlAW.E.
i'9'J1). Cykbic: . ~
fS,R-..:I'"
_ _ ar9f\ lllood 811, Illll).9ll9
1111. 1\twIgIl .... J T* BJ, T.... Sf,

"'-C UJ a.IctI AR PIIniJ Utl (2OOl)
C1orlc:Jlwoc 19tiI
V(lIJ ~ ~ III
iVl*leo"'aii ~ .........
......... 11-0II 0I'IgIrI1IllI1l'I ..e-- of polyc:IOIllIl I> 0lIII1II ~ ll/oOll, Bb:xl 1001
21 312142,
c.I;n)'"
SW!tlIf9 ~ geo-.by gane ~
JClin lIfvesl111' 529-537.

KlnIll M ~ ... ~ V
~ 5, V _ K. StJZ\lIQ I( ~i '"
_
llOt
(20'J61
III"""
~ ~rJdrvg hIII$/lOIl
~ 1Mi$IanOe1 (1JDR11.nl king
~ Il"*" flRPllkPlg
. . ---., rJ
~ IIuUmIII In "'~ s~
" , .. KnIIqn 8
E o.dIn C
(2006) PJorylllpllOeyle
_
Stnlin
Onool n 2~12ll3
ms- ~ J WIII:W; I( FI'lRIn G
(1984). T-ceM:h ~ lklIlI 1ympI'ana, 10
lIlIOy rJ30 _ , IUppI.lI1ing ItII1i1loklgil; l'IetIft'lgIIIl8IIV IIllI IIcl rJ <*WeIll _ _ _
AAI J 5urlI PalhoI18, 4!6-465

11M. K' obIf A 8loehclom J, HPIIr S,
Bunitr 10, Seier 1 1("",, D, Winkl" O.
IlIngefw l.l Schlenl< RF Ilemer 10 lidIIer p.
Oohrolr H S~ S 12006) AddoflonaI
~ hig/l-flIk /e8lUfW JUCII" 1IQ deieIorl,
t7p cIeIetion, and V3--21 UHogII dlarllCler'lll
~ 01 l),P.70 and VHmu!jlOOlI 5l3lII
'" ltl/'or'Ii; lymphocyIlc 1tu,emi8 J CIOf't 0nr::0I
24 96s.975,
1111. Krober A, SeIer T, 8enrlet A. 5uIinoer
1. 1lnIck ~ e, Licht... P. DoMer H, 5l!lg1l1'1bal.'el"
5 (20021, V{HI mutatoo IlaM , C038 II' PresIIkln Ie>'&!, genomic aber1"a lt()l'll , and IUl\'1val ln
UP Mol PBId 81 249-25011207. KL01II PJ. Dwoald GW.
S/weIc)s
OJ
Hanson CA 1'996) Hemdl<Aogle ~

~ WIIh ~ 01 r.:hn:m>some 2l)q
1 ~ ~ rJl07 pabenls "'" J
On PIhlIl06 ~ .
I2CMI. Kurzroa R. 8uescHlamos CEo
~ H FrtInIICh E T...cter st. Socikino
M PilIIl S Till&z 1>1(2001) BCR 1'e8fr".lfIge'menl-llllQ;llMl chronic myetogern.lIleIAenII
c.n 0nc0I19: 291So2926

1209. KusIner JP. l He GR, 'MnIroblt MM,
Clrtwrlghl GE (1971) lQiopalhic refr.lDry
......-ad. J
_ : (jnoea' iod OJIloralOfY
1197A Kroft 5. ~li-5aad R. F'M W, 8llli.

PrllGUrlQr BlymphtMa!11C Ifllnl fo! mBlioo of
grllde 1 IoMidoe OIlnlYr ~ Am J ~
~ 0117 patients lIld rPvIeW o1lhe ill

erature, Mediooe jElalbrnorel 50' 139-159
1210. Ku.ssidc SJ. Fromm JR. ROO5OfN A L' y,
Crli1nO A, Nt>I'WOOd TH. WC>:Jd Bl12005i FOOf
cob" I\ovI cylometry shows wong concordllnoe
With bonll marrow ~~ ami cytrJg8""t
ice in the eva luattlll1 for nlyelodyspl~.ia, Am J
Clio PatI1Ol 124: 1701 81,
1211. Kuslid SJ, KaInosKi M, Brat", 1 RM,
WOOO 8l(20041 Prominent donal !Hlell popII.
laliornl identltiedby flow cytoretry In hislOlo7cally I"IlildJve lymphoid proOferatJOtlS Am J Ctil
chronic
I~ n l p h ocy t i c I lI u kll m l ~ ,
Blood 100.
1410-1416
464~ 12
lil'llfl~ve
deorden .
II lhlI ywV--
UI1 . Kvaanid<.a HM ThIIIaJ ScImlI-&aefl

'" DoehlV.z.,!lovdlR.~N lederto,
5cNoa1" HE (20011 Bone mar'!O'I' . . . . . .
~ove po-OOJIOIIIt elfic:iInqo f\ ~
nPi. dlsso"C1l1ion 01 lh\::Qc.~ 1'h(1')
o;IIra'Iic ~ *-'IiI. I
IIlIl JOn 0nc0I19 2994-3OO!l
1211 I(vaIt\d<IHM -n.IeJ ~
A ()eIiV ~ R ,....... N l.edIr to
SlJ....-HE(2001 ) ProgroIlIc""'llidrJ_
mar.-o- II IIIVO!XMII'C po-tQ,QQf CIIIII Il'Id
""'J'8I(ltO'(lIII _ _ rJ Ph" dTooic
""'*"""
"'1'JlDlIIIID. . . . . - - .
lIlIOy
on4'.l!lJllll*U BrJH-..oI1t2 7277JS1

1211. K~ Hlol TlIalI J. WIllden C,
z.,.0\rICh R. DoIIlI " ~ R Pfii7 ,
~ fkItn '" ~ !rn"W)'i
~ e..-1lO 101-119
1220. K~
ChIll N;, lMlV It ~
J,Jt,. O'IrnCS 0.. TX. TOdI: 0 HoFe (1991)
n,
C056< NK ~ ........**"1IU! ...

_i<ld~BrJ~1l7S2\5
1221. KwtIl\ln.a..AC IM1gRHllll91}

'1101&11 . _ ' ___
llV1IllI"""" I1ernlIli:II 0nc0I 1~ 7179
1222. KWCIIllI Yl la'n CC. Owl T\l (2000)
~
.....* "'....
Pc.1~ ~i,*"""olifiII"aIIve
_rJ ............
c.a k-.gt. a
0.-
and rtIOlIcWl" ......,.... Br J

HoWIIIklIll0 191.2ll2
1m 11-'11 'fl. we..g Kf 0.. tC. liani
RH 0 - JK Un CK 0... TJ( 11995) Largt
gr-... 1yqtJocylI . . - . A AJlty 01_
CMlIl II 0... ~ 1vn J ClIl
PafJoIl03, 1~1.
1224. Kyte RA (1975) MlApIt m"*",,,
""\1:1
oIfIIlQ~
Qn Pro<: 50 ~
122$. o(ylltRA Ger1zl.4A11995) PmwyrpIemic ifIl\'kIidow CiIlitII and lIIXr3lor'/ IN!Ins;" 414 ~ S4mwI ~ 32 4$-59
1226. Kylt RA. Gertz 1M, Wllzlg TE,!.usl JA
lllCY MO, ~ A. FonMCI R, ~_
Sv, Offord JR, llflOO OR, P~vak ME,
Themeal TM Greipp PR {200J). " - of
\021 P<o!Jel'llI ""th nt'WIy ~ mo.AbPlI
rrryeIorna 1>I.1yO COn Proc lB.213)
1227. Kyle RA. Grew PR(1900). Srooldenng
m\ihplo.! m~ N Er'9 J fMd 302: 1347_
,~,
1228, Kyle RA, Grt!+pp PRo O'fallon WM

(19861 PrlrMry SySlflmil; amylotdosia mullivanatll ~ naty s< s for prognostIC fador! If1 168
e-o. Blood liB. 220224
1229 K~I II RA , Raj,urT\j, SV (20061
M{)roJdona( glWTlffIO(lIIttw 0/ undeIe.'\'I'IIOIId Iigrlficanao 8r J Hllematol 13ol: 513-589
12M!, K~ RA, fl.lIjku'llil! SV, ~ TM.
L.non OR. Plevill< MF I.IeIIcJ1 U, III (2005)
PrognoelJc leclor1 r.cI ~ at0\IICtll'ne of
~ 1>1 mooodonaI 9ifllI'IOl'IItlly 01
PlIll'K> 2000; 113:411-.4 18
P.!tIoI121
1191. Krotowslu M, $ollar K, Krauth MT.

FodH1gllf 1>1, VI~ t p. Humy HP (2005).
~ 01 [ldemI 01 bone ~ . , .
0IIl nfiIIrallOn II lyMemoc mnloo;tolis v.....
01 C025. correIIloOn ~ wb-.tlrJ a. 0.-
1212, KUSSId< SJ WC>:Jd BL (2003). f O\Jf.

cob" now <;yb'mlIy iO/I;'Ibfies vl:1uall)' at cy1ogeoa1lQlty abnormal bonll rYWfO'/ll ~I in
!toe "O"lwp 0/ oon-Clotl m~ern!Ml dr$-
_, " ~ Irl:Jm IllUl Cllll ~

. . AmJOinPI\hol 124: ~
1213, KUZII!I T, Nakamura N. HMiWmIo '1',

s.-. y ~ 1>1 (2000). Tl'le dl<l'~1Q rJ
257260
1231. Kyle RA.
1199. ~ f. Sdutl C. K.-n W

Hiclclltlnlnn W Hat~ T. Sd1nrt!ll" S
(2005) In'4*101FlTJ IIlI8IIonI n ~
loc1W; ~ on o::lIAoc*d'IQI>
EilIlIi'\.&on
WU!i (EB~ dillu!ioe ~

!keIlymplIoma ~bel-.E8V~~)
~ A.I(\lfUlPJ
Il'IdE8Vi-)~II~p;llltJlaIl(lI'Jpn
OR Plev-. IAI'. Jehlk Of fMlltli R.1Aeb1

U.II RIIw....... SV(2007) t::n:eItnnell'ld
Jc.n::-Rea1ll: 12.13-t24O
~rJ~(~)""
_n~"mlIllPl~
l214
IlrJ H.-n&lI 130 196-2ll2

80 Snw1II RE P..-", J,
P.-.on lC. Hanlon CA(1W1) ~
. . . . . . . 1 ..,...... ......... lIiDdIr dIIlInd
'an" t.",.._qII* ~ HemIIol
PIIIol5 I~205
1201. Kuehl WM, ~ PI. 12002).
~
120CL
I('*"
..... ...,...
_
. . . . . . . Nil Rew
ll"l'k ....... n
e-- 2
17Solln
0IIlIn "'" J
CIin PiJlhol121J' 8S4-a5
KvnrId<a HM. T'- J 12004) eo...

m&n'OI* ~ metIIDd$ 01 QUIYlIIbIOn Il'Id dIlingeI eVCIMrIg II ctwonc ~
~clIIordln, IiIstJl H<slopahli 111. 124!>-
""
l215. I(-.:b liN. ThieII J (2001 The

""I*lrJ ~ !ludIl!S (WI SI<lgOl!l
"
SIO'\'MIl in 'l$te/'IbaI "'o"iloc~
ctrOfWC ~ ~ <lAd po;o.
~
nto
!If3
SenoIl
Hemo!Il
1ll_ _
lId~, ~
l~
EO, n.n-. TIA.

HochII\eldJM tanon
.. ~ N Eng! J Mecl358. 2582259(1

1232. Kyle AA n-- IlIA ~ SV
larson DR.~. "'" OIM:l..ll ~
A Kill...., JA Uellon U III (20061
PrevaieIU 01 IIIOOOdonII gIIIIIfftlIlldl, rJ
lIide1ei" IIgnIcanoe N Eng! J MiBd 350f
1362-1369
1233, II,. AA. T_ _ 1'" ~ SV.
ClIoolI.fl: lifWI OR, """'" MF. MeIonU,"
(2002) A ~ ILdfrJ ~ 11_
~ ~
0/ unOoell!fT'1rlfd logMI-
-.ce N"1J I>I8d 34li 564569

1234. K)Wj RA. Theme3u TM, ~~OOW SV
Remsleoo EO, 0lI0n:I JR ~ OR .......
MF.!.\eIb1 U. III (2003) lor'ig--l!Jm'l!oIlofHlp
01 IglA monoclonII ~ rJ lnMr
nWoed ~ 8loocf 102 3759-3764
1234A. lIdJenaI F IWger F, ~ Ii
BIonP.HotA e.t&.cnuE ~ C
~B. o..r.u I Rous5oeiH SeIII G12(07)
~T.QlI~QrD
IOd lalJorwPy feelures III _ _ II
lIIbeI1b u.dOle (8aIDn'o'e186:
282292
1235. l.ae /tolE. Armed L Niron WR (2002)
e.-..IS....,..,.,..~
II\llPlaStlC ler9'll:lllllyqllone blII lieIs b cIJ.

. . . . . . ~ fran eeco"IWY ~
. . . . . . . . 011I ~ Nn J CIII
1"IitloI118 n3-m
1231. llllOrtilla I VUque.! I Agifre X
liIT.t'/'Ol WJ. Vqmanos JL. GouIII!I A
CaIIIIN: WJ Odefo.., (2004, ~ ....
...-..r ... AIot.4ollS
3G21~
''''''9W'I GoNsO.,. ...... e.-
<to: 119-189
123J, L..i.L ~ C Z..oetil ..

FIItlIfM V~M ~P.W. . E
~Pf1995)~~
IQoIle ~ ........ ..re.. l1p dIIiIIonNo ~ d\n::lIInlIlCl by . . . ..,....

lc(Jo:.- nl a "'" IldderaI rJ PS3 __
lIeN teuatrr119: 37(1..381
1231. La It AlberDA CNrJgKl.. N&on CS,

(1998) F~ rJlid-2 IUP*
we. Lll
...... non--HOOgiuo.:; ~ IWy 01

718 caMe ..., <:tlflIP'I'lSOl rJ lflII9hlII lillie
~nl~8-ceI~
Mod PJlhgI 11 ll64--ll69

1239, La R. w.s l M CIwIg IlL AstIer DA
(1999) FrequerqrJC04J~ rlllJdIo
Hods,loin~.A~rJ742CiA1n1
funhet ~ rJra-e C04J.
**"-
...... J can PavIOl 1I1 -1&6-494

1240 l.aoo5I (;oJ. SIiIddeld M, GrIll T (200S).
Determ'nal\li of I~d"""'lelood ItMage
~
~ AInl!lev1rrlro.lr()l241Q5.738
1241. t..vnarII l , Oasn.gue N PIAlord K,
DenoI:G, IAanameB (1999), A .--t.oIk:Of't~
TI'loU-ALK '" ~ ~ CIIlI ~
Cf$;jt!ld b~ a 1l.2)IQ25.p231 t'ansloclbofl,
!lkxId93, 3Oll8.3095,
1242, Lamant L d8 ReyT"liei A, Ovplenlllf
MM , Rickman DS. Saboord)' F. Gil.nalo S,
BrllglllfeS L, GauIard P, Espino$ E. 06lI0! G
12OO7j. Gene ~. pn! !lSIJdl profiling 0/ systemoc:
itrI8plaslic: lar\lHllll iympl'loma rIlVllai5 dI!et'.
erns bllsed on AlK status and ~ (llslJrld
r'I\OI'?hOlO9lC AtK+!oUbll'Jl'\Ii Blood 109 2156,,~
1243. taman! l , ~ RD , DupIwi\lef

r.u.l. Arml;lroog F. R~ A. CI1hIrIat:t\ai 101,
Raji;ln-Se(JarovlC E, Ragnab J 0elI0l G.
Espnos E (20031 ~ ml'OS'~ IJee'v)'
ttJaon (MYH9): a Mw pWNf fuIed 10 AtK '"
lIIIiPiasllc lafge ceH l-;mplloma. Genet
~~JT 427~32
l24oC. l ilTlint l. I.Iegge\b f. aI SaIIl T.
Bruo- t.
de P"elS 68. ~ N
Bam"""'" A Rvboa I. TerriM-\.aIXon'bII IIIJ
Robert A. RwIl F SctialtIlf O. ShoJt.iII.I Uon
S DeboI G (1996!.....h inc1dfIlDt rJ lie
~2 5~,p23 Q3S1 . . lIIocIIionil anapiISIc '-91
tell ~ end '" lIO< 01 0IIlId00l'I I'l
1tldgo;"1~.~ol~
~.
hMCf(lIa~
p..eo ommunostalfWJll
Blood 17 234-291
1245. ~ G ,\rwIibll C
G\'wI A. Soigo011991;. ~.,...
dIaI'l 'eadIon, and
~~_Il-._""
~
1246.
~I S5
~
l'f"hPlDrna 8
G, OtoW A
References 403
lu~td'l
R Mnlloro C
0 (1991)
~eyndranlt"'" ~IIW'
fUoM a dIIlincl
tWmIIOI 78 161166
1247. Larny T. LOUIl"ran TP Jr pf199
fOIl
~_
Iv BrJ
CI.oowlI
tuIClI(8 IIrge
pa.V
- . . - Illood Rt 13 2JG-2"O
12.... l - r r l~ TP .Jr 12003
CtrGII . . . . 01 ~ pUir ~
....... s.r-~'-O-l8>'!lI5
12
!..In 0 Zlwr1g T ~ 5 2lwll; 'f
S/wl
Wq SS e.Jd $I bhn SH
Hi;lIlotI:l ~ lMcMo9 B y~ M. WIIk:h R
~ 0
~ P I'IoIlIIWI N (200S)
Ger-.c _ _ 1'1 tnl*egeresillfld~
litMIitI
__ HOdQ_,n
10
Iymp/IOrfta
319-418
125t, le GooI S Talmarol p. T~ C.

t.IorMu A Gar8nd R Jug~"" N
~ f GaIlmI T UipIed N. Uor-.. P
~.11. A~-I.cneau H (2lXl1) The
'*"tlIl "'_....., -:I ~ 01 doIlJM
"9" Ik:eI IyfI'I(l/IOIft; willi
18l and
81;2. lIIYC . . . .."..,." Hw-*lflOl
Il'.
'll" 1l)S.13oCl
lao.
v lRwo F C!wtllII F. 0Innl

Il S<ICbl L ~ 1.1lnIl
lJIC*)rId
R. a..r
.II.~"'(\9EllI)~~
~ cliIonleIs not IISSOOMCl . .
E-...a.r
W\IS
llWd -*Y' J Oil
CInoxIl16 20522059
1261.
LeBootPE(19901).~siId<
WI ClennftII c.. 12: 37So389
~,,=
m 9, ~ O. Grdey G llAS50ll I,
CIporakl NE ~ til..
0 F~ TR
Hl:XMIf' Rtol, toni! t.lS 12(06) RisI.. of IIlOflI)doneI ~mmoptltl)' of urodeMmined SlgMI.
1261 A.LlIBoo1 PE Burg G WllflOOtl D, ~
~ (t.lGUS)
12&2. LeBrun DP 12OO:l) E2/l. basic lleIi.
a.rs
ma amoog
and ~ muttiple m~
African AmerIcan IlIId
...mote _ .
arllin ee UnitedSlams Blood l Or 904906

1249A Lj rds 511. MUfTay T. Bold~n S, WIngo
PA(H199) Canoer "BtISIICS. 1999 CA ~
Jc.,498-11
mo. l.JnO" 6J, Kobmsl<y N 6am1ltd OR.
At\tIt DC Ilud<l8y JO, HoweIs wa Gdd S.
~ J. Neudorf S. 5.... FO. Woom WG
(1998)
DiAno:lMl~, blcllogy
ar>d
OUIro.... 01 .cu~ myeloicI leu ~_ and

rnyoelodflPlls'lt syndrOme ... dlIlhn .....
[,on lyndr'onllI Cl\iGrer1' e-- Gfo"p
SUIII5 2lIlll nl2891 IlIood 91 flO8.815
1151. l.IngItnke C o.Azq U ~ 0
200$ ~ aI no.r. ~
mM~"""""~"'"
~-~~......
,...IA...."..., ldIIf*cIlor
(2006)
W()IId
Clll~,.rlCll!lOrl
~,lfln
OIyaMl2aOO!l
of TumOUr1; Pi!l!'lology lrod
of ~b'llumo<J'J lARe . l)'ll!'l
loopl'lell~ IraMSC"ptiO/1 factO'S 'M human

M8rT'lI.lI Fn>nl Iliosr"8 s20&2Z2
1263. l echaptZalemoo E, Chail,f'leD, M au

ll''''' MH, HlIioun C. De!;Vll\J ' D, Glulard P
(2001), Ahooiatiol'l of primary ple!J!'81 elfuskw1
Iyn'ViomI rJ T~ origI1 al'ld hu"""" hArPMWuI 8 ., II"IumII1 rrtI"OJllOdt'ftcilny WIll
~ men Arr11 Pall10llAb Mad 12$
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3SO 239-2'8
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. . " . . . " II CIWO'.: ~ ....",..
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12Sl l.BrOII P BcdJnan UA. $In:lBeo J.
Lmgo 01., J8tIe ES 1'990) L~ lymphome of Irolermed181e <:iI!ll,... baloon
AI'l'l~~.&Oc29ol297
..... ~. . T<l!I~ ~ .
~1IQ2llIfroma~rrUbcen
1255. Lnoo RS, Soot! WI. McCurIIIy n.

V~JCw'ttICl. (1996). ""cfIJ'Sa!llllle ..,I/y.
lis d PQIllrItl6O!lMI lyTnprq:ltoli!efillMl (ljsor
den dIlImin;Jiotl 01 dorlof.l19ClPeMI ~
and icIInIibIorl Qi ~ ~
~ c..c:. R80s 56 AJ78-4381
12~ . laawIIIj Mj, KemO JD. GoekM JA.
lIlrl!ud)" J CIi'l 0r>r0I2~ ij12.ij18

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WIIilIm ME
SlQu!II'ltial 1>d2 aM cm'lc oncogene
'Hfl'lInge"'lflls Rssooaled "rir1 &Ill dirloelll
IrIr'lll!ormlllioi" r1I noo-Hodgk,n's tymptIoII\a J
c-. in_t 198\1: /l.t 1~54 , 1 ~59
1267. ltg rand 0, Perrot JY, SimoniM G,
B3udarll M, CadlO\l M. Blanc C, Rarr10fId 5,
Vrguiol F, M ~rM1 JP. littOOM R (1998l Adu ll
tIlp/'ler'lotypoc .cute W."".M: an ~t<tv ""th
pool PfOI1'lO"lI 'IItoidlis rKl ted to ...,fal'Olnble
eyIogeneticl and P~ O'f'll(~ .Pfft
~ Ilt J KMmaIol100, 147-155
1268, Letlh CP K~cl<y KJ. CIlen 1M,
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OR WId: J.
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ll'lefiljly-mlaled m~toid leu'ami;) a model
lor 1e<J ktmog&nelllS 11'I humans Ch!m
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t)"'lPllOmls oIher than HodgtirlS <Q6a!lt
SQnro9Ir Verlig ~ York
1274. LIllIIert K. Feller AC (1992).
lii,lOplI!t'dom' of nonHo:1glan's 1ympt>oIrialI.
SprIngIlr VtlIIag 8@rIin
0.,.. UJ CIiIMl<y D (1997) pSJ>OOii 11111

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F'anc"is de Cytogene'ique Ht>matMlogique
Abnd !*l. 41544159,
1280
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V Fenau. P
~me
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fW B IlrJ\Jrlj C. ~ G ~ C
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~ A so...-.t Clno::cIIoqy G<Ilup study BklOd
lit- 3323-3329
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lnIJCancer5fl m .18!.
1287. levirle RL, lClllllUl l,l , I-lurlfy BJ,
Ml. Beran M. S1oI'!regerI E, Ber9"f R,Clark JJ
Wills SQ, Ngvy(lII llit , FloI'M NJ [sley E
cMJr1ic m~ *"- .., IClAI

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lie lllvl<emiI IX dwllIllC ~ lalMniI
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0 ~ It. ArlitIylI
o ~C~AOIuaF daVlwA
SIIlRnt E Poggi S. PiIen S TOIl P
lAononI L
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IlIood 105 nn.n19

I2I7.. Le.... RL. ~ A, T" It.
DG 12007j Rae 01 .wt2 .. !hi
veo-..-:llonp'f rJ""....,.............
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~ FR. ~ Cl (1997)
LensD.De~PJ.IWI'ioudiRA.
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YcC<n'leI T ~ .... 0 - lU I-1lIId Dfl
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1265.
Fnmr. G.Ibll D PelnM B ~

KJ
f1IW _ _
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JD Bemard OA, Heinlid:I Me ~ DG
OnJ~e. B, DeOl'liogqt MW (2005) !tit
JAAZV617F IICIivat"'ll mulll~ ocan '"
tID. lAzza'IIOO W OIWO E ....... W.

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MId 108 14-20
~
l ~nnert K, PalWamsdl MR (t97q)

Ma'll ~k and mast 0IlII ~asill a re,,*w
Hrslop;lthology 3 349-365.
121&, leonetlK,Sleo'1 H Kaisetlmgf(19 751
C~ ..." and fundiQ-lll 0'lI!II'lI b !tle clIAifo;:abOn of maliglml ~18 Br J Career
31SUPPl. 2"29-43
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~iI'lganf~~
NIII Rev Genet 9.16$-l'8
1283, lfW1ll AN(19931. ~ mIIIgo

i'III'ICM. lhIlI"'Ilr1JII'Q epdamic J NalI c.nc.
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1214. L"",'ne EG, Arttl'" DC, fro.znm Q,
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Surq Pa'h(ll 27: 1061\069 ,
1291. II JY, Gaillard F Moreau A
HIlOOI S8lOll Jl labors$e C, MIIpifId N
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Blood Cell Mol Dis 35 37G-383
1m. ~RH.I-bCS Co>:JD WlblrO
DI!IIaII K, Ale....en R (1998) SoIi1aly to
pliImacyIomlI' 0lAl;00le tnd prognoelIcl<IdorI
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1:Ma. LllI>GIil R. Hart~ng l. HoIl S, Pet1<ire 51.
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~ irMlMng P'f\oT-eeI . . . . . 1ro1
lorI.lHC IllOiKlJIa Am J
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e.ow P.
1.M9. l.uptM M
can Palhol
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P TlI'It G I'~ 0cNI IllIUe r:I ~
0InlIMe ~ llIood lloI 30&9-350,
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(2001) lr.Io,ebt,........ ~ IlddIraI
11"01 ........ II hl.lr*cl
s.... cenc. 109
15J&.l!1012
U52 . .... z. UorrlJ SW v--. V to t.l
~ JA c.,; X . . . . . 0 Li Y loIolMI PI<.
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c..c.Glnl:~'66.112 .116
1363. UigIItI IT. Jaru, C. E~ BK,
SfIII9III R..IIe ES Ileta"Il CW,
~ J,
Moms K Barnwell R (19841 AA eftecM .....

~bldt",or.,","'!~~1
1
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. . 1'l
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8wrlI F f2OO1) lupus ~ n;WamIj..
I\IlIt ~ Iobo.fw ~ Ird_
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1355. MldleyAC GtM'I L '-".llC, 0I'!nlb'I
P ,l"'\l8fl M (2007)
I~ ..
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T CIlIIym-
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Tw U u led \fQm , patte'll MlI1 blaslie MlInI
cell ~ loU Hemaki 81, 148-1S4
1361'" 1,4.1" B. Anastasopooloo A, KIUIf'l.
~ JC. TIlOdotoW: I,~en R. CfrbclN
A. 011 Wolf....., C (20011 An'Dng dillule
*ll' IkeI ~ , T~1!nlIocyte
netlllClli'ld COJj)o lII'l<lpIfSlic IkeI ~
I.hbt d1_ ~ iellLI'es. Am 0n00I 12
1355A, Mad. ema ~ IC (19'M) aem..~ <:en........ An.... Reo; 1rmuIol12, 117139
1356. ~tmItn KA, Bemell MH, VIOJ(jn..
H8 Va>ghlIn f;G (1992) OiRgrl()$l' llI'Id g-.l.
Jrg 01 flDduIar ~ l"Iod'1loll " au. .: I
1IIId~ of 2190 pa.t>enI$, In!
hp Patr-.ol 33:
R.,.
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ZtIang J. Lane F'J (11190), The "YI,lM;or, 01 B
cell clorlee , Curr Top MICfQbioI Immunol 159
37-63,
1357. M3eOf1 WR , l evy NB ,
K~rtln PJ
SaIlany KE, EII:IlIlii!~ MY. ~lltV n. Cfilig FE
1I1\61\CC1 1, ~s CL, Gull.... t.tl , Park JP
COusar JS 120(1) ~~T.
C8II ~: allllpOlt 0/ 1' ~ M'ld com
~ ... l'le\M~ ~ ~ T<:ell
~,Ml J $<Jig Padlol~' 285-296
1358, Macon Wit ........ '-E.. Greet JP.
co..r Jll (1985) PncortciI ~ T<lIlI
~ k..."I1-...... 01 ~ ..."".. VII..-.t
d perip/leral T<:ell ~ Am J s..y
PllhoI19 297303
1351, ~ N l ..... 0, IOIIa R.

Horsman 0 Conrocn JU,
M~
RO (19!l91 S...,. ~ nor'I-&rtllf1
(8Im!,UAlI ~ ~ ~
~ If'd ~ctncII ~ JCIn
0n00I17. 1558-1567
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~oI
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(FDC1)1I1Ol/o
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J~
~50 1475-1486
e-
1361.
~K.
T
T
K f''*u1tlmI T.
K.-.r- ... OrPo!wuy
406 References
a ~ 0I~
c:uia.- T-cell W'od ~ , J eut.n
QllerlIOO1 T-oIII ~:
P.-:JI18 235-2.(7
13&6. Magro CW Ctt'JlO!Q'l AN. t.b'nsoo C
. . . K, Pm;u P. WrIght EO (21X161 C06~ ~ 8Il:l iIs
do/hInII'JUI
Am J CIn P8IhoI I~' 490-501

1361. u.r. A, ~ R'N. Nwiberg AG
ScmIIMr NR Kroft SH (20011 Prec>not BCIII ~ Jymphcma A sIIldV d .....
c:.II ltI<.:Ionll bloocl and bone mlI'ft!'Ilo irwoIwmeot and ......",. 01 ..... 1iW,1I<#e. Am J Gin
~
PalhoIllS 86S-lI15,
1368. UIlIIs A Pugn
we
RodngJel MA,
8eneaH:I wr:, Ca~ F (19971
MMlle cell
Jympl'ioma rorrelilllOll d dnt:aI 00\aIITIe ar>d
bIok>c)iC /eall.OW "ilt1 three nO$IOOgic wrIarPI&,
J CinOrlcol15. 1664-1671
1369. Makl,nima H 110 T, Mom~ K,
NR'aurwa H, 5nlrr\Ol.laira S, KamiiO Y,
Nal<azaw:l y. Ictl1l;awa N. lXlOCl 1.1, KOOJly~sh i
H Kitano K Sarlo H, KIYCISilwa I( 11tV. F
120(7). CI\6rlI<II<ir'le s)"5~ <lI'Id tili$lJft onfiltm
IloI1 illllQ9rll!lSNll NK-<:elI leu~em . l au\; Ras
31 1237-1 245
1370. MRlco'vali L, Gllrming U. KuandgM A
De~R
PCl/la MG, Pascutto C, I ~ Y a r n lll:; R,

~ idl5 A, Hildebrandt e, Bernasconi p.
Kroipp S.StruppC, Lalla/irlQ M. ALJI C Cnlola
M (20071, h ne-dependMt prognosllC srorir>g
sysl<Wn !or predatlg suMial a<'O::l IwI<erniC
evOOIlon in ~tic syndl"1eli, J CM
Oocoi 25' 3503-3510
1371. ~ l, Porta I.!G Paseutto C,
In'MlllUi R flooj
M. Tra.-agino E Pa!lS8lT"Cltlb
F. "'elmi L. t.tallioli 1,4, Bemascon, P

l.Immo M, ~ M (2005). Pro<p:!slictac:
tw1 nI ....~ in ""f8b:lJ'5PlllSliC rynd<omMdaaifIed aceon:llflQ to WHOaIWia I
biIM rtJr dnelJI ~ maklflQ. J ClI> Oocoi
23.7594-1flO3
137Z. ...... SH. 8r*>~ V Hio:.lP>5
LA ~O(lJlllll)~davo
~8.I1 .14.-.dXIllT~
.....emo.lI s1Udied OV lIuorestenct In MIl

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Gene! ~ 103
c..eer
111).116
1373 ...... RB. MaIIes E C3II:MJ<y D.
~K""""""PS Hc*lanCA(19951
CIlIeroecM ....... III T-QII ~
. . . . . BrJ~IJ2"2U2Il6
1374. MaI\IM J, Betgsaoge! 0, K~ R
.10(\ I.lallll\lllment.
Andef10rl K Itdsl ~2OOl) 1.4~ llooI..>gy

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.m
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1315. MalyvI,ov.II A, 00h<lI T von de< lehr N.
A;.11ondi S CoIv;nn 1.4. HIymeo M. $4lrud< C,

G<ander O. ~ U, Sar9'&I' 0 (2001), Tile
~
1/,jW- gene hCOC4 ...
in tvMn T-cell1Ml ~
Ieu~ ""til !unaIottII ~ b
~ 1i!1'*'Il Canter Rts 67' !56'1.!5616
v.--. T. EblIn
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lin
Moo\a
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Yegesa H. Widl hi . . . . . K.
J,
I(DIl<. K.
H. P.r ~ YO Tsuji K,
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I>IMt M
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T Vao'lI T, KiltI40 P. Cft&i

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Conipno'I ... __ C'Jb"*Y AM J CIilI
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b . . q'Il*lgII: at>
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Bc.eIts . NEngr
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11M center eel J Oil Clrlta 11 3lI04-J809
1311. ldara/lob T. Hummel 1.4 Foss He
LwnenH ~ n P ~
1.Immf<I H.Demel G. 1h(Wl J WWIh T.
I2000l HodgI,in Ifld ~ _ "Po
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ing \tom a glIrfIW'IlII_ B-alwMtll-.
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DA F....... J CtwIKW ~ JM
SnIlet ES (1999) 1~ ""l)IIOIClIIl7: a
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phcwna<. iOtnbllcaOon d canmon lI"'I!c aIIIr
Ibon1 II Sazary s~ iltld rnVCOM fI.Ill.
qoi<Ies Br J DermaIcJI 147: 464-415
138Z. l.4lto X LAlnqIon OM, CnpulO\ll"&ll I S,
Rus~~JonlI1 R Young eo, Wnilta."," S
(200-~1 McllIcuIitr cyIogenetic dlanIcIanZ8tion
0/ Salar)' 5,,-.drome G&nIlI Chrcm:JllOlflll
Cancer 36 250-260
1383. Mao X. O,,:hard G, LillingtOl1 OM

RU61" "J(ln8Il R, Young e o , wniltaker S
(2003) Go'lnebC alte,ation5 ill primary CUIII
000U!i CD30+ anaplastic 18flJ' celi lymplloma
~"" Chr~
Cltn(eI' 37 116165
1384. Mao X. O'cnard G, l jll<ngtOl1 OM,
R u~&.llil-Jones R. Yoong BD. WtltIlal;er SJ
(2003) A~lion n O.erI 'pf!l5s<on 0/
JUNE! IS i>l1OCl8IId w<th Cl'IfT\lIr; Q.J/MlfIOUI T
C8II~ Blood 101 1513-15111
1385. U!lo Z, ~ l. Raffwld
1.4. lU:t1ter 1.4, KII.9"'i J 8unlIc C, Hao1mIrIn
E, Rudlger Tn. .IlI1te ES
~ HI(
0lI G FIn:l F RoetrtNald A (20071 19l1H
mulabllnlil sutul and donIilIty _ly1iI 01
R!d1ter'1 r..>siormIbcIll Am J Surg ~
32J6(lb.I614
138& , r.IlnAolI T. ~ JC B.-.oo E
Rtid'IlwlIKI<. T..,. S HoIowoocl K ClI::Ior M.
~ M. I'IIen SA. ~ MJ. Samni S,
0..-.: I.
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(1999) ClIK&calliodgl:ll's cIeease Ifld foIaI.
~ I
pI'I'Jp(.-d . . . . . . InIhld
Onall t 181-192
1319. .-..c.- A.. Medwll1 U Wet. CI.l
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ItUdY J ~ 0n00I23 9234'l242

1)1ll B. Marc.oct;! G l,\larry K, WMn\ln SP,
1I.,1,osallljevic T, Pasdlt1 P, larlQIr c, '*Ozek
K, Baidus CD, earrtf AJ, Poooei SL KohtlJE
llN)/\ RA. Bloomfield CO{2001) Hq1 elPfIf'
1ioo l!N'lMs of It>a erS-related gena. ERG, prtdiet ad\1!r!;I oolcoma and improve moltcuiIr
ri<;H>a'lO!Cl dassiflC8lio1' 0/ eyt"\l'l!"llltlcalv rlCf
mal acl!t @ myeloid !eui(en1a: e CarIcar iIrId
leu kemia Group B Study J Clin Ontoi 25
3:137-3343
'3" , Mane I. Rooyn J, Maltalf! DO. F'I' tdP
C-"" M. Wi ISOrl T. Fu 1/;, Sloddwd J S<Xltt l
Hart5a~ M, lOrsnenbaum A, Akin C, N.J\mlJI
rB,N oeIP, Klo::I'l,l,[l (20011 K IT oeW'~
tiattld I Vlltemoe ~ witn ~
snd FIPILI /POGFRA-assodated dltonoc
~ leul<em<a iQ CIISIif'ld . .bel J
Mlrqy Oil In'lI'l'I,lI)(li 120:6110-667
1392. !.matIe x., Cazals.<iolem 0, ~
J. l.ioW F. 8*>hud N, Slliie J I2IXl2
ll""\llhOmls in meumaiold ertmIis . . . .
~ .... I\'II!lhotreI:a a 3-,..- ~
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1393, Ma1IDn P K8IWlg '" KMUqlIn M
PIIlt:e S. 01lnen S F..-.:h EJ. E..,. E

(19951 C~ and dinieIII rorr.llile1..
1M, .......... atJI..., [ II 01 dlIlIIII-
.,..,. 16 lIui.enII9 96>911

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HiImeI1 p. +i:J.IIslon RS, Kay N, SdlIewl/Iz T,.,
~ N120051 ~lo;c:n-.!ofmor>
~lk8I~BrJ~
130 J2S.3.'U
13H . WiWtIllt P, Mlehau, Jl RodIl"n J
(1991) PlIilacllll"~ 1Ptl-1 chronic
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drllnc ~
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Magaud .IF' "'ezetlI C. TItt H VPer JII
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IlMI'I TF, Berge!' F. e.md HW ~A..
S, Frank GA, K3p1ant>klyB IB M6llw P
"-wareadl RM ROdIgiir T, S\IM1 H KUppm
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KriJll' hlilt NBtwrtc Projad Molecllblr
Medlaoi,m l ... M'*Il~ l ymphomH (20061

brBAkDOlntl
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ilrTd R8&d-St8fflbolrg C&IIof d'I!~ Hodgk;"
tympt1or'na, CIInoef RN 66' 10332-10338
1402. MAl1inel CitrTl&nt JA., Vizcarra E. Benet
I, M3r1J9ilI1 I Tem! MJ, S<;OAno C, ArOO<\& C,
Tormo M, ComN AM. Gilrda-Conoe J (1M).
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COOIne< 0, RonMn M IWIIlkl M, ~
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'*
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.:17 """"'" Am J Surg f'afloI29' 5-50-560
1~12. Iola5aoro& C, KodBma K, ~ W,
Abe R S/IunIzlJ H, PII'Od, A Kert H CerrQni l

lUP<J5 erythemil10sus PilnnlallillS
prOOJndu!;) t:llric81 hl$1~
and moloK:l.Wr analysis rJ rJI'Ill uses, J Cullin
Pal~:12, 396--4G4
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T~ ll'QI$an spectrum 01 'IO<I-lioclgl;in lyrnpIlomas WIth prominent in..olYerTl!ll\l 01 sub(:y.
II '*"" fat J Cu!iln Palhol33 418-425
1414, Masln~;cn S Flateeh H. WllfIl FI E
Moora .10, Elomwitz MJ (199ol ). f1epatoop/llniC
T -ee!l lymphctma arl Ull\JSLJ;O casa of a gamma
della T..ceIlymp/looJa with a blast-like lerminal
lraru;!orrniIOOn HumPattlol25, 1021(\8
141. A.. Ma! uko K. K3tO S, HlI9ihlfa M
TIl.d1id.a F TIl!<AmOlO Y Iwwa K KillO T,
YIlmilmOI1 S l.llzu5hm1Y. NIsh IOka K, TlkJ~ II.
YlI'\1IlITlOIo K (19961 Stable donal @~pan 5ion
~ T cek .-.duoecl by boo>e m.YnliO IrlWlspl1ta-lioo Blood 87: 789--199
1415. ""'~ S, Nal<amura S 1\obayasI1. II.
YOIhidII T, I.Iabuda T, Sugimoto T (1997)
o..on ollne tong ami at d\rofmsome 2U ... a
paIillrtl..., <:tw-onK: i'lI!oJIrOp/ili loo.emIiI o:y
Q8IllIIlC fma'ngs '" ct\l'I:loW:: lI(!u\flWhiliC
--... Am J t-iernalrJ~' 1].7f>
1 ~1 1 , MilIto M. UoIejo '" Vtuenaas R
Algar. P Serd'ez&alO lol. MarIInal P PlIiI
lolA. 11m) 1031-32 aIIk lois 15 B hQOflll
l'wIOOg III Denil: ""'9"'al ~ ""'~ Am
J P8ltd 1~ 1583-1589
(2005)
l\uIlu5
c--.IlIJ~15J21"'215
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.. WoIarIW\llI B LUi8IoS S. ~
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IiarIson CA (1 999) 1$OlII8d i$ol.:t'IomOIOm
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t>eha\l1Ol'. AA1 J Surg Palhol29: 16!l21680,
l.uBA McOooneI TJ, oe_ N,

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SJ (1989) bcl- 2.+mrnunogiob\llln Ifanagooic:
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cliIeII '"" lalu*wy ....... ~ J*ienII
BrJ~12
382_
1U9A ..... E 0.:. 0 ..,.......,.

Iltt9" ~ GaIIl.aNhl E ~ A. F....
P.FranooV . . . . E loIoIItIOy
~T
I'\iIn FM
Kor5mejW
derrmSlfatf exlaMad B elllI "",,"V(M and
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/.Iic:nwr8t"~~ ~ . .
~ Irtm lne lKllE type 01 ......,.
lJ.l1}'" DorM!s ~
apack \Mail._1Q
rrwl<ar, BrJ HaolmiIIlOI12S' 129-142
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AnIlrwws. EA ROl)':U Iol CroaIInclS Btoob
L Wh"'-" SJ (1999) ~ ~ p53 9""
"lIlIl*n 1lll)gl!tlS I poIItJIir
b- ....-...0'" <JdI*III III . . IWI""",,_ 01 8ltfanc:e:I
~ ~ J m.as.l:llimlftII1'1
\llllaItIc
........-.g PRJ,ME .. e
"*
317-321
1"1. McMmiI 1M PaiI<al J ...... .Ii
~ KJ "*- L llr\nWI9 RD
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11 ~ P. f_ LM y~
itnnlIlIr>phto~ ~
WS!kJlleo'.JJlol. . . . . FBs..~
JA. DuCWI 00 "987~ SlIge IH loIcuW Iylnpi-.. dInlllt , _ .....
~
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'45<1. McIloN(l996) TII8d'oers.l,olBCR

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!J1I"'lOtj18s ~ ~ ~ il t:If
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~....
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""
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ttIlgde
]V,
00lMn
~.,. ~
1ll'Il:liann'-a~_e.or
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n 1'3
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P1~R-A&. c:I1fllnc IIJ'IIbO
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1
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'"
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..... P /20(6) ~ Q/ he JAK2 ~w:

"""'*'U ......... 11'I CIasSQI tiodgo' iy'nphDr'lII anll pmwy ~ B-oeI tyro>.
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~20 157.15li
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IropCIlllyOIin 4-ani1>u~ ~ 'IrI3H

~!woon 6100(I96 12Qli.\216.
1450. Meektr Te Hardy O. W"mIln C,
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~ 8
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.~..,.~~~
.., gaon or_
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lXllI"4*~ ~ ~
GetIft
Ctwan:!somes: e- 4' 35J..J&5

,0452. lHkld; .... l.Jc,tJI; JO (1999),
~1""~"Wm
trod....., , * . , IIIl ~ ......._ d
*'*'
IMI~"""'"
llIoodiJ 3111.
rlJCUr'enl It1;22} tran$loCallOn 01 aeulll

.....eryoc'jticlB\JKemia. ProcNat! kad Set U
S A96 5176-5779
1462. Merlin; G. SlorlIl MJ 120061 Osngerous
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1463. Mesa RA 1ian5Ol' CA R~i ,u m;lf SV
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c:I~ corre!atiorl!l of boIle "''''lTOW angi<lgerle
Ilia .,
rnyelofi tvoSl~
"" Ih
m ~ rMt apla~ia
L~
",ero.~ ,*-,1,(2001 ~fIndII'Ig

tJ . . "F'1L 1PDGfRA IuwOll Il"'II II
___ =
1rNInlInt{IWG-MRn LtlUI< Res J\ 7J17~

14S. ~ DO (1991) 0ats0/IcaIr:fl and
_ _ or mastIIcy1oSIs. ~ 'iIaIlla- J
IrMIIl DennatlI96: 2S-<IS
,.
. . . . . DO (1991) The.... IPiee<l.
IfICI IymjlIl noxln ., ~
t:lIrm*' 96' 45S-C6S

l t11. ~ E leGS.j (19b8) l.ecUe
t63. ..,.. It.
Rodr9Jaz It. P\ql we

F (19iTl E...-and,.. ~
~ l ~ c'
' ,
al'"
or
!QIpmI or . . 1893 EfIlIIiItII!llll!iIlIioll ,...
~"'*Ql-...at:J~
1461"- .......... E 11863)
~ pahJII;:yt
IQlII
.~
IIY'IbCI
........ anll~T-{lIII~
~'1
In... 62 31(1.312
1479A ""If; J at a112008i, A 44-~-oId .....
""ltl fBlio;lua Illd lawn, III II'oe pdUI1I1'y .",
ce-ebIIum N EngjJ!.led (" PAlSII
1180. Mri.o_ "', Grots N I1ailgar "
f'oIId'llI' U ~ T. GaGnIt H (2002
ReepotlII 10 ... ba1 ~ 01 l!UbsySIIm
~ eel IvsIlocyIIslS an ~
~ nicalOf Ued Pedollr Or>::d 39'
58''''
14n Uinkov
M. Potschger U Grois N
o..::.rza WIl (2001) Bone_

~ ., ~ 011I !'IiIIocraiI
~ 8Iood eanc. 4g. ~
GMt...- H
ElInIU H. ,..., L DII V_ F, AuIIIa.~ WE

wm_y G SdwI'IItz N ~ C 1oluIII
. . - 1\. HOOgII E. ~ SJ 0 - .
F OOIV'III' H SdUd I' ......, R ~
118).\1.
I t&2, ~I<I~HS_I.I~
N ~ U. Kaalsd't I' ~ G.
G/OlI< H120051 Lange1IIns 0IIlt ~
..,. . . . . F'elIIaI' BIooa CIocar45
1483
""'*' GO.
ao2~1
O"FaIon JR. 1*r kJ
(1992 ' ~ dyIo-.
JllPiII The ~ II POOlS ~ N
ErojJWI<l3:<11919-1923
1""', ,....RT< E..-uAR,~
S
W lfjS1.!. SyoIIn; _
CII
MIl ~
m i . we.,.. C Sdw...- B JalIoD S, SnN
S. ~ ,. SdwIl\gIf S Sdlocn C,
...... 1M _ 0rlngIrI JJ 0. Boar IlL
. . . . . . . ~PllIIoI25 721-130
' 415, LlIuI~" ~S
P\aMIIt R E_ t.lG. ~ E KoIN U

GI-' J ~ F lJIl SlId U ErJoItt C
SzezeparlSlu 1 NIOgIJ f+( ~ BW
;<;M 4*' H BrmyHJ lurIIJ TI'<IJ.NqllL1.
Ilio!d .... ~ E .........,... E s-Ae
101 SehrIppe ... HaM OA. ~ 1
~ T ~ T "'nc:hIiII: R
j2OO61 TII8 Ioll.L NCQllW_ I'JI/ ICUlt
............ LIuI,_ nJ.184
1471. 1.Ich-.J. Jl. Iola/bIIl I' 11993 ClYtlIl'
myelOfTlOl"lOCytM:
(C"''''LH
""'*_
myeloilYiplaslc
Of """""'. . . . . .'t'e
.."..
~1leU1L\'flIfIlOfIIlI9J5.t1
1412. r.IIo.1IIlI5 SO.!.4cKN RW. "-'ltU" DC,
6n.ming RD
"'Yl'bd
('~J
~ ~
IIuk_ and nIyIbl\'lPllJllC ~

dt'tmlI a etoW:aI arld fI'lI'.lI'P/'IC IIuay t:J S5
BIooa &5
1173. M>ch....
Lm(lflllH.... J,
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tIleS
1J1i,1l1312
JJ, _In GIMI'&n
FJ,
.an
VllIl HH (1996)
lhrorr'll:dic and ~
rna~.Il50CI8ISof~
ltl(llllymphoma22Sl1pll1141-56
'41 4. ~ Ichor F (20011, C~mr1k; myeloi-ll
WBmII blasl C1\III ...-- from pI1)9IfliIclr;
SlamCeh251 1141118
CO. LawlI J
(lWJ ), Trve hl">oeytl~ Iymplloma 01 !mal
1..15. Mlllttiren M.
F~tc!lI<
mtesllne, An1ll1!115 ollwo Sl00 pmt&ll1po6Jt,..,.
0011ur(;l)ll1~, Am J Cion
(2007) PmTlal'y~(f'MF).POSlpcly
eythetnIf _I ~ 1posl-PV I<IFI, llOII
-"'al hOmbocy\hemiB ITl)'BloftJms<s lposlET I<If) blasl phase Ptolf (pIdFBP)'
~ 00 ~ bI' II1e ..,tetll3llorlal
'IfI01<>1g ~ for ~O$IS ,~ trod
J ClIrI
t .t6i. MIIIlgIroIhG Wall. C Score J SIIbeo1

R ~ S IiIltr*tl C Popp ~
~ 1 Eiben I' ... . J IlUer t.IC
easel
IlarOf,j G. ReIlly JT. Dupriez B Lelll rle R,

IlolMe-Kerdiln r.IC. 'Nar:IletgIl M, Campbell
FJ. Sil.al RT, Varvlll()Ch, AM. Deeg HJ,
GisIIInget H. Thomas O. Odet\ik.e 0, S<::>tlIIl'\l
LA.GOIlib J.Hel/lO:l< E N;merSO. Kan!at).an H,
OriW A. VM'dirJlan .NI. TrneIe j Tf/Itln A
s..o.
Clog
~36
Blood!l6 3374-3380
''''
CabnIIas
408 References
0"llXII3
14. Me9.a RA, Vtnlo\'&ek S. ClllVilllleS F,
,..
among
CIIIIgIIOMS
I coIlaIlorlb.. Ilud'I
IhlI ~ ear. andl'lllhcJt,gy
Pn b"
~~"""'.~~
.15 1216-1.
_arl8bo 11 or
phomiJ
The....",~ ~
. . . . . . gftllCl
~~orfoaaMrlym
MelD N. CMo..-r.<y D. Gillon DA
ctwlllic Iyrwpho<':)o1Jc ....1:HfllIIl and prolymphocy1Ic

IiIuUIni8 1 CloniaII ..., Iiob<nb'y ~ 01
300 ~ and ~ of " ' _ (1986)
' 451.
ubi! die 1l1~lIQ'I4ki..-e Verdauung bill witbelto&en 1t1i9lllll , Alb~ Inll U""" Wo!
5 141
1461. t.IIIIII C NaI'rllrI BN. a...u 15,
WirlDllrlI CO,!,lam RB. e.t:oI M ~
CR.~CC [honDO MoIIITP(19115)
118malopa~
0na:II5 861~74
1444. t.IcMIrAa OT ~ Mo\. e-,.
PO CllItIIfl RJ ......... If) 200'~ 1.1.1(.
poIII'" dA.- lqe lklII ~ 01 ...
,
I)9Il ill S60 <;lISe'S 01 aggll59M! ~ ' I
Wltn
faalu"" 01 inllfd.lgllillllg l1I!lCUlum

FM~
100' 285-292.
1476. M!ettln&n M. Fl1If1S1i1a KO. Suen E

(19tlJ), HodgIun'.
~,
Iymphoeytit pIfl.
dOn\i<lanee n<OJlIf. tncr-.d nsk !Of IilltIMqoenl noo-Hodg!<""!yInftlomaS c..-ur 51:

229J.23OO
1411. MileI D+t, F~ MH, Stepheol K.
l'aIli'licl<l, 1<1. ~ H Wea.... ...
Gn.rlbIrgIr 1. 11'1Mlpt1on F. S/lInoon Kid
(1996) Palltll'ft1 <.>1 ~be ~
io:NolwJmelIl" ~ ..... ~
~ 1 8lld f'AIlI\Jl'*1l ~ 0IS0rCle01 6lcxxI
p<~
~ RO Var'lg B F.- WG. ""' Ell

120021 Prmwyaa-ulotollir ~
.. - . . . n I 01 cinoc.aI ~0JfIlt0.
_W;(lI,.,d"", lIrld~"""
ClIrI 0n00l20-&41-655
1486. ...,.,. J ~.-:. f'IIfI)' JA
(19ll1 Fokit cerlIW ~ t:J ..
II t:J '1'_ ~ ..... julda fWPlJId.
c-. AIn J s.,gPllIIoI21 .48U88
1411. ".....,., F 11993) The ~
Il:8Ila'lO or ctIllnc ",j'I/oIl ........ L""
SIIfIfII l' 1115

1_ UIIIIIrI8fl F Levwl G. Helsol PG
hdL(1916) Non-!;nJom~'"
kin ~ dIroroc myeIuo:IleukImia. .. J e.l ~ 11
1624-:J';I
'489. MI15lildes CS t.Idd.... OW KlrWII S

~ T Ctoau/larl 0 RdIn10n fIG
"""'!ho He Anienon KC l2001) Tha". 01
Ih8 boolI ll'ITtlW mi(:roe,wir(lMlllll .., ...
~yliology
of my9klma and
I~
IIgIlII
canc:e ill IhlI dlll9lopment of rruI eIII<;Ii..

lhlnpiel fiemfloI Onco! Chn Nt'tVl Am 21
100110:).tVII-1Illi
'490. MltliIl K, N9I1 A, Feine< H, Sdl"* II.
AIIonIIO F ( 19lJOIl~ ~Ior'na\;).

toll In till aCQ ulled irnmunodefK:iency I~
droma, Eildence ot E ~\eInBarr w~.,fecti;ln
and 6-c" " cklnal se le<:llon w , t~OUI m'lt
'earrangemeol. Cancer 65: 1345-1349,

1491, Millis ilJ, StainR, Rappl?Olt JM, IvU:r
JH, W"'Il5kW1 HJ. AIpeI CA. Smilll6R 11989
~Bncl~~(l\,*
bone
rnatfQIofi
"58
1492.
lIa'1spiaI1lalo1 6loud 74 27,*
MrNI H. Ta!<ak!1W3 T, NaIatIuI S

1twl1la V Iucho 1\. iIllla$I 1\ (2002\ DNA
~d!he~t'e3I<)'d\aI'
~ ~
gene ., pyoI'IoIa>:'M>:Ir
000:I0gy62.241250
10 3. ~ V Kunyarn.a K. ~ S
ClnlaMI s. SaI:afnajQ H, MItIuo T. En'lI N
IYIT"(lhornI
118 <4JlJ20
~l~T~~
'41& ...... TP Grog.! 1M 0IIibI0v S.
Ohno R T0lll0lIBgIl '" (20031 C~ '~ ~ acute ~ . . . . \N.IL
CIo61~
llfOIrleo-.v.e Mb9'" ., . . - non,~

a ~
~ Onculogy ~ ... ~ 83
1400-1-'66
1419, .... TP lJIlpman SM, ~ Ct.I
SI"'*' OJ Gqan 1ltI 1988) fV,.OR ~l
_
jl/'IIllo(ypt lftllK;O llIItconII for
1iodgIk"'.
~_
_OII~.J()n
witI
d)1llll$oa
Jap8fl
' - - ' _ Stuely Gn:tJp-AM. 92 sll.C;
a-
Haen1at11120- 56-62
t f N . ~ G f't:Ipcw SW
8 ~ S, Reel P F1ssokI N Sd\nltJIli.
R RJIz O..... I' L....- F (2OOIj AID
~ I(lenIiIIl$ orI!IltlIIl:UIr lqIll
11 ~ ptI(:UIICf5 ~ I'IIUI IkeI
..... ~ 107: 24ro-2H3
l oWS, ......... Loft8'd C, 00nkJn T
co
GollIITR. Shw1Ml2005) MoIea.IIIr profiWlg
1521 . M(ll'Il;I WG Kco1lI\ PJ. Te"eo /I.,
IIIld ~
GI di111JalI ilIfVll 5-a11i !ymphoma lde<ltlfleS
~ k l M II . prim;Ny ",trtvascuilrl~)~ Cancer66474..0419
lll.lIl ~ 'Sil9O"tll, Blood 105 18510
Hanson CA 12002) Distinct bone mBffOW!;oIjIn\l$ In T-QlI ~ ranular IympI'IocytJc lBulcerroa

~ DyP1W,,"1I sectioo~liOatll
Ooo:lnwl RF (19'XlJ. lmmu~,ic:8I

IIWoes Il'IdK:ale 1Ilal mMgnirl
1495A. ~
M AIgiIrt P Matell MS,
~J.PlfIIQlIlE FfWlOMF.c..d'lo
u.g.&alI~ ~
Fl Pn ..... (2OOJ1
-*'liI1I rae
, III dIIIerenI
J Suri P.-o
~ condolIOnI
27:1l'J5.i02
1496. M~IeJO M. Algar. 1". Mateo MS,
SandlezE!ee1o M. LIorwl E. MOOtn,'I MT, Pins
WI (2002). ~ $ITlIII B..::elIIym(lho/I'IfI WIIh
p'eodonJo ... ~ red ~ ~ diIUse
__ rJ ~ "*\,WW zont
~7
~~060:2230
raobust SlJbtypet indud~ 0I'Itl dlSfa<:terillld by
""
1501.
sIiln 1orC08.lIA_l trld lP'~ B Illooxl

~
S.
ue-l~
toa-D,E-..J .... F
fit..
~_A.
WImor N Menno C CImpo E. ~ E
(2003) ~ aro;l drIociIl ~ 1II

bcl-21IgH I'NITIU'lQllf1'lIII\llI in !olloculer IytnpIloma.leukl~44 1176
1509. MotItMrral E Vll.amQr N. Re\l&!'l&i'./C.
~ RM, Tases 0, Bolch F, /<q.IMI Jl,
VI...,...CorfOAI ./I.. ROl.... n M. ROl.... C
tl9ll6~ ecr. .-.- _
III 8<-tII
.268--21.
1522. Monca 'fIG IlIealn ~ 00gIn ....
....... '" K..-. PJ(20061 NI(~
"'~tt..-.prfttll)'lI'l~T.(lII
~,
"'igh\ ~
inlO
pamogeneti$
Laulcamia 20 883-8&6.
1523. Mo!U WG, ROOngllllz FJ, Hover JD.

Kurt>n PJ12005) CWIuselat9' B-c:elI~
""II 6*IChYe peIIIems II spIent Ind bone
"*"OIO~do~"""
~~-"'-"~or
oINoDCISe$ MrxlPard18 495-502

1524. lbrII E. e-.a C l(IeBy C V......
JHaern&ll93: 111_116
15l0. ~ AV. RidIrh SM. RoOonton
HM, St",fford JC, Gibson BE. , Klnse~ SE, loon
TO, IIQra A,J, Mtlo:hel CD. HatTison CJ 12007)
1491. MoIlI,o M. ~z J UorII E,

s..d'ez I" CImpo E . . P CnHbIl E.
~ E. Pm W. 119%1. ~ ~
zone 1ympIlomB, I distinclr;e typeof ~rade
B-ceII lymphoma. A dillol:opalhoklg~ Iludy of
13 C8S8t Am J SurgPIlIhDi 19 1146-1151
1498. .... P I1BrTmIr1lB ~G.
tIops(! Ar;amplII'_ sae, II 258lMNf* Br
PrognDSO$ 01 o::hihMl.... a:ulB ~

lalkemia (AU) n MId'InvroscmII ~ ...
Id e..-.aLCanai8 T~E.~
l. LauBMO Id(0'0031 ~"" V3I18t>IM lor
mill'9flNlI ll'artliformation tn 452 p>W9nts WIf1
as, mplofnalic IgM rnonodonil ~lI'ry
Sen-in 00r;0I 30' H2. ttt.
1525. t.lorriI SW
UN V_ _ ldEI
~ F i1987) 0Il0I0cM '''P''I'iOn III

lllHC ~ I. . . .
1'1 &oaIIlym-
"""""01 c)loOl'lOUn. 2110AMP21~ 5Iood 109'
o...-KG ShIl:wcON. ~ [l. lOOllAT
232723lO.
119!'itl F\IIim 011 ~ 0iIN ALII.. tl.

ruc;lelU' pr-.. gttfllI NPld in non--Hodgl<Jl t
~ Saeonat263 1281.1284,
152M. Morton lid. 'N3<lg SS, De_ SS,
""*'
~1lI~~.InlJe-:er
" 32-39
14". "tlIIf p.lMmInlIr B, Eblr1eI'I.(;ooska
M, F9K:tllIIr GE.!'lofmam WJ. SdlfTHttadett H.
Otto HF (1988) Pri rrlll'y ~ cIMr I;llij
Iym(tlO'l\II 01 8--cII type V~ Arch A
PIf'CII Arwl HiAJpalrO Q 1M2
1500. UoIIr P ~ G. Iobro.J1 F
LatMllel' B ~ M. K.iIIeI S.
0Irtan B (Ullin ~
01
do!er CIIIIl)'llt " ' _
correspondl:'lg tllBr
IJlflII sIBpS 01 B eel ~ Blood 69:
108110ll!i,
'501 , UonOB l, Warn>:" R. Rosao J j19ll6) A
IP'*Y ~ nodB ~ .-ill fMlures
. . . . . . III ~
011I dIIIarwe114 _
Am J PIh:Il \22
w....
'*'*"
*' A
,..,
"'.."
1502.
e s.nu. A
Beng D.
Renlo e, ~ 1 c...,. JL dif At9'I' e M,
~
~C ~2001) T~o(low~adll\jllsttlC
Iyrnphood !issue Iyrrlp/'lOnla

in srage I wIIh HIlia;ttao;l.- pyIoti trPcabcn
l.lnlB'I1I ~ . . MQl.-aI t'IIlliogIc
~ ted
...."
...,
86.
1501 ~.fl:07IgII'I M 1\l 4'l*' R,

StNuIBr 0 ~ T,Vtrl Roos! D. Sd1IIIIrC,
~G, WoesliefOO QeI;:qn--$dlkJler
M (\ 999). Pnmar; atrltfal rlllI'o'OIIS S/'S*!' Iymp/I(lmaS are dlln>'e'd from I1"<'ml'lllklenler B
c:eIlaana IIlllM a~ o.JSagll 01 .... V"
,..
J.l ger-.
Am J PIllhoI 1S5 2On-
15ll4. ~llI"II'fI
" - I"
lot
~ R ~yK ~"'11f1991
"-'talm 1II .... p53gana II nol a ~ IMUe

01 Hod9~Jl If1d RfltIl.S\1I(nberg ctHt '"
Hodgloo's dlsBaSll, Blood ~ 17 5 5- 1760,
1505. ~or'IgIIl M. VW1 Roost O.
So::NIe< C. w..- 00. ~ M (2004)
PmIary ~ _
8-alI ~ II . .
c.n...-..",...... ~tIi1 .....

toor-=~ BIoodw.l1_1B75
1506.
fit..
s......
PIw s,
Bllatt M 8ertl:lo'ulII Me, M V,vo A.

8nPomalit A, Roncador G. Fan; B, PIlen SA
(1995), 80rlI marmw IindlfIgs further support
.... hypolheeo, It\D1 _
t",
CI)'OIIk.>tluo
Inernull'fpe " II ~ Dy iI IIIOIlO(:lcrI-
,.,..".j
118-al1~ lIIilL~20:
119-
,~
15G1. Warlc S Savq l(J KIAok JL

F....miII<. F. 1<""'" P Woiwn .. Wu 8.
F'IsquaIu(;o l. NotWerg D.~ RC. Cloll t;.,
P. Ladd C, Pd..,. G$, Silas G. Ham. NL
Da'la-fll'l1lfll R. liab8mlBnn TM. Allar JC.
1511.
8, lMII.- E.. Altern RP.

~ RM, Owr.t.&I-AnkolUl KA.
..".. ~
s.or. SI< ~yO('997).~ol
the chronic lymphocytic ,",ukemia scoring 5yS11m "-'lh the monock>n.1 antobody SN8
(CD19b) ......J c.. Paf'd 108 3n--3821512. McnlP.l~E.&aP ~B

6""'" W ~ p Gc:8IIn S. 6auIn F
GiMIItlredll C ll992l ~$ ana ,..
""""ol~~II"a
rwpor1 on 80 pMen15 J ClI'I Oneal 10 1078-
toes
""*'
H;vtgIl P, Weisenburger 00, uret MS (2006),
Ll'fIl"\M1a incideoc1! ~ ~ WHO tOOtype ....... lhIItd $blIe$, 1992-2001 8lot:xl
lor 265-276
152t .
01,
Zeltr>ea
Ii)
di~
In
Hr:lOgU'I. 0 . - I.Iaur:tJ P ArrnIIage JO.
DlttN v lids l-ClPfICOII W.... & Nn
"p;o.mlol"\ly ()! IiodQ kin',
~pp61
MI cenle< "lft/J9 nongIIfmI'III cenII!f. deter
1531. MuIaMy BP. Ng Vl, Hl!mdIet IlG

McGrath MS, PallB_ic! nl MG (20001
1511. ~ P,
Bb:ld 106 338J-.-33M
G.oJdon F.
~ III
'--IJIr~V Dollol6ant~.
LeaonJC.
~A~~,~Y
C. Berro C Hem'ooueII S. PnD.. V

(2004) llIlq>o9Io: .au r:J tefU'l'I ~
ehn Ie~ in pallBr1t~ witllllbscMulll erylhnxyIo';5 HaematologiUI 69. 11\14 .1196
l $2B. Mouroer N, Brin J, GuttIbrechI C,
Emilo! JF. llldlo'n P SebbIn C !Ierg8r F
8c*y'" t.llnI P, TJIy H 8ouIIldIIIIf> R ~
F ~ P, Co6r B (2llCl3). ~_
KqlInB H ~ T l2000l l~jll&\lS

"lures 01 iIWM"" NI( cell
~ wrth ~ 1IllOWis.
~0I<1i and lB VINS irlllK:lion
CMOP (R-otOPl ~ Dd-2-.&Oa1ltid rl'Sl5lanc;1 10 cl'ltmothfrlpy 1'1 ekltrly

PltienII wiIIl d'fIuse Iwgtl B-aoII ~
IDLBCl). Blood 101: 4279-4,84.
IiIlliXl8ttdogy 37 363--371
1516. MOO N. Y.llalleY ~ t.I, Koba)'lll'h
T. Aui J (1M) F')'oIIlcn>~ tym.
1529, Moun....- N, Br~ J, ~ C,

RttyM F Glullrd P CQIlflOtr B (1006).
EAonIlIlg . . ompecr 01 nklunab 0'1 bd-2
IISOOIIed ~ to CHOP i'l tIderly
~ "'" ..... IlI'gt ~ ~
~91715-716.
1529A- MoirlIcI N,......... N.he J. ~

E. DflImef A, FelIBr A. ~ CJ E_ JF,
BoualJdaliah R. BnsIy A DIebold J. HaioI.IO C,
CWII&f 5, GlMlbrechI C. G&u'ard P (2006)

Oncal bo:lIogll;aIlnd Pl1hoIoQic8I ~ in
151~""'~T-<lIlI
"*' ....,fAdlAl
.. ~
db.IdiI
GeLAl'"
..... C8I~
lblIIklill~
!h:lwrlg _1IICD5an:l
~1II
COlO AmJClnPllllOl122 122-127
151' , Monee 1'fG, ~ D.HI..", CA

(M11, The e~ 01 !he ~ cyklloxic
prolein granzymeM by largll l1anlkr Iympl'lotyIiC ~ ol lXlll't T-ttl iIOd ~I( ~ ~
aage' .. ,,",ll*18d &ndIng -.nil ~
JtIlliIIlIirlg , . ~ II line doeOl\Mf1
lit J Haeo'rlIloI137 237_239
152(1. ~ 'NG. K.IIWl PJ. tlliOlon PJ,
15Jll. Mf69, K Htmnen K. (III II ~

A llbJrMBld CO 11991) CloricaI sign,ficance
of c)'logeneticll iM IK:U I ~ mytlold leul.emitl
Semirl0n<Xll2( 1131
1531. M,llZf'k I( HeinoneI'I K. lawfara D,
CImlI A,J, Kodur\l PR Rao KW ~ I.IP
~ RE, MoOlt JO. ..,.. RJ Sd'ofIer
CA. lJloorr1fIeId CO 119911 AlUI p8lier8 ....
(III 110"'O acW rny@IoId ....... JI'hiI Ind l{ll.
l1J(p22: li23) ...... a ~ llI/lD)nlt to
p.et,ents ..11I1 ottIei' tran'lklcetlOl1 5 Irl'iCli'Mjj
band 11q23. a cancer !Iflllleukl'fl'lia group B
leIJka6mia, Br J Haema loll 20: 1026-1 036
1535. Mueller NC. Gruffllrman {l999), The
IO'I,trld~ol~~
6IIIl Prad ReI; CiIl ~ 11 MJ.557
..........
....
.5 '1)!q33-pl1 2) eano. Res64. 2'6ol9-265'
TIIlen A.. ....... CAl20(3) o.roiiili",01
lr-'ormabon 01 chlor.: ~ .
. .1._ dntaI. morphologic. Iro;l cytogenIli: r.alule'. Am J CW1 Patllolll2 \-14,
HoIAd-"J.OII/Ia'lA CIlegriR N... S.

Ttrvyt-Feio:ltI.-. J (2005). CeI 01 <:ngI'I, \II"T"-'
"""'OIliJCY'C
tOoIm1nI T-alii Il'lCI naIJ,Ql luItr --co'JI rigen

t~., iI!I cases 01 gr.-.ul3r IyfnjlhocYlIc
JIOfTTlaI cytog9h8llc5: are we ready for I PfOll'

~~ pnoritiZed m(Iler;. doi~?
Blood 1(19 ( 31..u,&.
1531 uroz"k II( Pnor 1Vf Edloirds C
IlIllfcuI:g G. Carrol A,J Srltr PJ KotUIl PR
ThIIKS I'elItnII t.Ll An::hef lY CIigo.rI r.&o\
V~ JoN. Koltz JE ~ RA.1lIoorr'iWl
CO (2001) ~1II~1flll
rf:IlBQ;lar gentIJ: de\edl(ln (If 1(6,11 rtd
1(1\'(16) in a prllSPlldll'1l senn of adults \\'l!tl clB
rlOYO ICl.<le myebd *,kl!ffl;J eanc.,,- Iro;l
llt\ilBrfU Gro..p B SllXl'1 J On cn:a 19
24822492
1534. ~ SO ~ 1M'. 1v
DC. ParVI .l.. 8rurrniroQ: RO (19&01
1535. .... GJ(2004
mined hy ornmunoh;,;tochemI91!'j Clf1 tlSSUOl

O'I'IICI1lI'Tay. does not C(lI'1'l9Iaif ..rlh l)JlOOrrlIl1
palJrjnIS IO'ilh rellPeed Ind rUaclory Dl8CL
~M""""~""'~
_ _ _ lilT ..0 5 0lIk Am J SI.-g PlIIaI
20 7llO-7(,6.
1511. MoncaWG(2007f The~
typic It!Itlvtet 01 NI( (:>lIs and NK~ linage
1)'fflllhollroI,IellllIVe dlSOl'def!i, Am J 010Pathol
127 881-886.
1511. Morice WG. ~ Jt.I. KI>'\I'I PJ.
l-W'IIonCA(2OOoIJ M
caMoI-......:
reIr4nOe 01 II'IIAIIonI; n ~presII(IIl

d\llnget 10 llOIJIlOAIt m~ llMJ ~/!rTlilI ...,
~T~P~S.
1513. Moreno C, kq..... M, Rmancla C,

~ A, 0uf0lIr C ~ F. MaSllflli E.
Pasquai F, Prertlo C (2004) HCMOGTl is
nowi ~ partner Ib POGFRB II ~
151 . IobIH COrnanSM.x.oZ.fOlll~,
HeIIy LE. ClonIIchon C. Howl .1M, ~
C, GreallM M (2002) Cl1roroosornt lI'Bntloca
ItonlI llfId ooverllWk&mOC ckJ<les ilfB9"lner. ted
dunng I'lOffl\IIl Ielal ~ Proc ~
Acad SO USA 99 8242-42.,
151S. 11I00 N Y........uo Y. Ttu.!u", T
!IlullY Blood 9lf 4532-4538

1531A.MrOzt k K. Bloomfield CD 1:10061,
ChrornosGmB lberrntions, gene mutations and
..,.-euOn (l'IangM, and pto;:9'lOSI5 on ado'!
XlIIe myeIOO........-na ~ "'" Soc
....... E<1It f>ro,pn 16S-77
1532. Ikliz8I: K, ~ G Pa:tU P
" ' - sP. IlIoorNieId CO (2007) Ch:II
l~ (III
BIooclll1:~70
~.~
~el)lll'lOll"ic~(lfpovnr;.
. . ~ ArdlPaIloIlib Med12(.~
ea.
1531. IUr,Jlrl SP, w.u. E. 0I000r.-. C
e...-.y 0
(1991)
~ ~
.....
1o.I ~ IlIkAI hIIIbry Iro;lIllSPCQl tI

~ III 50 ~ Br J HaIrnIr:lI7B' 2Q6.2(lI.
153i , MuJlIghan CG, I<ennedy A, Zhou X,

RidtkeI, PNlOpt LA. S/'IIJ M!eff SA, Downir'o;l JR
(lOOT). Pedilln: 8CUW m~ ....k _ W'lh
NPldl IIIUIabons II ~ by i 91"1
~ pro6It...... ~ I10X gIflt
t.~ doslnc:I !rorII r.ILl.~
IIluIoerRa ~21. 200).2009
IS4Cl. MI,onn Sf. ~ Jt.I. .ltJnItt A.
AmlotP, RuSlin Wi. R.-I JR WNt!liIer S
{1M), CjntClli sncl Pl't~ IHltoln:>genelty
11 cul~ garTlfTll-deolta T-;;eIlymphoma',
reporI r:J "'M ~ iIrKI a ...... lIIl11t li6Ior
lur. Br J DotrmmI 13!l 916--llll I
I~ I,fun$N
rfC
~
S
~ A12OO!1 e- 'l-JOOB - '"
'/NI oIIl ~ ..... "*'"'IIDid ...... end ",.
1"'*IIi~~ Nl"lJl J U!1C1358 183$.\848.
15011. Munoz l NomdedeIJ JF VI&emor N,
Guard.. R, Celom..- 0 , Ribet'l Jr.t, TDlTB9 JP,
~ JJ, F..... no:taz C, llonWlll A, ~
Of llin:l ",", $IncNl N. erur.r S sen.J
(2003) -'aM myeIood ' - - .." ldll
'.'.lgtnlll'll$
c1W~ . . .
P'flll'lO* rf1llEl _ .... 01 b ~
II , . o:\IItedul 1II resoduII ~ - .
leuI<8rnIio 11. 16-82
1542. MUlliMmi I, Go9Jsev J FtlUmttl.!C,
G/()r1lJll C, JaubM F 12002i Q.,1"c!ion 01
rI'I<lleW8r ~ ilben'aloo'" II Iangtr.
h'. ... cell hIAocyIl:Jn 01 bone tUn PlIo' 33
*'
...'"
15013. IoU--..I,l
~T.~N
Ohnll H Fllkuhlr. S 00..- 101 il997i

RtlII'.'9tr,.. elIIh BCl61i1""41'1 e.OIII ryrnpI'ol;l ~ Leul<1mia 11 St.clPl3 31&-
320
15014.
MlJQSlIT, Nl k.amura
S KawaUChi 1(,
References 409
Ma\:iIuZ.e" H SaQo C. I...... T, N

It Sl.om T, Silt) H(20001. AA
~
K. TMl'iolQ
d
lqt &all 1yTnphoma' <:iInieaI
paIloIogoeal" ~ ~):) 11Iru. l8fgI B<:ell WlOmIl .uodIled d1

~ J.,rwtomI 9r J HMmIIoI
111. 826-8301
1S4S. I.V.e T. y~ t.l SuzUa R.
~ 1.1, SIIkI V TIn*U J, llqI.... t.l
I, Mon Ii- YOi/lIlo T. ~SI2OOT)
lnIr..-a,W
~ (M.9Ct.j
ur.n
.,..8-011
lIdo~ SluO)'d96~"'",
l:ilIl,.......kl . . ~ h e W o o
IJIfIIllY of a>5 8Iood 1011
t~ . YI.rII: JJ e--.n SA, Vol W ..."
Iioul:tIlS, ~ JA. VIII ~'" JH ,M
NM, ....., PM, 1QwI........... He.
.'&-485
~ GJ Gundy C. . . . . CJ.
~JJ 12!Xl&l lrNu~ lIfO"
tIng 01 c...- '9'*1l -......,. prUo:b

dnieII /lMOOIlM II) ~IIOP III ~
~ ...... ~ Ik:eI ~, EIlood
105 2916-2'!I21
1541. """'" JJ ..... CJ VOl W VIII
I<roNll JH.......
~ GJ,
<luclI,IMJJI2l106) """"'.......,..... 1'0~ ~on 8cl-2.CO\O~ 11I..IoI' '"'"'"
*.
lIiofl~riU.~IIl~'"
~
nodiI _ _ 1II9' B CIII ~
Paro:i 20lI 71 04-723
1541,
S 1191l8\
u-.
n~lIl~tw"""R_
.......OI.OX,...,..
5tmIl~:llI 9>13-
1549, ~ S. ~ P IlIlId H lalIo

J (l WTl. ElPIlW"CII rt... ~ V. .
Sl4y Gto.oo"""
,....
trill "llO'I on dlIiQnoIlIc _
....,
.......-.c lI'..-...on by tr~ Sen'Iin
-~,.,.
,...
1S5G. Murphy
se (197&)
0IIIdh0al 1'0'>-
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sa, Hl.oPI
p9&:l~
A ranclorrOled .... of oomtonId rnodIIl'I "*." fA

ISS'. ""-'flhy
HO
o::hoIdhood I'lO,\Ho(lgl"n'. ~ c.nc.~ 6JO.tl37

1552. M~,,'Y ", C....... EC .lorIo. DB,
wr>1'l OH 119%) Sl~ 01 tht ""mll'lll/lisllr
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8ISSCIl:8Ifd T teII lymphome, 1Vn J Patr'lol 146.
...."
1553. Muadler! M,R.....,y K, Bri Ul'lirlgllr A.
Baur "'5, OudeJarw JJ. ROW& A, H ~n

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15M,
NilCM'lan JB, ~ NA. Sa!h&r H
CamitIII
e, FOfllSt>er E, HIlIrisof1 CJ, Da6lugue
N, Sdlrlppe 1.4, PuI CH, Bam G, Si lvfrman

LB, JriaSd\IILJb GE (2Q071 OulOOl'l'oll oj
~l in d1idtlll\ ril ~ lKlJtlI
~S/lc lt\JI<emiII, BlOOd ' 10 "'21' 15
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1551. N. . . Y. Triebel f . ~ C (19811
P1n~ f'8iIlllOIsal d. stlJdy0/ 51
_
krI J IilImaloI II} 129--136
15M . ~Y,WaIo.l M,~A.~Y
~ S (1996) If'rt9:1osls d It>e ugIClIl
...... b IlOII--HodgkI1 ~ ~
-.n(:lT(n(~~d
l1c-.woII~~
, ~92
K)OJbuGeU ~Znh~
1511. NHaIllln F Tats""" E. T.1Ii K

KiJ'IIagiIo S, ~ Y Saroo K. Naka....,. Ii
,..... N, Abe T, K_ 0 (1996)
Cot~
01 oekii18oce
ltlg)
~ lr8IlSfer-.e
(TIlT) and
' 0 _ ' a<.:liv*",l gene 1
(RAG-- 1) two QI5Cl$ tnd !lefrooed CIII Io'llIs
t
_10: lt59-1163
1511A. ~a N 0IlIIl_ K Aliil 101.
~
Yl2OO1l
()emcn,ntion ollHlNn:
DNA ollld-2 nI ~ '-Y d>lIiil

.. 1uIIt:o..-~n1~~
~ t\:IoI'l hl _
paIiIrll J
EJp
!iamIlDp.'
9-13
1552_
5
~
cr...
s...- H ~
K. FUl\4OI U.
T Y80 T $.aio;lIiY.
AJ,
casa...
A f ur"9 JJ, LOd<..- J (19931

altar
l~ ~ Hodc)l<J" ~
pos~llllymJlllopolllericr4 dmtdllr '".

reciplenl cancer 12 25$&-
""'" trln5llltnl
un.
""
tardut:Cl MG, sea... E, B..."n "

E, PItd'Iio t.IC. Rtmolli D. R;,gone G,
Natom f fl'OnWl M. N!JaI 0, V. . S.
Lorrtlirda GA. B-... G. N8poIItno M. RiMo
G (1OlI6f Skrrllloming 01Saly fAIl....,....
SOFl.cX~ tigNIng and ~
ol co~ IV Blood 101
Ctpv'oi
H(l8.1115
1m. !WlnIalaII H, OtaY Il.-ri M. TaklludI
K SuzuIlJ R u.uo K MIlliumIn T. Y", K
KJIlI Y,........ T SaWII:Ia U. UrytIlI S,
s..o
T. T~K 1(Ao. . . . IrII
UedlI R.
N...........
AtMa y T...uY
S (2001) On;co.
~ lMUaoI 01 pyoIIof..- - - . : I
~ ............. .....,-1lI\OOhfIng llll
~ At-lOncolla 122121
tm.
'tIrIniH ~ K loIIIu;IY,haD
,.,.T,8rGJS ~H ~
H, ~ K
31.366
1565. Nakarru3 S, SIiola lA, ~ A,
Yatalle Y, Ko;m<1 N , Motoo1 T. Su4J" R.
I'lJogitrnj Y, 0QlI'aI.l, lh;II'i.rlima Y, Mizogo.K:lli Y,
OkitfOOll:! I.l, Sekl I.l, Koshikawa T, I.lori S
StICIlI T (1'1971, Ar!8PlilSbc liIrge cell Iympl\ormI . a dislil\cl moiectJlar p.athologlt: eIllilr a
reappraisal w,th speCial relereflCll to
p8()( NPMJALK) e.pressiO<1 Am J Surg P"UlOI
~ 1 14W.'4l2.
1566, Nillcamuf1l S, 1'80 T. Aoyagi K. lIla 1.4 ,
f UjlIhtmaM, TS(JrIIlyosfllM (199n I1eIicobactllr
pj'lorl al'ld primary gastnc lymphoma "
~thcJIogjc ilI1d~
ear..:.
alla/y
SOl 01 131 patients.

79 3--1 1.
1561. Noil<ashlma Y. T;,gawa H, Suzuk, R.
~).
CUIInI _ _ b' tnIlPI&k *ge
hllllaPOC _
~ AmJ~"'aIIoI121
MeS-,. 1>.
i2003) ElI'\eII'I-8M vinowMoci8l8d poll'

lraMplantaOOfl 1yfr>phoproIof_.. d'lOI"der
after ~r..oo.a ~ "*1I\lY
and~I~~
l1em r.eII lra\spIIlnlatiofl fol _ . 8I.J1Oim.

lTlurlll , , _ Ild Blood Mam;rw T~
II 583-59'
1m . NiltlWani BN AnderIoro JR, ArrnItage
JO, C"'aIi F, Oklllokl J, Drllct'oenberg MR.
~ NL, lMctflfl(lan KA, M uIIerHllrme~n~
HK, Ullrich FA. l'I'eke"tlurger OD (1999)
C~nlcal tign,!lcaflCll ol JoI loculw lymphoma with
rTIOl'IOC)IlOid 8 ceAI, Nl)r\.HOOgkin1 Lyrnp/lOma
Cla!'&ifiC<1tlOfl PI'OjtCI Hum Pathol30 263268
1518. Nllhwalli BN, ~ JR Armill 9ll
JO, C..aII, f , 0ie00ld J. Oract>art>erg MR,
HarTili NL, Mld.ennan KA, M uller-HemWi'1~
HK, Ullrich FA, W~Mll~uf9"r DO (1999)
Mdlgf\Ill zone B<:eI tympI10ma A cinicll corn.
PB'*'" 01 ~ llrId ~Ied tympIlood ~_ ~. Non-liodgkill 'l LY"'CJh0m8
ClaI"'1lOO Pfoted:. J ClIll 0rl00I 11, 2486-
lSM . NaOOr RG, C".eIarmtll E, O\edbum A,

08. ......, MO, StId J, K ~ DU
(19961 Pfimar'y tIIIMon lym~, dtttind
Kamtn S, Karube K. 0IlsI'tmil K. lAula K.

IWwa\i H, Morishoma Y, Na+;amura S, $Ilrl lA
~,.;,jfl
atl'a'f-b3sed comparatJve
2492
~ """" ~ wilI1 ....
~ ~~
oI!\3llil'<e I<jlkl< celilym-
1511. Nalllw..... BN uener GE, WIer W
1(apoI;', saroorna-anoolIc.d hwpn
",/IfW,
Blood 88 &4~
1S56. ~R(; CNodblmA.~G,
c...... E SaId JW K- ' I I OM (2O(lJ]
HumIolITl'fll,l.J....o.i1cy ~ ~
-:I ~ ~ <Jopdn
Nn J s..q PI1lIOl 21, m-J02
l ID. Nagtlt Ii WOflltItc: ,1,$, Oh CK
o-.:tvy SA 1 - - . . . S, SuNu y
WIlaIIlII DO (1995) Idoii.......' 01 p;lIf1l
nIAJIii)n ., fit ctUt-,1il; ~ 01 ... pro.
~t>.laI"'~blooO_
tINr cell 01..,.. ....., ' - ~

. . . . . ~ l ~. . . . . ~
,.... olaIl SOIJ 5 A 92, 10Sfl0.105601

155.. ~ C CI'q:q Ii Shnle 5 BallI8yI
(20051
a.n.JS. ...,"Re,~ ... ,~ CR
p/lorrIftuk.m dlfter9n1 gerotrW:. ~

~ ol ~ NK-a!I lllul;emiII tnd
lItIrtnOO!Il N~-all ~ . lIasaI Iype
[).oon
Genes~
~cJ~~'Bbxl68
00, w...berg CO. "",100mb CC (1986.
*"*' !loI1ht llIlJlllIlOIogo
~ lor lhe
C8nelJr". 241255
1561. Nak.ltl<,ita S Y80 "I. Hosll,da Y.
WN1
Yamamoto S, Iuchi K Aousa K (2002)

~.-asaooalad !ymllllonlol JlMN of
106 ~ J CIrl 0nccI20 .2S5-4260
1511. NIIe6nit 1rAA. Jaffe R S1arzl 1
~ AJ PorW K. 9.ml\atll JA. Mal.OWQ
L 110 M Lt)Cie< J (l!lll8l. The paIhology 01
post,
" ~klr.lM dioorlJerf
0CQ6Mg .,
$lllIIIlg of tyCia;(loMI ~
_ ~ A,onJ I>iIlhoI 133'
173-1112
ISIlI l<iillu.ii'ltlm Y. ~amhI P HIi EO H3nI

CP Tlblhiraro R Sthn tHo CoMtn Jl.l,
GrillZlllgt< 0 Rl-.:lt> M. ZIIIiO S PohIIrlIn 8.
~N. Baal: "I. ""9dor A.Sdq-G.
NIlgIer A, 81""1 GE, Ltvy R. ~ RD.
IS (2lXl8) u)2 lI'OliIIll UJft*lf'
Pf1ICIl1I......a In P*'*'" -119
1m . ........
t st1. ....... Y.
""~P~
S33
1513. IUwIIlC. Orv~ Pl. va..s.

R, Mnrm P, ~ C GoJmal E. ~
.l., GatiI O. ~ F IgIlJIias L, PwlI
Mol AIgln P f2llOOj p1611HK4) ~
., Iiasiln 01 ~ ...,.
J P1h1156' '565-1512
lS101. N....:l F. ~ AD. HNd OR
!lcn:Mllz MJ c.rct AJ. lltIn:I JI,l lr'l< t.IP
RQlWII """. ~ GA Sc:I-.. t.lIl.
S/ialdI OJ v.e. TJ,
OJ 1191l9'1 AQ.tt
lIlilN _
0QICleS Moo
p/laklqy
~Af,PlI* .. .l..~GS
tnd'o...,........... ...-llgnInl
108-111
1$75. NMh R. M<S UI\tJ P ZtfllbeIo R
~ G LwgInrl TP , (1ill3). Cb'III
-.0. 01 coo. W""'oIlIoII.. . - - 01
~~ BIooclal2363-23llll
1ST6. '-II RIo. D.lMy R, Ston!l J Georgta
GE. 8cMtrl JD Ho:*rWg LA KrJII GH, ....
MD. IoIcOoNgh llJ, 0... CS I)perw J.
lema'Wll Cf. Pa-MOC S SulI8ro 1< 101
SunclarNuI J. furst DE
tympIl .-.odeletiorIs '" Iot.r case5, Palhol llll 4<l
12003. He~ T~ ""'"

ptona ill. paIierf'" Crohrl'I~lrlllIlId
..... ~ L.eul L~ ~ 531
T~33.,0,
15R
F.,.,.. .. (IMi lk:eI i1..... illdo;nIly pI'8-~ III ~. 01 g:JSh: MALT tym.
pIlclrN ., ~1oA:i::W.18I ~SSOOil8ddlf'Or>.
1l; . . .,,IfiIJ~ 1.')2'1211-1219
1511 NNron S. Hin K. Su:rlI T IklM
I~'" H. ~ma .. Na_ayatnlI A
~ A ~ H Asai J t1988)
1r'IIerlIg0llrlg c:et s;ycoma A 1l'IlJI1""'CJlogIc.
f!lCIf1hlID9lc llrId 1l1TlJ"'*9C ltuay at
1512. NmI VE. JaIIeES 121X!5), Tile pallO.

01 NK-aIll ~5..:1 .......... Mv
4nal PathoI1Z: 21-301.
1S82A. HavllO'O JT Rlbll<. Jt.l. Mate JI.
Granada I Jurcl J Balle M . . F. hiu E
tJgf
(a, 1.KCi2. Q321 rao~,
etI~_~~.,
(XlI'Illl.
pm>ary ~l.Ibon II ee sk",

d;rucopa!tlologic. ,mmmolllSlooIlllmocel and
IIlOIaclJBr alllliy$es 01 """"" ~ J Q.tlWl
PaIhol 27 392-399
pI'ii:iinaI _
T,YIiwIhjrI Y 5ai<Ii I, Yau- N FIlJII S

(~I T_
~ grtIlI.liIJ Iymo/ltlt:y1iC
.....,. octVIWlIl
~ ~
btJatl - . . c.I
, Bone Uanoor
F\Od'IgaIIIi T V--*' L Tv>eyosIii lot
....... ~ . a n d ~
-.t c.....61 ~568
15M. ~ S. Kosnika.. a T, K~ II.
l<iao.ayillla A. Y~ lA. Imai Y, Ishii K,
F..... N,StCoTll994l ~aIIIl8'
Su LO, I.e 80iI PE, Kim YH, Kci1Ier S (20001,

Co--expre&SlOO 01 C056 eni COJO ill IyrfI.
!l31~5
u-
e.
oaI~RalId"'~
~""and~
~
..... ....mJ
0nc0I26 441... Sol
vvw...- RA. ItIilt9"8
"*'
1ll<Ae<nia
IilIltl
".
IlId f AllU IIU
~ ... ~
~ ' Iht I"edlolMc Oncology
Grlluo~
L~13.1)5.141
ISIS, ~ R5. ROW! PJ. t ..... FlJ

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_
A ............... _1 NEr9JMed
2M. 15,.,55,
ISM. ~ BP. ,....., NA IWIIllr ow
locI<... J Fung JJ. S-roloov SH (2OOll
EpsleirIBarr .-.ua-<>egaWe poIH'~
~ lk$OrCIIlI$; I
arIIIy'l
kro
J s.,g PalO 24 315-385
.-..a
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1590. NgS8. l aij KW, Murugaya 5, LeeKY.
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H197.' 101.
1591. Ngu~ DT, 0iM100d LW, ~
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irnrnJrlc:Inlodiilm 2' 6Q.6ol
1592. hI~. Baosi G RorodfII; O. Hol'lmiIl R

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IrrIIJIIIlOIIrrmInopIItIilJ 13 101_ m
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19 5. Nltme\'f' C"I. N1CO M 8-.0 G
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01 cMIald ~ 1\ Ah:a """'"' Rill
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F.... A(; , liIMIIt K (11191) t.kn:qIoid B-OIlI
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1606. "'o,l1...1IjIIIo l, e-.- Jl., COI1ley
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In,
DBN_
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!iond!'ow e,bneIic ~ d CV34+
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""
0II'r'itle K OCt J lledI M.
l eu,
u.no
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N_.V.SIiIoK.~t.I,~K ~
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~oI"~lIt1'1ft1t'to
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~.,~
_
CIk ~
20" 8249-8<'57
1125.. ~ H. ~ K. ..... Y
~ lot. WOlIbt T 1200rI av-
PlJ"iIed
-...... 'MIl FP1Ll-KlGf'RA

IuIti:rIII'Id 76141 ""*"en hll'\llf\llllllrtJoo,
~OII~"'~
. .d......., &'J ...... ,)4 547-5019

1621. 0M0
H FU'1Nn 5 (19911
01
d '" IlCl.6
~ II 8-aII f'\o'!lPlloill ......- l.M
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1636 Okiiroo III
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___
~
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1637. c.V,~"',ZI'clu,l(,CoItIIJ
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l ID. Okuda T SIi.IrnoIo S 0t9Jtfli T
*'
........S~KY~T~
S HtliS ImMI1uIwS(I99t) ~
~ IhCICIOliIIld WIlJl . - tlIV1l
kJef*~ AmJ ...... 3e 321323
1640 Ok"" De
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l~"""'~1#nJ"'"
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1641. Oi-oey 'iJ Le s-. ,... f2007

E _ o I recwmg~~
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............ B!' J "-tIItlI62. 6S9-a'ii
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...._
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1617, PiIIetIa E. FItfTllrdll M. ~ 0,
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~~ . . . . d.~1stIo
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Em]
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~ R-m Co.A:i ~
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...... a'ld
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- * " I'WtrTtlo-
C\'II8Ilia.1n VMJ 20 3tl1-3&l

16U PIfIdoIIi F loug/lran
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o.e-
TP
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1696. P.:N<a P. Ma'l:ooa G. R'4II*IAS
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l.-.:ln RA. !lIoorTI\ekl CO (2006) ""'-
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Pfil\1'OSbC
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C'/IM.AII'lllbl::enW SUl1 CanoIr&S 341-348

16&4, ~ F, Fngeri F
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741.745
1685. Pent F. Frigen F, SondonlI lA, Lu<:iarn
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\686. PIlQUlllIll Rl. llJnclaw EM, P....re RV,
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e.-.
synOro...... 6Ioo:l82. 59G-~99

1687. p~ A, Allin C. VllienlP {20061
P3I"ogerwIM. dncaI tuhnt. and lreIt\'lllflI
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1iaemIlt:ll19: fl9!>.615
161&. Pardarlanl
A
IlrQafl\ll'l
5R.
P.l8rIlo.Ier SF. Fiyrtn He, ~ RP.
I.a$/lO TL HoCL U cr. 0ewaId GW TMlwi A
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IOSnJPI*. SIood IGol 303tI-JOol5
16t1t. ~ AD. l--.. RI.. ~ T
~ y, "-" RA.. I'I.-..gn ... s.r-OP. EaaI lolA. w..tl'l AP Hogarl I'IJ
~ RF 1AIlM MIt GllliIInl OG TtIIInA
l2OO6j ...PU15111J11k11a1l'l"'Y'*i.........
.,..,. . "'YlIlIJd cllIoIllIrt.' a Iludy d 1182

~. 8lood 108 304723,47&
~ d KIT moIaIIoos
-e)A Ik:\llIt myeloicI .......,..... ""'" i'Iv(\6;1lId
.8.2\): a Cancer anr:Il-.1<errU CtOI4l Bsw,J can Qlo;.oI24 )9()43911,

1696A. Pedlka 1', Mareuco G, R1WIfI AS
Whitman SP, Mrozek K. MaIIerr; It l.angIr C.
8aldut CO. lhiIO W, PoweI BL Baer UR
Camlil AJ, Caig&;ri MIl, KoIiU Jf:, l;JfS<)!1 AA
BIoomf.eld CD (2006). Wims tumor I II"
mutations independenttv pr~ poet out:orr.
,n III)J lts
With cytogenoltlCally i\OI'ITIlII acuII

Iwkemia. A Cance, and L&Ul< emia Grwp 8
stud\' J ClHl Oncoi, in press.

1697. Pa&q""letti P. Festuccill V, ~
II Casale R{1991) The oatLJr.ll Nsloryilf mooodooaI III"'1rrJOl13Ul'1 01 undetemwned ~
~, A 5-lQ 2O-vear I(fuw~ 01263 c-.
Ada I1aemaloj 97: 1,4119,
1698 Pasql.l3luOOl,lI$O AMa<t.~P,1l<:t
N, Pacini R, Tabamroi A., Carino 1.4, IlIQernI B
~ A. t.Iar1nuoj R, N!colelll (, TiamE
tJ.elollo G,Specdlia G.CWltlrI N. Di RaI'l'ICI'WlO
f. PtIri 5. tAecua::l C IoI.1nOeIl F, I.I.vlIIi
F.... B (2006}. MUlal8Cl nudellp/lolrlllll
delet1$ donIll iIUliine;lge ~ I'l to<lI
myebclleukenia ~ 00 'M'lO ~
lIOO Blood 1(184146-4155
16HA. P~ l. WigUua A.. F~
N. iWIIim C. '-' A. a.bri l CIlIgn RS
KIIln U K~ R ~ K. 0IIa-F.....
'*
R (1998) 8Cl-6
"**"IdIr9
B
101\
~ I'lIlOl'l\il
QiWIMlIII
alb ~ d KIffIaIIl: h)'I*IIIAoulI-de Ig Ix> Proc toiall Acad ScI
lJSA95.11816-11821
1699. "-qualucci
r-.
1. ~ G.
ChI9ri RS
KullP"'$ R. OlJIlIFaW!tll R l2001

~d"",~"
Ek>III 00It.M ~ ~
.'2 J,.Il)16
1100. "-n:lnli F. l.WINrtla l. 0!tInII E
e..C, e...v.t A.. ~ E ElarA::hi
101 An:wi L CaberkJn S PaKllltI C.1..a1:zalWlo
10112003 ~,.. . . _1'1 rtU'll ~
f IlIlly 011 . . ~ ,.. 01 ~
..,..... . n ......
~M
1).1'
1m. P - . I I F, ~ ....... E "'tani L
~ C L~ '" Bem8sconi P
~ 0Ik Pt,I CoUIilo 101 , PaIcuIo e
CC'Ille III ~ 'II 12005,1. ~
,...., fA llCJl'Iqt"."Ml a 1IirIljlt
SM)y fA 23 pIlift'IlI Cancer 104 1ll32
'**"
"'"
~ F.RtmE
17m.
~ E
L Bwlamn P V...... M Orl:ant\

E M:to"" L, BruumolnJ E, Pa$CtJllo C.
c:.zzot- ,""
Morra E. Lazz.n'lO '" I~) Lilt

expecl8t'Iql ~ prognosllc Iacbs lor _at
"p!JlIenV. WI!h ~ ';ffiI aridll$$f1I'I101l1
I1rombocylhemia Nn J Mod 117: 755-T6 1

1703. PllIIa'TlOnt, F, Vane,I L, Mal!l~ L,
Rum, E, PUf\QdIM E. Makxr<ati L. Pa!oClJ1t<l C,
Mom! E, lazzaono t.4, Cazzola t.4 12(03).
CIf1ltaI ut lllt~ of the I bsoIut~ number ft dfcu.
Iati~g C0 34pos iti". eells in patients wilt1
dllOOlC
m~elopro/<f ~r~lo .e
diSOf11trS
HwnIlologIeI M 1123-1129
11Ool. PIII/llOI't $..I,
ClwtsMIs JM
H, IW'tI Ir,I, ~ P,," Stile! CA [2(03),

Pllldillnt ~1IslIc syndromn and
~
"'J'lOo..:..:x,.tc~ 1'1III ~
p_.
of nXI8nc:e 1l1d,.,..121 7!l8-767
. ~ Illdy
....
~J~
1715,
$..I, HIm 11,1. SliIlIr CA..
~ P s......., GJ, Gtilo:n S Rwvw

llRChaaeIIM(1!l961 ~ ~
. . a ..... dee~ww:ta_ll't'9"
'UIlC1COTIiI~ Blood!lS
1U2-175O
1711. PaIII Il8 '*"*-l AN 5ct*' CA
Aculil ~ ........ "-'
1006'
,............ Ool. bIlIIl CJ1Ii!l t.o_

~drN(16)'l(16.16Iand.~d. . .
..... LU RoM 3D- 22S-2'32
1701 ....... AD
G. Hedge U,....
J GIInI 101, ""'" S. ~ A.. PalnlnIS NJ.
MaorI 'Ml (20051 L~ gta'Il.lbIIIIlllIII: ...." rJ!he brain at MRIIMg-
"*
MerJ4&W8<:eIlympto'na a SUjy d !IS l'i5lomoIptloIogIc IPIt*\.m based on 109 c;Ilift

t+.Jm PIll'O 30 118--187
1713. " ' - R MaLoIes E IlrJIo--Bat4cUI
v UIIi- H HIdges l.I ~ J. Der '"
~ 0 (1991l. So!l8ty all . . . . . . ,

dItIncl T0IIII ...... 01" a_lorII'lolT lIfO"
~ 1BuI<_~ leu~ 11 1009-
W"
1714. " ' - - 1olG.
NtI le 8eIu
..,. ~ Xl, ~ S. Kernwl St..
COIWI ...., ~ EW. ~ El
y~
(1985) IncJ..-l nutnllen 01 _

. . , . . .....,. till I6IOCIiIIed .., a 116:9) 11'1
AM.L Ml J i"lWnM:lI18, ~
1715. PelnonTC wet>erIey-Mell'l G \1919)
TheCllUIIII . . , ~ 01 'o:l1OlllllhJC eryItwocyaI& c-.1.lIb H.....,. 1 189--196
1716. P8<1f1rser1-6I"rgaatd J. em.lill_
DH, Desl<t F, AndfIrseI' MI< 120(6).AI\emRvll
gtrlt1ie pflhwaj'S ar'l<1 l:(l(lp(lralil'lg gene6e
lltIroomlll'Iti 1'1 lhll patt>ogeoosis of therapv'lIlated m~.Iody5plaSia ar'l<1 acute mtolOod
~~1lI'ni!I L.uk~mia 20, 1943-1949
1711. Peh SC, Kom lH Poppema S 120021
FrKlUflllt pre1flnce of !IUblype A VI' UI in
EjI'"".!larr '<'II'IIS-omIaIo!JeS aI Uq32 I
11'1 T eel ~ irMJM two orocogenn
Pruc,... AcId SciUSA 96 ~9-2961
171' ~ C B"rIIe $ ./ego
G........ D RobAarl:IN.?r-D
RawMJ
RPM]
A.'ftd III
rJ al56 /NCAl.I) on ~
cell II a !IIa'nwt of ~ cell
..... _
.., of ...... JUbseI of "'lAIPe
mNIar!'4. l.eU<fmI 12 19711962
The
'*""'*
1120. ~ B Temer-laooorft MJ,

0bIm 0 lIlilInc T. PM! Y. ~ Y.
C. EdIn C, $dltniII. C, ....... D.
e-c
~H.V_JP.t~e.
CoAIult G.
1labo~EloiIeklt
A Thuret I.
~ ~.~G Del"G.~
P8n;. J
f"OO,]
L~e-pred~
HodgIunI ~ 1'1 chklren .........

~ __ .... lymph r()(ll! re&ICIOtI---e
SIUdy rJ the FreI'Ch SocifI!)" of Pediatric
~~2312M-2n
0nc0I0gv J ClIl DnwI21 2948--2952
170l1. PalIe C, Auperm A, GItrrafd Iol, Mochort
1721 , PeIlIl P, Berger R llerrfflm A, Srooet

JC, TSllPI A (969) Mok!obr aMlysis of a
1191. Hpl t qJ2) hnsk:x:aliu1 occumng ,n
CMe of h'Ulnan alpIla herJ\"f chai!1 dl"l!ls e
J, PrtkMon R, Spoalo R, W'lS1oo C, RapI\aeI

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FABil.M696 "'II lor inlllrmediare risk B-(OlII
r'(;"N!odgl.lfl lymphoml in children and adolll$011'15' ~ ia POS5<bleto redUce treatment lor !he
.-1y ~ ~lB Illood 109 2173-
".
I nt,
P-.l C, Lfl
T~
A.. Cayuela JM,
llMja A. ROOIrt C MoIne V, D\.tIlutrtll l

(19'11)~~~
~
cnuse dImg melhl*e,* !henl-
lW b f*lI1MII A/ttI 0fIrmII::j 133: 861-371

1110. PM M 8wI' E (2l)Ot) ~ T~ ronc:ludlng ..e !UbIypes)
lMr'W'IlXlI'QIIlL _ ...........".... 89 un
".
1711, .... y Ilt'lo E, Rogj) R. ee- E

Kl..... S IOn', e LMzarnl '" Ban:nr G,
..........
Sww:ci "(199S)
~1
~~"""_~rJ"
-....dtoiCllJPllW*YC
..,
sliIlt5I>011 ...,. d 86 e.- '!I'UIicolr*ic: 'IIlIlly

toft III E ~ Drpiz&lrl b" ~
IIId T..........-.t of Cance< eutanflous

L~ Prlo::Iject Gm;p J Cllrt Ono:d 13
1343-13So1
1712. PIuIl.I, Slr*r J, Gollnali U, fbJsMt

NT
LJ~
M, QrIi1f'l(\i E Klfisy C
T. Morra E ManegoIo:l C.
lamnno Y , Ltagnni U, IoloIler ? (1'199).
~ 4' 653-M 1
1722. Pelopone$l:l jM, Jr , Kinjo T, Jea"ll KT

120011 Human T-<:eI leukemill vius !;'p411 Ta ~
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101.106
1723. Pam]( I!l91). The~peIlemof
~ ~
TllIf'Sfiant Pruc
23 11011103
(1_"
'124, Perez..Qrdonez S, f<1andson IV..Rowi

J
FtIIoaAat ""'dnIIc <*I vmr- ~ (II
13~,*"of.<isln::live"'ly AnroJ
Surq "-I'IClI 20 9oW-955
1125. f'eI'u.Qrdonez II R0:>9 J (l'i9l1J
f*"-~cl!iltumor
_01111_
Ml J S"ll PaIloll0. 116-191

1721. ~ E. 0fI S V PiAl! A
P~ A.~ r,I~C,UItldII
F. ElMn CD, te ceec r (1997) P............

an.1 cMi:lII ~ rJ 8cU Il1d Bd-2 ~
oonIo'p... '" noxlBl dAM IWglI B-aII .,.....
~ J P..-a 163 281.2@6
1729. "'"" Ar,I
~ot"ofri
B .........
~ '" ~ J
('i9it ~ ~ due t:I a poIIl
1I'IUlItIIiDrl1l'l ....... ~ofC095-.o
...................... Iyo~. . . . . . qn.
_
T-ClII~. and HolIr;;orII di&~ F, Wcw;nann
e.
LC 6loorntIeld CD flr\JrI*Ig
AD (1918) 8IllIl CNlI as an inlIiltI ~ \IIfItIqI
.....oileIloon rJ cIwtlfIIC ~
A
ft!l2Y0124poolIenIs. NtI J Uedlll)- m220
1731, PfIllnon lC Brown SA, CrouoII
r,lladtnCWlc J 1191l6) Appicatoon of tilt
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l'ephtroe tliop6ie!in !he clas5i1icalion aI pel>enll
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1732, flelflrson le. Park ,~ JL. IIrtlM DC,
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17$3. Pelerl<;ll'l If. Zhang Of (20041 ThB
811
in levkemog_ _
_EIIP~21,~1
mo,
laJ._
rr.
~_locabon
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17M ~ 8, JIrllil f. JoIy B MnI-
Gama N. TIIy H. PICfll.*d.ll4.Ilr.-e J, 08neI

C Mehaol S Abd-AJ.s.nad 1 ~
C, 0tIl'....urue M... Gaulowd P (2OO2l
~ ~
~~enIIy~~e . . . . .
PyoI'o:n<...-:ilMd
_~ot""''''''rand'''oa;:aaillf'lII
. . . . . . . . B- nI T<:eIlNtU~ "'" J
~ P..-a 26 rn-732.
1735. ..... T. 9agol 101 Wileonle R

8e)toI-8arry '"
v.,.. B 0elBtrey M ....
CJ. ~ P JoIy P Gr3nII" F
(If
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~l ~ ,
T, Daloc 5 M~ynadol r,I

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~ 6 MlOUld l WedlSifIr J. El'IJOl '"

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T.
""*"
A. DeItat-Larue r,I.... GaUaId P

D (1999) C04' CD56. eutanIOl4
~. , <hIr>d ~ ri!Y'
Gt!qlfI FfW'ICIS ll fhJde lIM l~
e - (GfElC" Am J Suo;/ PaihlI2J 137-
..
'
I't Se!tWl o.gn PIIlhlII IS 144-1504
1731 . . . . T. Oebu-l.wue ...., CIlIul O.
1121, Perw~ E. ~ I,Ill Mailio

G ~Senz R
W, de Coca fIG
GlIIrcleJ ~ G Ab>soJf,I,. t.
~...
0 I'orIifIrIi G.Wwnf
P, Fan:eI ... Arno:Ud L 11996) " -
"'*'"
e--.a.-.
~ ~ ~....-.c.b'1
iderlIty rlIk 01 prtll)"MSiorIlr' 1'!lOI"lOdonaI II*"mopeIlofof~~and smcbr

on; muIIiPI rnyeIoma bas8d on rMJIIipW. . . .
law cyIOmeIy ~ rJ bone mar>o'W pIaanw
17)1. ....... T. 1.4e'fe'" CJ 0alIc S

R Milynad.. Y. Mad\e( l
e.-rov. 0 V~ B. T. . IdA (2004)
TCL1 ....:l eLA ~ '" itgrenullr
cell
Blood 110 2586-2592
nauII kJIIr 0lIl <;ngI'
w,-.-
COoIiCD56 rw'i0lvOeil'l'OC
~-ClIII
Med~
CIinPathol 122" 301'13
au"
~ lymphoma IM!h
C052 .. ~ T-oef ",.......

I. . ......,.... 92 566-561
1741. ~!'P, " - ' " S ...,... C
I'aoIniS ~C.P~C""""
G v.-. G, ~ L4 PlIan SA \20071
IltyeIo::ad _ _ d ' " an ........ CI\IIIi dI
jlIlnice Reportof me CIIIIS and . . - dI
........ ~5O;802.a
1712. Piltri SA. Aseani 5 eo-. IIC
CampjdeIi C.Bacei f Pia:ir::' M. PlaaJge pp
AgoiIJnelIt C, A!Joli S, NoYero 0 ~ r,I
Pon:ltIni '" GfIntie A. RI\IIdt P, F....-.xl V,
VrIceIi D, PiIen A .1", Galbolrra R, f.1Ino e,
ZlnlerilPI. 6fIcciuni '" (2007).Myeloid W(l)o
mac ck>M::n-pethologic, pheoolypIc and cytogt-
l'HItic _ 1)'SIs of 92
Ill!OI)IisrIl5 (~
tymphomasl arl!lllll. lluhme
21: 340-350
1143. P<lfIIl SA, llseani S, LeorlCim t.
5~">!1i E Zonzano pt , PlccekJga PP, I'W1 A,
Jr. GU1ti M. faMi 6. Solis Ga. StooIi (20021
1io:Id9kin'1 ~. lh~ P1~1 .....
~ J ClI'II'aI'd 55 11;2 flti
17". Pfter, SA. GaldanoG bIzanoPl. F_
G.ullwd p. ZUox:a E PllII'I F I*ta E.
SabIIn ~ $, Pll::ci:llIM JoI'tlton PW,
Gi8niini R, Pe1carmone ~ D
F'IrX:a.'IJll!'P t.t..-"T,AklnkI"'CMIl~
(2003) """-'Y mecinW4I 8<.IlI ~
,.., ~ of BCl.~ _ancIlD'MlII'ite~rJ"~oon"""
ot
DCT2 EIOB I. and PU1 . . . . . . . . .

J ~'62' 2.3-253
174S P*Ili SA.. Gmgatl ~ +WIll M.. '**P C*'IO E cr...,.J( ~ _ R. o.d G.Oa
WdA PC. Fain S ~ RO G.iWd P
GaIllr KC ~ PG .bills ES IO'l P
Knowles OM ~ OY. IoloIl $ .........
Henr'**- HI( Pa;& WI.. ~ E
M
Su lJ. wa-e It\. WIlissLM (2OO2l TlmlfS dI
hoIliocytes Il1d l1CC89OI"Y derIIiIlk: CIk Ato
~,.,.
ss.
ommuod
ncaI ~ t) <:InIMr.:aiKln !rom
~ l~ SIlJCt,t
Group biIsIKI on 61 C3SIS ~ .1
'"
1746. I'Iltn SA PuIfoo:l K, MOO S, "'iISOf1 DY,

Saba",ri E, Rorw:adOf G. PIceioIi M,CfIccareIi
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Faijni Il 119911 FIllQUIn! el prlSlioo rJ !!Ie
~ Pr,I . "I.I( d11'T'1ll1lC!uWf1 protein In ."ap.-.stiC
....gfI-ClllI lymphoma. ~t!Ol)tJC ~
Am JPatlloI l50' 12011211
1m . I'>ldlowska ME, FlaIow1g IMJ. ~
.... Pm40us GS (2007) C04'ICD56 hemM>
detn*: flIICIPIestn fblM/IC flIII.QI ~ cI!iI""""
phome"l flIIOIlIe*cellfI'pn!S5I11~
dIo"4r1lo: osI ~ar 8OCA--2 and ll'OCk.Ice

~ AmJc:..Pakill211 5--I.s:l
17.... ...., K Sdorroon R, D!Iubw'*llI .IJ
SinclIor-StnII CC 12004) ~.dyI*i ....
dnlIc oalI!IlI!tO'lI a fllPOI"I rJ tu ....-..c
~ III'ICl ~ of . . IIIrIbW
I ' ~ 283-2'11
17.'. PIom E. M.a!r.ttwlnI5nI. t. F.e ~ e FdW C, Gtonst K
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1'1
T-oel ""UIItdIot:
1127. PerrorllI T. f rizzera G, Rosa J P 986)

~ A ~ic sll.<ty of 60 CI$f$
PaIlof 27 121-
W'i.~JW "'-'n A..lopel~C

()fao A.. s.t ~ JF (2007) Nl!w aoIet4 t:I
FlO!BIl.I. Bas:so K Zl4'O S Wen! p. Klwl U

ZI'\aII PI. BlICl.:arIro M. DellI F _ R
SA(2OO7j GeI>e e~.....,.. 01 PI'lf'>. . T oalI ~ lII'IspfICIIialI . . . . . .
WlCt ~ and _ paIInIiIIIlw,,** .
oats J ClirIIn>tIel 111 123--8305
1740. ~pp ~C ~S
Z - Pl.. ~ SA 1200'1 u;r- rJ
"'"""
mo
_,.+
JParo 1M
~ E PUiotr:l Il ,JcrIea '" 1dltlIIt

tterrnMrIk ..:, f .,; B R.....- E P6Iri S
PuztII F, Wdf-f'eeIers C MJet 0 S\IIi'l H
t.Iaon D GaIlef K (1998) Co-fI~ 01

CD19a (JCB117) and COO by ~h~
l'tmotlomI J Pe!IIOI 186 l M}-l.tl
1751. PinkelD 11998) IMlfllnliallnll ~
References 413
m~
leuI<OlITII.I from mfll(;tQn; dis-
Blood 91' ~367
1752. Pinl<usGS.SIiclffl(19851 ~'.

lJII-., ~ ~ fVpt, r<Jdu.
1Ir-ll dIIIrld S'lIily? lJrlq.le5lWWl9 profilelor
l&li VIIW1lS of ~ cell ....,
by !1IClI'IOClI;ql-*'Odoel1O lIul<OCYlt (:OtI'tlI'l(Ill
~
.,..,
..... and 8AJro JP.rD 118 1~
ancet '" PQSttril<l$lllarrtation ~.

bYe disofdets: correIlItion Wltlll>is~
tuIlcalego<1ft InCl EBV SIa\lJS Transplanlatiol1
ll(l11\>- 184.
1715. Ptw1ll R.
~oo
P, ~ M. Ferro
L4T, COfI'ltSNtti /10, Pef(M'lO /10, ll<InelIo l
Iltrrler9J lAG (2005) T-cef
fllCeQIOI' glWIYl\1I
li gnt ctli-Ifl I;lepo$<tlQll d'$NSI wltn r9nal

invol\'lmlilll dtUl d1.IfIlCI8I'IiIicI ai'ld P'1l'l"
noslil; **>r6. Am J Kidnev 0.. 42 11501-1163
1m . P..... S, FcunIlIine T, RBtIekl 1.4,
.leiit' E5 , I'lRiIlugI 5 (2006) IQD plltIb .. llM
ceh ~ umque IUbtel 01 f'O:llIWIr IvmpI'icq-1B preclorlwIInt ~In Iyrrclhoma. Am J
s....g PIlhoI30
~Z
1153. F'wlusGS s.JNI(l9ll8J.~'
lII08 rearra'lg(!mer>l ~ fTII/bPe>: ~

ct\iIl~ '~II'IP*r1l5
1MIh ~I T~ lymphoma i\'lXl5l& ....
lli&ua.~pliOb' ...... ~ >Ulu-
godBII5eZ8ry srncwomel MId ~ ..,...
BOIII"..,.liIlIOn L8
pciyI::".,iiC tIIlicn:Itn. Semon 1tiItnIlllI38, 11).
mIb'V"'" ~ """ dncaI, !IIII)lr.JgQl.-.a ~ fnd-.. Br J
1m , P.-.ud Hcnwne Jl,
0Irm8JI1S3 56!>-513.
1766. PonD:n M, ~ G, GWd VE. Del
Clft) B. ~M. ~A., Pdoo S
[Mnoroy l Cogne Iol (l9i4l l.4onodonII

~ doI(loMon dII-. (RnII
cekpea6c;~
1Ir~"-":'lor
H ...... oI~ctII~
126. I*\BOIII....... AmJ F'<lIOIn 111
PInIo "- ~ RE, Grtnt 1I1.

TIWeIWI Ct.. 8eIa-Il ON (1990) ~
17~
~II~""
llIl.)13
Mod PIh:Il 3:
e.. S
PIll Rtqg 1/ eo.;

..... P(2001).
01 RBl II IIWlII-ClII ~
l7S5. Pw.,a'"
J,~"-~E
~
~by~,.RHA~
..., ~ "
/IICfOII'f~ . . . , .
IIood 109:s.tZHoI2e
175'. PwlpOI Ill. CollO F. 811I 5 __ P
frWyIdI I F~ I'l ~ . E.
A.,CIfIPll E {19!lI~ pl6(1NI(.oII11l"'t
c..-.
~bydllllDnl,"""""Il'ICl~
CISIISII A., P - . C (2lXXl~ lid< of co 29

(bItIl "*'PJJ...:J co Sol (lCAM-1) ~
onolecuIe5 WI ....iJIWl ~
HuIII PIIlDI 31. 220-226
11f 7. Ponroni M Bergef F. ~
CitlIwlt C Tif9IIIf' ''. n- "- FIl'Ttfl AJ
0II"0rv 5 T"","" ... 00gIIcn C, W. J
Cer1Ili t.I lIMWi M LmlinD P. . . . . T,
~ "- "-"it E. Sandlez J. !llRy .!'f
RIll III CO'lalri "'- ElInorl F. ZUoca E e-.I
F IknKri B (2007~ Rea:;INe ~ T
otlI..... ~ ~ iIll"lWY cenhI
_ _ sysIBm B-cel IympI:lomM. Br J
l. c:aLOIII Ill.
1WMlilol1311: 316-323
1718, PonZOI"' U FemI!I AJ /2006),
..-..~ .. ~0I'tor.
. . ~ ? ....,..,... ()lwi 1<4. 1'-
1lII:Ii't "'..... P ~I'l.~

E Car!lIslI "- lqm.()lrl C. ~ E (199n
11ft. Ponrono "'. Ferren AJ. Campo E
~.
- . . . : I " ""'*"'*l1nCl
~ ...... of~WI'tym.
~
1757.
1lIood11 Zlln.15l&l
PtJ "-
o..o.lnCllOM 01erp-_ 01 p161N1(4

III'IlI pZlW;I!1 III"'" lit MIOOIMd .iII
. . . . . _01,....CIII~
Blood llll
1758. PlnI M. llrO\OI'I OC G.- KC, U DY(1990) COJO IXJIIWSOlll'l i'O'I-HodgkIll
~ l l'*'i*!-*'QV17: Z11118
17$9. Pllrnw1 SO H.-.g a. ~ cw
~ EH. CIo JD, 8IfliItI JG, w.u lM
Wang J (2ln' t-Il.>dgIm~. pott.
hriIPInI ~..... l:borOtIlHl'"
PTlD) ~ ~ 5-cIlI pnD
bom eh:tlIy MId ~ AIft J Ssg
Patholll . 7~76
1760. Plltalugt S A~ TA, WIrJdarska I,
5~ M, Clltin'llWl JJ, t.IIlcucci C, I/IIro Otn SM,
VBn Of VIIn WJ. Wo/t- PIII.1l C 11~) Bel
m.zeo
6 e1preuoon ", fu cli Vlt tymprlOId
t_
IIIId WI
8-c&Il oon-Hodgkln', ~", J Pa!hoI179

145-150,
1761. Pltt.1uge 5 , VlJtIoefG, Criej A. MIIlII A,
Nuytl J. ~6 M, De Woll PC (1996)
P~noslic Mgnl fiClllCe of bon-e mar'uw
trephine and ptI'Ip/lerIJ blOOCl ' "*,,I in 55
patltnts w.1h rTIIt/1Jle cell lymp/lOmI leuk

Ll'f'lPI\omiI 21:115-125.
1762. P\tI8Il1,lol 5 , W...,..sb I, Pullotd I(
CInW E. ~ SW. VII'I din 8M WoII

PMlBlS C (19911, The m:lOCJdorIBj ~
AlKI . .~.... ~ ~ IWlype 01 ~lil;
ltrQt 011I
aI!Id WIth 2;l23iAlK
~
_'.~1II, Am
J
PIoh:ll151' 313-351
1163. PMI R PtIIgnno E. r.laadiM. ApI
l. lllll'b8llli l,lloc:aIIllI F Colla G, Ruggeri
SA et.lg M. O'itllt R p~ G. ~ A.
inpwII G (2006) F...aiontI ~ 0111I
~ ~ ~ IIgnlIIlon IllIntI. . CEBPB tn:l BCl2Al 0'llJetl Urge!
~ JCliIItI_ 116 3111-3182
17601. Ptnl HA '*""-" "- SdNidIr A
Medl:ItC M Choq.iII 5 ~ v C1ItrIr.IM F.
ON F e - D . ~ E "'-"-BrI.nIII IoIF HntfI I. ~ 0 .... It.
Co"...H . rt P p..,- M. TOIM"iOt 0,

"'-!y .... 0..0. P ~ U f2lXl!l1
~""'01~"""
414 References
H2.
F~
F. Mauurxhelt l YO!tIIOO T. Mula!lll

T. PWi s,A, 00gI0II C. Zucca E Ci.iilI F
~ 5 (200n 0eI<W0n <ilqJosIs and
~ of ~ llwge 8-oIIlympi-. prtIllOMIs ana perspecMs from ill
....,raboi.
mo.
i1'IBe1il9 J Clti DncoI
a:nsenIUI
25 3168-3113
~
e. ZhIng B, Grf!9Olre
MJ.
~.P ~"', BOnba\mD.

PfbusQI.o& MJ (1999). The ~6.8XllZlpll)
nnllocaDoo in II slenl eel m~iI\I'Ill

dIIOnllI ~ II i'lO\'eI gene, FoP, III fillroDlatl
facIor recepIOr 1, Blood 93, 1381 13ll9

I'llpperTlilS( l960) Thelli\rlll"iilVoIitIo
'mm~ noh lst(llo9icil l
sl. ini"ll pattem 01
~
1m.
Sttrnberg-Reed
28 l aa-19t.
~, J
Hl5lcchem Cyloctlem
1112. PO\IPIIffiiI $ 11:/89). The rl8IUrll oIlhf!

lymphocytes surrCKKldingRew.sI!llnOOrg reI~
In ncdulllr ~ mphccyte pre<!cminilllCll and in
Cllhe< ~pIls rJ Hodgkin'. d:SGaS8, Am J PalMI
13S. :151351.
1773. Porw P. Noonan RS, OraLi
/10 {1m) ,
Spito&ctomy in agno<}lII1it myeloid me!'pl&si.I
8k>od 93 21322134
1774. I'QrIlcd< CS, DcrneiIy Ga, 0r1 J. 5traus
D. ytflal<)-n J.l.eiBnoll A. No)' A. O'Came:> 0,
"""""'ll. 5,
c, F'wa
1771, P1dIIl JTi1OO1f ~ mer;tw.

__ . - . d ~
_01~
"
TOWWd G
P.
SWbrl.~ M.RoecIA.
type) p .1l~"~"'~"'IlJl"I.11
of ~ l.'I'..-. KdIty h "6. 965-
on
1710.
e. C. 60IMiIl N,
x.
... TiQIUIll. lit Bolon S. noRIIoulI E. L-.lil C, e.t.qlI 5 F _

P.~H11OO2) FlIIOlIbltlJfOV'O*tID"
r*ra! of CfBP/Io...,.. ill ~ . . .
de IQIIO xuIII ~ IIUItme: <Ii sU:I'J' IrllllI
lit /locuWI lMMlli F~ /loIIoc:ril~
~FAl 8kIod 100 2711-2723
171OA. PrftQI S ~ 5 AuclluI J
'II'" P P..., G. DitooIcl J (1992)
~
",..,. 01 ~
&.rtIt'11l'IlI~'"
011 ro>-8lrtII'1 ~ for ~

""'" gtflOlIIIt . . . . il .... ~ Elr J
H.-:JIIJO 2132
1181. Pra SK jlW)f Irmu..........
srnII
I ""'1 01 13 c.Bt
. . . . . . ~ . . . . I......."*':N
11 1_11
1782. ~M E1C*\IP ..... 1.ytbnl
M. SII'Ichu N::.. lit '- rA.,1kolIII F. ~
CA. de l~'" (2004) F'fognotIc lIdorI"
Hor)g"" ~ LM ly:tlllllomll45 1133-
"'.
1183. Prlyb'fiskl GK, Wu H, UlICOI'I WR,

f illllfl J, ltoltllWd 00. FelgwRE ~
jA, NoftII PC.s-tllcM-
SM. KIdn ME. 'II.
MA, SII\aIly KE (200)).
end
IIUllcu~
partllCUllhl-lol<. garnrnl'diIltI T
eel I)'mp/'Ior'IM iII'e Oe"v!'d from d.fIa<tnl
VdeItI!lll~ 01 glmmMl8lll T ~
Jr.klIDilg n2: 11j9,

1784. Pui CH, &~ rllp~ lol, Ribeiro RC,
N'llffift)'\'" eM (2004) C~iklhood a'od Ido4HCM t Iympllcld and m ~e lcod l&ukelTllll,
HerlIQtclogy Am SOc liemetul Educ PrOlplll
'11845,118145
1785. PtJlfool K. Lamant l, Espinos E, JIs"ll
Q, Xu l. Turturro F, Delsol G, Morris SW
(20041 Thtl - 91119 normal Iod ~_

rel.ated roIet of anapj;l!IIIC ~ ",\ale,
~I Mol Life Sci61,1\13fl-2953
1188. Pulto<o K. 1I1'n1lll L Mom$ SW 6<ItIer
l H,Woo:! Klol, Stroud 0, DtlICI G, L4Mon DY
DA (20041,
(1997i O&IktlOn 01 ....pIal;lic 1.,mphcmI
,,",-~~dC DZO~
kinMt (AlK) and riIO:leOIIr proleiIl n~

mill (NPtol)AlK proIeiIlI .. nonnIl lind
p*uc .".. ..,;m the morlOdontiI ,"hbodv
~ll.
RleG-S~"" dBsslc=lI Hod1'inIa.

Br J HaemllIoIl25: 101-1013
inS.
PtJrwo~3k:l /10.
J.OO$!;Y G,Ivay
K, S'tmky 0, ~ R ~ K. Walkei' H
TurtM A GoIdIlOe N-l e...>ett /10 (1996)
~~ ~ idenlified by
~ b~. IV CO:W iM!rU'
IftIS'OO II awlI ~ leuI<efl'lilo U2
~U82') 8kIod81 1162-1169
m!lA. PouaIo G, MImiro C. CtooallCl M,
t.IodaIo MI.. Ceselli S. IMzzI G SullMI S
F _ F. T.... P. Morell "'11!l9() la.
P'e ~ ~ , nec;aIM C VIM
....... ana ""ell ~ 8kIod
Il4 300173053.
1m
PIlUI C DAmoco Ill, F~ GB,

C\nlIlI 5 1'. ...-0 F. ~ S ~
G. ~
S.
I.O(;JMIi
F (2003\
'*'"
/loL KI Bloocl89 13901-1-404

1787. f'lAs;p/leI MA. -'d.ml RH /lo$dl J.
PlI_ _ fB (2004) ~ ~ 01
JMloll ~ .. h~ IM'ftIaIed IIogenIIiI;
~'" 10IIh cyttq;ludoi loIotoId ~ 01.1
IllCl ,,~ . .....-.oe for. p ......
---...:_ e/IIIel rI ~7 JUr.lL,
&q t.lanow TI'8I'II(lIInl 33 113-115
1188. PttIIoDT.S,o_tlR$.Oka'lOIol 0....
JR(lm ~ m . .... W-O~ ditti'CIIn. L&I ~ 67: 5-23
U8l. QIIlI Y. G _ /lo. TiIIt" MJ
~ B, 01 MM 1A*......... 11K
{1995}. So:J'I1IIk ~ .. ~
......",..11 cc~~~1k:II
~ 1lIood1l6' ~
mo. Quarterman MJ, LeSher Jl., .It.. 0...

l5. Ptoo\illisCG, t.lulim 5 (1995)
R8!Jdy~
~'" CD61llls*ve 0Jla080us T-eel ~

phcll\il WIth Ion9W irwoI'<e.... nl /10m J
O....1IIOPatool17. 2811\I1
I1U 0utIn ER CllIn CH. '*lIoct KG
Fot.ng SII, FiirII M, levv 5 (20011. The B-otlI
~ d II tllIpllIIli5 C WIlt (1'IC1/)-llstociiIild nan-HcdgkiIl ~ bQIs Iht ...
E2
~ prlll8ll, IfI\IllicJ\Ing HCV 11'I ""'"

phcli'..... _ Blood 96 37-6-3149
m2. ~ PG.1(3jIIdie SB. 8ehlIr OW
.Jc:flnSoo JT, s-do;M st1 (1997) SIt*l'
gltnI:llynlhoid IIIiInIes ~ .... ~
~lnKInI.ll~
_""4Il_(Ilj'lllC. an:i ~ 1Ildv I1YIII

PIif'oI26 850-a61
1111 0uIi..........18Z l. lR.--HII T

FerdF ~W""'J,~L~E
.IIIlt es, RBtIekl t.I {2003}. _ _ rJ
p111t4l1 ~ ~ cr:*' 01 "1)1llCiI1IIll till~ ...... 01
011 ~ (t.1C4
"**
~b'~_ilIolIIll01'3'81
31"
H94.
~ l FtrIll F. ""
lR ~l.~tM.Kl9ntDW ~
.. JaIIESjl9llll1 ~T-1:IlI~
IiIIII\
~ 011Io of 1k:II"",
l'IQlInlgtrlill'flli!
_ _ ee-.!lin' _1Ileaion Mi J SI.rg PIifII;t Zll1-
''''
1115.
l Frankln'"
I. KIwI8cs l.!9'eih l(N ~
C. Br'IIIie K. Fla/Iei;l M.. ....., IT 11.
~
~_~lI'OIIltrJ
..... NKIi CII ~ km f'w' ~

pnwIIBrICe 01P53 ~ HIn P1IIoI
''''''55
1798. OuIrlarIiIla-Uarllnez l. ~ III

KlIer G ~ lol Gimboa-OoInngut "'" " " - A., lur>a-CcntrerllS l, CIllrw A
I1oe/Ier H, ldohIr /10 fltlld f (2001) p53
MuIIbOnS ., nI$8i natural lA!irIT-011 Iptphorna lrom MeJia) assooalIon... 1Irgtl:eI
morprdcg~ I:tId advanced distasI. /10m J
Palt1cl 159 20*-11(15,

17111. OuonIllfiIoII-Milnnez l KII/lI;I'S FltIIl
F. RlI)'eI E. T8IU)';;--fflilj$llWl J, KirqrM OW
Sf JafIe ES
110001 FUIlllrlllnl EBV(.) T~ iympIloproIIIr.
at,ve d,~r klIowl'"il llCUttlctlrortic EBV
inte<.1Icn a <:bIinct ~Ihologic s)'TlCtoole
Sorbitra L, Rattald M. Str_
Blood 96, 3-451,

17118, OUlntan.llalolartinez L, PmBl uga 5
MielNng C, Klier M. RudeiitJl M; DaI'leS-HJJ T,
An;r;lasoy N, lolartinez A. Vive) A, Duj'IW J,
Jaffe ES, Fend F, Raffeld M(1006), NPM-AlK
depIInOenl e. press>oo cf the lr1lnsaipllcn lIaor
CCMTienhiJl\Ce1' ~ prolIin beta in AlK
~lO$l1p..t anaplastic
large
C$I lymphoma
Illoocl
108: 2029-2036.
17M. Rabbani GR, PlIj'likv Rl. Talfwj "'(1999) A Ioog-Ierm stud)' of palientl .....
dIronoc NlIInl kiler eel ~ Bt J
~ 106 96lHI66
1800. RtdteIi f . Mau.BR e.rtn E, On A.
I'omBb lol. MaICIlo AT 12002)
AoJle,....,....
0XVk........".,--.~
.......... ~? ElI'JHaemttII69 1~111

lllOl. ~T,Or3gosOB.BaArP
(19ll1l
GIsIl..llMfIill1l
~ ~
oIlll1lll1oaJEllllJOIItId ~ - . . 10
m ,.....
XI ~
Gwotl_OIOIJ
102 10163$
~ M.. $hubel B. Wolrnr S
PwIp:IeIc "- ~ U. F"",,**- M Ch:II A
WI paIierS _llW. T
~ .-raIlI& IiIeIoog ~ CIiI
18111.
l200Sl High . . . . _
c.anc. Res11' ~
111I). RIaIi:Il JP, 0.. H
w.n r.t, 0elllIr v.
SchtI.- J, DrI.*a' B. ~ C. SllIII II

SbJi W ....... ct. 1'.-..:1 $, U1IIloI' PS
~'1Ip1I$SIOrI
(20061
d\aII9" ~
.... PflllIItsSIOII and NIPOI'8t on dwtIIIIt

........... P!uc ..... Ac.-I SCi U 5 ..
'"
1m""W, WrIltIl JJ, tClbll E, !II
IIt3A
~
~ 01 lI'UBl toIocl.- .,....

~ (iIomol>$WloIIId ~ ~
C10AeI
geran . . ,1!Il;21 ....... ~ . . . .

e- ReI 1987 412!lJ7-2!>0'2
11104. ~ A. ReidIafd l<k. ~
FI ~ M... Hasserjwl RP120061. '" double~ CO'+COO+ T-<:ell pcIIlUlMon II ton'Ime:Nv bJnd in ood",w ~ pr&domt'*'i HoO:l'in fymp/lornil, "'m J CIon P, thol1 211
......
1&05. Rao KR. Sawllsk ~ A Cronkit. EP,

ChfrIroB M) Le'W)' RN, PfSlfm8cIo BS11975),
ClrocaI IlIg><>g 01 dtronoe lympllOeJ1i<;
..~ BIood~ 219-2301
1 .. R.nondo SC, PIlI CH. tIfncod< I.l.,
8fMI FG Filatov L RIVlII'I GK P996)
~...,a1~ (51~nCfllltlood
IClM' ~ - . - l.flNriI lit
1107.
"'"'"
T-celI ..oIpb' ~ ~ ~
7-cel1 ~ ~ on . . . . . . drI-
ell '-*JgICIl end ~ acly

Ea:I 0ImII0I I ' 31.)ll
1111 Rnat 8, Stllll'IrI ..., IUIit JJ (HIM)
~ 1)"llIIOOIf" ~ 01 SIlIIII
......... .. Iludy 01 13 ~ .. "led J 47'
221.22ll
O::mil*ln ...
cases ftWodl SUty
G<tqt of ~ lor HIV~

TIn"Gl'I Am J an P(hI l01 n H62
111.... RaprIlIJIO!I H. Ile-wd CW &AW JJ.
Rf I.uke5 RJ. ThomA LB t1911)
ReporI01 .... ComrMIM on ~
~ 10 SIagng a/ Hodgb:l'l
o..ea. CancerReri 31 18641965,
1119 B. ~ porl Ii (1961\). TUfTlOf'l; a/ ....
H~ 5ysl!lm Washrrgtoo OC' AfIP,
1820. RaPPllpor\ rI , W"'ter W, H"ks E
(1956). FolIlWla, lymphoma. A re~yaluatlO!l of
lis IlOS' tlOll in lllfI $dl9rTIll 01 rnMgnant lym
1Ilomot, baaed en a IUI\Ie)' 01 253 CilIn,
9. 1i2-l121
1121. ~ T. Kue/II t,I. Lod~ t,I
.Iorv--. HE. Da/'Illt,l (2005) PoIsitlII roII& lor
**"*'II
RAS
JI'OJIIIIians on "" MGUS III loW
_
Illll ., l/lII inlranIIclubry II
cum...
en...
cancer
.. _
~ ~
p!IInoI eel
8lood 105 311-323

1122, RaIIer* lZ. ,..."... L Toy T1. ChInL
fW
W GrtilIn
Ra KR.
w- A.1<qIt
M)
S/IlIlh WJ IIuaon PG
! I ~) T~Ek:lII~.Am JSoJf1l
~
12 43J.. 3
1514. RandaHRE. Wibmeon
we, MulliN~
F, Tl'1Q MY, Sb!1WJ 11976) "",rlile sl/l!ions of

1~)ghI cIl>lon dIIlpo5ition, Am J I-ded 60'
",.""
1115. RarOMl , PU\llt,lC FIbnI F, Si\lMlI l .
l, GII:Un'i A (2lXlO) F-..rtIIo 01

~ on d1i1dhood' I
SWy 01 ... ~ Il< J 1'\-.01106' 86M

1"1.. RIIIdolpII GJ, ""'9fI V s-u w.
~ ~"*,"",,IO"""
IilIloql ~ . . . . NIl ~ In"vlol 5

611Q
1117. .......
Rai _ . h.~.' S. WwtlbIf 5 ....... 5.
.... R(2(lDt). Hr:xlgUI--lM lQhl",-' lytIIditoIoer II d*lrIn. dOlI dIIII frnoII P'*QrI$pIlonl HoGglun ~?
P.-. 0.. Pah111 34a-J6O
1"1. RaplIael t,I. Gen\IIlomme 0, Tl.6tl t,I
IIvron PA 000ID0lcl J (1991) Himpel!loloyic
fHlorK of Iligh--g rade non~ k",'5 Iym
oI'o<>mlI5 1'1 EteQU ~ed immunodtd'c:'lfllC)' ' yr'!.
<J'omfl The ,rencn SluO~ Group 01 Palhology
I:lr HLIIMIn Imllv lodefid .ncy \ll r~ed
T~1l'(II1 NrJo Pill td lab Ued 1t5 15-20,
1111 Raphael t,It,I AIJdot.on J 1.11""" t,I.
0IIIduNI HJ Vuollilumtl t,I, l.enoor G....
CiIIItJrtdIt C. lem.'\1< CliIrlo:*l J (l9rHf,
II"'."........
)G. NeuboJrg OS. ~

~ 'OE Grw-o-. A.
JC.
TJ t2004). lN'1O COfllPI'W3
.......
~~~
lIOI'I SlfU ~ of dis&a$e progr. .
IjICflln ctJooic Iyfrcnxy\ic leukenlla , N 1'lgI J
I.led 351:893-901
1823 ~ AC, GIeeI1 MJ. Kw:md.' ..,
Keronedy
F...,tQl1 JA. Eyoos PA, O'Coonor
SJ, RlChenls SJ . Morgan GJ. ,Jack AS, Hillmen
P {20021. r.Ionoclooal B Iym~&~ W1tn trill

d1l1fllct9fl$tiCl of .~ dlroni<; ~k:
~.milI ... p~ in 3 5%01 adults...~ 11.
mel bIOQ(\ ~ Bloo:ll00: 635-639
1&24. RallI A, 1lucN"'ICiS LU. L. Tilw S.
II I on ~
I'IlIbd~ SInwl 00'lC0l 3U59--J6ol

1m
ReoI8r A. Will C. W~ A. SchocIl
C.lllII u I. Sd1~ 8, IlergerU,TeIorII
N,Arullah S,Yin JA,V~ D. BarMf HI',
TaylorPC, 0'0ntc0II "'. IlenedIlb F. R~
C. Koib HJ, f-Iochh3lJ' "', Hv/lImllM R, Chase
Res 28 7i1-l103
~
CA, HarI5O!l CA.
~0Ih
.....um.a c.-.oern 1526-1~ .
1826. Redaelh A, Bel C, Casagrandoo J.

Stephens J, Bon.rnan M Li 5k,n B, Palho\lC
(2004). Cinlcll and epidemkJlogic bUfl1en 01
d1ronic m)'llklgenouli leuKemia. E~pert Re.
AnlicancerTr.4,85-96,
1827, R...... A, 1.II&k1tl Bl, SIep/lIrts JI,l,
ElonemarI t,lF, P~ CL(2005), A s~
iterllure _
a/the cirU and
01 IlunJIIl 01 IICIM tymprotliasloc .........
lAl.l.l fur J ear.:iEngI) 14 S3-62
1121. R. KJ Kadol LIE K."uch: t,I. Ko Yti.
Go JH. Sulunwy.t J KtfI\ OS 119981
~ ~ ,:Alt!). ~ T
011 tyn'Vo'IIIl """ ~ QIIrnWlIl tl8I'to
WI. Am J ~ PIfloI22. tw:w;5
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..a rw.,..-...,.c "*9.IOeS. hairy and
fulA pIOICIIl:lI lllood 111:332230.
1829. Rf9l'" A Slarl< P. BldsIeJl D. L8Iao
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mahgnllrOltl ar. JllfI futI'IOr1! 01 .mrnw:ylcllO
dendn\iC . . . Am J Surg Paf'oI 29. 12741283,
1831. ~ llJ( UcKennil RW I<I'Oll SH
e-",*,*
1141. FlIrllIDI Ul . Rober1s RA
u.w TP
J/Il. le8WIc
... !lrantI RW.

_1&_ "",,00 OIIflWC ""*~
lIngtf
ceee
HIt JIIII ES. ~ RD.

E FudlI
Do\. $pIIrUt, F,*" R!,o-.J. RotPMkl
.. SIIOOl LW. c;rog.. TN120011 Loll of I.lHC

.... " QIOIIIld ll"*""'~ II difIII!,e
"'9l' Ik:eIIy!1'Icl/lomIl is r1lllIIed 10 dIa8llsed
lu'not m-nu1lOSJ~ IIld poor palienl
&I,uYioai r&gIIdless01 other PfllQIlOSIic l&Clors:
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I147A. R<J!l .lA.. I.OIIll DC c...W.~H
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1135. ~M,~$PugtlG ,
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~iIClOry !el'I1il1 ..... ringed ~
'5110C",100 OIilt1 malted lhromblxytos;$
~tolog,;a9 1 71fJ.no
183ti, Remstein ED, Do9~n "', 1OOfSOO RR.
PatenloM",. SF, Fink SR. L... M, Dewald GW.
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ptoonIi
re'>Ml a 'eN'W1I IGH.ac L6

J
I.l<M ()agn 1. ~-356
1839. R_iIle A. 0uMneI II. Cllarp&nller
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..
JlII*~ ~~ .,"
.... I'Igh fQ--IwIP1 (VII e ~ L.U
e-
- ..,
~
WIllI - - - . .....
(3liQ21q2!il Of Iul'I*IgcM hIlIlocallct> . 3:3J
11l21 ll261 Am ~ 79 374377
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1834, Ret1IrE ,Gteini.ti Rabo1schW,KeilF.
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choomolll4".posnM aeul!I tym-
~ ~
..... !.,..........
~
~
1832A RetIlr JT (200S) Cy1ogenet>c IIlCl

IfCIIllI:Uir genMic .... 0"
MS,
'IlIIOolIIo
1&25.
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~ K. Gei&lfrC. ~ GL(l992j
.....
~Illll~~a/
acquncl --..lOliIJfIaelq ~
PahII
,...lapOsIlion
JAK2 V617 rnulabon", rt'frlClOry l\IlIIIl1iiIlIfith

~
$idefDbi8Sl$ AIOOIIId lItiIIl mar'otld
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~ E....J Carar 21' 1.cQl1405
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t.Io.J.ory R l:llIIIc.:' G ElnluMIt P (2006) "WI
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~. J (:In PIIfIoI!Ill. ~
1843. ~ SA. .k:W!:\InlMI ES ScIq:l
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L~
LH.
E,
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rJ thtJ HL.-'o ragoo, indudi""il homoZ)'gou$ <Jekl.
l~rrVooma
lAoIecular Prolllrrg Projed Biood
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GMIa-Io G, Bonn f (2llO5).
eorr..-
P"*9 (;j
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doiDfden II'ld _ _ Ita'9I 8-
OII ~, Bt J ~I 34
~ cinQtI ~ n "",,1I
~ l ~ 43.
- . . , , 45 1**8
151).1580
1148, R>!l O. le.~' F. .... C

~ 5, Us/moroIr A. ".... P Wt1l T
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n '*Y
llII
W - - - . CarIcer T_ Reo 32" 36S-
'"
1151. ~LE ,~JFl &..-JJ

o.bomI Ilt.l. VeIllsquaz WS Iti.aqoifl P
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LJ,l (1991)
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"*Y
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Neonlan
RS
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~ lie Ic:AcuIar and II'Of"OClCYD:l Ek:lII
lXWl"()OI'lfI'l. lIb k'rYesl 8(t 1593- 159!l
IIS4 Robyn J L.-y 5 IkCo't JP

~
J. K-.. YJ, PId< S ~ Tll
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AI)
(20061 ..........
~ollllllllllon9fIlI
..e
on
flPl lI!POGFRA~ ",. . _ IOPI*

~ Sf J ~ 132 286-192
liS!. RoctQd '< .
1olJ. ~
~ (<005) ~ 1lo.AaIr"' ~ .
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","'On
1844. Rles LA 81 1/ (ells) (20041 SEER
~RO,II.ulOIIJl(2lXln
E~oI
Ita'9I r.elI W--
rn:.n
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lypft 1:1 dIboI lItge 8-a11lymplloma . ...", J
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-.cl~~I'1'~~.lid!
~
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~
Ucl.IugIIIIn
~ F8F~l~Mol
sn-go lll . . . M
c........
~J
F (199ll11 F~ IIrVI c.lI ~ ..

. . . . . . ~""oIlIn~...,
llP.orZIt ~ ...... Blood t3 2202
2'"
193 71~7 .
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--~
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Crtn.s . . . . . ~ !<lie? In/IAronI

80MI Dis 13- 1()2~1(J:Jj
1 172A. ~ RN Kall3lMnnl S. RoserbtA;I
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we. c-... F
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1862, ~J ~",I<.IIlRl
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l_l~.1
....
_
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11165. ROItIMg K3, Morga/! MIl (2001)

CtAIneous ordNfmflllle 011 ~
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RfIlatlOO of lj&1lf! np'" J,!OO p-henolyp4 10
~
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1~g.1M7,
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~ T, l<ltlIJ,KaIIIJ 011"""
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atlI~ Bloocl9ol Jll:i!.3&f
1869. ~ A. WnghI G
Cormrs,ll.l, Campo E FW. RI. ~
RO I.Wer.HermIlinl< If!( SmelIncl E8
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l, WiIIoorl 'Mi .WI8 E5 $HncI'I II. ~
RO POMIII J. DA,o Pl lllO9l 01. G<.....TC ~ 00 SIrp WG
8J
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wv-
cr.n we.
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T
N E"IJI .I Med3012 87s-aJ
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RooAet UR.~OO(2006J
.... c.lI lyn\:JIloma
lge
lroo1
lin
IIdoIInl nRQI .... l:8I large gnnoI.- no

~ ~ ,."" PaIhollab Med 131)
Cf.idllIl..". tor dolluM ~ ~
MIT lymp/lomI syndromes lflduced by

ZNFl96--FGFRI "
BCIl..fGfRl lu$ion
Grogan nt ..... TP
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CealIIn jGFHC) IrlCl. . Groope F..-.ca de
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VCAM-l lind ELNoI- l 1'1 engooIoIcJler ~
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-l-WrIlIfnIl HI< ll998
re-llileasel
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~ Nfl
Meo:l 139" 41O-f ~
IIge . RW: A RMdII U. SwenlIow SH
~ M. S1reIbel 8 Proc:clp G TuID RIl.
Cook JR (2007J E>hro?dal ~ zone 8cellymphornlls oIl1lll ot:JJIar
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JaHa ES, Soilocinsk. KA, Iion:AI<tl MM(11m)
Inc<tased ineidence 01 Hodg 'in's drMaM Iller
alloge Mi<: t>one marrow transplantation . J C'in
1899. Ruro:l O. K~ y S Bw--oCol'1lIfl S

~ fl, Kedmi U IoI<JW< E, Gural "SMfran.TikVllS, Ben Neriah S Ben Yi!hOOa O
(2005) ~-rnIaled leuk&ml9: dI1itaI~.
aclnties and analysis of i'I6W moIeo.ilaI risl
Iactors fn 96 adlJ ~ patie!11s LllIJ.e<ria 191 91 9-
ow
Onrol17: 31223127
188l1, Rozm!n C,
Mo-nt~rr't
E (1995).
Chrl>nic; Iymphocyti(: iflI<kernl! N Eng! J MflCl
333. 105.21057
1169, RubensWn )l, Fridlyarod J, snen A
AIo<1pe I( Giru.ingM 0 , !l8tCflelor T,Tf-'!f P
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. . . J EIll Meo:l203 2.f2S-2431
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LaYefllnll ,,", MoItna T, Broosse N "'udouIn d.

Rambaud JC (1991). Multiple lym ~'
polyposis of tile gaslrointeslinallract. PfOSllllO"
1M! d1nio:Jl>8t1lo1ogic study of 31 QlSl}S, ~
O'etude de!
l vmphomll!
D;g.,.tik
GaSlJ'Oe<1tellllogy 112 716
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Aggfessil'll Na\1Jf3i KIII6r.ee.llookema I.,-t
<i ~ve eases aod Wl IeW 01 tile 1iweIure. Lu.
l)'fflllhomil.(5: 2.1272.Jl!,
191)2, RydII' J. WIfI9 X. Sao l Gro8s SA.
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(2006~ ~~
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~~&t:8 E. Pe<a J,
Omenl J, Gf51ena A (1996). Oillu:lE! large 8<*I~: is morpl'loIo:1gic subdivlsoon use... in ~~? Ell J HaertwIc" 50.
sa.-~,
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.. ,......
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O. '-"1lO E 12006~ loIrie cell 1ymptunI.
..... ~ aro rrdiIaAar pIlrICq8l_ e

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Schhn HJ. 8Ium f. GolM. MM, Sd>uIze f,
G!allt.- E. ~ R fuzw; L (2001)
fOlilW! denclIik c..I ...a:wnI of IIlll tpIIen.
~k!lJ&.gPltlol16 ~
c.a.. MIdeJ'oI U
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CXlI't'tflCII'l 'IIIiIblt -"'''''''''lCJ ~
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_ nllWiapM Br J ItIeal*lIllll 35
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...." Blood 88 iJ8.4645
It. SIIllJca t.I. ~ Po NgtIIlinI l
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J, T.... G CItI\Id'I J. &:to.ollz M. t.Ulen J
(1996). ~ regessoon of~ ...
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~ Caro:er 67: 23112326
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~. KopmI S.
Hayalhi Y, lkUC.I K ~ I,
T (2001) M)'eb:IpplNIic syndro're

in d'okIlood .I ~ Skldy Ii 189
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lUI. Sashodl G, T....... u 11 ShOjI r.
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S, SaIe5 G. Berger F. Jing W, Ptlk.. GS
I1at>emIarm T QW.fiMfa R, rtamli NL, ~
JC, Goktl TR.ShippJ.lA (2003) The molIclIIar
!I\lflBlUl'll of mediaslJrlll Oi!ge lH:elIlyr\'>pIIoIlW
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lymphcJmils IOd $hares rl'iltlJl'e$ ",'Ih ct3uicaI
Iiodgl"n lymphoma, 6I0o:I102' :l671:l679.
l j4 5. $3vllo E. Gan'lp(l E, MoIit1i<l M, F'inyol
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cydin 0 1 plOIeon e. pre5SlOn ill ~ marQlrI'" zor.e lymphoma I.\Qd Pathol 11:601-606.
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S, FOl\lOId MJ, BI\lnnef MK, R~ CM,
HeIlop HE (2lXl6). T~ of solid 0f9II1
I t H , SiOt;:tlel~ M.
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Head 0, Moniconaa;1 MJ. ~~!et C,

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:lllO2. sr... L.l.iIn\I 1oC. LuL A.J W'( K-.ong
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rIilInI UI8IfT -<;'181 ~ Am J PIltd
161 2123-2131
2IlllJ.
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~,
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myeloid W enia .-itt> ~a;21). a sWdy of 1M
..Iapat.- Chi:Ihood IW( ~ Siudy
GnJuo Ilb>d 107 1806-1809,
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~10 ,
~M(19911.Oiagno&lr:;t:!IIe
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2tl3. SIIlM M. ~ S, ~
II, Abe .... ......, T. Taoeshl& .... ~ hi
FujiIl'lot:) J, ""lIUCh J WiQIa A 119951,
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201,. ~ B. 8ani9a I' ~ J.

JIln A.. ClIIa.F.-a It N!Jq "- GlAlere.t 1,1
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~ $JIldrOme MIC! at>*l 0'I''b<I
Wen-. ".,."
dI'IJmo5ome
5 abllQl'II aliM&
~_Lymptwlma48
2101121 ....
2016. Shiv.Il<IJ'IIII L A/I'rwiltgIt JO l2OO5"l

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2017. SInJ Y, MarMll hl.. Gabre'erJe la'y01ypie abnormaIlOO5 of lI'ie c-myc iocll& associaled wrIh c--mye !t)'steguialioo IIIld .... rno< pt(>llftlU'O" .. multiple myeIom;J Proc Na~ AclId
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2011. SibJud V, Bey4oI.flarry M, Tnleb;M Fl
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alec! Hadgl<.if'f$ diseasIl ear>tains Iate<1t not
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1517.1536
2023. Shefn\"" LB. saa.n SE(2003). NeMv
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upc\Ile (Jl prognaAC Ian and
lMoIIlme"t Cur CfJIlll Htmelol 10:290-29l!.
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20.25. ~ C. SPINI lol, Cltlf!lll R
T...... R TIdMdloR.lJlottwiA.~
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and 00Ae0me 0I1lf11'*Y ...... ~ In
""'emiI
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J Or! 0nl;:aI21: 3:94-3&64

2026. Sn1' IN, HuO 0
SW. KMIiKIn T. Lt
e.. ......
vam,......
.N;
(2001)
~
.,."..,.,
'*" t
J SniIl
L.nlI'I AA
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!1Ib-
mlI'/ lilt bt dnc:IIIJ ....... Am

Jan".... \21 197205
2e21. Slu 11 ChwlJK. Wong l(f. K-...;I YL
(2002) S!**~dgllllt ~ II
,..... ... e.I~ 1113.~
.... ......, Mo J PIhJI fflO S9-tI&
2021. wu. CllF V 0.. .,IIl;, 'o'Ion\J I(f
'--"iI R. KIlIOIllI YLl2000t ~~
0I.-..e IC* II""" dlrOll ~ Mo
J~
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1803-1~
2021 Sill U. Wang Kf Owl.,lll; KtIOII; n
l~.
1419-1425
2030. SIurndIf IIF. CcIlncn ..... SI.dIIt

SB ~ RO(1999) ~ Ilrv- e.I
IympFloma a ~IC WlII/ysIJ
I-lerMloI Clno:II17 137-10&8
2OlllA.$kmdBr 8F, e./U. ~ flO.
PaIlanall B. f n.nw L K'llP U """ 1W
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mylllod)'Slllesbc S'f'ldrome. Blood lOll' 1!.41.
Wrlg$ II
~.
GtClCl
n-e Koellymo/"(ma
OncoIS, 65S-664
SlI1y
P HtiI G, Eidl HT. StloIl H 0iIN V .IO*lIl A

(2OOSJ L~ ~ H(l(IgIun'.
flT. Woof $H, ~ R.

I\r><lInan J 8e<wlelI C.
Gc*lmarl ...., Guhl F. Knll!jiarI HM. LmIII
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, .........., i'I "'*'ll fie dYanoc~ 01
dWoric "'l"bd
~ to- . .
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~ . SlICt' ~ ..... J l> Orc:d 23
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2041.
~. Lnall AA l2OO3l- CIIIal~~il306~"
.IN Ro-Iey
~~ar.d""""
W ~LA.(;/'I(IY.~TA.lJmMS.
sr- Sf.
(lWi'}. an:.l.IIW'II.JI'Ctlgc. and ~,..

Ull$ rJ 11\ ~ 1JrrlIlMpl...... _
.~ ~".,." abromII ~
MltIOOl*Joll$. 8loacI89 1141-l~
2013. SalIn SK Ju1g rr. KWn OIl. Kill .Ill
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N
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E.-01~~l
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."
11995),~~
MLL
2037. StNlh 08, HllmsM.Gowlallcl E.ChIng

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~
..., FonaIxhe.~1
KIh P V-. P 12(05) h I ~

- . . . - ewIar'Ioe lor Ille 0IlQi'I of .......
__
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gtII8C . , .
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e-.
6787~
lON. Sperr WR W~ S, Iiomy tiP,

~ hi SnorobdII, F ~ R,
$cllwM"llf'lI"" I T~ E SoIabar e,
Ha9II1 'II GeiI8Ir I( 0'10I A. l.ecInlr K.
V'-'Pl19Elll) Srsseme~_ _
- . . . . iIClM ~ leY~' feport of
. , e - n dIItIidio-I fJ .... e .../osD.I!161O VlIl& J ~ 103:7"1).1.9
2017. SpiIn AS Ball BJ T_. fl!l17)
T1lB ~ bbld .. tIvurit ~
""*-- sw,. of50. - - , ~
~ Cll'SlS $o2llI J HM1IalDI18 ?>-38
20M. SpwIaM V~E NaAG. TnlIU
l2lXXll. t1.mlln ~W\.IH54OC>
alad 1blgUI', lMMIe Samin cn:oI21 ~
'"
206S. Spiro U. Yandel OW li C SainI S.

Ferry J. PooNlson J. Kan."" 'M'l eas.m. AS
(1993). llnef ftIP(lIt Iyn\pr'IomlI of doru IlrigIn
lIl:l;I.mIll'nlhe por18llep9\1$ 01 1 ~~nted
..... NErqJMed329. 27-i:'J
2070. SI*i H. Lanoer U PhiI>ps.lf (1~).
~ of human T and OllhKal klIlIf
ellu Blood 85: 265421)70
207l1A. Sp\$ H, 6lom 6 .JaIeto N.'., Wei,.er K
Versd'll r8f\ Me, van Ooogen JJ Heemskerl:
MH. Res PC(199111 arty stagas In !tie deveIC(lfTIIlf1t gl human T, natural XlI... <iIld t!lyrroc
dandnIit Cllk. lmmI.I1oI R8'I 165' 75-86
2011. Sprval'. JL 120(2), f'oIy<;ythemia l'9t"a
myth" meehilf1lsm5, Ifl(! rrooagerr\llf11 BIo<xl
100 . 272-4290,
2072 Spry CJ, Davies J. Tili PC. Olsen lOG,
Oakley eM, GoOOroIn JF 11 983). Ci nical fea
turn ot fiftllll n pa',ents with the hypers
OII1lOP'lilil; syndr~, 0 J MOO 52' 122
2013. Sr1nl~a~ SI< , SarrpIe JT, S,xbey IN
(1996) Spontareous IosI 01 i/iIai ~
~J'Iflll
Epstein-Barr
"f1J5
reao:;tivallOl'1
" BUf1<itl'l l)mpt\OrTIf cellllnol. J Infect 0ilI

In 1705-1709,
201.. StaaIV,tiaf1l A. LaTIIe'-CaMa,d V.

RIIAl JP, DOon J, G~ MJ, ~ S,
Witz B. .lon-ieaYx P, l.erornpte T. RIoV(2006)
IAe- fJ de I1'.MllltlJlll basllptMk leukaemll
~ (tileria and 1l'!'Iiew of!lle ~J
(199J i CloMltty 01 d1lO11it neutroph,lIc

lau'-"'ill aSSOCliled \11m
..ng ,..
~.
8l'IB/y1IS
X-lrol<ed probe 1.127 !leta. J CIIfl
P!IIIU 46 297M
2011. $WIley ". tdcKema RW , E...... G.
Bn.ming RO (19651 CIauilaboo 01 3!>8
,*"of AQ.llt Ml"bd l u - by FA8O*-
na
~ofdnl;alllfl(l~.,
.... In: Chrtnt llfl(l """lIuMmilII "DJItI.
BIOOII'IhIlcl CD
Pubnhars 9oIb:l,
(td.)
"'lIrtlnus
Nifhof'
1.1.11.
201IA. SansfIkl AG 0Iab0Id J Noel H eI
~ K* C*1':aIior, lor ~
tAnc:aI 1 292-293
2071. SUrt B.~J P ~ hi lJ.Illl O.
0..... S ShIlO.l(odlIwI y ~
R. NIl S (1995~ " ~ ~ of Uol-U5
a<x.- If~ . . . . . .
aaem.d
_t816)ipl1.p13) 11 . . . " . _ , . .....
~ 19)(plll113~~an:l_of,.
_ _ I.U All 19 367-379
201V.. SlrfJ, Ba-.l o...cz;g U "'MIoI
J, IoId\liIoA K ~ C ~ Gl*'ll"
~ Ih9tfl ~ l.IOS ~
of S<titypM. . . t , , * - , fll3CWl ~
"-* 8Iood e-:.r 50 0&$436
20M. SWll Tf; ........ WA FVw tV., Ho
w.-.l
hI ........ S ~BP,RowftlJT .....

TR, 51-. BW, /II HarlIasly Rl (19&41
~of~and lyi,ijIqii....
- . ........ ~InlllI~
Mod t>npy l.nlIl: 1 583-587
2081.
OP.CadI JS. PwdIrwlI A
Mr:Qn RF Ut!ltW)
1..... A (2006) r.FI.
s-.r.
n.
W51S.-.:I JAIQ '1617 ....- ....,. "

.....
....." ....-.:uv
-. mgad
.., ... ....-.:I

Haer''"**9W 91 EC~1
~
tQIrt
2012. s.-OP.o..:IGW ~Tl

Po.eI ..... lAl;:Q.Ife RF. l . - RL ~
00, TtIIeri A (2005) Tilt JAK2 Wl1F llCIJdI.
'"II t*lf knelt mulItIiOn ~ '""~
hetlI'nbolh .aIypot::l(~.......
den iIIld ~bc syndftIrrla Blood
lOll t207.1209
2GI3. S18eflSmII OF', Hanlon CA. l.-.c!I1I L,
TtlWi A (2001) I.IyelodyspItai Mlto Itlrcu B
(lislirltl tntlty? Lu "" 25 e29083a
2084. SIHo9me Of', HKkM14 IV\. Porchaf

JC, l .she Tl (2007) c..do:1ate ~ ""talIon
ilMIj'Iis fn ~ lCQuored ~
anemia (rafraclory IIlfmi9 \11th ringed!lderOO-
2(116. SInlen GR. JitwrI B, W ' " M,

W~ CA {19!lO) Chronic r>eulroP'*;
lOn. SlIro:Ian GR SIW'5 FJ .
Jones l
. . darI'Md
&om ~ ~ ails 8IoolI 66 """
ee
2OIll.
sa.. M, l.Il:t>iinIb-ZIaglar B,GtoliIIJ
l"lll* A. W-..el
MOOglI'l and
P (1962)
~ OIIa~~SOfClIIt
101M c*a ~ Inl J
e.-- 2t
",.'"
20tl
s.n.z FIG
Ga)ron PS. . . . . .
.JC et.rtooo M. ~ "'l, ~ ,,$;,

.kmIt;Irlt HS. SiiIIllf'" Trigg WE ~
R ~ O. Bley.- WA (H1fI61
C~.-.:I~ ...... ."..
~"""""~of...,.
,..-row fWItllOMll tep;lfI kft . .
ca-.:.- Grolcl. J On ()UJI 1.

211M.
s---
38S-l9ll
RIol. ~..... H 12006
Oandnllt '*- ranaiI*lg ~ m....

iMvoq. Cu'r Top t.IoIUoI~ 311 11
se
~ F, Solar K. BaIaMn L
ViIllInI P Ho:tny HP (2lI(Wj 1lcnI_ ....
lOCyIOM lltSIOC:iIled
IgM ...,.. pi-.
2Ot5.
.nen
eel rnyeIorna L.U;

209f,. ~
L~ ~
K.
w.-
601-<<l5
hi ~ KA.
Maruy_ K. E__ PO It
a-.
ShImon KM (2006). lnIarsIUI
IMII
~ at <':lI*Irtll tnakpt)il'll .........

fraquenI mectwiIrn rJ NF 1 i\adJvBtioII "
III'1'lbd~ Blood 108. 16801-1689
2091. Slam I.IH. SouIitr J, ~ M
No<aIlIra K. CankH\larl N AurliIs A.. . . F,
KodlIR P993), MTcp1 a ncwtllll"'OII1l1
~ma<l d'Iron'ooJome Xq2e bllll*:alo:id t>1Plt T

'*l ~ ~delta ilx:us "' IIlIlIn T cal
~ 0I'It;0ger;e 62475-20461
2098. Slefry W, SlIlIlel A. MoelI.II V (1992)
HTlV '~w pIeomorpho: T-all ~
gllhe $Iun.lhe ~ ~
aro:lMTlnI h1slory el1 5 pabefllS, Bf J l:IerrYIm
121).56-46:1,
107 113\22,
206\1, Sttin H, 0i!l!lI V, MaraftOti l Jo. A
W~f J. Hummel Mll 9991 Tha lIah.o'e of R89dStfl<nbet"g celli, Lyrnp/IocyIic and HlsllOC)'bc
CIIh and '""" l1'IOitO.IW biology '" HodgkI'''S
Kyle RA, Ra] 'Umaf SV. Fonseca R (20011 A

pract>:al guodol to OOf,ning higl-fllk fTl)IIIoma
k>r <;krx(;!II h1aIs, paIiItnt ~ and ~
Haem~ tol
disease, In HodgkiO"
Arm<fageJO, 0Ithl V,
Oi:Maw Mauch P
edt..l~ 'M~
&W~ ~. ppI 21
"'.",
'"
c* ..., lIIItIOq'ft
209t. Stewa~ AK, Be<tlSa\leI Pl, Gretpll PR,

O,spenzieri A, Gertz MA, Ha)'lTllln SR, Kumar
S, la<;y MO, Lust JA. Ru&5(ll( SJ, WitzIQ TE ,
EJ,
182-1.
d ........' q222. Ht.m PalhoI 38 940-
Blood 91'.96-501,
Cross NC It oo:l),
Myaloproliferat'.... diliOl'Olln wdh lfanslocali:onl
of chromosome 5q3135 roitI 0Ilt>e p1aT9M.
oo,ivlld growth (actor rltC8Plo, 6ll1~ Acta
2085, Steer
1Io.-na_ ......... ~ An--.on

... ~ Ii1t d1arI Ull'\'IIIOI Cane.- 66'
(2007) AnaplaW:; ~ ~
<M...e IlIr\Je 8-<eII ~ ..... B compiex
~ and aypIi:; 3' AU< 9'JfIlI rnr.et'OfI 8)
~~
lOt1. StNI H, Mn on OV. Gerl!taI J,

O'Connor N, Wanteoal J. Palasen G. G.K. Fiillni B Oaisol G. lernU> H (1985) 1'hI
.ltP"II'OIl rJ!he 1bIgbn', lBeaIt--.:t
........ l<i-l " i1lolidiB "., ~ "'pI'Cid - - . e...:lanoe !hat Rtad~
kl6l!i), Ltc ' ROl't 31' 23-626.
20117. S1aon H, Foss 110, D.lo1<op H. UnflolI

T,0eiI0l G, Pu/lord K. P\8'1 S. Fakni B(20001
Ct>3O(.) ~ ~ (;IJI ~. t
........ rJa~ ~nlcifl.
caI!alIlInI ElIoOO 96 3681-Jllll5,
lOla , S1ltin H. ~J. 1(rdV1tfH. Sc1I;IIdI
III l'/IeIlI V (1981~ I-t;IdQUI n ~
ReId eel anIogItI(s) '*'ttfd by ~ .-..n.on
III iI (;IJIhlL.28)......., lrllIII HodgUI's ...
_
lnI J c...c. 28 .~29
lOIt. S1aon H,
M. LerwWI I(
~ P
KC
DY (1.).
~.-.:I+blgl.aI_ III ~
evltiJIadoI' ~ s cIiaMM 01 ~
~ lDllain J ~ AlII J (.:III Paf'I(lI 86
""' 50 ~ (Pans) 64 361365,

2015. ~ o. ~ PM. Al Hor'nII S.
HI*:hr6on l lee HN. WIlda B. Wang SA
H. Hoovnel M. ~ r. W..... T.
Demel G, F"1Ii B (2001). ~T1on or
908 IIOBF.l a->d 0ct2 1Il d'** Hadg!<"
dIMasa but not in lympllocyle pradonlfln
H(xlglun d~ eateIallIs ..... ~
aa.
2090
s.ton M...... T Fa. HI) laImtn
leId8oru~t
SR. (MgJi D, Roode<
ca, Roy V
01 tt-.rapy l aul;erri09 21 529-5304.

20991..Stewart BW, l<!eihl>e1 P (20031 Wtri:l
Ca'lCIIf Re9M IAAC PIll$S.
2100. Stilgerobauef S SdIal!Il&f e, lJIIaAt A.
L.itOotd'l P, GiIad S. 8<r.$IlQ A. ..... IolR.
Ud'tler P. 00hfIIIf H (19971 BiaI9lic!Tt<llaliotw

in lila An .. gantllllT~ laukemiI.
NlIl t.Ied 3. 1155-1159.

2 101.
(19904)
s.... CA.
0!eas0lItf, .J,I, F1Id'IIIll Id
NeutofilIrorniI10S1s and crildhood
1eu~i1~
e--
Br J
70 969-9n
21ll2. Sbroolo NA. "loIona,- we, ~
OS. e.;,.
BennetI JhI (1990) C/lrQno:
m,elon'o:lllCiCyK *"'- L . . - . 1660UKCCSG!UIy
c.
no
a. J, lae
BIt. COOII J
Ci*nD.CoIu!I
A. Moore SA. O<itbt R.FiItOo 0 "...,. PVi
GrAl.(). ~ OG (2005) The
....
lUll ~ _ _ inI'Ibb ~101 . . . .
2103. SB>wr 91,
~E,~J
TEl.f'OGF~ inl F!Pll1.p()Gf~
i'lII'O It'IOi in OM,I. 8lood 106' 3206-5213

2104 StnllIm 6, loeallllW F, BadIf P. EI1lBfT
K, Kfe<"ltn e, llI'AI F, F\lIAr M. Slaot>'leI 0,
s~ t(W StcIIcek P, 8at.mannl. '""""'"
eM (2001) RnacI II'lIlInMV ~ to

~ ClOn:lf ~ 0 ~
cylopIflilI In ~lIclhood Bone Marmor
1~~3n.J33.
SV-WelclfJI It StiIvw t.l. K_
211)5,
~ F. TanlIow ~
00rm0W 5
t.l.
F~ M
Snlonbch-Klupp 1 Z . N. GouIongef H
l.IoMg H (2006/, . . &'ld ~ lIMIl
~ ...... ~ dral progrlOSit
pnInIItnlll~"'~
'*ocIuclIon fA i
ll'l'9'O*
1O';ln,
I.aokL~41
""1-450
21116. ShucMIl JA (2001) IndcIeo'Il T-npIlt.OIIIIc~ ..,011 ~
11.,..- '-kIIy A'ld ~ .... ~
.. _
Am J SuIll PIfloI1!l 411"'15
tl07. 5__ SE
098ll) Tht o:fInnc

_ _ _ _ . . . - J InIIIa 0. 1ST
...."
tlOl. sa..se J*es """,*M 0..,1(

ElriOn KiI ~l'IIt A ~ MI. ~
we ~ CW, Wa'lll J FiIdw M.
....... CM Lil"'V a.".. C SiIv-1 E.
IWl ~ V_ _ AA Grolmcty T ~
To\ l..--lD lIlJ (20011 The dr._i al
~III"""'''''---'''""
P..............
lII"'*'e F.
~ &'ld liII1It*we ~
'JIOl*-
BtxxI 98 19'200
tlO9.
RR
sw..w
~ CA. R..-l/wd E
917} l'rt9lOIllc~oI"UriItloc,.,.
. . . odopIIflI; ~ - " .
Blood 50
.,,.~
2109A. S~ 8, Hober 0, WoI'W.- S. 010I

A.~ M(2004J F~oI~
... aIlerI'aIior-. inwtmg MALTl on
auoc:iItad IyfnphoId _ _
IIIUlXU-
if!
.... ...... s;:.;,..', sJ'I'i't>M
Clrl tAnoIr
Re!lO 4~
2110, Slreulle1 8 Su'llOlli1ld\ol{t..w I,
~ l ~ A. fMw' D. Sl8bflI1 ~,
S)Jlle t.l. TI'9Uli1gW F LuI:as J, PI.-pok ...,
FllIIIWlel< t.l. "'*'-- T, ...... -HtfmIW;
ttK Cem:ini l Rar.llIrer t.l, Ct10lI ... (2Ol.\oI/.
Vil/IIltlle fr8Quenciefi of IMl T 11~!IC'o
CMftj
genetic lIbemIlkq in MAL T ~
~dll'Jnrl! silll$
2111,
Str~
LI\Jkemi8 18. 11221126

B, VlnllU tr U, lllfT'4)f'9Cht A
~III'
1.4, O>oll A (2005) T(3 ,14)(p14.1:q32)

involwlg IGIt ano FOXP1 II ~ rICMll r9O.IfI'8I1t
cMl<no5omaI ~beml hon in M"'LT ~mphoma
LeuI<emIa 19 652-658
2112 , Stl'e\JbtI B Vinatzer U, W,lIheim M,
R~~",
M,
~5:9HQ3J,qZ2)
~
".
ChoU
120061
Novel
fu5es ITK to 5YKIII IIIspee;118d

T-eelilymphomi l.&uO;emlll?O 31l-
2m.... St1rWWI BW, KlIOIIueI P (2003). WOl1ll
Cane Rl!(lOlt IARC PI. .

2113. Strom 55. Gu Y, Gn.N<....5K, PIeroI
SA "-",,,,81(20051 RitklKlcnolmytlod~
pINk l\'fIdromM
1 e:ate-<:or\trol study
t.e....... 19. 19121918

2113A. ~ 58, VeIez&l'olo v EIIty EH
(20081 Epidemialo<,ry fA ~ tyn~ s.rw. .........45 SoIl
2114, SWwp C. ~ N ~
,. AU C HiIdlItJI3ldl B
R Gefmrlg U
120031 Rt!lrIttcry - . .
fAbII8II
.......... ,. . . .11: .....,.. 01
':.'
iCl:OIlIIIg ~ lie WHO ~ I.euk Res 7T
"'''''
2115. Su U Cte'l RL lIII OT, lfl KS 0.....

0:; !l99'l ~ Wus (ElM inI8aI T
~, III d'oldhood EBV~
~~IIIT_""'J
.....,. ' '''' 1219-1225

1111 Su lIN . ee.oor.z I, ~ WH. IiO
1/ 1I G. Voss ,", Gasooyne R. Zhou v (20031,

Aberrlllll .~ ot T-plastWl in Senty
CfIIs.
Rts 63: 11227127
c.......
2117.
Suat6z F ,WkxlonI<lI,~U9JeIF
~ t.l,
Ua1ln-Ga'tia N. F:net .lf' Do*ll

GNtrd p (200)1 H~ ~l<I
T-<:eI ~ ilI'l \II1UStI!Il case with donicaI.
1iIt:llogic, .-.d ~ ~ or 9t"'PIWlIlIa ~ T-<::eI1yn'{lIonII. Am J
Swg Pa8lol24 1021.1002
G
111& 8uIJn'o'o K. Hnno N. T(IyO$IImI Ii,

CtDS. M.-.oH Tai<awF.VazalJY.Iir'lII H
(1993) UulllIions oIlIwl p53 ~ III ~
~ syndrome jt.lOSJ A'ld t.I05--<ltrMJd
" " " - Blood 81. m2-3J26
211'. ScABo LE. CIerI CN Morill 8A
..... KL UcdII t.lM 11990l ~
laM
.. lIduIs "'" J 0In ~ 901
Uol1 H, Sugmon H. l{iIWII K, Qs/I;mi K(10041

~ nalInl kiler<*llaoJ~emia fll't'ilhd
~ gr.u.lym~...._
01 c,fC*llI.
Ie HI( call ~ 18. 163-nO
2U' , SlJZ\jki R. VII1'\alIIOlo K, SeIo M.
~ YOgln lll '!'$be Y SudoT,KIXIIrI
Y, t.b:ishma Y. T~ T, SMJ Ii, I.led3 R.
Nal<8mu!11 S (1991) COT' and COS6'
mytloldlllMllnll killt. eel ptVl' ecule
""*-
a dlIIinct
__
entlIy 8Iood llO-l'17.2>42t1

1130. ~ J, 0IWirIlII K. T....... M
~IIl,~C~ N.T-.raK
K*\ldIIldI1991l) ,....~ ......:a

nigh ~ aI ~ Wl,II I)'Pt A
A'ld0lllCi0n ...... N .... .....a98'11 Leuk l~ 36.567-578
2131. s..t 01., Golortt> HM ~..o.
'"*'"
""
V~ Jill (1~1i) AaM ~

...... &'ldtwOllDx,..... . - - . . , ....
IIlIlltlon!llllly d d.""....... Ill) 3
.. 1 IlIPM d lJ9lI CiIIK Br J ~ ''1

11\6
112OA.
K s:...sJ ~l. ~
I,l SIIlIIl u. ~ F. ~ J
80rnll 0 V~ BO.lalel' TA.. ~ J
Mnos'......
__
GerllIl ~ 1 33--JT
2132. ~SHOOl)4l
2f29. SoIIIrI C . . . F. Imtel lol ,...,. F

If1l81).~~'/lIIIl~
s..rm..
l200n
"*"
.... Fl.T)-fTO &'ld

01 slindIflI
~ <N
.", in paliet'Its .... 1'lOI'TIli
~
leI.*Iwi.1 21 S5G-!l51
2f11, ~ ICE Cd' l K. 'MSOfl AG.
Go4*' Ill( lI5tiIr TA.. F~ J (20011
FfeQUII'lC'f d .... BQ.2:1gH 1YT8'9!!"'l!'~ II
I'IlImlIl ~ f\'ClkaIIon$ b lI'lIlIlOI'IW.
IllIl 01. - - ;, IJ;llllonl!, wit! klkl.IiIr ryrr..
or- J Oil ()'a(nI 19 '2!J-I24
1121. Sun ~ Charlg KC, Abruao lV. t..i R
Y(lIl'el .... .IonIs 0 (2003) EpocilImllII ~
'-clDrJICIl*lt e.Pf8$5iOtl fl /oIcI..IIa" der'dr*:
CIllt a &hind iIsan oIlo11cUa'd ermbc cell
-a:wnaa'ld Ca5lleman's dlsease HII'rl f>aIIlOI
,. .,...,
2123. SutiIlI M.J snusw JJ Sollhllr ....

c.ntlll BM, PuIenJ ScWlz KR , l3clrooIiIz t.lJ
"'ema ,. ."
Ga\'OOft PS Carroll AJ
(2005)
ItgtI ronconJente from I/IIieperIder'lllllJdles b)'
ll\e CNldre~'. C3nee< Gtoop ICCG) 8tlCl
Ptd<atro:; Onc:oIogy ~ WOOl ~1Ing

la_llbla progr>osis With romtooed trisomIeS 4
10, and 17 lI'I tfIi!dren ""ith NCI Standafli-R.",k

B-prllClnOl I\cule l Y"'lf'hol.'l3-'t>c Leu ke'l'lla ,
~s 0n00I0gy Group (COGI inrtiati've
l ......erro.a 19. 734-740

2124. SUVllfdllC N. MatlSllv1jlivic 0 Krag uljac
N PanllC M, Dj<>rdjevic 1/, Ja~~ovic G.
CarTlllrik,c-ManillOvlC 1/. CoIO'I'ic M (2004)
Acute penmyelosis WlIh myelo!i)rQ,;i!;: dtnical,
~typIC IIfld cytogenetIC study rJ
~C3S8S levk Lymnhom;l 45: 1873-1879
2'2 5, Suzuk.awa K, P~as E, Gajjar A,
Abe T, T~S, TallIK. Asano5 Asoo It,
KIITIada N. VO~(l/3 J, 1/ !I ,Yl94j
1denIilicabon of ~ bfeaIo+Klonl dIMer '''9(\11 3'of
!he rtlopIlom I gene at ~1 a<,soda!ed With
l!le 1I'aMCtiQtioI\al aetivabon 01 tneEVIl gene ...
.cot.
m~109efIov9
invIJI(Q21Q261
I~~emias
";I~
8lood84 2S812ti8$
l U6. Suzuko H
"'sano
Ohasllt H
I\onQsIVla T t.!urMI T. SaiIo H, Holla T (19991.
C1con*y analysis 01 refi"atby.-.nil ..,.,., nng

IicilIrobIKlIl MniItaneous study or cIonaily
I'1d ~ fAbone ~ progenIltn
laJk_n lJG.l34
2127. Suzu~i I( ~ K . Kan.obe K
SuN....,. J Ohga S Ishii'lara S T,.,.",.a K.
KJ<uc:tj hi (2llO4). C1ilio4*louklgital_ 01
~ WuI
1 <it!ed TfM(.QIII tymdIIotders (SlN$f'ft (tln)n1C
adMI EBV inIedionl 01 <:t>1thrl &'ld I'Ol"'lI
In!J 0n:0I24 116$-'17'
2121. SuMi R, SuzuIIWya J, ~ 5,
Mill S ~ A 0nMi S. Gondo Ii H.ro N
pIIOpo(lifeo . . .
au.
e-
~1oItuIIr
~, . . . . . . ZllNI ~ 8'ld
_
~ Ivfl J
PIft;I
a..
122StW .101
1131 ~SHI2OO1l T-<III8ldNK-<lIII
~ !r'""""",*'" eliot
dln HI J CIirlP.-u 127 .1'1134. s-do. SH. . . . . . - JA. ......,.,
tJ. 0hIh<II t-lS l.iIIIr TA SIIIl5feId AG
PIl83~ Cenroeyto: ~ a ~ ~
It..,...
~1IId~~"''''''
~ SlIdt' d 18 _
8ld
..... ""'Jf'IIIOll13 18'-191
2135. s-odbo SH IJIz GL ~ IdE
('993) 9d-2l1fOW1l11 CIn'OCylC ~
f*3lIn .... -..:ty l.....- 1 1456-
....
1136. S\oer'ltIovo 511 WWIerll5 ME (2002)

FJtIfI\ CWIlnlcyk k! tI'8nIIt ctII ~
etil~ &'ld ~ _
aI 3
de<:.-JM ...... PdloI33 120
2m,
Amoi:I ..., Wlleml Me ('995)

01 ptoINl '" 0ri'llcyI~ r.ell lymptcmois . .." .-.d -.ihloJl
r~ rJ !hi Bel.' !cydon D1 gene
Hum P&!hoI26 999-1004
213a. Szt.z~1 T. PIJtIQ8ff"WillarnM MJ
LllIlglIoI'a~ "''1'1 , ~ WA Wrjkrn>js 0\.1 , van
WerirJo;l ER. ~n I':longoln JJ {l9gel 19 flIavy
d\,)in genu tU"tlll9""'ll"1I in T-oeII aeutelym
phob!llIlt!c leu~ema 1.~ibt1 pr9dominant DH6
19 and DH7.<1g_lISIIjlfl , tar1 rewll to rom
p1ete I/, [).J ttlan-i/l98fTIll!'15, and alll raffl in T.
0lMl recllll!Ot "lpt1a t>!lla ~ fllIll{l8. 8lood 93
4Q79-4OS S
1139, Srpurka It, Tiu R MUlugaun G.
AtxIolI a 5, H5I EO, TMeli KS. Sel<_ MAo
MBOIjewsI:i JP 12lXl61 Raltacsory -.NI ""'"
MQ'ed 1dMobliI&ls ilUOCIBled ....tIl IlI/Iriced
Ih~ (RARST), IIlOlhet~
~~' e condillon charadlinlOO by JAK2 \l617f
'lIIIIalion Blood 108 2173-2181
21400. Tadatt....Htath l, Pillalug8 S
soo.. l. &Me)' M ~ 1,1 , JIllf ES
H&tri$ NL
E.(pIIioo of ~
(2003/ ~ ztnIll-oIIl~ .. (:hi.
d.en atl(l JCUt'OII IIl).oIl5 Am J Sutg PaIIoI 11

522531
1141. T~ A8 ItIlIl O.811 M) Cwtly
... Cwrtnifts 0 Banr.- NIl I2OO5l ~
~ j.:qund ~ IIlOnlIIIy)
CM.aId tIy gandtlOW T"ii4IlIIl-.,1KJ IV
".
Suguro t.l. TIW"', S

~ K 0I<arll0ID t,I
~ Y ~ S, Stlo 1.1 (2(IOSl
~ d IJI'O"e pI'OlIIf b "*'IIicf.
kill 01 do5lIIIel ~ aI cIlluIIllf9llk:e1
Ii
~,lllDall06
177fl.lnl
1141 T. YC """ t Ho P8h SC QOOIiI
.soc..
1I'\lIIlIaIIic~.~~ ....
. . Vwch:lws1>ldl441 1000-1006
2146. T__.....a T, Ham 1M' luo WJ
~ S l::lIImIa I,l, AlllMI I( I100S
lois 01 pr9$SIOrI fA ~ __
....... 1NgIf>-2 ~ ~ 1 ilOOf P'O'1"
rtOIIisllle:-d~~t,&
p/>olnI h Je.ut 118 218221119
2141. T _ T. Luo WJ "-" IE ~
101, IudlI I( ~ I( QOO3I E4iU ....
1Ild~0I""'0II~"""
lfom l'\'OIlOti'"""""'*"d ~ 0IfldI
0IIl0ps on ~ ~ ~
~~-~
riIcl<on
CirlOIf so !M. 85ll-a63
2141. T_ _ ~; I( Y~ It w--.
r ~ ... (1m. AckI: T-<lIII ......
&'ld HTtVl.-.ed~. G.m_CiIl
Rw32" '15
21'9 . T....., 101. AlcamRu t.l o.t- K
KdIIIi S KJkWli 101. Suzu. . . J lJics ~26
2150. T
N. SokoIoIl L BarIh I'If p9STj
E.n
ary tvmphoid a~normalrlie5 III
s,;.gr.,'~
s-dIootStl,V~Wllu~LR,
21C2. T
Maul K
IrlMlUllflC'l' at EBY associaIion a'ld ~ __

lion'" !he lMPl gar-.if1C056 ~al
h >JWfIl" aenxJigl!$IM'I lrlIct Palhol 1m 54
\58-166
21"". TIjoNI It IiroImII Y (19911
~ d HTlV-lIlI .. ./aI)in and l!le
WOtIcl In ~ on AdIJl 1-(AI ~
and Hnv~ ReseilIdI lGirro ~ OIl
CIncef Res8ch1. TakilIUar'*
!'tm. To/I)'O. pP 129-149
2145. TlIkiNslI E ~ K. "..... T
Y~ 101. Ema T NaUmIn S i2OO5
lnn~ 19t9t' T-<III ~ c-.
ftIIlllI1 of CO~WI and AlJ(~
W"drome (ralKUum C8II _ _
~~I"'"'J
Mod 43' 50-65

1151. T8Iao.Ib D, ~JE. SI>lcIloI B.
iIld'OiWIn ~ , Iltoom6eId ..., PwlcoeI< M (2001).
C/eI.:uIl bcq marrtllIt
in _ _
with difluM large B-eeI ~rnpIx:.ma. ffilJI:s fA.
piIoI ltudy P~!floIQgy 39 580-585
2152, Tallman MS ~ RI, Sd>/IIIf
CA.. A/lpebl<Im FR. F _ JH, Ogden A.
S~d L WI~man C, BIoomfoeld CO ROfl'I
JM, W"""" PH 11 9971, AI ~lI'8rlS-relinoI llCid if1
IICl!M promyelocytic IoMernta N Eng! J Med
337,10211028
2153. Tallman MS , Kim HT. PalflM E
~
Benflllil JM. 0e>0tId G, Ca-Wleth PA. W_i~

PH, Rowe JM 12004) "'wt a nlQrlOCytlC
1$oJi<_ (Ft9IIch-ArnerIca-BriMh eIasIifa.
lion M5) does tI(JI tIav!l a *'tl'SII prognosis I\ifl
ol!Iet S<bt)tlM oIllCl119 myebd 1euten"Oa.
~ /rum Ihlt ~ Coo!Jocluiw Oncelogy
GrnJIJ. J Clrl 0r<:cJj 22 12~'2ll6
21S(, TamaslII J, AdoYl'I e KOltIII A Ciol'eN
l Androkovics H TOIliIIoA. ~ G. Blnl::zt, L
8agdi E. Ktenacs l 12lXl6). ~
p:ntIIIClIlla T-OIllI ~ MIl mg d>ro:m;>.
~ 1 an IIOdVomoioomll 7q eQlOIWaIInI ~
III dlromosomII abMrrion V-u-s M:h 449"
"'...,
11S5. TII'I BT W...,., RA.. ....,., [),A (2OOSl

n.~dB-anrlT-OIllI~~
rte1llI IIId ~ ....... III T-OIllI rym..

p/IorrllI$ 1 ~ ~ artgollO'Il~
T-OII ~&'ld Ie'tIIlnI T
(JII ~ . ~ ....
~ ~ ",*"lIIOnI
""".
.-.d WIIIO\ll
J I.Ial 019 8
2151i. T...ai<aM, SucIiIT,"-K ~

'" SaID K Kimuta F ~ It 1Az.......
T~ S 0hgiI S, HIIBt.e K. DttIW'Iold Ali
Reference s 421
N. . S ('9llfi) F_1gilncl1l hI.rnin.-um

"'" Utd 2 317322
2157. r.-.v K..., U TogIIlI'I K F,..
H.w-.btN
..-oeA ~
II: Sd II
T,
T (2tXlIiL
CNtnit 1lOIftIP* . ._
fit f1P1Ll
PIIiIn
Il~""'m,..od~
IltJ
A.
S {lOO1) Curr8r4
__...., "....,....1
~ peIll>
opi'IICII
~.
ElIood
R8w 15, 121131

2171. TIIIIIri A, 1'IKIInalI'-' (2OOl) CIJIocIII,
lII"*- r4 IlIrao8uIC 111II1* II'IlO ~

.... 0IIlI---'
Oprl ttIm1Illl\ 5ll-04
83: t52t$
2151. r. . SG ~ JH, u... LL

P6ctds KE 12000) f..-dlOnll ~ b"
SAP" 2St~~d human ....
....... ~ . ~111" X-lr>kecI n-
pllapo........
"".""r....
syndromll J lmmunoI
165
2159.
p ~ F. vn., O.
IsaK S, loQ II. Conl... JF 8efger F (1998).
L~~~on
leu _
lviclInce lor B pherIotype oj lhlI
1lIi'n(lIaIeeIt, f ur RespirJ
12 102-106
21&0. T80 J VitkIerrarna E P 999) EpU8IIla.r 'o'II'~ poIymorpIlic B<.eII ~

~lMl (I1!Of'dMl l/\ II1e Illngr; of ~
drIor1 wlm AIDS: a repon o1 lwo cases, Am J
Surg PalttOl23. 560-566
2\61. Tf<J
RolllIl1$Oof1 KD, Maoo& II,
H~
A. ~ Rf 11998). Epsl8frl.
BiIIT ";fIJI iEElV) '" ~ 6I.rtitt's lymphoma rmiKlJlIr ~ d P'inla)' WInOI' !I$.
_ Blood 91137]..1381
2162 r.,.". M, N~ CL4 F!39* ....
Song x.. ~ J. JufllJ A. IUIMrI K,'"
H,lJctIJO GIoII80(2003f, Sa!NllclMalOli
II PTPNll II ~ myeIornonocylC
" " " ' _ " ' ~ sytlCItarftllS . ,
_
III)W.:od - . . - Nil GenIl 34 1"8-
'""
2161. T-.u 101, ~ It ~ M,

GcJbl ... ~ I(, ~ N ,:2006L
~ II'lIIyM d etItOI'1IC ~
1Il*-'" .4,101 s/lorllooII;I goal1'NJl(Nl
a...
7.... A. 1bIIt J, caa A.K....,..

T. H8tW'l CA e.os. G,
~ S. ~ G Mesa R. Rely Jr.
21n.
HM
s.w
H V..-.ucm AM,
~ ..... _bal1hrtlmbocyll'le, ard

pnnlIry ~: ,~ from
.. ad hoc wrllmlborlal e.perl I)droel 8Iooll
1101092-1097
2111, Tlhnl rd'll R. Irrvemiz.zl R. Gr3ndien A,

Z hl votov sk ~ B, Fadeel B, Fon;tllom AM ,
TrevagllooE, SamCl8lss.oo J, Hast R. N,lwon L.
CluC>13 lA, Wibom R, Helistrom-Liodberg E
(2005~, Ablrri!lt rrYIOCtlotIdrial ~oo d,sviDullOO
I/lCl n'IIhI\IllI:In arrest dIaracleru:e \'J8/1)' err-
~WG.c.oM5.SlidJWI2005)
T.ffotrI A( ~1
The doitgl'lOSis ol poly'

c)'lhemil WIoI'll: new IiIt/$ a<ld ok! dictIImI. BMt
Prad: Res OIn 11881111lcJj 19 455-469,
216e. T-"-, A, EIlloll "l'-', P,..""",,,, A
(20061 Alypbl ~ disofdetS
. . . . . ...., ~. Mal'G Cll1 PItIC
--- .....
815530563
2ITI , T..,. A ~ He. T,*,,-, TM,

"*"- RV llflell) CIvllnot m~
.,...,"~~.
_ _ Mllyo Qrl Prot 64; 12-46-t25ol
2171. T
A LMho n GlIIlinIG 120061JNi.2
II...,........_ .......
Irl E'9 J
)53 141f>-t-411
21n. T
A. lMtIo
~ SN.
s..- oP. . . RA. li CY. WadlIqllol
Grt GO l2OO51 TIll JNQMi17f) ~
. . - . . . " , II """,,*,,_ IIlIl "'l'IbCI
n..
lIlICfIPlMiI: ."..".. ~ and
drlal CX)t.
st.
TO,.l
124 56$-675
2110. ... 8el9t RL. dI!I 8tuIl PC ~

JJ ~ GJ. ..., d. V,... CJ
(2llll31 Al.K~ IflIIPIa* iargI-oIIlyrIIptonI ".............. pool ~ 10
~T<tII~ ~
~
43 ot62-4S9
Ilet9I Rl.
...s,-nc
0ucIetans JJ.
CJ (2OOJ)
PfOIl'"CI'lic MjleCb-
. _ J PIlhol200: 4-15.
2112. \Ittl 8ergll RL CluO&ja'Is JJ
~ GJ. F'IlIbll K 'MlIIIl'IltI R.
F_ 8, Qlgn A. Uo!otef CJ(2000f AlI("",",

IlcrI in utrInodllI .-.apl&sllc Iar~ cal lymp/lomIlIvour\ syslemlc~ wilfl (pr'mary)
00ClIll ~ arMi a good ~ ard
octUl'1 beIOte dls....naaoo, J CIIl Pathol53
445-4 50
2113. Terre C, NgoJyenKhac F. Barln C.
Mouil.Onll;cl MJ, ECiache V, Leonard C.
Cnap;ro E, Famal H. Booyo<1 A, RouS>llol p.
Choquel S, $(ltn tct1il M. DWr.1JIi p, L~
V. Caslaqll S (2006), Tnsomy 4. a new et1fOmosomal iIl)rlOtmal,!y In WaldenslrO'lfl
~lmtmoa . allldy of 3'9 CoISlI.
l..II.QrrA20 1634\6)6,
21M. T.....,...FIIOslIlirI J. CtlIIO E. FiIppI
~ ~ 0,
R. Coie..... l.l, I'llrIoct.
C. Hoy It (2lIl ~ lIrve-<*l ryr.
c..o.r-m
pIlOII\II-'" ~ ~ dInl:aIy
~ IP'CNII .. bclf> HIV~
. . , ~ ~ -'"' ()ICd 15, 1673-
""
T~1klsIM1
21as.
B. JIlIe E5 {1995\
s..
J .IIftI ES, 1M! PR

H. ~ r:Ni 'flIiIrlCIn WH LMgc
01.. TOIII:) G {1'il'}7j The roll rJ ~ fie
IIUO.nI ~ b y ~ , ..,
If-Ill " ~ p r o l I &
~
'*'* .., 3SCUIr Ga1IilII
fI'III9Ii"
Iy!II-
phomI 0IIft<:ol3 ..,.,..,.. IyqftJcI .....

(MALn &"ISIf'IlI ill pedIaITc HIY~
~ AnIJ SI6i PIIhlI 19 357363.
211.. TlfUP4'tItlI*l J. z..ow P. ~
JE
EL ~ L ~ M TOIIIO
G. JIll E5(1998) E~oI _ _ "',
s.r-.
~~andcylr.ll;nt~
.... H 1 V ~pebenl .... 1IUIic4'lIit
a..M .., I"'W1lA4iof1lp>~ lItllr>olsllll: 1~1-1642
21M. TnbJ hi 8o:nanJ G........ G
CIrtu'I C. R"iJ}IIl O. ~ E. F'tIIo::IlI S
c........
RUl P, P3SlIllO R
.-
v..... G ~ A. T....
S (1999). 3Q21 100 3Q26 ~ aI;irIor.

........ 11 aeuw mJ'8lOblasbc Natroa: bioIagQI Irid diIIcaI JeMJ.ns HIlOlI'l'Iakllog 84
2190. Tl\lIf'9<lwlll M. Fim WO. VllIeYa<tt'o

KK. RO\lf'Il!l KHH,.it" Samuelson E, Pe~ L,
Kuzel TM Rosen 5T ( 1 ~7) Rocur""9 ,trueluI. 1 ~ ab<1ormal;bes in perlpholral
blood lympt'oJcyleSofpatllf1l5 with m ~ fun.
\IO'dnlSezarV syndrome, Blood 89 3371
3~n.
2m .
l.I
Tha~
M. 0klpIde O. Beet..,."
~
TW,
8eIu MM R.,..,. JD(l99Jl. Clnc.Il. lllOf
~ ~ rJ
lyrIIIOid ~ cn..:w.
Ill by both 1{14,18HQ32.q21j IllCl
1(814XQ24 (32) 01 1(822)(q24 qll) ~
phoIogc. Ill
pe**
Oloo"..,."aCan::er 2 ' 41-158.

'l, ~ S {2005~ ...... 011 ""'"
~.., donII ~ Vll'l~21
r_I.""'I""~'
e'dlbll ~ IlIII"l-=
II'tIIlIraI .... ....- eel ~ \llIIIZ.

"'II Ohf ~ V{H) lIII"I UoIl
Pehllll: 331-3J9
2113. TI'IItJIIno:lrl C. 8asaOI'I 'I, 8IrglIr F.
RiIu. C.
G. ()urnaNt C, F-....n p.
CothIrB(l997j ~ ~
.... 1JI'tI(lIO..brtal MId l'lOI'lgII$Io:Iil........
lympllllmil be/lIM;Ir Nysis rJ 1M peDelllI J
s...
CIIl0000l 151624-1630
21 t4. T~C,6e<~F,Oumc:nlelC,
~ I, Ilw8Aa F, Felman P, Sa .... G,
Cootr.. B (2000).Mocos3-a:;sooated tymprlOod
lissIIe Iyrnpr.;.rna 1$ a dl$Semfr\alfld d i _ III
OIl! thifd of 1S8 palll!(1ts anal)'zoo Bklod 95
!lO2806
2195. ll\ieblelnOtl t C, Felm.Y1 P, !lerl)II F,
Oumonl!ll C. AmIud P. Hequet 0. Artad1I J,
C"e1-81ucllll E, Sali&$ G. COdfltll' 8 l2002l,
TI'83blW1I of 5PIeooe troargO'lal ZOl'ilIk:ell ~
p!>om. 111 ansll'SiS of 81 palllnls, CIIl
l~3,4147
21M. ThoIblImorII C. FIlma!I P. CItlIt

8IuChJ E. T'_rwGlehe!> A. SIIIes G
IleIgIr F. COftIr B /2llll3). SpiInic II'lIJgII'IIo
.... ~ liIiIr>d. cb::II IIIIl peIlo1DQaI-*J I.MIoeI()ICd 4' 9S-1G3
21' 7, 1hIblIrnonI C. " - V, FIlIna'I P.
~ K, <>-ao S. ,*&m. E. LClIiocl B,
~ 5. GIulinl P, f9Q.IfI C. T _
CJIIlI!l A.
L Betl.co F. e.orrt.mD,
~ F. MIIOWIi!III 5 ,1,- .....-, H.
SIIII G. Coder B. Berger F ~ R
l2OO4i SII\IlI ~~, IftlI9lIIIl
e.wo
tr....
lUI"*,,etI~.~cIIrIt
21... rtwdI C Koeh S, er.rtz,g E SIIudIl
c:al1lullY BIoorl &4 2121-2125

2174. T.... A. I.IIu RA. ScIlroed8r G,
fI'I'lIIoerllJf
11...- CA 1I CY OewaOi GW (20011,
bllfl
C. l*IlII' T, Sdlaich '" Eh/'IngII G (2OOl5~

P<e.1iI!lCI arod iY09rooslic Il1*l rJ hiPl,lI
rr'IUlIloOrlI in 1485 I(loJI ~ with ICM
422 References
III
ficlopllhl:)
261-2t16
221M! n..J.K-.-..nt1M(2003lo.mc
1ItfiIlOp"""*,, diSl.lflltn ..... ~
cyIlIIriI' ~ SIll1Y lit IlIO ~
syswns\PVSG. WHO) Ofl aJ6 pIWIl
Am tWnIluI 82' 143-152
22111. ThJelI J. Kv,lSr.cu 11M (2003)
~ ~ lit -.bal blJlIbo.
'*'"
eylhaemalrom~~
..... dlrQric idoopi1lhic myeloIibroIiI by liIl:fMrl.

....1I1r11l'/1is of 00ne "'Wll7IfI' ltat.......... dIfI.
ocoplIthl:*:lgi<;ll lludy ('Ill 272 patilll" l1iilO1

MlopIthoI \8 93-102.
2202, Thllie J. Kmrvck. HM (2004)
Pfe/lbrotic cllrwic idiopalt\le mye~
~1ll"IigTIa? fom Halmatol 1 11' 1$1 511
2203, l h'<!i' J, Kva!nidce HM 120051
DlegnostIo lmpacl of tool! marrow ~
ogy In ~ycyth.rrua _ . {PVI til!itol
H.~20 317326
221)(, Thiele J. K.asnlCl</l HM (2005)
~ k>dIlgIind"lmcodloplhc
~.
Orocxll J2 J80.~
s.rr..
2205. Thotle J. K.WId.a HM (2008)

ao~ C1tetII b" difterInIIIa.,.
_
rJ
III _ _ fIl)'IIl>
~ ~
SetrIn TIltarrtt I1IIIIIlIl

32 21i-2Jll,
22Ol. 1lIotII J, K"4$ftd.I HM (2007)
...,....... . -W!Ws.. a 1<OImI?
011 ~ MId ElJUNET Gr....
Paroobootlg, 74 fil.96
22'G7. T'-le J. I(~ ..... !leIIIIl OW
Zortlft 7K. ~ F. Reske D lAlliIf lD
e--
scr.lIrlJW{2OO:lf ~..,~
of~lIgIIfOIlg~fIlDI
......... IIogen!oc lkIlII
lIWI'CNI _ _
......... c:hrtne~~
e>.periIrIoI 011 160 peMrG, IlonI
lAarrow llilflSPlril26 21!)-281
22lI8. ThieII J, K~ r+IoC, CZlIIId C
{2002l, COl4. progeIIIIor c* '" ~
(pllr!\iIf'j) myelo/lb<oisls ro"!IP&'lIt"" ~
CiltlOrl bet-. spleeI'I !lIld borlI mIITOl'j is_. Ann HilmatoI 81: 86--89.
2209, TheleJ, KvaSrnel<a HM. DIaN V (2005 )
...'*'*
Borlll ma rrow CDJ4' prOlllln,tOl CIl IIs in

PMId. l p~lII
ehromoSOi'!le''IeQ'Ulv' chrook:
~flIfatl\ll! d'~~
loggj SWd~ 01' 575 paIlel1lS lllUi. L)lI1to'nI
46 709-715
2211. ,"-"J.K~ ~.DiIhIV(2Q05l
1IJNI (lIlInIl poIycy1helIIIa \'If3 Mlh Ilto'r\tIl).
CflOeIs I1IImdn;J - * I I I 8YOmOOq1I\IllII
-",*!"IIImIld \13 213-219
2211. T'-le J. K~ ..... DoeN V (20051S1IndIlWIIIOfl 01 w. . . - ...,...

doeIl 'iOO'\ ""'I~ b ~
..........., of diIIferI . . . . ~ ?
~ ~ 20:633-6U
2212. TIIIII J KI<aIldI HIll OlIN II
FIIdlIf 11:, IIichoels J (1M) Qnieo.
~ ~ iW'w:I<liIn'*Ile.--of
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StIIrl G,,...,. lol. KMlw'IslJ A. flaIl\JIll N ...
tV.. Beelen OW lloIscN.owskl 1.1, ZIr"o6II A.
KrOt9l" hi (2005). Oynlmes of bonI _
eIIIo"9M l/\ paIoInlS Nlth ChrotllC ~
'*-II BIoool90: 4(I!l').<41115

211l6. T.-uye-f~ J. .IIfflI E5. 8urll PR.
Ho(lgkirlilisease' dna cor<eII01 tiO\a)I.in p,_ ..,n .~ lIs'lIt
otIIo",**"c:es rmuoth:itXl.'iU1 IIlIl

.oprol.... ....-..onof~~
of ~ n ~ ClIl*ltf of
~ IfllCN,l,. _
KHl7 ~
~ 1m>8 CelPIfO'rolk4 ~64
2137.
2113. tt/llllA.li C'I. Willig 1E ~

lItI. (llloJrIQ Sli. Prr,M;y RLl19ll4f,CM:nc ~.
OW, StlIi.dI JE Tosato G (1999).

ClIf'lIrwJbal chImokN'll eopteSSlOll II II!$f,IM
2111. 1bIIt J. 8fIq-.z Fe Be<tIdl HP.

F. S, FIId8 R. ~ HJ (1993) SpIw.:
dIoRlntrr~,"""'I_ylllll
...... Ilt J......-cJ 131 320-328
~~tvm-
"""
ZO'lI k:II ~ . .J/Id nw-.e 011

~ pho(liWd~ prolIIts
~1'lIllItIclllIr~ 8IoocllG3.2727
10
1IIOC8Md
pI'oOplOlllli
m)'lllocl ......... jNol.f Blood 101: 4011
bonuJl:;~
21.2. '......,.H WMshSll, ThorwIuIM.

....... A.~O,t.ars&onC ~
gre
AlJ(~
1ilf9ll0ll~
~ ~...,
BIooclIl3. 2463-2470
2117. T~1IC:Is1lJrl J. TtIIIIId< BK.
E. VIllMIIll.HI, I..arson RA
IlQS!lOll and E~ \'IUS SlIlM in

pedIIrlt ~ ~ ~ J CJ,n PiIIloI
2111. ...
""
Blood lOll 247253

2179, Tlilell w.. lo<l8S MA. Perl\JflS
~GJ
2168.
klw-m..
s~,
1Il-.b~ lnlJ~&3,.3J..43ll
""""* ...........
"'**"'
F,
rllAUl G. HlJIonaoI R. ~ OG 8Ioom6IIkI

Ni (2007). PrCIllQSIIls and
IMIOn8It lot ......-on 01 lhe World H...."
~1lOn dlagOO$lJC cnt_ lor poly.
21", T* AM ....... JA Tllio:* J. UI*

YF (19ll61 ~ a'ld ~ II ....
....".... IlIoolI 61 423-'38
211S. Tl1WrQ WY s.l J. ""-I T I>l" " - $,
~ M F.;j Sot. I200lll Pos4-tr-.
plInl
II priIInc renal
PdK PttiaIr 8lo<xI Ca'lcer -47
218-:123
2161. TeGeIdlI .... Barate C, IolIrdil E ....".,.
E (2007), ~_ Illood RIlV 21
1&3-200.
2167 . re!leli A (2000). Myelo/ibrOSIs .. ill'l
",ye\:)i(l rTIllliplKja. N Eogi J Mell 342: '25~
c.r--
CD. Verdtnlin
l!lrolrj Pf'Q,IlI(llt In
MM KIlgmI OW ~ M. P-. HI........
~113 76).m
217S. T
POGF~ ~ ll'I"II II I
Will ;I
~ d .........". Inl J
Nslor)' d
~~andtleirdll"oit8llM~
~ fI-orn bone....".. ~
LMJ~ L ~ 33' 201218
"yeIo~
/oIowIng allogeneic
!tern t8l
~ . HistQj H1~ 20 87~.

221~ ThotIt J. KvllOldo.l HM, F8CChettl F,
f.atlGO V
v"" _
WJ,
Oruo A (2005/
e~ ~ on~ bonel!WlOW
ibroI" and _SfllIIIII 01
OI~ulan ly
~90"'28-"J2
2215. ThoIle J K. aII1Q.a HM f..,;l'ler R
(lm~!loot.-.oor ~~ on oYonc:
lII'fIloIIIonou ...._ lCMl.~ 01
.....,... ,........, lfrQI ~ ....
~ ,,,. 12<11.125ll.
22't6. Thiele J. Kv~ 11M 0rJlJ A
I~ Bone _I~ III "'7'Ib~~d~
llIlIWOidI SerrwI",,"2 l&.t-lllfl

22't7. n-. J. K-.:u .... sa-~
A. c.hI V (2003) 80nt _
r............,,,
~ ~
..
111~
IwfIPI' il dW'/lI'IIt dO-
1_ _....",. .tl "71).
.~
22't1 T... JK....... HI.. ~

A o..n. V (20031 O'l-.:t 01 IrlII.- il
tmnc ldIopIlIic
.., . . . .
"'......, ~ ~ on 30i Il*IllI
LML~.t04~~
22lt. TI*J K~Ht,l, ~
A. " - S EngIlt K. SCIII> P,' - ' ~
III I\"IIw CF.
00 ...........
r.m.tl ~ 01 ... l'fI'*'llI a- n'lCIU
-*' ..... ISTl511) on bont - . . .
lIIIlft!Ion ~ ... dWllNC ~

iIuUmllI
mo.
1tIlopIIhol19 1277.1.
~J. K-.:uIf.l.S<:Mw~
11.. lriow:tI R CWII V /20021 FlIIcloHc>

~OII(UIong ......... bont_
~I'I-*11~(m.
~ l i l ~ RAy 01 120
- . I I AmJ~70'28H91
T""" J K~ HM, Sctma~
A. at. TK, 80mbun F. ""--'n C,
YIlguim-Gflh"..., Iol frCk"'Po/ll H,
ml.
~ C.1.edar LD, OlIN '1.lricMttl

R Sc:hIIIllr HE, NIIllIrlI 't, frSd'* R (2000)
Bona marroor IeriJlurM &rill cInc.IIlrOr9' on
..'"
(/VtI'IIC~~~w.. ,muI
IIc.riIr ~~..-.rl~
Sb1\' on 61 . pailIKlll Lauk L~ 36,
2222. ThoIII J.
K~iWIrlII
'Inman
J
on tt-.
~ aI Cl\l'GnlC myeklprallleralMr dotot'.
dars a klrgoften pear1. e.st PrIcI R.. Cill
12OOll) Iloot
HM,
ITl<MTl:HI' hlst~
,nterferon ltl-efapy...... ncceesceoce in ! itu

ltybridIz'aIlon study 011 l1ell/1.... bio\lSi8$ J
Pattvol191! 33' -335

mao TlIIlI J, WiMlld<er R. KI'a$/lId<a HM,
1""'" 8R Zri.ovidI R. F1Sd1e< R (1994)
EI'rO~'1
III pomary (i(hopatlllCl
oslecmyelol!tOlJSlS' ~, PC....-.~
tivII) Ind ~~ Am J 1iIrMKlI46
"'2m.
""
Thomes OA. FlKIerI S. 08ne... S.
...,
~'jtJIIQIIe
tytI(I,_
(I.IOS)"
In
........ unoo~1I: ~ 01 bont _ _

. . . . . tiopty IPIllfI'I!ft J CIon PIklI ...
"',..
2227. It.11e J SdwrIll 8 F\lCflf R.

~-oa 1AI. 1..otwInn J. F.... R (199ll~
o.a.on oil'll lXJllbI gent '" bont _
~ .. CMI.&'ld"""~
lIrve 8<AIlI ~
on Rdlwl"oorom..
lIo.ol._ 18 J.26.3JO
V~ R.
r.u.- E.
~~CC, ~J l.MMo
80nIctl 8 (1*1 1iOdgUI'1 ~
c-.FJ.V~S.WiwI1aWG.~SA.
~ ........ ~ on PllW'I\I MIl

<ilkIrllnI ~ ........ lOdllIollIlI:~ . . .
Mod PIIflol" 301312
2212. 1~ C Grra 't ....ll(W ..
~WollrInI8 a...-Mllnll. GUw H
(2001) PIIIIIn IA(l _
01 ~
..... on~.-~dialI
lrOIII lie OA!.I1X 63- and ~ Wtd
ShIn J 8r.nlI ... H1l1l8ll__ Fe KeaiI'Ill

I,lJ ~ F. ~ H (2006),
~ ....... nyper-CVAO .,...
b" III r--.. 01 ;J(UI1lcnoIt WId

8urUI-typa ~ (r aculI "" .... KbIaMit
~
-...-. c..c.- 106' 1~1580
U30 1 _ E, ~ Oit. s--. RJ

WllcfIr\Iflll GJ l20001 R.sk of ~
nong....-awill ~ ~ lr( J
cane. 68 497_502
2211. ~ w.. SUrd1 J. IilIrtOson
SE.. ~ A Worog a, CIscr> S. I!raI'Itt
SJ, ~ J, Zlwlg X. St Y. IC"onney we
('2(Xl5;. ~gIttlle....- on ......
lie ~ ~ "'l If\lIPllJk
~~~lIfVecel
~ Hi,m i>lIfO 36 "94-504
2232. ~ DA. G<l;a A (2OO.t).
~ 01 to! EPStBil-8aoT wu:s WId I'll
ongnol~~ N Eng! J 'lad
l5O- 1J2&.1337
zm Thoms C, Basban 8. PmfIl 0
R~ R
Fnd1ylflll J, Uel'l 11
~ 101 e.na 1'lW. Filler N; (10011
C!YomoIornIIIberrnonI on ..-llI0mmurdllllalie T-OII1ymp/'lllllll and ~ T-OIl np/lom8 W\&IIllCdoed A malri.-blsed CGIi
1PI)I(ItI. GenII. cr.r~
46
c.ar
,, ~
s.won,...
22).1. 1l'onIon PO. BellBsC,

ShIh
G. Pooock C, Wo<herspoon "'C. MaMes E.
CaIoYsky 0 (2005) Rd'IlW's tr~ 01
dVoroc ~ Ie~, TM po!ISItllI
rolt 01 ~ and !he Epste.-.&rr WII! In
lis palhogeneIi&. leo...- Res 29, 389-395
223-5. Toaco E, Uw A, Pms M, Fat.... B
(2IXl6). EvoMog CO/'ICepIs in tt>e palllogene&!
oIheiryceIlN-OO, Nat Rev CJCer 5. 437
...
2236. TOtco E, Pileri S, OrIeth A, PaQrli R.
lIbamni A,Frengi.'lllli F, LISQ A- Di,llIi<l D. l o-
Cooxl F, Falor< 8 (2004). PAX5 expression In
5135:(1
2226. 1.... J. Qullmann H Wagntr S,
f ' " R (1991) ~ il
B. AngsIer
C, floc1> A, s.up. A, I( opper l. UlIOIt'lly A
(2C04) R~ ' * - the fhJlIlonIl
stalwol VH~&rIll ~ o/dIllYM
lICIJM Ieu,_s, higher 8~ioeage speaficity

than C079a and seloct i~e assoaallOO wdh
t16:21)-.1oJle m~nous lau,emill, Ca'lCtll'
RIlS64 7399-7404
""*'
$lud)'. Aro'1
~C~J~.....-.oG.
227:3. ThIIle J. K~3!lnd<1 11M Z<ln iloVlch R,

Diehl II (2000), R&levlrlC8 of b<Ine marrow teaIurM in !he differenll3l di<\lgooi ts betw&&n
"sentl~ lI\rOrl'lbocyll\elnlil iII1d ea~ ~ ltage
idiopat/lj{ myeK>f,tH-o" l . Hlemlt ologo:.l 85:
l t26-113<1
2221. ThiIIIt J, Kv.~ HM, Zlf, koW::/1 R,
De'I V (2001 1, The v.... 01 boI'lIl rr'\IffOW n.
IIllogy .. ~I,O\I bf!lwIen 8lIIly ~
~ ...-a aM MWldIry (...ell...)
~ ~1l631i8-J7..
....' dinIcal,
22U TrlQUIly M.
~ 1 9 .~1 3-43 7
2225. 1lwlII J. Koand.! HIol. Zam.-n G.

Va-diNIl J, Oiehl V, luetIi:IeIt U. SdmI1Gr3eW A l2OO.t) .\cult ~ ... tIl
~. 'lilIcXIPartOOgocll A4y on.t6
tJilIenIs. n:iJdong ~ 01 bont ....
~
/oIooI,o"'4l Ann HIln8lll 83'
. . . 01 dlrorroIomIl abllormalo!ial in Iolkvltr

i~ 8iled!l.t 1O.t3-10.t9
22.ta. T~ B,Fuloll Z.C _
2231iA. Tiemann M, Riener "10, Cla,;"l A,

MeYlll' U, Dotffei W, ReIlIlr A, PEllW3I"esdl R
{20051 ProO!eration rate and ou!oome .n ctWdItln With T~ ricI1lke/1 iymp'lotna. I din.:pa!hologlC study from the NHl-<lFMstuo:ty
\rWp LllIJl; Lymp/loma 46 12'ilS-13OO
1237. TOllllIlIM M. Sdlr.loef C, Klapper W,
[Q-,1n,] MH. ~ E, NorIon A, SergIO" f ,
Kbn p . 0\1 G. Pilen S, P~ E. Faile< AC.
Mon H, .la'men 0 Hansmam ML. Kriel<en H,
IkIlIw P, sen H. Un~ M, Hoddemim W.
"-arMCII R (2005). ~Iiloklg\'. cell pn.>I!eraIIon iI'\dO;tl! and c:lPciIl CIJt:XlmI! on 30f
. . . MIllllllllle QII ~ (UClr
~ SlJlly from the fll'OPl!'
UCl toeIwort< 8r J Hatmala 131' 29-38
2211. Tlen 1iF. Su U. TII'li Jl..lJu "'C, i.lle
FY, Chen YC, o..-g SN (1997) CIoNIi dIft>.
moIOII'lIl ~;III and ~ b"
don*; il nasal TInat\QI k/lIef OIl !ym.
~8rJ~97 621-615
tnt. r.y H. R(\50S, It. $lamalcUlas 11..

L~
8, iltgDIgnt C.
I(ur*l
11..
hlonanluif .. 8llItard C illl9.tl. ~
PllclIll"Onc:d37 1[18.114
2243. Tollil G (2007) lhe
llll"" ~...,~ .. lhoI\c """"

pIo:yIIc ....... IN L ~ q. 1081.
",.
224.t. Toc;n G ~ U, ~ Alton l. ~ 0 l-WOI'I ". Ilof&olg J

~G,~J.~C'CJolIG
~ A (2llQ2) ~!IlIAIilld III

V(tf)3-2ll11"'1 ~ I ,..IIItIIII<:I
ctwora: ~ ......... 8lood \lit 22t\2,
""
T~
I(
Y."", Y. s...;.K. ~
IoU'III( (1001~ 0 - . ; IlIqJiIIic"'t"l'Jlltl.....'~'~l)Illlolm
POGFR8 cll",,_. reIPOfICle<I 10 ,",,"",b
101. ~ U
""""'~LU_21
190-192
1246. Tobdorl G. sw.n H.lImIrt I( \19101

~n~llIInobIoI.
~ ~ ~ /rom genrwlllI-
C8'h oellI '"" CItll'<'8d rudII ~I,

41 168-182
Br J
c..c.-
2241, TotnIlIS./olonKL Sal.alnS,OIIwnIK

12003),8-0lIl marI.. ~ lcor+, COl~)
E~
wu.......,
P'f')IhorI.IIIIOallI
''''II9*''*'' il the JH
\)lJ'IIl,Leu.lyrnp/lomll .t04 121730
ell ~ WI!Il
224.6. Tomrhl Y Clhww. '" Oi ~ II

Has/limolo 1>1, YiIO\I WI. K.m Gf, Aolilll I(
(1997) EPliteon81uT \'INS il ~
live l i - . 1'1 me SlI'Il:>-naIIi regKln, doH
8ssociatron WJIh CD56+ irlIn>J~ and
l'Oiymo rv~k;'et'culos<l morp~y. Inl J
Canc8r70 l1--13
22.9 . T()rdjman R. Matintyre E, Em"" Jf,

Vaillns, F, Ribreg II, 8u~1n ML, Vare! S,
Broosse N, Ht<mine 0 1'996). AggmSlW!
acute CD3+. Lallioemia 10 1514-1519,

USlI, TOtI3kCl'o'IC E, Nilll$en S, Vyberll r.4
12(05) M loIl<ld;< ~ec! ,on In immunohislocllemk-lll c1etection 01 C'fdin 0 1 1'1 manllt Dell
lylT(lfloml. Am J On PillhuI 124 782789
22Sl1A. TorlaO.l:Mc E TitI_ A, Ding 110.
0elabIe J (2OO1).l1le ~ lIc:lof PU ,.
_$II')' 1m 8-0lIl ~'I e~!oed
... ~ pteCIolninMlOI. but 0'W;lI dIsIicIl
1iodgI'.on'l d _ Am J Paltlol 159' 1807.
181"
2251. T~E. T~G,NguywnPl.,
8n.nIrJg RO, DlllDt J (20021 The ...... of
n-ou-!> ~ on rtW:Wf ~led
MId ~ 1ICIionI. ~ ~
~..., 8-oII1nIllM. Am J
PaIlol2'li'
s..v
1lnmO.
22U. TorIikcNII: EE ~ HV. Hwn S
(2006~ A rr.-gnlllInt phInoIype on fokUllr
IympI'IorIIiI _111418)" -..lId
__
orGfy C)'IlgenIIc
typQIl 01 _ .
g.llllOI'II ~ J P-.oID 25&-26.t,
1251. 1~ .Jt e.t)' ". So:wtn l, T _
~
.... ....,.J KnpIDW.~IIl"ES

(2000\. U-- dIIlI T_ ~ of".
MId
136. 1024-1032
2254. ToroJR L~OJ,I>abbv 't,Sort>.1I

L, Rat\eId 1.4, Sleinberg SM, .Ide ES (2003)
Glmma-della T~ ptleno1ype assoolell
,,;m
~ demlased ~ ..
1lIOI41"""'~
eo-.
8loocll0l, 3oW73<l12
2255. l ortF. CImIciloE. BosdlF,H.ns 'tL.

lobttsetral E. Campo E (2OO.t1 F...... IyrnphtI(I neopIasrn! III paIIents .... m.l8t CllI
tvrmhomI. ~ 89:31"-319
2256. 1011 F Pr>yoII.l. PIlllml K. Rotadcr
G HenwocIftl l ~ I. KI.Ift.,
.
tiC, IOuon P. louro:ll C, ~ G
D.
~E(2001) UoIetuIIr~oI
"LK \r.II>9llCiIklI. ""'Ili'IIIlg _
(\lSJoMLK) il ~ llo-gIr CllI ~
L-lIbbft61 "19-.126
2257. Toully EA 1I920)
1IliIl1Oln8\lll, ....
A c.- 01
,,~"-"JMedSDllil)
16-25.
2251. T<UIOI C. ~ C. L.-. l

PIlllmlIl.. 8erTwll f, Ra.- T loIIIon OY
0elId G !2OOGI. Fi.I'h<
<:I III
delio.,"''''''
lMrVy Ii ~ (I\lI'qIII ~
2p2J 11\ "l.K~~. 2 _
Il~ A!.I(
fuHd kl Clla.
(cWnl dlW' ~ I l . Blood Il5
3204-l2Q7.
a...
2251.
22"5. lo1.l11 K. ....
mICftIeOJlIic.
T~
O. Sarb 00 Xu L I(ati
J 1. YT. til GoA S. CIIeI' L I-MIIr Z.

IlrIn9n AA Iloya J1, ...... ... ~
KC TrtoOn SP (006). Walt OIls on
W8klenslrorns ~ SI4lllO'1
~ eel growVI
~ Am ()r(;oI
C015ol1CD40
IllrouQII
17 127!l-
""
mo.
T...,....K. Ot,.-. K.YCJIIIl8 Y, Itbe

T, Asan:> S, l'fr8i H. ~ K, I-da 1,
~"'~S(199:11 ClncaI .......

~ . 0 "....... -lQl palMI!;
Ii
....,~~a~
lIludy il . . . LeuiIamiI1: 4~
2281 . TrJl;ll)' L. W1-.dll1 R. DoV AN,
5>*"1, Ortiz P Gam-lI.If,
~ano.A..lBIer
M PIlls UA '003) MycosIs MgoideI . . - .

COOOi~1 ~lIIat>on 01 rnulr!jlle ~
II'lVO!wd In lhe lNF sign;lIng pathway 11'1
Ilxprfision pro6Ie stud'f, 8klod 102, lOt2-
,..,
2a2. Tr 8 ~ A 8a~ L. C<lIIet.

eauchu E, Mcrej 0, GallO S. Ffrenc:t1 1,4 ,
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JP, Salles G, Coolfllll" e, Betger F. Falrnan P
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003 baIo;lhilic .,Iloos lymphocytes I dls!lnd
dlnlCO-patl1ologal andmoIeoJler 81'\111)" ElIood
111: 2253-2260
22&3 , T~A , ~.,F. Ben Smon
E. CalIeI.&oc:I1<J E, Felmen p. ~ L,
G3Uo S, rn..oa.:.mont C, CI\IfIoI C, Col!fiB,
8ergef F. Salles G (2005). AnIIy!iI<:I VH
margNl rooe IyIr(lOOma re'oWIIi
m8r>:ed ~~ betwMn ~ ...,
nodal tumors and ~ lhe exiIlenoe 01
<*nil &eledQI tiaElmaIJIogio: 90,..7Q.4 78
2264. T~ 1\. Felmen P, ~
8alChu E. Gal20 S. 8ll!eggoo L Bryon PA.
1hIItIklmonl C. Codfier 8, Sallas G, !IerlI'l" f
(:10061. A cil~ study 01 nodal
~ rore 8-0lIl ~ 1\ rtPort on21
genii in
C8S1&.~.t8.162173
2265. 1 ra_Giehea '" PldIlugI S

GUirll P. So:wtn L I\b'lIO w.. ~ u
JllIle ES r.'OO5). ...,...,. gqy mr.- .,....
pIloIM !he rnrssong .... ~ '*MI:
~ 1 ~ &'ld IIllIlAIlINlIlIl'ge 8c:eII ~ .lin J S\,rg PaIrd 29" 1411
1421
22li6. TrenlPlll P, ~ C, Uut'IIll: G.
~f.OoiIIIloI-G ~ ~ IlnlUlIlIlP
References 423
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"'lh f1l8...-.glW11 0/ the plal<Mt-(jen.ecl
IIowIl !:to< IiIl'Ia moer ,.. ctroc.ll.-.

~ for STl~n'GMc 0nl:::cqIne 22- 5702
"
2261. T_ $P HunIIr ZR.
A..
EMIl EP, "' . . - S L.. C StnQ 00

~ E XU l. L.elIu Il. T~ 0
Pau.rJM CJ. IoWwng R 8rI"-llln ,I,R
Momn Ct: i2OO61 ~ olllmtll
W3IdlrlWonl5 ~ AM Onml
17 43lIof91
226l. Tnr-.
PuIoo:l K
(2lIOOI ... , . .
__
c.rc
l
E
DV P*o fIG. F... 8
IALK~ ~
<-'.,..
jATJC.AlK) II ,
c-. ~ ALK~""-':_
c..e.
R-.lIO" 7'il3-798
2:26t.
J !IuIII.# 8Mllt N, ~
MJ. F", LA ~ RH, Gl!u fG Sl.ccap
P WQo:dIt ES (200 .....,.. 01 ..", ...
"*-a
~
~dIDdIr
.....
. . . lit iIraIl FwI'I ~"j,*,. T..........
lilliill' ~~, AlII J TIIf1ICIlIrC 5
pIl(I'II;L
r_
n.",
ChIll<en's GenoerGftl\IIl Blood 90: 2635

1271. \Jeda C. N;,;MOtl M. K;liIwaki T
UCh,yama T, Ohno H (200-1, eoe l ;st&r\l
~ 01 ..-MYC, BCU, lIIld Bet6
gtIIIM II 11 d64e IW9" B-<IlIlyrnp!'lotn.a. II-. J
Hematll79:52--5ot
2279. 1JroIe<Ijc ... . Coorad C KMniIrasI"ev J.
A5IgOt K, COlZio It. 8I.-g G Oumn'ler R
(2OO5j COI<-C058' '-Iodemic1\o!lOlUSnli
Ill*' 11 ..... 'liiCJ'bd Iler"O*c eel phanoiypII.
I1IM!l PaIIol36 1Q20.1l)2~.
mel. vannge. JoN SctuJmg E. ~ T.
PtiIippo II. ~n:la K Kluin P (2000)
~ FISIi ~ 01 BCl2 ~
JM(2001l
CliIgnoIIIc~
of ~.
lhll\Ul8$lhcallOl'l
oonsetI"" propoul. l.e<Jk
Res 25:603-625
2291. . ilII den!lol(h 0. j2O(l.t1 ,,~
MilIl ~ . , alIenoI ~ ......
II'IIectionlI .nd U'noof tIftIInCW? L.-at
0n00I 5.738-746
22U Q'l den .........ElwW< MM l2OO1l
PavoytnlIII nodtInaI ~ II tH,.
MIn ~0n.99
11.16
1293. van dill e.g A .."... L ~ 5
11Ml Iigh e~ d tht CC dIIrnokN
TARe II ~ celli A ~
lllIPIInIkII for tie d . . . . . . . T-eel .,..
..... HodgkIl'Jyrl'iph(I'IllI M1J FWrlI1S'"
1685-1691
8Iood 8ll
~A.P:-m5.~
'*-
MaDr1OnQl'lI:lsioo IU'nPal'd3$31!>-325
%285. Vailluetlil JR MedeI'tIS W, Ra!Sldakis
W~mze R T",1IeI'l CP (2OOtl AbeffBnt

e.preswn ol the lyfOIioI kifll6e ~
EphM Irld lha ~ Iacb' twill ...
SezarysyodfOrne ~lJ1Ied by 9"'8 e.Pfll$SKIfl
~ Caocef FlIS 60', 557&-5586
...
~ ~*
" '"
co.if tom ~e-.Ilb.xl
aooe). Gero3ri: ~
-.wus status
20
2205-m'
GZ HaG S Wy co, ""'" L, lin P (2006),

ExprlIMIOIl or 8 celHlpeclfrc lICtivalor prtr
leI'IIPAA5 irt llCUW myeloid leI!lo.emNI \O,1h
l(8:2 1~tI22;q22), Am J Gin P;l!hol 126 23~
'"
2286. V:tIent P,AA'" C.ESOlOO!>o L, Fooi!1glll"
"I, I-WtmaM K, 8rod<"", K, c..steb M, SpIl<T

WR. KluinNelemans HC, Hamdy NA,
Loor.olary0 , Robyn J. van Doormaal J, SolIa r
K, H3YSWtrth AW, "'rod M, HlIflll i n~ 0 ,
H&llmann A. Trtgg;anl M. N;edoszylko M,
Schwartz LB, Orlan A. rtomy HP, MetC<llfe 00
(2007). Standtirds and Standardtl~ t ion ., mes~, <XlOSeIlS<Js staWrients on diagnosn , If-..enl rllOOfTImendalio<1s and resoonoe
enIen.I
J Cion Invest37 435--0(53.
2287. V/Ilefll p. Al<in C. UolicaIfe DO (20071
FIP' L1.POGFRA IS a rmlecuIaf marl:t'f 01
dw\ltlt: ~k ~18 001 no! !of s~
e....
'"
In~
37' 1~
~: ~
1)811_
127l. l.lct.R 5, r.bwdo F ~ '"
Gr.......... ~ Ml FlIggICW "'. MIlIIIlI
V v.gDL ~G RuooLP (I~) i"lIgIl
~ rj ~ --Il"'O"'l ~
bOll II ~ ;.u ~ 01 HIV~
InI J
c.ro:-.e. 581-585
l2T7. t..ldrI FM s.t. tiN Gt,tnI PS.
MuOC TnwlllE
J
T~OG,~
PO, SenIeI l,IG R....., GH
111J'}7l CIIa . . . . IfIl:I ....... OIAtOIIW
424 References
00n0;IIn JJ Stnu T Panzllf

~ ER. IlIlnt '" ~"..". MJ
2297. van Doom Fl SchItIer E. WIlemze R

(2002) FDIIo.iIar rI'lyl".OSIt 1~ a disIIfrcl
diseaSllentity \011h Of Wltl\oo! M60d<!ted IrJIicu.
I;) r~: I cfInicopalhoklgie and~"\I(I
stud)' ri 51 pIItienta, Arch Det- rT\il t~ 138. 191
'"
2293, ..., Doom fl,
"'an HaseiellCW, V()Qfl;1
...1IdM PC Geert. ML He<JIa F. de Flill M.

Steljlen PM, Del.. ... SK. en Vlot"n WA
Wil8mze R (ZOOO) MyW511 fI.IflgoIdfll dl!Plllltfl
evolution arld prognosiI d 309 0u\d1 palilf1ts
Arm Dermal:ll 136 504510.

2293........ n
5'11,
Oelabill J.
CoolevtlS L.DeW<JHPMIefI
GOO
V~ p.
e...wens Jl (19971.
(CDIl6)
E.~ of 87-2
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Hodgkfl'1; deeasI, leukaefnll 11 a.6--851

2299. va'I Gort> J WIIpIlg l . ./Io::I:lbw K l.io.I
YH l.JFY.OeWegt(RA.LJG(l99041 EpslIln-
(.!003) IMp:lIis .nd lrN\fIIefrt at s;Wlmie
8arT"""inlmal T<:e4I~I~
pI-.e ~ ~t rtlia*lM) on
Id, ledToef K.llemett JM. I,IeII:lJIle 00
,.... 00 (2002) SnouId!!nng ITIlSlIJCylo-
....... 0lI\l J PltIollnel~1

23OG. II H8IeIen CN. TlIOnIlnI J ... <Mf
Pula SJ
tklr'1gIn JJ ..., liMa Q.
VIoIen '11-' (199ll1 ~ IlId< _
. . 11 ncMl !AlbIype 01 sysIPmI: IIIllSkqkIIiI

.......... PfOll.-r> lit ArdI AIIeryy ~
or
In. 895-717
rille art 8t J
IiaelMlD
2m. VaIetIlP,AlunC SoerrWR.HomyHP,
127 13713lil,
22M. .... . . P Horny HP, EscnbaI'o l.
LoM BJ, l.J C'f SdwIrW LB. r.wone G.
'-aJ: R ...... C ScJIar K. SIll!!T WR. Wdtlf K.
8Iwlrong 1m P . - - t l ~, ........ K.F
L......... II
DO, ~NI, 80ImIIII
""'**
IlIKIy
.....e e.n
Aclli
wa--
2307. ..,~OJ YfI'ItslW.HolJhG
Cronwnelo'! lUI.
~.IN
IlfWCl YIP
119'17) ~ ol ~
M-
a.saIHOOgkll~ .~
'*
".,
L. . . . . 18 1911
22M. Vale<lI P Alun C, $pefTWR H<:Jmy HP
QI stu:fy rj 119 ~ ~
c.w.
l,lRO-PCR W9Il Ind .....,.
_ _ am ....
2295.
leorIc masklcylo$lS E....J COn
1275. Tz..-a. ..... Krvgmann J. Fend F,

F~ ~. GtW R ~ S (20031.
PmgnosIoe ~ of C02l:l.~ II
(~) ~iI"''IlIeolClllillc~1l
olal ",RNA e~ allcM- ..... P21~

po:l!IIhedwtnc ~ nl atllII
lie ........... Blood 87 521),5211
_9"'*_
2(),20221 0
22T3A.Tsiri\I01J6
__
PQqI H,I,
_~Senin...........a14751~
2305. VS'! OvertJe;:e L Edtn It Tp J
ER. KtlIlllI ... .., [lQngIn JJ 12Q(lt).

TCIltI9""lI
II ctIlltlDo4"
.... cncv--8-ALL' ~ ~
1131.1733
2296. vanDoorn R. [);Io...... R, V _ Wi
OIlt-l.""'nu JJ, van dtf Rllit-Helmer EM
21738. TIUkarrw:M Y. Kat>.unoiltl Y. Omura y ,

~ I, Iiir1lt lot, TnI1imlI H, KoniIhi Y12006)
Subcu!llrollO\le ~ T~ lymphoma
~~ fliIaIlrlltlmlont wHl1 ~ and
cycIo5.ponn II I"!emMIld ~5, 2 1-~
2274. TI'JkasIokl 1(, T8U!W'1 Im,1 H, Y"""'........
!d, IilIta T, l.Uata K, Matda T, ~"" 5
Sohda H. Idomlla S. IdedI S. Kala...... S,
yatMda '1", ~ 5 TomotII\)lI ~ ~1997)
IoMgtMlOO ~ Ql HTlV-4 pIlM'\It ill __
kin 10'" dIflic.Ij COUflllI 01 .... Tl. freQuent don-
a.--
2'-' .... FlheeF.~A,lIIF r.IIIo

N. GokrTwI .... CttlII NC0996l p11101ICR
S.
"lW'IPIInl lymphoproIiIafaions vlllicl3le$ ...

WCllId HaaIIh 0rgInizaII0n d&ss6:alioo Ifld
IUg9ISIs n:luso:Il olllond IoIcWr ~
1J '257-~ ,
2J03. V.. Neeo' FJ. ToonsnJ. VOOflilVldef

PC ~ R, .... \IIoIen W'" (2001)
ll"'....o,lIIkiicl~fld*nn .Adylll
10 dWchn ~ by" D.IIdl
l ~ Wtw1<Jrlg Gn:lup 8t J OeoIr-.Il~
351-3601
DIM. .... '-op 1<.. de GrooI C (2OO2J
........ loIa.oW tIIifU*; 0.11 UQon origrl
T. ...,
w.ng
lln-l182
e. .. ..., PO RaIl T
~ J RaoMl Onml BooI Phys 50: 1tl-1211

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CD5ll ~ 112)CJ1 lor ~
arid CliIgnc:8I 01 ~ Am J Surg P8lhol
'/11th dilllJse - \Ill B<elI Ijrl1phoIrla Onoology
SIud. Hum PaIhol20- 321).32!>
PO lSi
tt'jQi(lna)Jt
Corral L SIIll: f Sdnpp& Id . . . . . G

~ WA Gtlcher H van Wwrog ER Luchoog
we 8aa:l G. lSi lNin hIA. CaangI G
IieIgor K. .., 0.- oo-..n din e.g, Hop
we. RiIlwn H, s.nm CR (1998) ProgooaIl;
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mspo;mIllCl!nlltmlllll, ..........al lWId ~rison
nPh
nodI." ... ...,.....,...and~
Nt KloIn PIoI (l!l96'1 Dred:visu*alion of dis-
1213. ~ UN. Uoha<ned AN.

0uga0I Me 8lool!I RE PalJrM Id 12001)
8lIIlic ........ eel ~ ~ will'!
fN1ulI-lype hi 1IlcJcakll, Ifld I>ypocipIoody 8t J
HaemIlDIl15 66--6fI
22M, VaQlrIi E.Nln:kAaSV. ~
S, I(eIe< CEo AJolleid e, Murty \IV. 8haga1 G
(2OOn, CylDgeroiIlic arBysis 01 B--uI post-
~D~J,~
~.lOI-.
Raap
_rJl"'WY~80l11~
E, Bo/la& G, M,ntzios G K~iJ 0,

Kot!nlIna'loo A, RapbI S (200 I). T-atI-ndI Beet tympI'Iorrul, ..... tyalI of dinICII /ealu'es,
5!lle'lt
fllIiIled oelI5 1'1 \hi
PWIr H,
GJ.
_II~~~""
T.
I'M . l - . t K {1989!,
~ lAd
" - " : e II Jill
()rmIen
RIPlMII t,I
P, EconomopouIos
MI J Clin Palhol
In SopJIl, 51225127
2302.\. .... , KfIIf.en JH, .... Sd*l\lC.lGJIn
.... oat~ b'f ~ DNA hi'
Q'l
25291
2271. T-.g P e-E.a..unA 1M
'l'f. Kr.- OU (1el161 lIbIo:UIr tfWIttIfto
/2OOn SoIdIry plllijllK~""''''
~ defiaerlcyIn ctlldllfl
a-o.. . 8eIg 68 419-423
HC
~~T"-dolfJ~PIN
~rrc-td......,,_on~
120(4)
II'" ~ nodi ~ "-"0121:1 1~1221

22M . .., 0.- VtIcIIn VH e...p.,, M
~ . . . . . . 15
F.~5,s.tIE.OawI F.~J.
Nt.
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per-' 1\.. 13 ~ "~II
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E 0. 80Ir CJ. ~ KK. Villi 1("""", ..f'l
~.,...,:lIIlIIlI.*'1d41_"'1
2Z71. Tsang RW ~Y(, PI*

Y. Be$k A.. Well w, tbIgpt OC S"-'
Kneken
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~~~?A_
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Z212. VIljltAP
Am J PIIhlI l48 20172025
4135--4142
2302. Van
2293A van elM Oon:l JJ. WaIl~ C

0esnIIl VJ (lll16l, The ",*gIlII zore II I'of
'-"~ IIlll1a MI J C*l1Wlol
116' 4~1'9
22t38 van <lin Oon:l JJ ~ C.
o.-lIJll!l891 MaoginII_~
.... in tAa.- ~ u$A'lg ll<eakpo:Jftt.rUIg pIOOa GrIne

CIncer
Z271. TtC*r W, ~ SJ. ~ GE

g",..""il9lJ7l ~ ~ o l
1~
01 etttdten wrtIl m ~ llnligen pos;IJ\I!l 1lOJIo!

lymphOOjasbc !eYkllll'U' a repon !rom ee
v"
Reportoltlfee~
... . , ~ _
~196.382-3111
2lD1 .
IInIdl (J#I 80ennI EJ .... <Mf
H8. 5ctluuring E VIIfdonct LF, KJuin.
.......... HC, lOuin PIoI 120081
iIIIpId d gerrrnII _ . . . . - d prfAeM

Ifld e1 .............,., tttIlpOIllIlI pocw_ til-
... III;Ja 8--<:tI
0na:lI 2.
I9l6-
ewaor~~ol~
sdIrosinlf H",.-,-s
~ b" ...-edId
197M2 8t J ~ 96 322-321
2J01. VMlde"'barglla E ~ C._
den 00n:I J WloclIrsU I 0eIIIl0I J SU Id
Thor.- J.~. JL, Mecuca C,
~
e.-
JJ, (1991) TranslI:lcilIaII11:14) 11~

It if"O'lltIy ~ WI\Il 8--ceI Iyn'Ip/lOrI'MiI
!:sf I'OI-ddI ~ eel ~. J PiMhDl163
1~18
2309. "'andenbergroeP WIodar!.QI. t.IK:!IuI

L ~ P, EIoogaaf1s ... V......... 0
H ~ Me, V., Hoof A, SeIIIslllg 0
RouIoMI F. ~ Id, Vertloff G.CllJ J
~ OG. ~ A. MiII'"1N" P (20041
CIioIcaIlIfId moIeaJIar featuresol F191 Ll .pQF.
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LevI<ernill 18'134742.
2310. Vardimar! Ni (2003) The noew Wt>ld
H+l8lth Clfya!Uetl()r\ classiIIc:ation of myfIloid
ooopIIIsms: Q&A ""tl1 James'll. "'3f dlffilfl
MO C~ n Mv H8II1atol 0nc0I l ' 18, 21.
2311 . Va'diman JW (200<1 ) MIHIodjoS'
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COhr> AS, p _
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Ie ()II lu'llof, In ~ head nl IleC1
lmOf, Am J ~ 23,9H8,
2314. VIIfl)/l Fl. V'i$M'93 C. PlalZllf ..
CIIfosIIeIII KM, Ctvzanoowsl<a K/i S- I(
E\eclo.lllilnn G. SeefIlanootI E, ~ PR
Nowak NJ. Stumm M.w-r-J CM. Galb AA
WIlen RI(, Dq!oeed M R05lIl1hIl "" ~
K.~P, Reos "'(1998) NIbM. nooaI
0f0IA ~ 00MIl fltl)IW protIi'I
~ i'I ~""'s,nctome CeI
91467-4762315, Vaeef t.tA.laaIa'i GS 0.. we. SoIl
1:,WwsLU, 8t)nes Ri(11995) Deroii'AI
l.omCWS ISIOl3lIIlId ...... b1r~ B--oaIIfIIig. . . . . ReplfI at Ine caes ...", J CIII
P#d l(ill 69&-701
2311, ..,... J, ~ l ~ l.
G*n:l F CII"IlO E. !lrllllueI P DeIIoI G
"'VI 0llI lymIderoIiIHodgkorl '.

report t:/ 10 0MeI Am J Solg
(2((16) Al.KilO$/IiYt
flIlon1a mM'I1d.ifl9
~
nOlluIIl
P~ltlol
XI 22~229
2311. Vassallo J
PM' RP. Soares FA,

I.lerem Y. Aldrld V. Rit*to KC. N<ota AC
(20051 H,1lOIogiCII o.l5kaliofl 01
U'2~
. - of HcldgI!;01'. !ymImma from . . SIMI t:/
s.J PUa. SU
Sao PNo !.led J 123 1)(.-
'"
2311, V......... H, 'lit OS Sd>uh MJ.

~ UM,""" J,~.(;q,aI A12007)
~. ~famo' bllf
".-ge fk:aI ~ II ~ Ul'ldar.

~
ctincaI . .....-:l '*IP'I', AM 0rl00I
18931;39
231', Vega f CIIang ce. Medeoros tJ.

lJdcl!rl ..... Ow>v.ga ~ lIu ce F"rdl CJ
'v'Ii:I'Ial AA t.lc:GMgorO,~"'(2IlO51
~ ~ ard plaai'iiIl:lIIIIk
.....
..",
~'-.-.,~
2321
......' IoIad I'ahJI 18
\Ia9I F. e-e. 1C.F1.
n-zv VA.
!'WI K.l..-.g W Jonaa 0 l2OO5l,
* ......
r. . . .
01~~~'*
llnc:als P~ n- Tl .e , .
ZIl1 , VIOl F IMdaaaIi U, ~C
.u. 0 ~ R t.utn A AMIau tv f2OOl~
l~liC~T-OII~1I
!lOlII ~ A IRlIOIIaI ~ ..,;tI blaI-
Ie ~ . . . . . NIt J (l
Patd l1e
'1~19
nn
V. F MedIll'Ol lJ GauIanl I'
(2007) ........,.p.... aM of.- 'iI8"""IICiI

T-<:eI ~ Am J can PaIhaII27 . .
'"e.n
2323. ....... MM, ~ BN ScHuu

l.A. Arbtr CIA. SIl;:wak 1.1.. W-lM
(1999) IrIdDlerrr r-tyi'~"*"-* proIilerakln
~ 01 a C3III .... a 1~ COUItI MI\tJUl
o:yIOIO. lha<apy Am J s..tg PaIIlOI 23 'PT
M.I
~angemen15 detecled '1'1 a iIlJbM>! oIlJ11l'1111'\'

ClJIaneouI foIIode e!1Ie< ~ ~. /to.m
alli4lly or pallfll'll! \\itll1hll l(6.8 ~q27.p1 2 1 atlI:l

FGf"R10f'.f GFRl fuaIon: Iwi:I !urtf\fIr UMI
J So.og P1II\Ol28, 748--755

20 Veog S, de M\JlJt A, ~-s.ry t.l
Villani L E ~ D. Chene G CatIotll A,
Hem8IoI J 5: 5~5J7
2341 . 'o'OIl defl DrllIIdl P. COcn EA (20021
l.ocaI1ad OJIIneoo!I smIlI 10 !IlIdI.o~
pIe(lrI\olJlIli T-QIllI ~ a NpOrt d 3
CUM $tlIbiI for -,.n. J "'" AcId l:IermIklI-46
Franck N Oedlelotle P. Souteyrand 1',

CcuviIe P ~ 1', Delal.f1ay M. Bagot 101,
cnnge- F, Frailag S. &lsq J, Pe/fW T,
CUlIoct'I A. de MaIl*1ll A.. ldfwlolI .-.. Wechaler
J{20001 T~ of mytO!ilS ~
~ arid pmgnosIIC Jeal.res of
.5
Frerd> Stud,' G~ d CuIaneiouI
Lvrnof'omas. 8Iood9!l. 2212-2218

2331. Vem.w RG. Goudsooaanl CS van
w. at lolA Sa'Iders 1M Huge<II W
~ AG. ErpeIIno:X CA. o.twftt R
~ 8, Wit- PJ (2W'
lAr.IIaIK:nI in
~ (NPU11 II acute myeloid
~ 1.....1 as&OQiIlion . . " .-.... lll"'f
. .Oil aa I n ~ esIabiIIlId gene
eo:preraaion ~ ..., It>effIrvQrabie I"l9'
rak ~ 8Iood106 3747-375ot
2m
V RmlIlN SP, CeIier C,
AsrWI V
JJ. 8arbe U ~ S,
........ 0 ~E ~N Cef1~ N. Fladbd--WfliM I (20031
~ ~ ....., lq22~ II dcnII
. . . . . . . . ~ in tM-adl:ry 0llIIc
"*"
e--0lJ_'*'91 ' 2S
212.. V..... A, Dal PoeIa G, Ilutl:::.eno F

r...,.",.., A, eo.FrllrlCIIo t.lC. Nooica G,
Ilrooo A. 011I UortIe, Epocano~, Ilallaght A.
Fn l, P!:Jatomo M Cordero V, $aroIIntI $.
ArMdorI $ (19911). Prognosbl;
0I1tle
e.<pmlion t:/ rm nl CD' on 3~ eaMS cf
3CUlI m)'8loid .... ktmia, l tc ....... 12: II)$-
_3f'IClI
''''
2325,
VenerC, SoIogo D. Berti E, Gt8llfli U.

5erYida F, C&r~ E. Ca pulO R. PasWllll E,
Larrtber1Mghl DG (2007). Indetilm'lin,1te C8II
tIisliocytoeis in "500etiot'1 witll later ClCe\J1>
renee of awle m~sbl; leukaemia 6r J
Dtrma~ 156 1357-1361
2326. Veoen D. Aqel H, Fr~ i'ICI\onl M,
Meneglol'li V, KramP&fl M(2004) Prev>tI6nee
of ilI!patltl! C \Ilf\III it1fllCtlOO '" IgM4ype!llOllOf:lcNI llIImmop;IltlY 01 ~ """'ftCal'lOl
inl Wa!deo:Wrom ~ Am J
Iter!lIIlQj 71 421
2327. Vertlorgh E A.c~len R lou," VJ,
BI\l...."." C DeIlotgt 1.1 Boogaens M
~ A Vm;lenbetghe P, Ver!loel G
(1(107) A ~ _ _ ealegOnZIlIOn t:/ low

!P:le~Iic.~lJIIIIl(Ionltle
e~oI~...,~l'Iona
. . . . "'1ft
NIl one IIllIaQ8 ~ on ll'wl
__ 21 668.f1n
2328, VettIuIgh E Adllen R MaM 8,
M<l~,
Iloo\IMI'IS 101 WoIl'~ C.

\IelTloeI G 120031 AddIIionIl ~ .....
~ A
d boN _ _ ~ II ~ IUllc*III'ell ~ III 1Ilf ~ . .,.-oo... f'rl:9loIlic

seomg S.,....., lor ~ IY'"
~ J ()wi 0rl00I21 2T3-282
v...,
232t
B 8Mod-R~ 1.1"
8lMIsy MH, Bt~ ... DubuI P.
o..-, U ~..I:. Tlilltl
f2lIl 'oIeCPII* 011I 00 PlOt QIty beQ..tl
Mallo'
01 chrmic myllloprolIIeraliYe ~ 9fIl'lll"l'

ad by ~ d !he plIIllIeI.oen.ad growIl
fIctor ~ !leI(I gene. I.... ' ~ 92'
531 5J ~
,6l-169
2J,f1" >'OIl WlMIIoo'!J<i S F~~ J, F'oadW

R ~ K. HI.-..n Ul.. o.ehI V. ~
2356, WrdI H. SdIakel U, KII:.hnIky F
WaiIIlewtkI R (2003) ~ ~
"'II Iil'XIQI<I'l <11_ .-- ~ r..-u
progr'CIIlI 1ft Inlerrrediale ..., 1d"llnCed
8Iood101 ~
23U. VOI'Idlortled EC PeN J J<loMII P
A._
*"""
Searr 011
(2OO6f.
aDIeO.IS
progr(l(OI
auIlI II . ~
T-QIllI tympto.I ......... b'

ItIgng lM lyll'lpl'Dnll .7:
..a
1SC1.l~
nu
PM. CWIr I(A. 5rTIf\ SV,
A,.... lH, RID KW.
~ ~ ~I
..-....x.
FoIicUar ~ ... I ~
~
~<:IrIcalCOUltl .
I eat fIP(lIl nl _
d ... ...-- AItIl
"'Ill
PllI'd YIl!.led 128 210-213

23U VonKhoYIlo, t luo l. ey.. MJ.
e-wy 0, Ntid Pl. Vadly JC Futn t.
" ' - _ L W - AD,
v_ . . .
(199nCl.ll*-rogd_~II""
~~.G.Mr;k8,ThledeC ~
.Ii
U SouceIl S. SdIM:h M. EtvwllIW G (2OO!I1

WIIneege ~ IOCXlOrding III lie WllrId
HeIIfl ()gareaIIor> {WI)1 dele
II
S
..... m~
W_ IAMLI"" I'I(l ~
kltI "'"
and
I'I(l
.ldepIllldeo~ ~
lISnfyslld i1'1171i61Jl*rG 8tod
111 1l!S6-1861
:zm.
Wang J, Bu OF U T. lhiIrIg R 2hMe

8X, OWl xx. Zhu XJ 12005) ~
~floo<T>'tIU'Ia""a"""'_
drtIc ..... ~~ ... ~
pIaIIic~8rJ~l53~
2351. W<rog SA ~ R1'. lOIN' ...

Sec:rvn-.fV,.b'les D,!tao S LA! 0 Zlqc W
loII/lci M. GlIIIi N. Woda 8 R.aza A 120081
Rehclory - - . , ""Il8d ~
~
...
~~
.....
bor1 JNQ _
and sIIOWS ~
myeklj:o........ iW"CI ~ _
~
1&tl1~
2333. V - lolH, Ge*n FA.1 ( _ JJo
. . . . . .gec:lIIilI ganell a IlJ(O:IIc T-llII
'""
..... CJ. ~
........ NatGen8l17'96-99
2345. Vol JA. ~ Sl. ~
Cl. Andl'il<o JW ........, M. AguIIfa NS
(2005) ~ - . . . . . a IUly 01 he
23SIA. W8ng SA. ()soo N zu-belgL .....
A (1m!. ~ d
tylDb!1C ~ by tlIOQle5lic T 'J!lIs Ii m,co-
""
~ irll;7.- ""'" ~ Irtm
~ D}e 10 UIo sIiIge dIsoliilse ...., J

PaIId 1501121-1210
2134, veeee- 101'" Geelen FA. V.. HiIStilMI
CW. Voont VIdet PC Geer!$ U1.. ... VIolefi
WA. 'oWamze R (1996) Primary 0JIinI0IA
'-9! Ik:eI ~ or . . 1019>. A dIsIiI'Icl:
lYIle of ~ lkeI ~ \IIIIIh ..
irlWmedIale prognCIS15 DlIIdl CU13fleOUS
l)""lhJma WorUlg Group M:tI [le<m-'Oi 132:
1))&.1 308
'"
5dlm,U--Graftff A. Fab&llU5 A. HBg"" V.

PfurMw 0, RM S. Hehlm1n R, ~
A, CrossNC. Reil@f A(20071 Ol~
or tmoe .-- imlJlinob.NSPCIlM Iuso1 ~
2m. VMIli W Faccheta F, Rosati S Ve<goni

F. Rosel E, FI$la S, Rwro.>lli 0 Gngo!aIO p,
Muserllli G, Frtuera G !2OOol), Nodal and
e>hOOd8llUmOr./om'ong iIOOJITIJl9lJon of pin-
easel
n1JdIIg .... IlI$IluCylI ,..... COl!S3
Mod PIIhoI 18 693-1001

2346. Vase .1M e.- PJ. lynctl .!C.
~ DO, Ktsair9W A Chan we
~
TC, Arnilage
IicUIeriIy
00
J()
1'9981, Ellad '"
n.
iMOIOgOu' ~ /or
~ 1lOI'I-HoG9~
Iy!T'oma J ~
ClncoI16 ~9
2J,f7. Vyas1', CnapIlO JO (2OOTl- t.IoIIcuIIor
lI.oglrtJ ...,., Oowrl tyndlQrllll"lSodaled
IIokerrill, CJ.o'r Opin Peo:Ntr 19 ~ ,.
2348. WaggolI W, OreIIoIG, ~ FIF. MIl_
DY,
~ KC. ~~J, W~I ~
.....,;yI:od mO"ocyle$i~OOng cells

as5OO;lle(l wittI myeloOd dosor~ Am J Surg
(1991) NF'U-AlJ( gene fuaIon ...,
P3IhoI 28 5l!5-595
2349, 1'1.",... SO, MerMel V, LllU~lIo L

119941 Similar pattllmll 01V I<appa geoe usage
buI d,f!Ilrll1t doog_ of I()fIl3b(: mutahon in
2335",. V!dal AU, Gol,sa,n A, Yc>shtda 101,

lMhieu. R. Nrlt>ioka K. Tehia F, ROOIlI1 l, De
The G (1994) Molecular ep.demioIog'y (If HTl V
type 1in Japan IlViderlQi for!M) Oi'stll'iCl ance,
trallOneagill with a particular geographical dill
tnooboo. AIDS Res Hum Retroviruses 10
15571566,
233e, VOl H, Chevalilor S. Garand R, Motsan
JP. Pralooln V. ~vilOOr ~C, I.Ioreeu Jr .
Soohoo JP (1989). Clonal e.~ oliymp-hocytllS bearlllg The gamma delta T-oell
reoepIor .., I palimt wiII1 large ...,..,.,laI lyrnpIlo<;yle d*""". Blood 14 285-290.
2337. 'lifoll A, Gertz MA (20071. Walden!;lrom
~. Blood 109 5096--5103
21. VI"}IkIl. laueri C, 8dli R. NbJ K.
NII'duccI MG, Russo G, Roli>steon JL. Croce
CM (1998) ~laled erpression of TCll
canon Tcellau kernia in mr;:e. Pmc NalIAcId
USA 95. J88S.3869
lm. V*"o U. Gaidan:I G. BolIO 8. ~ G
Al.dIio E, Bettn M. CaM R. FIllib'le FI
Nowero D. Or!uc:ci L ~ G. Caplt> 0
p.w; G. Satco C, ZagoneI V Cwbone A.
UWa U. P""*tl G, Sagloo G. R~ L
(1998) ~ogemeo0t5 or bd-6. bQ.2. c-myt
IIllI liq tlelelIon n Il--<IdIuse Wge--ceI n~ etnr:II rflII!vance .. 71 palIenIs. Ann
sa
~.
haory 0llI leukemill. proIyrnpI\o(:yt 1e\"emtIl,
Weldemlrom'. fT18CrOIllobvIintmil and myekr

rna Blood 83 364 7-J65J
mo. WahnerRoedlN DL, Kyle RA ~ '99 2)

Muheavy d'1!\1n di_ preseollllioo I S "
b-en lgn monoc lonal Qarllmoplllhy Am J
~malO'
2351.
40. 56-60
W"~roe1"RDed4er 01. ,
Kyk! RA. l19!lB1
HllI'o')' d\3In clisea-. In M ~lomII BIology nl

~ n l Malpes JA.. 8ergsageI DE.Kyle
F1A , Aodet1or1 KC. edt a . lord U_ity
PrN' New YOlt. pp 6Q.t-938
2352. WlhnerF1oec1laf D1., Wrlrig TE,
l.oetow II I(~ RA (7Ol)31 ~
d\;lrri 6M_ _
or 23 CIIM. Medb:e
lBal1i1'1we) 82 2J&.2S0
2353,
WallSA.E,~ulP
SaodJW{l990l
DiIgrooaIlI d ~ Iymln)ma II efIuIiln

frMI ll*nIS .... AIDS by ganI ~
men! Am J CItl PtIfloI ~ lro.,7S
23~, W~ C. Curll. C. SdwwlIger S
Schullhel1 8 l,Ielz geroth G SCIlorJI C,
L~E.ErtlenP .....
Ha/erW:tiT,
~ "- HII*TIam R en. HC RlllW A
(2llO8~ T _ ......... III l'I'IIInib II I
cIlrtno': ~ ......,. - - ' "'"
ue
ClncoI9 5&--61
1lS(9 4',
2~.
\fIzlr-.s.J. ~ R, \ImI M.I

~ MJ CldiItll,., M.Pl J "-'OiInaz loll
c.anz loll, 0t8I He (20001). CR::aI ....
~In"
Blood 90: 1712 1713
..., I CDKSRAF'2
luIlon 11'I'" Gerw Cl.on_1'III$
~ 5 95l5lS
2355, Wltl C ~ G, ~ C.
e-.
q33,q'2q2~1
20.
HI. (20061 S!JIerwe ~ lI'lI'lt ~

...... ~ T-oel nell!k:ell ~
Nn J s..gPaIloI 30" 128-132
23588. W~ SA. Wang l HodlbIrg EP
MlllIU'I5ky A. t-llVn$ HI. IiassarJIIft RP
120051 t.o. ~ grade k!IIcuIIr Iyft>~wrfl'9'~me . ~
~ /eetlRs. Am J Su'g Pah3I 29

1491)."96
23S8C. Wang 55, Colen W Cerhel'I JR. ColI
JS. Morton Ul. Ell9I'S EA 0... S ~
RK, RoImwI N C/Ia'loci SJ Har1ge P ~2(01)
Immune med\ar!iims II ~~,n tyro.
p/'I(lrIIa: prrt tIJe<;Is ~ Ihlt TNF G308A..., 1.10
T3575A ~,.;m ro>-Hodgkil't 'l"Iphco'I'l8 ..... tocIors. CIcefRes 67: 5OoI25OSol
2359. WlM"flIle AA Jones 0, ~ ED 120(7)
MorphologIC -.d ~ YMianIIri
~ T-<X!I ~as nl T<:elI1ymp/'on
mtmic!l. Atn J CIion Pethel127: ~1 1527
It "
2360. WiII1Ike RA. Kim H, Fuks l , DorfmBn

RF (1977). The r;oemlenceoj IICIO.riftr and (if.
l\I1fI plInems .., nod!Jlar oon-HodgkOn's ~
phomes ",," lflCill\Cl! arid ~ cor
relation Carl{:f!I' 40' 1229-1233

2361. War'l!fl HS, Chn5b~nserl FT, WIll CS
(2003). FUIlCliorIal inhibilort h\lman ieIJooc)'If
"'ligen ctass I receptors 00 natural Uler il'K)
ceIlIIln pallfln19 with chronic NK ~
Br J H"""",-,~ 121 793--<1()4
2362, Wm.nglon I T, Dl;ilerty D. Gllossmlll
A.1.WrIIl5 J, IbraIWn S, t.. R (200n UyeloId
~ -.11'I delfboo ri 5q III Ihlt sole litotypic aI;In(mlaIiIy !he dncaI and p;llhologic
IQ8ClrUm leui< l~.3 161.765.
2343 , WI!&'IabeO. l.lIIlJyama l. Annua K
~ I. Anlvll H. I1.-i U, Uelao K
MsalDT,Osame t.4 (19981 ~d

YI5ClAIr endo:JIheliaIllfI'MIIllacW1va:5I::ul;w per.
~
fac::b 15 ~ II ero.F,*-
(POEMS) syrd'ome ...... ~ 211m
"".
23501, Watanuk,.YIyauchl
R. Kop"" Y,
TlUVI'I H. HIII1I T GolD N. KaI8IWa S, Saio
M Mon<oaIoH T.... T (2005) ExtnUiOId

UWIin arxl o r . . , ~ by I""""
"O'llIlblaI..-ody T332 ~ willi
fMXIr'olI '" dlIIuM .-ge Ik:I!IlI ~ Il'Id
ilIll.tlt,1les PiIhJl h 56 324-13O
2365. WtdI D. RDberl!; I. VyIII I' (20071
~ of Dooon ~ .IIt:1I Oil
References 425
Chtld FfIlSj Neonatal E.d 92 F50J.F507,

2:J.6fi. Webber SA {1m) Po.Hranlopia"t
lymphoprQll!etlI~ ..
0iI00lerI, a ~
oomplocaIm of tQkj 1lIg.l ll~?
Peooll T~ 3, lI5-99
23fi7. w.obet SA NafItoI DC. f""* FJ.

0IIIr>eW::h p, Il'Jrne EO. AddotI<zjo L Kn!rl
JK. CanlIrCE (2006) Lyrnp/I<;IgI.........
~ '-1:~. a
on:lIt$"
~..,., lancIlJ67.23J.239
2361. W.... T Weber RG. ~ It Act:lf
B. MljW-PulIU B. ~ S. 8uIodlget R
~ R 0t0erl~ M SdwoIdIk P
Redent>et9w G. LithW P (2000)
CIlirilansloc ~ ~ II pn.
"*'1 cennI.-.rwouIo IiI'*Il ~ ~ ,.
~IW9f!k:lll1ype s..nP..u 10:73-84
230. 'Nfittwtb M. oa,. PJ. Nwi F, ~
Ell.. NJOIlf o ltD. ~ HA. ~
MS ~F ~JRl1996) Tht~
--.on '*"'-' E ~ ..... .-.cl
t1DdgI<.., " ' - I I ~ III~' I!IIuod
81 382$-38Jli
2371. W....c
.E
u o.y PJ
Noggll F PooooII
~F~P9~1N
I-WltyPS T ~ F ~
ER. ~ A. El SIfo, UR Widaw F. N
1.1. ~ C ~ T, R-'Ii R.
T * , - K, W..... I{[) e.n-..... JC,
N'/O"lP "- RI)'IIlI.lS
JR ll9961 ThefIIIt
sr.nm
w.w.
~ ~ .... II HorlgkIl'. ~ lronl
ditIInnI:
AId! 0. a.:t 14
2731
2371. Wtir EG AI ""-H.an U 8Ilr:sli DA.
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...., lIOOf o:wur. l.IoNru 21' 2264-2270
2372. w. EG
K Lee-. P,
!loI'tMllz UJ /1999) A..,.. aFlIlbud~
can ~ 61;reana aeuII ~
Ie IIt.oUmilltom IlOIlJIIt B ~ """ lev
COb' /low ~ ~ lor ~
e-
**
or-dItIdoon
L ~ 13. 566--567
w~E,uanleyPW.eo..MhlKcb
2373,
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2374. W_ nbur\l&' DD. Ande,son
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J,
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~
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2314A, Wai$i LM (2000), EPioIflirl.8IIl" >'iruI
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""
2315. Wel5l LM. !l&rry GJ, Dorfman RF .

Batlkl P, Ka'Sllrl ing E, CUrtl~ J, ROSll' J.
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lympIl rodel 01 proOabliI M iculurn (;flllinMge
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14' 4()S.414
2376. Weiu LM. Bind! JM, Pi<Xlui VJ, Lir><
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CilSlIIS....,~riec)"lIoT"*l~ Il"""
Blood 61 47....18,
ES Uu XF Cheo '(y,
Shballl D. l.4edwoII U (19911 OtIlec!IllI1lftl
~ ~
23n . 1'1_ LM. _
mil ~ II
ilI'9'J"l\IIlunob'-lic lymplladenop;iltly and
aryoommunobleslJC 1y!nplII(llonop, t
IQo';Mlalm
01
E~'"
Blood 19 11l$.IM
23nA W- LM, ~ LA. 1'1. . . . RA

sc.- J (1i89) DMeclo:1 01 E~ IllI
genorneos II R*-SlerrtIerg t * 01 HocIgl.ll',
NEJU320 502506
nn. W_ LM. SIrIcQr.!G. DorImIn RF.
I1CfIWIg SJ warru RA. Sder J p986) 00nII
T-<;tiI~II~""
~""~1ynI
~"'~AmJPtIQ
122 392)9'
426 References
2319 , Weest LU. Wilmoe RA SIJaI J, Oea')o

ML (1987) MoleoJ~ _ I\'lis 01 the 1(14;18)
ch'oo>osomaI troll1slota11ll11 II malignanl ~
~ NiOnglJ Med317; 11B>11M
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Louis ON Oelmonittl F. ~(J I (1995)
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2381. 'o\IerIzmIn S. Gteenberg ...
n.or- P
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II d1Ildhood. by PH~ GPc.I8b RA
Kyll. SdvlI!< CA 1 .al 2nd eel, NlM YllIiI
1~1 In
6i5e<lses 0/ bIooci
'MopIeIlOC ~ 01 blood. C~
'*'D"lbc:
~ NN YIlIi 1.75-3-168
23S1A.WtIUmiIn S. JiIIfte R l20(6).
Uncommon IUbOCybC dOiorl2el5 1Ile r>llIl.

~ 011I I~ Peci.- 8lDool
eano."5 25Wt>4
l3I2.
w.. PF. 8<tJIlt.y GJ (1994). TIleJlio.
peh:
trypeoeowo:ljll" syrDoone Blood B3
2759-2179.
23U. ~A.~C.~
S SiN A. Jell! ES. Soaber! P. Ra\IeIIo 1,1
l2lXXIl ~ 01 ilIIafrialy e ~
lII"- II ~ USI'l\l eDNA . . . . eeeIIlk:akln 01tMIm as ill . - ~ ..-t.
. b ' ~ ~ W -Blood
........
2314 Wencln D. ~ C. GaaMl P

Coiffler 8, Tily H. CuiIis D 60ehn A.
RO ~ R. .... bowI J
DielKIld J de uascaret A
GInebedlC C (t99n FIlkIAa' BrgoKelI,....
F....-.t A
jtlome Duled willi ~~1.1Il

~ 0189tIM5 n:llded II !he U<kll?I'iII
.-.d ClIIllll&'llOI' WIlh tie Q\iIt(lIIlf 01 d111!rM
lergt B--celI ~ Groupe d'Etude dfIe,
l~<leI'~.JCIi'IOocdI51654
""
2385. "'eng,.p. Fe<rl nio M. Lee W UomI

)P. Stwrm." lB , 5.J<ld>e.zInu'l)' C. Biadiorr
SC tooll AT.~ JC 1'2004/ Acli'<abng mulillll::q of NOTCH 1 .. hurnillll T cal atult IymphOOIa* leukem.. S<:ienee 306. 2~271.
2386. Weng M>. M.blIlarol JM. Yaslu~
Ohtanl Y ArQlngel ML, Lau A. Wa C. Doll
6'anco C, R~~ CG. Sai H, Tobiai J. U y,
Wolle MS. ShachafC, Felsher D, Blackbo SC,
Pur WS Aster JC (2006i c-Mv<; is an irrlp.
lilnI dirlld targe( 0/ Notdl I in T--cell iltUla Iym.
ptloblasbt leukamil!i' ymphom ~ Ganas De_ 2ll
2096-2109
2387. Wanlger MA,Gesk S. EhflIch S, MartrrJ.
SlJ btIro JI, Dyer MJ, S>eberl R. MoI~ P, 6a ~ h
TF(2007). Gai nsofREL In ",nmary mediastinal
B-<:&Il ~ r;oincida with l'II.ICiear <>tOUm<Jlillion of REI. protein, Genes Cho"on"osomts
Caoc&r 46. .4(l6.415
2388. Weniger MA, Melzne< I, Menz CK.
w....-
S, &ct.- /IJ Dorscl1 K, Matlflllm. T.

BlInt1 TF. ~ P l2006i Mutations (J/ the
Uoor eupprelSOl" gene SOC$-1 i1 diUeal
HocIgI<Il1 ~ In ffequelIl and assoaat
l:ld willi ~ pIlospIlo-STAT5 iltCUIUiOOn,
~ 2S 2619-2684
238' . Wenlge! IdA. Pu!lord K.Geslc. S. EMdI
S sw..m Ali, Li"t' L. Uar!fl-8ublYo JI
SMIbeI1 R. 0jW MJ.Uc*er P. BarIl TF (2006)
GaIns of !he ~ BeLllA..a
"-ldlIIr ~ or Ba. 1V. XL) prOWl
. . - . . i1 pnrna')' ~ EkellymltlDma ~ 20 1880-1882.

2310. wn .. ~ C GIIilmn A.
~ PP A&Qri S. SabawlI E
F,
F... B. t.IrAa T. PM M. .&l\.<sl T, Pu:iolI N,
bIzero PI. Pel SAi2006l. t.tner e~
a.ca
,"~alT-<:eI:~,i~C
~ ~
~~II~~B--oII
~ ~ ~ 0 / 3 7 _.......
uSIIQ ~ ~
P'I*ni lllTi'f"
CGH) t _ 21' 246).20169

2394. ~ ~, a.uw..w.t.ooo
IoN. "--CE, D*tlCf. ~ Nt ~
lIJ tail\III A ~ UF, "-tan Te
12OCOl TIlt I'OOIAl:.s 01..-.,. 8 ~ 8
.-.d 020SI08 -...on II ~...-.
an ~ 0/ 1*IOll~ ..........
~ ~ I 1. . ~ ~ & J
~IIO'a846
l3ML ............ $P, NthIf KJ, FIl'Oll L
8alo1oI C. 8:J:rlIIII 8 CMItt> so
c.ro.-'J
M Ger.vge SL l\oICl: .E
~RA.~CO Caflgul lolA (2001)
ADIIIu rJ til """f>tpe . . . j)'IdcI!I P'JO'"
Pf1'OSIS on idI.4I <II nooo aculit mj'lkllll
Ieol<eme '"'" IllIII'III C)'tlgenIliQ .-.d lit
........ IIIr4Iim ~ 0/ fL T) C3'UI
.-.l ....._
grtII4l S -.:!y.
ReI 61
~ II..V~
e.-v..
24.2"12-2"19
2391. Wtt>t P, AItli S, Stn:lm E, ~

Sit MU$IO M.ZIfIUrlII>L, raj... s, l:lomhoIw S.
PilerI S (2004) Nodal~l;OOlI IymD/lOma
iI5$OCiIIted "'" monoc:lorItl ~-dIain and
huv)'<t\UI ~ ~. ~t 0000I
5.381383
2392, W..lI PT, Zoonp'- A PeIIn AC.
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MD P-oIrOltlc K, Pilsd'1l<a P. l.aroIJer C, !laId..s
CD, Wen J, R..,.,. F, POWIi' BL, Kolitz JE,
Llrlllll FlA. Caligouri MA, Mar= G,
~ CD (20081 , FLU D8:l5i18Jli mullJ.
tKlnSare Il5wjat9d willi poor dilMM-frM 11K
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1552.1558.
2397. Whitta kllf SJ, Smith NP (19921,
Diagnostic viJue 0/ T-<:ell reoevtClf bela gene
rtil rTatlQfmenl i/IiIlyM llI1 pilnphenl blood
~ 0/ DlItitlnt1 wtlh \lfYlhrodttmI J
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l.uuaIIo L (1Sl9 1) AnItps of Dell. \JIIIlma,
linddeb T"'" ~ genelll1lllyC(l1i$ ~
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EloorO A. Gr.- .. (1999) Pr..- 0fIglIl 01
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Subject Index
sq- synd rome, 90 . 102

Bp l 1 myeloprolife rative syndrome. 72
8pl 1 stemcel~
S)T'ldr'()'T'l8. 72
Bp t l stem cell syn d rome. 72
Ac ute myeloid leuka emia (AMl), 15, 18 ,

19, 21 -30, 38 ,43,4 7, 50, 52, 53, 57,
59,62, 68-73,77,79, 81 , 88 ,9 1,93,95,
97,1 00, 10 1, 104 , 11()'1 22, 115-1 17,
124-1 44 ,130,132,137, 140, 142,145,
146, 150-152, 155,100.178,365
Acute myeloid leukaemia with abnormal
marrow eosirconns. 111
Acute myeloi d leu kaemia with gene
mutations, 118-123
A
ABL1, 15,24-27,32,35.36.39, 44, 48.
65,69.80,65.86. 15 1, 171
Abnor mallocalizatioo of immature
precur sor s, 91 , tOO
ABA, 325
Accelerated phase . 25, 32. 43. 46
Aci d pho sphata se. 135, 136. 138. 177,
270,273.354
Activ ation-induced draminase. 32 4
Acu te (malignant) m yelofibrosis, 138
Ac ute (malignant) myelosc lerosis. 138
Ac ute ba sophilic leukaemia. 29. 13 7-138
Acu te eryt hroi d leukaemia. 2 1. 22. 27-30,
121 ,125, 130, 134 -135
Acute leukaemia, NOS. 151
Acu te leukaemlas. mixed p henotype , 22.
23,35, 72, 14 1, 150 152, 173

Acu te leukaemias, mixed ph enotype .
S/myeloid , NO S, 152-153
Acu te leu kaemia s. mixed phenotype ,
NOS. 154
Acute leukaemla s. mixed phe notype,
T/m yeloid , NOS, 153- 154
Acute myeloid leuk aemia with

inv(3)(q2 1q26.2);RPN 1-EVI 1, 116-117
1"ro.i(16XP13.1q22); C8FB-MYHl1 , " '-',2
Acute m yeloid leuk aemia with maturation,
13 1-132
Adult T-cellleukaemia;1ymphoma, 163,

28 1-284.306
AF9, 115, 172
AFP.339
Age-related EBV + Iymphoproliferalive
disorder, 243
Ac ute mye lo id leukaemia w ith mut ated

NPM1 ,120-122
Aggressive systemic mastocytosis, 54, 57
nwero-
Acute my eloid leukaemi a with

dyspIasia-related changes, 29, 124- 126
Ac ute myeloid leukaemia with rec urr ent
ge neti c abnor mali ties , " 0-123
t(1;22)(p 13;q13): RBM1 5-MKl1 ,
117-118,136
Acu te myeloid leu kaemi a w ith
t(3 ;3)(q 2 1;q 26 .2); RPN 1-EVI1, 116 117
Ac ute myeloid leukaemia w ith
t(6;9)(p23:q34); DEKN UP214 , 115-116
Acute leukaemiasot ambigl.O.JS lineage, 150
Acut e m yelo id leukaemia with

t(15;17Xq22;q12); PML-RARA, 112114
Acute myeloblastic leukaemia with

matura tion . 110
350
Aggressive NK-eeilleukaemia. 276-277
Ac ute myeloi d leu kaemi a with

t(9;1 1)(p22; q23); MlLT3-MlL, 114-1 15
Acute monocytic leukaemia, 133-134
Acute undifferentia ted leuk aemia, 151

Adalimurnab,
Ac ute m yeloid leuk aemia with mu tated

CEBPA, 122-123
Acute leukaemias, mixed ph en otype with

t(v; 11q23); MLL rearranged, 152
Acute mooot::lIastiC 1eIJ<aema, 128. 133-134
Acute promyelocytic leu kaemia with

t(15;17XQ22;q12); PML-RARA, 112-114
Aggressive eptdermonopc COB positive

cytotoxic
lym phoma, prima ry
cutaneous, 303-304
Acute leukaemias, mixe d ph enotype w ith

t(9:22)(q34 ;q11 .2); BCR-ABL 1, 151-152
Acute megakaryoblastic leuk aemia. 29,

30 ,115-1 17,125,1 3 1, 134 .136-737,
139,1 42
Acute panmyelosis with myelofibrosis, 29.

138- 139
Acute myeloi d leukaemia With minimal

d ifferen tia tion , 130-131
Acute mye loid leukaemia with

t(8 ;21 )(q22;q22): RUNX 1RUNX 1Tl ,
110-111
Acu te lym pho bl astic leu kaemi a, 23, 52,

104,1 15,130,1 42 , 150, 165, 168 , 176
Acute myelomonocytic leukaem ia, 20, 2 1,

29, 112, 115,11 6 ,132-133,134
Ac ute myeloi d leukaemia with

t(16;16Xp13.1;q22);CBFB-MYHl 1, 111-112
Ac ute my elo id leukaemia withoul
maturation, 116 , 131,132
Acute m yeloid leukaemia with 11q23
abnormali ties , 114
t-een
AggessM>NK_
""""""" """""'" Zl6
Agnogenic mye loid met aplasia, 44

Ag ranular CD4+ nat ural kille r cell
leukaemia, t 45
Agr anular C0 4 +C D56 + haematodermic
neoplasm , 145
A ID, 25 1, 324
AKT, 27 1
Alem tuzumab , 27 1
ALK, 163 , 234 , 254 ,255 , 267, 283, 300 ,
30 1,306 ,31 2-319,326,328,334, 349
ALK -po sitive, anap lastic large cell
lym phoma, 31 2-316
ALK positive large B-ce li lymphoma,
254-255
ALK -posjtive ptasrnebrasnc B-cel1
lym phoma, 254
ALL,35.104, 115, 128, 130, 13 1, 135 ,
136, 138, 142 , 151).155, 161 ,165,168171,174 ,178,337-339
ALL with favou rable trisomies, 173
All-trans renroic acid, 113
AL0 17,3 15
Alopecia. 298
Acute my eloi d leukaemia, NOS, 130-139
c -catemn. 102
Acute myeloid 1etJ(aemia, therapy-re!ated,

NOS. 127
u heavy d'lat1 disease, 100, 100-199,214
Sub;ect index
4 29
a naphthyl acetateesterase, 21, 78, 83

(J
naphthyl butyrate este rase, 21, 78
~ltu'(JTt)l'xYloperia.
AML,
see Acute myeloid
100. 107
leukaemia
AML (megakaryoblashcl with

1(1;22)(p 13;q 13). 29, 30
A plastic ana emia in c hildhood , 106
Basket ce lls, 181
Arsenic trio xid e, 114, 117
BCl 2. 14, 15, 159 , 160, 163, 186 , 195,

219,223-227,23 1,235, 236,238,241 ,
242 .250,25 1,264-266,315
Artemi s, 339
As ympto matic (smol de ring ) plasma cell
myeloma , 202
Ataxia-telang iectasia. 27 1. 336. 339
A ML with bal anced Iransloc alio nsl

inversions, 110
ATM (ataxia telangiectasia mutated ),

182 , 231 , 27 1, 336 . 338 . 339
AMLWlIh cytoplasmic ruc:IeophosmIn, 120
ATAA. 30 , 113 , 114
A ML with inv(3)(q21q26.2), 29 . 30 ,
Aty pical chronic myeloid leukaemia, 26.

38. 52 , 7 1,85
116-117,125
A ML with 1( 15 : 17)(q22;q 12), 112
A ML1 ,36. 104. 111, 131, 170. 172
Atypical ch ronic myeloid leukaemia. BCRAB L 1 negative , 8lJ.81

AuernDds. 78 ,83.89,91.92.97.100,
10 1.11 0 .11 2-115. 11 33 .1 35
AM M,44
Amyloidoma .2 10
Amyloidosis. primary, 200 . 2Q9.21 1
Autoirrvnune Iymphoproliferative
synd rome . 165.336.339
Ana plastic large cell lymphoma. ALKnegative. 317-319

Anaplastic large cell lymphoma. ALKpositive, 312-316
A nap lastic large cell lymphoma.
'common pattern", 312. 313

Anaplastic large cell lymphoma.
'composite pattern", 313
Anaplastic large cell lymphoma.
"Hodgkin-li ke patt ern ", 3 13
Anap lastic large ce ll lymphoma. hypoce llular, 3 13, 3 15

Anaplastic large cell lymphoma,
"lympfohisticc ytic patt ern ", 3 13
Anaplastic large ce ll lymphom a, "small
cel l pattern ", 3 13
Anap lastic large ce ll lymphoma, p rima ry
cu taneous, 300-3 0 1
Ana plastic lym phoma kinase ,
see A LK
Anne xinA 1, 192, 193

Angiocentrc ilTm.JnoproIiferative lesion, 285
Ang iocentric T-cell lymphoma, 285
B acute lymphoblastic leukaemia, 150,

16&170
Bilinealleukaemia. 150
B lymphoblastic leukaemia, 26 , 165 , 168
ButlE!d<. grarule, 357, 358,300. 362. 364. 365
B lymphoblastic leukaemia/lymphoblastic
lymphoma, not otherwise specified,
168-170
Blast phase, 23 . 24. 30. 32, 65, 112. 117,

138,151 ,152
B Lymphoblastic leukaemiaJIymphoma
w ith hyperdi ploi dy, 173-174
Blastic NK-cel1 lymphoma, 145
B Lymphoblastic leuk aemiaJIymphoma

with hypod iploidy, 174
Blastic p lasmac ytoid den dr itic cell

neo plasm. 29. 15, 141 , 1450147
Blastoid mantle cell lymphoma, 229 , 233
B08. 1, 251, 267, 324 , 326 , 328
Borrel ia bu rg do rferi, 166 , 214
8 Lymp hob lastic leukaemia/lymphoma

with t(5;14Xq31;q32): 1L3-IGH, 174- 175
8 Lymp hoblastic leukaemia/lymphoma
with t(9;22Xq34 ;q11.2): BCR-A8L 1, 171
B Lymp hoblastic leukaemia/lymphoma
with 1( 12 :21) (p 13;q22); TEL-AML 1
(ETV6- RUNX1), 172-1 73
B-ce il lymphoma , unclassifiable, With

features intermediate be twee n DLBC L
and Bu rkitt lymphoma . 234 . 265-266
4 30
BIasOC nattxaIkiller~, 145
B Lymphobla stic leukaemia/ lymphom a

w ith t( 1;19 ) (q 23:p1 3.3 ); E2A- P8 X1
(TCF3-P8X1 ), 175
Angiotropic large cell lymphoma, 252
Annexin A 1 (ANXA 1). 160. 186 . 189 . 190
Biphenotypic leukaemia, 150 , 151. 154
B Lymphoblast ic leu kaemiall ym phoma

w ith recur rent genetic ab normalities,
17 1-175
Basic leucine zipper fac tor. 28 1
API2/MALT1 .163
BDCA-2ICD303, 146
Bence Jones pro tein , 197,205
BF1, 287 , 304
Angiolymphoid hyperp lasia , 52
Ann Arbor staging system, Cotswald

revision, 322
BCR-ABl l , 15,24-27,32.35,36,38,39.
43 , 44 ,47.48, 5(}.53 . 64> 65. 69-7t . 76.
79-86,138, 151. 152. 171
B Lymphobl astic leukaemiallymphoma

with t(v:11Q23); MLL rearranged, 171-172
Ann Arbor staging system, 322
BCR , 15.23--27 ,32.35,36,38,39,43,

44 ,47,48.50-53,64.65.69-71 .73,76.
79-82,84-86,138. 151, 152,171,180,
182, 237, 251
Benign monoclonal gammopathy. 200
Angio immunob lastic r-eef lymphoma .

162, 163 , 166 , 177, 196 , 283 , 30 7, 308 ,
309-3 11,351
Anisopoik ilocy1osis,45, 100, 105, 138, 143
BCl l 0 , 195,217
Benign cephalic histiocytosis, 366
Anaplastic large cell lymphoma, 162, 163 .
234.255,289.290.294,301 .306,3123 19.328.349.355
BCL6 . 159, 160, 162. 163, 186,219,223,

224.227,23 1.235-237 .241,242.244,
250 .251,261 .264-266.307,3 15,316,
324,325,340.347.348
B-ceil lymphoma. unclassmabre. with

featu res intermediate between DlBCl
and cl assical Hodgkin lymphOma, 234 ,
267-268
B-cell prolymphocytic leukaemia. 181.
183-184
BMI1 , 231
Bod y ca vity ba sed lymphoma , 260
Bud d-Chia ri synd rome , 41 , 48
Bullous mastoc ytosis, 55
Burk itlleukaemia variant, 263
Burkitt leukaemiaJlympho ma , 168
Burkitt lymphoma, 141. 160 , 163 , 165.
166 , 176, 233, 235, 262 -264, 266, 337340 ,343,348,351
Burkitt-like lympho ma, 265, 266
C
CIEBptJ. 315 . 316
CA E, 2 1. 57 , 79. 130 , 132 , 134-136, 138,
140
CAlM-AF10, 178
Campyfobacter ieiuni. 166. 198 , 214
Canale-Smith synd rome , 339
SubieCl index
Carcinoma showing thymus-like element

(CASTLE). 364
castleman disease. 213, 258.309. 355. 363
CBFA, 111. 112
CBFB, 28, 29, 111, 112
CBFB-MYH1 1,29, 111, 112
CCAAT/enhancer binding protein , 118
cCD22. 131, 151
cCD79a, 131 . 151
CCND1, 14. 186. 195, 206, 229 . 23 1
CCND3,206
COla. 161, 177,270.355.357.358.362,
364-366
C02. 56, 57. 62. 70. 72, 79, 112. 113,
131.132.1 46.154.161 .163.177,246.
270.274,277.279.283.287.297,299.
300.303,304,3 10.315.318.326
coo. 23 . 146. 150. 154, 158. 161-163. 177.

224.238.246.248.254.267,270,271.
273.274.277,279.283.287.290,293,
294.297 ,~30 1 ,3O3 ,304 .3O6,308 ,
3 10,31 4.318.324.326.338,343,364
CD4.79, 112, 114. 131-134. 140. 142.
144,1 46.161-163,177,224.246,248.
255,262.267,270-273.279.280,283.
287.290.293.294,297,298.300.301 .
~08 .3 10.31 1 ,3 15 .318.324 .325 .
~338 .340. 349.355 ,357 .360.365
C0 4 positr ve. primary cut aneous smalV

medium T-eeillymphoma. 304-305
C05. 79. 146. 154. 158. 160-163, 177,
180.1 81.1 83.1 86. 189,192.195. 197,
216.2 17.2 19.223.227.23 1.234-236,
238.253.273.274.283.287.290, 293.
297.299, 300. 303, 304,306-308, 310.
315.318.338
CD7, 23.101 .116.122.125,1 28,1 31134,137,142,144 .146.1 54.161, 163,
177, 246, 270, 271. 273, 274. 283.287,
290,297 , 299, 303, 304, 306-308
CD8. 161 163, 177. 237. 248, 270,271 ,
273, 274. 278, 280, 283, 287. 289-291.
293-295, 297. 298, 300. 301 . 303, 304.
306-308,310.3 15,31 8,324, 325,336338, 349
131-134.141 .142.144 .1 50. 366

CD15. 61,79, 101.1 10. 112, 113, l 16.122.
131-134. 142. 144. 152,1 72. 238. 244.
248,250, 267.300,306,307,315,319,
324.326,327.333,347,349.351,357
C016,61. 146. 155, 161. 163,273,274,
276.277,287,355
C01 9, 110, 131, 132, 146. 150-152. 169.
17 1. 174. 18 1. 183. 195. 201. 205. 223.
235.250.261.264,266.338.348
C020. 15, 146, 153, 160, 169, 173. 181.
183,186,189.190,192,195.199.205,
208.216.223.227.235-237,241.
242,244,246,248,250,254 .255,259,
264 .~268 .306.307 .324 .326 .328,
333.338,344,347-349.351.364
C02 1. 162.216.220.221 ,224.227,311 .
324.333.355.357.362.364.365
C022. 138, 150. 152. 100. 181, 183. 189.
100. 1ro, 195, 223. Z35. 241. 250, 264 .266
C023. 70, 160. 180-182. 186. 192. 195,
216,219,221 ,224,231 ,250,311,362,
364.36S
C025, 56 , 57, 60-62, 70. 72, 138, 163.
171,1 89,1 90, 192, 195, 283, 287, 306,
315,338
C056,23, 79, 101,11 1, 113. 114. 122.

125,1 28,1 3 1, 132,134 ,1 40, 142, 144146, 155,1 58, 16 1-164, 177. 201, 203.
205,257,274,277,279,280,287,28929 1,293-295,300,303,306,
307
C057, 161-163 . 224, 255, 273. 274. 277,
287,324.325.338
COOl . 23, 101. 105. 106, 116, 117, 136,
139, 140. 142. 144
CD64 . 79. 112-114. 116, 122, 131-134.
150.355
C068. 61, 79. 121, 133. 134. 140. 146.238 .
315,327.355,357,359 .362.364~
CD71,92, 135, 142, 144

C077,264
CD79a. 110, 146. 150-152, 160, 169, 177.
181.183.186, 195.205.216.223.227.
235,241,242,244.246,250.251 ,254.
256,259.266.267.307,324.326,328,
338, 348, 364
CD94/NKG2 . 273. 275
CD99, 140, 177
CD103 . 160. 186, 189. 192. 195.290
CD27,259
C0105.92
C030, 140, 163, 164,235,238.244.246.

248,250.254.255,257,261,267,283.
287,290, 297,298,300,301,304.306,
307.312-3 15.317-3 19.324,326-328,
333,334, 338.342.347-349.351,355.
360,362,364, 365
CD 117, 57, 59, 61, 62, 92, 101, 107. 112114.11 6.1 31-135,1 38, 140-142,144 .
146, 150. 153. 171, 177,205
C0 30-positive Iymphoproliferativ e
disorders, primary cutaneous, 3O()..30 1
C0 138. 160. 195. 197, 201, 204, 205.

235.238,246. 254,256,259.328,348
C033, 23, 61, 79, 101, 110,11 2- 114.1 16,

117. 121, 122. 125, 128,131 -134,1 37,
138, 141.142, 144.146,1 50,1 53,169 ,
171. 177,357
C0 161, 155, 275
CD34, 20, 23, 34, 44, 45, 47, 65, 79, 92,
96,100.101 ,105-107.11 0.11 2-114,
116,117.121 ,122,1 25,128.1 30-135,
137,138,140,142,144,146, 151,169,
173, 175,362,364
COK6, 186
CD35.216, 227, 311, 355,357,362 ,364. 365

C038, 101 , 116. 125. 131, 146. 151, 160.
169.182, 192, 195. 20 1, 205. 235. 256.
259, 264
COO. 23. 61,138.173,175
C04O, 160, 336 , 339
COto. 150-152. 159, 160, 162- 164, 169,

171.174. 181. 186. 189, 192, 195, 197,
205.216.217.219.223.225.227.231,
235.236.241.242.244,250.253.264,
266,267.306.307.31 1,348
C04OL, 324, 339
C014. 23. 6 1. 79. 81, 112.1 14.121. 122.
C054, 250, 253
CD26,299
COB positive cyto toxic T-eeill ymphoma,

rimary cutaneous agg ressiv e
epidermotropic. 303-304
C011b, 23.101 ,1 12-114, 121. 122, 131134. 138. 277
C052, 205. 270. 271, 306,307
CD41. 105. 100, 116.1 17, 136. 139.1 42. 144

CD43 . 79. 146. 160, 181. 186. 216. 219.
223.224.227,231 ,255.264 .287,306.
3 15,318,326
CD45 , 61,1 17.1 37.1 69.173. 254. 255.
261,267.315,324 ,326,327,339.349.
357,359.362.364 .365
CD123,79. 138. 140. 146, 189. 192. 355

CD134,324
COl 63. 79, 133.134.141.355.357 .365,366

CDK4, 178, 231
COKN2A, 178, 228. 241, 242,298, 349
CDKN2B, 228, 242
CEBPA. 23, 28-30, 118-120. 122. 123. 125.
126
CEl , see Chronic eosinophilic leukaemia
Ceutvoes.
- dou ghnut. 3 12
- clear, 306
- flame, 205
- Gaucher-like. 205
- hallmark, 312, 3 13. 3 17
- hand-mirror, 169
- Hodgkin, 238 , 247, 326 , 327, 329
- l&H . 323
Subject index
431
Lacunar. 267, 326, 327, 330 . 333
- Lancenans. 35 5. 358. 360, 365

lP, 238. 323325, 333
- morula. 205
Motl . 205
plasmac ytoid dendritic, 78, 79,140,
145-147, 151, 155,294,355
- popcorn, 323
Pseudo-Gaucher. 33
Chronic rnyelomonocytic leukaemia with

eosinoph ilia as soc iated with t(5:12). 71
Cyclin 01 , 18 1. 183. 186, 189. 205, 217,

2 19,231,235
Chronic neutrophilic leukaemia (CNl). 23 ,

25.38-39
Cytokera tin, 254, 364 , 365
Cvtokeraun-oosinve interstitial reticulum

cell tumour. 365
Chronic NK-celilymphocytosis, 274

Chronic NK-Iarge granul ar lymphoc yte
lym pho proliferative disorder, 274
Chronic pha se. 26, 32, 70, 72, 73, 85 , 137
Chymase, 57,59,61 ,62
Dacryocvtes. 42, 47, 138, 143
Reed-Stemberg. 182,234.247,250,261 ,
300.3 10.313.322,327,337,347,364
CIMF, 44
Darter's sign. 54, 55
CLA, 146,297,299,3OO
DBA.44. 189. 190-193
Reed-Stern berg-like, 243, 306, 310, 337,
Classical Hod gkin lymphoma. 164. 165,
Deep juveni le xanthogranuloma , 366
347,348,349
1 82, 25O , 267, 31 1 , 31 2, 31 7 , 322, ~
334.338,339,343,349
DEK.29. 115. 116
- Sezary. 299
- Touton, 366
CereOOIorm nJCIeus, 270, 296, 297, 298 , 3)1
Classical t-t:O:j<rIlyJ l.n:ma type PTlO,349
DEK-NUP214, 29, 115
Clattvin-AlK, 255
Dendritic/hisliocytic sarcoma . Laroerhans cell type, 360
Cnarcot-tevoen crystal, 52, 70, 359
ClL
Chediak-Higashi granules , 90, 92, 100
Clock-face. chromatin pattern, 205
Childhood mverodvsorasnc syndrome.

27, 104- 107
Cl TC, 254 .255. 3 15
Chlamydia pneurromae. 166

Chlamy dia psnta cr. 166 . 214
Chlamydia
uacromans. 166
Chlorom a, 140
Chronic ac tive EBV infec tion, 278
Chronic eosinop hilic leukaemia (CEl). 23,
25,26.51-53.59. 6&71 ,73
Clear cells. 306
see Chronic lymphocytic leukaemia
CLTC-AlK, 254 . 255

Clusterin, 3 15
C-MAF,324
CMl, see Chronic myelogenous
leukaemia
CMMl, see Chronic mveiorronocync
leukaemia
CMMl with eosino phili a. 27, 7 1, 77
Chronic eosinop hilic leukaemia with

F1P l ll-PDGFAA, 69
CMMl- 1, 76, 78
Chronic eosinop hilic leukaemia. not

otherwi se spec ified. 5 1-53
Coeliac disease, 289, ?90
CMM l -2, 76. 78, 91
Chronic granul ocyti c leukaemia. 32
Collagen fibrosis, 42, 44. 46, 48, 49
Chronic id iopathi c myelofibrosis, 44
Common variab le immunod efici ency, 336
Chronic lymphocytic leukaemia(CLl).

15,159,164, 180- 182,183 , 186,191, 194,
196,197 , 229, 233, 270, 272. 351
Core binding factor, 111, 112
Chronic Iymphoproliferati ve d isord ers of

NK cells, 274-275
CREB,283
CoREl . 228 , 267
Crohns disease, 292, 350, 35 1
Crosti's disease, 227
Chronic myelog enou s leukaemia. 18, 2327,3237,39.44.50.53,65.7 1, 79,

104. 112, 117,137, 138, 150-152, 171
Cryoglobulinemia, 166, 194. 195
Chronic myelogenous leukaemia, BCA ABl l positive, 32-37
CTNNA1.102
Chronic myeloid leukaemia, 32
Cutaneous anaplastic large lymphoma. 300
Chronic myeloid leukaemia, atypic al,

BCR-ABl 1 negative, 80-8 7
Cutaneous ma stoc ytosis, 54, 56, 57-58
Crow-Fuka se syndrome. 2 12
Cryptococcus meningitis, 284
Cutaneous yO T-cell lymphoma . 162
Chronic myelomonocytic leukaemia, 26,

27,32,35,52,56.71,76-79. 8 1.82.
85,91, 128,133,134 ,145
CXCl13, 162, 224, 306. 30 7, 310, 31 1
Chronic myelomonocytic leukaemia with

eosinophilia, 26. 68
Cyclic AMP resco-se element bI'ldIng. 263
432
Subject index
CXCA5, 162, 189
Cyclin D, 160. 206, 231, 235
Oeodnnc cell sarcoma, follicular 363-364

Dermatitis herpetiformis, 289
Dermatopathic lymphadenopathy, 297
Diamond-Blackfan syndrome, 88
o.fIuse cutaneous mastocytosis. 54. 57, 58

Diffuse follicu lar lymphoma. 222
Diffuse large B-c eil lymp homa (DlBCl).
141, 160, 182,195, 198,216-2 17,220,
222-223 .233-237.238,240,242,245.
248-250 .252,256, 267,310-311 ,315.
326, 336. 340-34 1, 343, 348, 35D-351 ,
355
Diffuse large B-c eillymphoma. activated
B-cell-Iike, 235, 236
Diffuse large B-ceil lymphoma. anaplastic variant, 234

Diffuse large B-ceil lymphoma assoc iated
with chronic inflammation, 234. 243,
245-246
Diffuse larg e B-cell lymphoma, cen troblastic variant, 234
Diffuse larg e B-cell lymph oma , EBVpo sitive. of the elderly, 243-244
Diffuse larg e B-cel1 lymph oma,
immu noblastic variant, 234
Diffuse large Bccetllymphoma, germinal
centre Bc eu-uke. 234, 236
Diffuse large B-celilymphoma. not
otherwise specified, 233-237
Diffuse large B-c eillymphoma, primary
cutaneous, leg type, 242
Diffuse large B-c ell lymphoma. primary. 01
the cent ral nervous system, 240-24 I
Disseminated intravascular coagulation .
112,1 14
Dissem inated juvenile xanthogranuloma .
366-367
DLBCL associated with chronic

inflamma tion, 234, 243, 245-246
Ervmroreukaemta. 29, 134-136
Follicula r dendritic c ell sarcoma, 363-364
DNA tooorsonerese II, 127
Essennarttuomoocytnaemta. 18,23,25,
39,4 1, 44,48-50, 64,85,104,139
Follicular dendritic cell sarcoma, inflammatory pseu dotumour-like variant. 364
Dohre body, 95
ETV6-PCX3FAB, 71, 72, 79
Doughnu l cells , 312
ETV6-AUNX1,172
FOllicular lymphoma, 160, 165, ~226,

351,355
OaNnsyndrcme, Xl, 104.117, 136, 142,144
EVI-l ,36
Follicular lymphoma, diffuse, 222
Dutcher body, 195
EVI1-AUNX1, 117
Follicular lymphoma , extranooai. 225-226
Dwarf megakaryocyte, 32
Extracut aneous mastocytoma , 54. 57, 6 1
Follicular lymphoma, in situ, 222, 226
Extramedullary haematopoiesis (EMH),

40, 43-48, 50
Follicular Iyrnphc:ma , intrafOllicular reoptasia. 226
Extramedullary myeloid tumour, 140
Follicular lymphoma. paediatric, 225
Dyskeratosis conaenua. 88 , 106, 107
E
E2A-PBX1, 175
E47,il-iEB.178
EBEA,1 46.236,246,248.256.257.259.
279 ,280,287,315,319,328,330.331 .
341 ,346,347 ,363
prmary ntestJnaI, 225
Extranodal follicular lymphoma, 225
Follicular Iymptloma,
Extranodal marginal zone (B-cell) tym..

phoma of mucosa-associated lymphoid
tissue , 214-217
FOXP1,227
Extranodal NK/T-celilymphoma. 146, 163,
Fried-egg appearance. 188. 189,313
166,248 ,276,277.2~287 .349
EBNA-1. 245. 328
Extranodal NK/T-celllymphoma, nasal

type, 285-288
EBNA-2. 244-246. 285. 328
Extraosseous plasmacytoma, 208
FOXPJ, 163,283
Franklin disease, 196
Fulminant EBV+ t-een tymphoproliferative
disease 01 childhood, 278
Fuloronln_syncl<are,278
EBV. see Epstein-Barr virus

EBV positive T-ceillymphoproliferalive
disease (LPD) of childhood. 166, 278
EBV positive T-ceillymphoproliferalive
diso rders of childhood, 276 , 278-280
EBV-associated Bcenlymphoprouteretlve
disorder of the elderly, 243
F
Faggot cells , 112, 113
Fanconi anaemia, 88, 106, 107
F~.
107, 165,272,277,287,336,338,339
Gamma heavy chain disease, 195-197
t-een
lymphoma,
Gamma-delta ("to )
primary cutaneous, 163,302-303
GATA1. 142. 144
EBV-encoded small nuclear ANA, 146
Fascin . 3 15, 362, 364, 366
Gaucher-like cells, 205
EBV-positive diffuse large B-ceillymphoma (DLBCL) of the elderly, 243-244
FASL, 272, 336, 339
Generalized (non-lipi demic) eruptive

histiocytosis, 366
Ectropion. 299
Fatal EBV-assoc iated haemophagocytic

syndrome. 278
EGR1. 102
Ferritin, 44, 48, 96
EMA,
see Epithelial membrane antigen
Embryonal carcinoma, 3 18
Ernpenpolests . 49
Endomyocardial fibrosis, 51, 69

Enteropathy-associated T-cell lymphoma,
289-29 1
Eosinophilia, 15,23,25,26,27,32,51-53,
55,57,60,62,63,68-73,76-79,8 1,
174, 196,219,282,283 ,306
Eosinophilic granuloma, 358
Epidermotropism, 270, 297, 299, 303, 304
Epithelial membrane antigen (EMA) , 163 ,
238,254 ,257,26 1,300,306,314,315,
318,324,326,328.357,362,364
Epithelioid
nrsuocvte. 185. 307
FGFA1, 15, 23,25, 26,39.5 1-53,64, 68,

72, 73, 85, 150, 177
Glycophorin, 23, 92, 135, 136, 139, 140,

142, 144
Glyco protein, 106, 117,1 37
Gout, 38
FGFA3/MMSET, 205, 206
Graft versus host disease, 165
Fibrob lastic reticula r cells, 355 , 365
Granulocyt ic sarcoma, 140
Fibroblastic reticular c ell tumour, 365
Granulomatous slack skin, 298
FIP1L1-PDGFRA, 51, 52, 62, 68-71

Rame c ells, 205
Granzyme B, 79, 146,1 63,272-274,287 ,

293-295,300,304,3 15,318,326
Rorid follicular hyperplasia, 225, 343, 345
Granzyme M, 162, 273, 274, 293
Rower c ells, 282
Gray zone lymphoma, 165, 250, 267
Rower like c ells, 3 13

FLT3, 14,23,28-30,1 14, 116,1 18,
119,122, 125. 126, 131, 147
FLT3-ITD, 14, 114, 116, 118, 119, 122
FLT3-TKD, 116, 118, 119
Epstein-Barr virus (EBV), 82, 145, 166.

182,233,240,245.247.260.274.276,
285.294.303.306.322.329-33 1.336.
340, 343,350. 354, 363
FMC7. 181. 182. 193
Erdhern-Chestee disease, 366
Follicular oen onnc cell meshwork. 159
Follicula r dendritic cells , 159, 216, 219,

222,223,227.231 ,238,306,308-311 ,
323,324,333,355.357.360.362-365
H
Haemog lobin, 23, 40, 41, 44, 48, SO, 65,
82,84 ,94 ,98, lOS, 122, 135, 136, 139
Haemophagocytic syndrome. 163, 252,
276-278,286. 295,313,.D3, 339, 354 ,
eeo
Hairy cell leukaemia. 44, 59, 158, 160,

186 , 188190,191 , 192 ,272
Hairy cell leukaemia-variant. 192-193
Subject index
433
Hairy cell leukaemia, prolymphocytic

variant, 192
Hodgkin lymphoma. nodular lymphocyte

predominant, 322 , 323-325
In situ follicular lymphoma . 222
Hallmark c ells, 3 12, 313 . 31 7
Hodgkin-like anaplastic large c ell

lymphoma, 267
Indeterminate ce ll t ustlocvtos's . 365
Hand mirror c ells, 169
Hand -SchOller-Christian disease, 358
HQX l1 , 177. 178
Hashimoto thyroidi tis. 165. 215, 216, 219
HQX11L2, 177. 178
Heucobacter pylori, 166, 214 , 217

Heucobacter pylori gastritis , 216
Hepat itis C vir us. 166 . 194,218

Hepatosple nic
t-een lym phoma. 162 . 163,
166,292293, 343
Hereditary x-nreeo sid erobiasnc
anaemia, 96
HES6.147
HHVB.
see Human herpesvirus 8
HHVB-assoc ialed multicentric Castleman

d isea se, 254-259
HHV8 positive rn.iticentric Castleman

disease, 258
HHV8 positMl_
t-een leukaemia
HTLV-1 associated myelopathylt rop ica l

spastic paraparesis. 281
Indolent systemic mastoc ytosis , 54, 57

Ineffective
88 , 92
haematopoesis. 15.26,40,
Infec tiOus mononuc leosis . 243-244 , 278,

326 .336-337, 339 . 343
HTLV-I associated arthropathy, 28 1
intec tcce-rrcoonucieose-uke PTLO. 34S
HTLV-lasso::::iated ~, 281
Inflammatory bowel d isease . 6 1,350
HTLV-I assoc iated lym phaden itis . 28 1
Inflammatory myolibrobl astic tumour. 3 15
HTLV-I associated nephropa thy, 28 1
Infliximab . 292 . 350. 35 1~"
HTLVI associated uveitis , 28 1
Interd ig itating dendritic ce tl sarcoma ,

367 -362
Human her pesvirus 6 (HHV8) , 166, 2 13,
234.257-260. 340.343
loreteco-c dependent molecule MxA, 146
Human irrvnunodeficienc y vi rus (HIV) ,

101 ,165,166, 247. 255 , 257-260.326,
33 1. 334 ,340,
Interferon-a ,37
Hig h hyperdip loid A LL. 173
Human r -cenieukaemra virus type 1

(HTLV-1), 166 ,270,26 1,263
Intestinal T-eeil lymphoma. 289
High.grade MALT lymphoma, 2 16
Hydroa vac ceutorme-ree lymphoma, 280
Intravascular large B-cel11ymphcma 234.
Histiocyte ric h/T-celt -rich la rge B-cell

lym phoma. 238
Hydroa vacciniIcmle-like T~II
Histiocytic cyto pa thic panniculi tis , 355
HypercalcerTia. 163, 200-203, 200
Histiocytic medullary reticulosis . 355
Hyperdiploid ALL. 173
tynVona. 258
Hgl eodotheIiaI venJIe (HEY),n-31 ' , 355
Indeterminate dendritic cell tumour, 365

Indolent large granular NK-celllymphOproliferative d isorder. 274
HRX, 114
HTlV-1 , see Huma n
virus type 1
In situ Me L, 229 , 230, 232
lntestmat malig nant histiocytosis , 355

Intrafollicular neoplasia. 226
252-253
~homa ,
166
inv(3 )(q21q 26 .2). 30, 50, 93 . 110. 116,

117. 136
inv( 16)(p 13 .1q 22), 29 . 30 , 104 . 110-112.
118 ,119,1 22, 129
HistiOCytic sarcoma, 35&35 7
Hypereosinophilic syndrome. 51
Histiocytosis X, 358
Hyper-lgM syndrome, 336 , 339
HIV, see Human immunodeficiency virus
Hypodiploid AL L, 174
IRF4!MUM1. 160, 223 ,227, 235,236,241 ,

242 ,244.246,250, 253. 255, 266,324.
328, 348
HIV infection. 247, 256-258, 260, 262, 326,

331,334,340-342
Hypo plastic MOS, 92
Isochromosome 17q , 27 , 79, 81
HIV-related mye lopathy. 101
HLF, 170, 175

HMB45, 357, 364
Hodgkin ce lls, 238, 247, 326, 327, 329
Hod gkin disease, 322
Hodgkin lymphoma , 15. 52 , 164 , 165,
166,180,182,190,19 1, 195,229,233,
238, 248, 250, 267, 268, 292, 29 7, 30 1,
307 -309 ,3 12,3 13,321-334 ,337-340 ,
347 ,349-351 ,355 ,364
Iatrogen ic immunod eficienc y-assoc iated

Iymphoproliferative disorders, 350-351
JAK2, 14. 19 , 23-27, 39-41, 43- 45. 47-50,

53,62 ,64,65,76,81,85,86, 102,251
Id iopath ic cytopenia of undetermine d

significance, 94
JAK2 V6 17F, 24 , 25, 27, 40 , 41 , 4345, 4750 ,62, 64 ,76,81 ,85,86. 102
Idiopathic hypereosinopnilic syndrome , 26,

5 1,52
JUNB, 299
Idi opathic myelofibrosis, 44
J uvenile myelomonocytic leukae mia

(JMML), 18 ,26,71 ,82-84. 104.366
Hodgkin lymphoma , cl assic al, Iymp hoc vte-c epreteo. 322. 334
Id iopathic paraproteinemia, 200
Juvenile xanthograruloma, disseminated.
Hodgkin lymphoma. cla ssica l, lym p hocyte-rich , 322, 33 1, 332-333
IKARQS, 325
Hodgkin lymphoma. classical. mixed cellularity. 322, 326. 330, 331, 334, 341, 35 1
lL3 A, 142, 144
Hodgkin lym phoma. c lassical, nodular

sclerosis , 165 ,267. 313. 322.326,327,
330, 331. 334 ,341
434
Subject inoex
366367
Id iopathic throm boc ytosis. 48

IL3 , 52. 72 , 174
IL6 , 189. 195. 245 . 259 . 340
IL10 , 245 . 340
lmatinib.1 5.36.37.39.62.68-72, 152, 171
K
Kapo si sarcoma. 258 , 259
Kapos i sarcoma herpe s virus (KSHV)
pos itive ptasrrebrastc lymphoma .
258-259
Keratin , 357
LM 0 2, 177,236
Mastoc ytosis, systemic, 58--81
Ketron-Good man type, 298
LMP1, 244, 248, 257 , 26 1, 280, 285, 287,

315,319,328,33:1,331 ,333,334.338.
341,345,346
MOS with myelofibrosis , 92
Ki6 7, 186 , 224. 229, 232. 235 . 237, 257 ,

264 ,265.266.307,324.328.357,300.
362,364,365
Killef' irrm..n:Jg1obul1l'Wi<e receoto- (KIR),

161. 2 73 . 274. 293
lobular pann icu litis , 294
LP cells, 238, 323-325, 333

Lupus profundus pan nic ulitis. 294
MOS,
see Mveroovsorast'c syndrome
MOS/MPN , see Myelod ysplaslic/m yelop roliferative neop lasms

MOS/MPN, unc lassifiable, 85
MOS. uncrassltebre. 89. 90 , 94 . 98. 103
KiM4p ,364
LYl1, 177, 178
KIT, 23, 25 , 28, 56, 60-62, 111-112, 118119,287
f...1ecflastJnal germ cell tl..mC:U", 136, 356, 357
Lympho bl astic lymphoma. 15,68,70 ,72,

73 ,141, 168, 176, 265 , 266
Mediastinal large B-cell lymphoma, 164,
Lymphocyte-dep leted classica l Hod g kin

lym phoma, 334
Med ullary plasmacytoma, 202
L
L&H cells, 323
Lymphocyte-rich cl assical Hodgkin

lymphoma. 332 -333
165 , 236 , 250-25 1

Meh::Mexate, 24 1. 273, 338, 350, 351
MGUS , see Monoclonal g ammopathy of
undetermined significance
lymphocytic lymphoma simulating hairy

c ell leuk aemia , 19 1
MICrocephaly. 339
lymphoepitheliallesion, 199 , 214-217
MItogen activa ted protein kinase, 24
Lac unar ceHs. 267. 326-327,330, 333
lymphoepitheliaJ sialadenitis, 165,2 15,216
LANA- 1, 259
lymphoepithehoid ,308
Mixed cellularity c lassica l Hodgkin Iymptona. 322. 326. 33), 331, 334 , 341, 351
lymphogranulomatosis. 322
Lactate dehydrogenase (L DH ). 44. SO.

63 , 122 . 178.207.246235,264.276.
282.284.298.341 .
eel ""<>eyt<>;is, 355, 3S8.J8)

Langerhans cell sa rcoma, 358, 360
L~ asso::iated WIth HIV rlecticrl,
Langerh ans cells. 355 , 358. 360. 365

Langer in, 355 . 357 , 358 . 362 . 365, 366
Large 8 -eell lymphoma arising in human
her pes virus a-assoctateo multicentr ic
Castleman d isease , 258-259
l arge 8 -eell lymphoma . AlK pos itive.
254-255
l arge 8 -.c ell lymp homa arising in HHV8associated rnncennc Castleman
disease. 2S4-2S9
l arge 8 -c ell lymp homa exp ressing the
AlK kinase and lack ing the t(2 :5). 254
lyrrV'onatoid granulornatosis, 234 . 247249.337

Lymphomatoid pap ulosis . 3IXI, 30 1
Lympho plasmacytic lymphoma , 59, 160 ,
166,186, 191, 194- 195, 196, 200 , 2082 10,219.339.35 1
l arg e B-cei llymphoma rich in t -eens an d

simulating Hodgkin's d isease, 238
large B-ceillymphcrna with Hodgkin's
features, 267
l arge gra nular lym phoc yte leukemia. 339
LAT, 137. 140 , 146
Mixed p henotype acute leukaem ia, 22,

23 ,35,72,1 41 ,150- 152,173
Mixed p henotype ac ute leukaem ia,
B/myeloid . NOS, 152-153
MIxed p/"lerK:1ypeacute~. NOS. 154

Mixed pherUype acute ~,
TJmyeIoid, NOS. 153- 154
t ymobop ronteranve di sea ses assoc iated

with primary irmune disorders. 336-339
Mixed phenotype ac ute leukaemia with

t(9;22)(Q34;q 11.2); BCR-ABL1, 151-152
Ly ~p hoprol ife rativ e
Mixed phenotype ecute leukaemia with

l(v:l lq23) : Ml l rearranged . 152
l ysozyme, 79 , 134 . 355
MLLENL, 115, 172
dis orde rs , iatroge nic

Immunodeficiency-associated , 350-351
Ml LT1, 115
large 8 -cell lymphoma , intravascular,

252-253
large 8 -c elllymphoma, primary
medi astinal (thymic), 250-25 1
Mixed myeloproliferatiVe/ myelodysplastic syndrome, unclassifiable , 85
Ml LT2, 115
MLLT3 , 29, 30, 114, 115
Maculopapular cutaneous mastocytosis, 57
MLl T3-MlL, 29 , 30 , 114
Ma lignant histiocytosis, 356 , 360
MLl T4 , 115
Malignant histiocy tosi s X, 360
MLLT10 . 115
Malignant mid line reticu losis, 285
Monoc lonal B-ce l! lymphocytosis, 180
MALT lymp homa, 160 , 163 , 166, 198 ,

209 .214-21 7, 2 19.341 ,343, 34 7, 351
Monoc lonal gammopa thy of undetermined signi ficanc e (MGUS), 200-202.

206.21 1
latent po lycyth aemia vera, 4 1
Mantle cell lymphoma. 160, ~232
LATS2, 147
MAPK, 24 , 26 , 82, 84 , 195
lCK, l77
Mast cell d isea se, 54
Lennert lymphoma. 308
Mast cell leukaemia, 54 . 57 , 6 1
Lethal midl ine granul oma . 285 , 286
Mast c ell sarcom a. 54 . 57, 61
Lenerer-Siwe disease. 358
Mastoc ytoma , cut aneous, 57-58
Leukocyte alkaline phos phatase , 6 1
Mastocytoma.ecrecuereccs. 6 1-63
teokoerymrobreetose. 44 , 45 . 46
Mastoc ytoma of skin . 58
LM01, l 77
Mastoc ytosis, 23 . 25 .
scet. 62
Monoclonal ga mmopathy, unanribu tedl

unassociatec. 200
Monoclonal immunog lob ulin deposition
d isease, 209
Monoclonal lig ht and heavy c hain
oeoosnon dis eases , 2 11-2 12
Monoc ytoid 8 -eell lymphoma . 218
Mor'Iornorphic B-ee ll PTlO, 347
Monomorphic PTlO, 343, 347-349
Subject index
43 5
~phic
T/NK-eell PTLD. 349
Morula cells, 205

Mott cells. 205
MPL, 23. 25, 44. 47, SO. 64. 86

MPN,
see Myeloproliferative neoplasms
MPO, see Mye1operoxidase

M-protein, 200-203, 205 , 207-213
MSN. 315
Mu heavy chain disease. 197-198

FGFAl abnormalities, 26, 72-73
Nod al margin al zone lymphoma,

paediatric , 219

PDGFRA rearrangement. 26. 68-71
Nodular lymphocyte predominant

Hodgkin lymphoma, 322, 323-325

PDGFRB rearrangement, 26, 71-72
Nodular sclerosis classical Hodgkin lymphoma , 165,267 ,313,322,326,327,

.w,331 ,334,341
Myeloid leukaemia associated with Down

syndrome, 29, 143-144
Myeloid proliferations related to Down
syndrome , 29 , 30, 142-144
Myeloid sarcoma, 28-30. 47, 73, 110.111 .
118 , 122. 140- 14 1
Multicentric Castleman disease. large Bceu lymphoma arising in HHV8-
Myelomastocytic leukaemia , 56
NOTCH1.178
Myelomatosis. 202
f'S'Ml .23,28-3l.114, 118-122, 125.126.141
associated. 234 , 258
I ipholllltWs polyposis. 229
Mu ltiple myeloma. 38 , 202

Myasthenia gravis. 196
MYC, 14, 36. 177, 178,206.224,225.
231 ,235,237,241,242,251,262-266,
289.290,325,340,348
Mycosis fungoides. 294 . 296-298
Mycosis"-"goides, ldO:Uolropoc """",,, 296

Mycosis lungoides, ISCL-EORTC staging
sYSlem .296
Myelodysplasia , 24, 28-30 . 34 . 43. 49, 65 ,
76,81,9 1, 101, 104,106. 115 .124 ,

125, 128, 130, 131, 136, 138, 145,356
Myeloperox idase (MPO). 20, 21. 23, 35.

57.83.107.110,112-11 4,116,117 ,
121. 122. 130-132. 134 136, 138, 140,
141.144.146,1 50.151 .1 55.169.
357.362,364
19. 22. 23. 2530 . 39 , 43. 44 , 48-50 ,
53.57,59.71 ,76,77,79,85.86,87108, 110. 116 . 118, 124, 125, 127129,
135.1 36,139-141 , 143,144,1 50

Myelodysplastic synd rome with 5q
deletion, 102
Myelodysplastic syndrome with isolated
del(Sq), 27, 102
Noonan syndrome, 82
NPM-AlK. 254 . 314-316
r-R.1c+ M1L. 120

~,23,2),2B,81 .B4.
111.118. 201 ,200
Nuclear matrix associated gene , 114
Myeloproliferative disease , 23, 25, 38, 82
Nucleophosmin, 114, 118, 120, 314, 315
MyeIoproIiferalNe neopIasm,lIldassdiable,
NUMA1 .114
64-65.85
Myeloproliferalive neoplasms (MPNj. 23,
31-66
NUP214 , 115, 116
Myeloproliferative varian t of the

hypereosinophilic syndrome, 69
Myofibroblasts, 355, 365
OCT-2, 25 1, 267
Onychodystrophy, 299
Myelod ysp lastic syndrome (MDS) , 15, 18.
..
Non-secretory myeloma. 200, 203

Non-specificesterase,20,21 . 112-114,122.
132-134.136, 138, 140, 169,354
Mu'Iicentric CastlErrmdisease. 166, 234,200
M.itipIe
Non-myelomatous gammopathy, 200
Osseous plasmacytoma, 208
Osteosclerosis, 42
Naphthol-ASD-chloroacetate esterase ,
21,33, 34, 41, 45, 49 ,57 ,76,78,83,
105,11 2.1 30,140
Osteosclerotic myeloma. 200 , 212213
on,
117
Naph thol-butyrate esterase, 145

Nasal typ e t -een lymphomas, 146
Myelodysplastfc syndrome,NOS, 103
Natural killer ce ll lymphoblastic

leukaemia/lymp homa, 155
p16N\"", 36. 224,241,251,264, 298, 299,349
Myelody splastic syndrome, therapy related, 127
NBS1,339
Myelodysplastic syndrome, unclassifiable,

27, 103
p 18'N~olc ,
206, 231
Neurofibromin, 84
P190,32,35, 79, 171
Neutrophil alkaline phospha tase , 35, 39
p210 , 35, 79, 171
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN), 18, 19, 22, 23, 2530,75-86,79,85,86 ,91 ,102,124,
127 129,1 40
NFl , 23, 26, 82, 84, 366
p230, 35,39
NFKB, 162, 163,206,329
Paediatric follicular lymphoma. 225
NG2, 114, 172
MyelodysplastiC/myeloproliferative
neoplasm, unclassifiable, 85-86
Nibrin, 339
Paediatric nodal marginal zone

lymphoma, 219
Nijmegen breakage syndrome , 336. 339
Pagetoid reticulosis, 298
MyelodysplasticJmyeloprollferative
neoplasms, therapy-related , 127
Nc-ceuteusaemta. aggressive, 276-277
Pancytopenia . 89, 94,103,106,115,124 ,

138,188,252.279,339,356,360
NK-ceHLGL lymphocytosis, 274
Myelofibrosis, 19,24 ,37,42,44 ,46,48,

64,65.71 ,86,92,101 .137.138
Paornyelosis. 42
NK-cell lineage granular lymphocyte

proliferative disorder. 274
Pappenheimer body, 98
Myelofibrosis, primary. 44-47
Nodal marginal zooe B-ceI tyrrV'ona, 218
Myelofib rosiS/sclerosis with myeloid

metaplasia , 44
436
Sub;ecl index
NodaImarginalzroe~
219,3l3
166,218-
Paratomcutar B-ceillymphoma. 2 18
Paraneoplastic pemphigus. 363
Paroxysmal nocturna l haemog lobinuria,
91.106.107
Partial nodal involvement in follic ular

lymphoma. 222
Parvovirus 819. 91
Pautrier microabscess, 297
Pautrier-like microabscesses. 283
PAX5, 23 , 110, 169, 192, 195.225,235,

256 .267,318,319,325,326.328,334
PBX1,175
PD-1,162,311,324
POE40IP-PDGFRB , 71
PDGFRA . 19,23.25,26, 39 ,51-53.57.
6O ,62~ .~70. 73 , 76 , 78 ,80,81 ,85
PDGFRA-FIP111 .23
PDGFRB, 19. 23. 25-27. 39 , 5 1-53 , 64 . 65 .
68 .71 -73 .76,78.80,81 .85
Pearson (marrow-pancreas) syndrome.
96 , 107
Pelger-Huet anomaly. 80 . 83 , 90 , 92 . 93 .
98, 100, 105. 106. 110
Pelgeroid
oenropnne. 114
Perlonn . 79. 146. 163 .255 .272.287.~

295,300,304 ,3 15,318.354
Peripheral T-ceillyrnphoma, follicular
variant, 308
t-een
Peripheral
lymphoma , Iymphoepi thelioid variant . 308
Peripheral T-cell lymphoma, not otherwise
specified. 163 , 165 , 166, 177,287,
297, 306-308
Peripheral t-een lymphoma, primary
cutaneous. 302-305
Plasm acytoid monocvtes. 78, 145 . 355

Plasm acytoma , extramedullary, 208
Prima ry effusion lymphoma, 166, 234,

243, 259, ~261, 340,342, 343
Plasm acytoma, exuaosseous. 208-209
Primary intestinal follicular !'ymptx:ma, 225
Platel et derived growth factor fl, 19
Primary intraocular lymphoma, 240
PML-RARA, 29 , 30,112-114
Primary mediastinal (thymic) large Bceu

lymphoma , 234, 250-251
Pneumocyslis carinii, 282 , 284

Pneumothorax, 245
Primary myelofibrosis (PMF), 23, 25, 27,

39, 44-47, 48-50, 52 , 64 . 65, 86 , 139
POEMS syndrome, 200 , 212-213
Progressive nodular histiocytosis, 366
PoIydonaI hypergam"l8Qlobulina-nia, 162
Progressive transformation of germinal

centres, 324
PoJycythaem ia rubra vera , 40

Polycythaemia vera , 23 , 40-43
Primary thrombocytosis, 48
Po/ycythaemia vera. po/ycythaemic phase.
Proliferation centre. 181, 183, 195
40-42
PoIycythaemia vera , postpolycythaemic
myelofibrosis. 42-43
Polycythaemia vera , prepolycythaemic
phase, 40-4 1
Potycythaemia vera, spent phase, 40-41
ProJymphocytic variant of hairy cell

leukaemia, 192
Protoporphyrin IX, 96
Pruntus . 38 , 41 , 51 , 55 , 69. 299 . 306 , 309
Pseudo-Gaucher cells, 33
Polymorphic PTlO, 343 . 346-347
Pseudo-Pelger-Hullt anomaly. 27,105.

116,124
Polymorphic reticu losis. 285
Psoriasi c arthritis, 350
Popcorn cells, 323
Psoriasis, 350
Post-essential thrombocythaemia myelofib rosis . 50

Post-polycythaemic myelofibrosis, 40 , 43
Post-transplant Iymphop roliferative
disorders (PTLD), 166, 272, 343-349, 350
Precursor B lymphoblastic leukaemia!
lymphom a, 68, 73
PTEN.298
PTGC , 219 , 322 , 324
PTLO, see Post-transplant Iymphoproliferative disorders
PTlD. cIassicaJ _
type . 349
PTLO, otecuous-mooonucleosle-uke. 345
PrecurscrT~~,68,337
PTLO, monomorphic, 343, 347-349
Perip/"erat T-eel1 tymptnna, T-zone variant. 3)3
Pre-p olycythaemic phase, 40
PTlO, monomorphic B-cell, 347-349
Pesticide, 166
Primar y amy loidosis, 200, 209-2 11
PTLO, monomorp hic T/NK-ce ll. 349
Philade lp hia (Ph) ch romosome, 24 , 35 .

36 ,39, 43 , 47,52,53.65,69 ,76,80,
82 , 85 , 15 1,1 52,1 71
Phosphotid ylinos itol a-kinase. 24
PICALM-MLLT10, 178
Plasma cell g ranuloma , 210
Plasma cell leukaemia. 200, 203
Plasma cell myeIcma, 100, 161,20:),202207,343

Plasma cell myeloma, asymptomatic,
202-203
Plasma cell myeloma , non-secretory, 203
Plasma cell neoplasms. ~213
Pesta eel variant d Castleman disease. 212

Ptasmablastic lymphoma. 166 . 234 . 243.
255, 256-257. 258 . 340 , 342
Ptasmacytic hyperplasia, 345
Ptasmacytoid dendritic cells, 78 , 79 , 140 ,
145-147 ,151 ,155,294.355
Prima ry CN S lympho ma , 240, 340
PTlO , plas macytic hyperp lasia, 345
Primary cu tane ous ag g ressive epioermotroorc C0 8 po sitive c ytotoxic T-c ell

lymphom a , 303 304
PTPN 11, 23, 82, 84
Primary c utaneous anaplastic large cel l

lymphom a. 3O()...301
PU. 1, 25 1, 328
PTlO, po lymorphi c, 343. 346-34 7

PTPN 12,316
Primary cu taneous C030-positive t-een

Iympho p roliferative d isorde rs, 300301
Pure id iopathic ery throcytosis, 41
Primary c utaneous diffuse large B-cell

lymphoma, leg type , 227 ,
228,234,242
Pyothorax-associated lymphoma, 245
Primary cu taneo us follicle centre lymphoma, 227-228
Primary cut aneous gamma-delta ()'O)

lymphoma, 163, 302-303
Primary cutaneous peripheral
phoma. 302-305
r-ceu
t-ceuwm-
Primary cutaneous smalilmedium CD4

positive
lymphoma, 304-305
j-ceu
Primary diffuse large B-cell lymphoma of

the central nervous system, 240-241
Pyothorax, 245, 260
Radioulnar synostosis, 106, 107

RAEB. see Refractory anaemia with
excess blasts
RAEB with fibrosis, tOO
RAE~1.89 ,93 ,94 . 100, 10 1, 104
RAEB-2, 89, 91, 93 , 98, 100, 101, 104. 139

RAG112,339
Subject index
43 7
Randalldisease. 211
RPN1-EVI 1, 30,1 16
RARA, 28, 30. 113 . 114
RUNX1,23,28,29,62, 110,11 1, 112, 126,

131, 172
RARS.
see Refractory anaemia w ith ring
sroerobrasts
RUNX 1-RUN X1T1, 29 , 110 . 111

RUN X1Tt (ETD), 111
RARS- T. see Refractory anaemia with ring

srderobtasts and thrombocytosis
RUNX2 , 147
RB1 , 36. 147, 206, 231
Russell body. 205 , 2 10
RBM l 5-MKL1 . 30 , 117
RCe , see Refractory cytopenia of

childhood
S1OO.355,358,362,364-366
Sclerosing cholangitis, 359 , 366
Sea-blue t ustccvtes. 33
347-349, 364
Seckel syndrome, 107
94-97 ,99. 103. 104. 124, 125. 132
Splenic red pulp lymphoma with numerous basophilic villous lymphocytes, 191
Senile EBV-associaled B-celilymphopro liferative disorder, 243
278
Stabibn-f, 366
Starrysky pattern, 78. 169, 176.214.229,
264-266
STAT, 24, 251, 329
Stem cell acute leukaemia . 151
Strongyloidiasis, 282
SubCutaneous pan nicu litis-like T-cell
lymphoma, 163,294-295,302.355
Refractory anaemia of ch ildhood. 104
SerpinA 1,315,316
Refractoryanaemia with excess blasts
Severe combined immunodeficiency. 336
Syncytial variant. nodular sclerosis

classica l Hodgkin lymphoma, 330
Sezarv cells, 299

Sezarv syndrome, 296 , 297 , 299. 349
Syndrome of ab normal chromatin

cl umpi ng, 81
Sezary syndrome, ISCl -ED RTC staging

system, 296
Systemic EBV+ T-ee illymphoproliferative

d isease of ch ildhood . 278-280
SHP1 ,3 15
Systemic lupus eryth ematosus, 196,294
SHP2,82
Systemic mastocytosis, 25 , 52-55 . 57 , 5861, 70
(RAEB), 23, 27 , 89-94. 96, 98-99, 1OD-
101,104 ,136.139
Refractory anaemia With ring sideroblasts
(RARS), 27,49. 65.85. 86, 88. 89. 94.

96-97,104
Refractory anaemia with ring srderobrasts
an d thrombocytosi s (AARS-T), 26 . 27 ,
49. 65. 85-8$

Refractory anaemia withL.Jrjlineage dysplasia,
88
sCD23,182
310.313.322.326 .327.330.331.337.
Refractory anaemia, 27 , 49 . 65 , 85. 88-91 ,
Splenic marginal zone lymphoma, diffuse

variant, 191
Sporadic fatal infectious mononucleosis.
ABTN2,177
244.247.250.261 .300.301 .306.308.
Splenic marg inal zone lymphoma, 160.

164, 166. 183,185-187,189-191
Spoke whee l, c hroma tin pattern, 205
ABTN1,177
Reed-Sternberg cel ls, 182,234 ,238,243.
Splenic Iymphoma/leukaemia. unclassiliable, 19 1- 193
Refractory cytopenia 01 childhood (RCC),27,
1M 107, 143
Shvv-actYnann-Diamcfld sworcrre. 88. 107

Signal tra nsd ucer and activator of
transcription, 24
SjOgren synd rome , 196 , 215 , 2 19
SlE , 196 ,294
Refra ctory cytopenia w ith multilineage

dysplasia, 89, 90, 97, 98-99, 100, 103, 100
sivi.
Refracto ry c ytopenia with unilineage dy splasia, 89-90, 94-95, 100 , 103
Small lymphoc yt ic lymphoma. 180-182

216,2 17,229, 233. 339 , 351
Refract ory neutrop en ia , 89, 90 , 94 , 95
Small round ceutomours. 14 1
Refractory thromboc ytopenia, 27, 89-91 ,

94, 95
Smu dg e ce lls, 181
Regressing atypical histiocytosis, 355
SOCS1, 236. 251
Restrictive cardiomegaly, 51
Solitary mastocytoma of skin, 54, 57
Restrictive car diomyopathy, 69
Solita ry plasmacytoma of bone, 200, 208
Reticulin fib rosis. 33 , 44. 48, 49 , 59, 50,

100.101 ,189,193,273
Somatic hyper mutation . 158. 159, 182,

186,190,192,195.197,201 ,205,207,
2 17,228.231 ,235,241 ,250,258.264,
325 ,329.347,348,349
Reticulin/collagen fib rosis , 60
aetcuiomsuocvtona of the dorsum, 227

Bencuiotnsuocvtosis. 354
Retinoic ac id receptor (1 , 113
Rhabdomyosarcoma, 137, 3 15
Rheumatoid arthritis . 196.245 ,350
Riluximab, 190, 193, 236 . 255
Bosa-Dofman d isea se, 354

438
Systemic mastocytosis with associated

haematoioalcer c lonal non-mast cell
d isorder, 54
185, 186
SOC- 1. 329
Sorafenib . 70
Splenic B-celi lymphoma with villous
lym p hoc ytes. 191
Splenic diffuse red pu lp small B-ee ll
lymphoma. 191-192
Sp lenic lymphoma w ith ci rculating villous
lym phocytes, 185
T
T lymphob lastic leukaemia/lymphoma,
161 ,1 65 , 176-178
T-be l, 189 , 190
T-cell ch ronic lymphoc ytic leukemia, 270
T-cell large g ranul ar lymp hoc ytic
leukaemi a, 163 , 2 72-273
T-cell proIymphocytic leukaemia, 163,270271, 337
T-c ell ric h large B-ceillymphoma. 238 ,
323 ,326
T-cell/histiocyte-rich large B-celllymphoma , 234, 238-239, 325
T-cell rec eptor (TCR), 112, 13 1, 146, 151,
158.161-164, 169,176-178,249.261 ,
270 ,273,275,277,279,280,283,287,
290 ,293-295,297,299-301 ,303,304.
307,311 .315.318,319,328,329,336,
338 ,339,348,349,357,358.362,364 ,
366
T-cell-rich B-eeillymphoma, 238
Sub ject index

$
TCF3-PBX1, 175
1(3;5)(p2 1-25;q31-35), 71
TCL1, 146, 270, 271, 338, 355
1(3;2 1)(q2 6,2;q22), 93,1 17
Vein Ihrombosis, 41, 48, 65
TCR, see t-een receptor
t(4;11), 128, 172
von Willebrand teeter, 106
Teardrop-shaped, red blood cells

(dacryocytes), 42, 44, 45, 49
1(4;22)(q 12;ql1),70
t(4;14)(p 16.3;q32) ,201
TELAML1, 170, 172
1(4;5;5)(q23 ;q31;q33 ),71
Terminat deoxyn..cleottdyl transferase (TdT),

34,110,1 16,117,125,131 ,1 37,138,
140,146,147,151 ,161 ,169, 171, 177.
264-266, 270
t(5;7)(q33 ;ql1 .2).7 1
WDR48-PDGFRB.71
t(5;10)(q33 ;q21), 71
Wiskolt-A ldrich syndrome, 247. 336
1(5;12)(q31 -33;p12). 71, 72, 79
Woringer-Kolopp type , 298
Thalidomide. 102, 117
1(5;12)(q31;p13),72
WT1 , 118, 119
Therapy-related acute myeloid

leukaemia, 127
t(5;12}(q3 1-33;q24),7 1
1(5;14)(q33 ;q24), 71
Therapy-related myeloid neoplasms, 29 ,

30, 127- 129
1(5;14)(q33;q32 ), 71
Tresaurocvtes. 205
t(5 ;15)(q33;q22 ),71
Xanthoma disseminatum. 366
Thrombocyt openia wilh absent radi i. 107
t(5;16)(q33;p13).71
Thymic (mediastinal), primary large B-cell

Iymphoma, 25(}25 1
t(5;17)(q33 ;p13), 71
X-linked Iymphopf oliferative Syndrome,

247, 339
1(5;17)(q33 :Pl1 ,2), 71
Thymoma, 364
TlA1. 79, 146. 163,273,274,287, 293,
295.300. 304,315, 3 18
Tingible body macro phage s, 220 , 227
TLX1 ,l77
t(8;21)(q22;q22), 28, 30. 104, 110, 112.

118.123,1 41
ZAP-70, 182. 23 1
t(9; 14)(p13:q32), 192
TLX3, 177
1( 10:11)(p13;q1 4).178
Toll-like recep tor, 162,262
1(11 ;14)(q13 ;q32), 163, 231
Topoisomerase II, 128
1(1 1;16)(q23 :p 13,3),93
Toulon cells, 366
t(11;19)(q23;p1 3.3).11 5
TP53, 14,36,93, 182, 187. 192,206.207.

224,225 ,231 ,237 ,246, 25 1,264,27 1,
287,299 ,329,348,349
1(1 4:16)(q32;q23),201
1(14:18),1 60, 163,164,186,217,222.
224, 225, 228,235,241,242,329
TPM3-PDGFRB,7 1
t(15;17Xq22;q 12j, 30, 104, 110, 112, 114,

118, 129
TPG-R , 142, 144

TRAF1, 250
t(16;1 6XP13,1;q22j, 28, 30, 104, 110112,118, 129
Transient abnormal myelopoiesis, 29,

142-143
transiccauoos
1(9:11)(p22;q23 ).30, 110, 114, 115,

128
T-LBl, 68-70, 73, 176. 178,339
Transientmyeloproliferative disorder, 142
t(6;9)(p23;q34), 93, 110, 115. 116, 118,

125, 138
1(17;19), 170, 175
TRAP (Tartrate-resistant acid phosphatase),

189, 190, 192,193
1( 1;3Xp36,3;q21.2), 93
Triphenotypic leukaemia, 152
t(l ;3;5}(p36;p2 1;q33), 71
Trisomy 12, 184,231
t(l ;5)(q21;q33), 71
Trisomy 21 mosaicism . 142
t(1;5}(q23;q33),71
t( l ,14 ), 163, 178,217
t(1;22)(p13;q 13). 30,1 10,117,136

t(2;11)(p2 1;q23), 93, 115, 125
1(2;5), 163. 164, 254, 255, 3)1, 3 14-316,
Ulcerative jejunitis. 289
329
Urticaria pigmentosa, 54-56. 57-58
1(3;3)(q21;q26.2), 29. 30, SO. 93 , 110,

11 6, 117, 125, 136
Subject index
439

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C International Agency for Research on Cancer, 2008

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IARC Ubrary Cataloguing in Publication Data

1. Haematopoie hc System Neop lasms - genetics

2. Haematopoielic System Neop lasms - pathology

Chronic myelogenous leukaemia. BCR-ABL 1 positive 32

Chronic eosinophilic leukaemia. NOS

Mast cell sarcoma

3 Myeloid and lymphoid neoplasms with

6 Acute myeloid leukaemia (AML) and

AML with mutated NPM 1

7 Acute leukaemiasof ambiguous lineage

8 Introduction and overview 01 the c lassification of

9 Precu rsor lymphoid neoplasms

Enteropathy -associated t-een lymphoma

12 Hod gkin lymphoma

13 1rnmunode ficiency-assoc iated

WHO Classification of tumours of haematopoietic

Chronic myelogenous leukaemia ,

Chronic neutrophilic leukaemia

Chronic eosinophilic leukaemia, NOS

Mast cell leukaemia

Mast cell sarcoma

Myeloproliferative neoplasm , unctassitlable

Refractory anaemia with ring sideroblasts

Refractory cytopenia with

Refractory anaemia with excess blasts

Childhood myelodyspla suc syndrome

MYELOID AND LYMPHOID NEOPLASMS

ACUTE MYELOID LEUKAEMIA (AML)

AML with t(6 ;21)(q22;q2 2);

AML with inv(16)(pI 3.1q22 )

Acute promyelccytlc leukaemia

AML with t(9 ;11)(p22 ;q23); MLLT3-MLL

AML with 1(6;9)(p2 3;q34 ); DEK-NUP214

AML with inv( 3)(q2 1q26.2)

Chronic myetcmonocytic leukaemia