Classification of Acute Myeloid Leukemia

Acute myeloid leukemia with recurrent genetic abnormalities

Acute myeloid leukemia with t(8;21)(q22;q22), (RUNX1 - RUNX1T1;AML1/ETO)
Acute myeloid leukemia with abnormal bone marrow eosinophils inv(16)(p13q22) or t(16;16)(p13;q22)
(CBFβ/MYH11)
Acute promyelocytic leukemia (AML with t(15;17)(q22;q12), (PML/RARα) and variants
Acute myeloid leukemia with t(9;11)(p22;q23), (MLLT3-MLL)
Acute myeloid leukemia with t(6;9)(p23;q34), (DEK-NUP214)
Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2), (RPN1-EVI1)
Acute myeloid leukemia (megakaryoblastic) with t(1;22)(p13;q13), (RBM15-MKL1)
Provisional entity: AML with mutated NPM1
Provisional entity: AML with mutated CEBPA
Acute myeloid leukemia with multilineage dysplasia
Following a myelodysplastic syndrome or myelodysplastic syndrome/ myeloproliferative disorder
Without antecedent myelodysplastic syndrome
Acute myeloid leukemia and myelodysplastic syndromes, therapy-related
Alkylating agent–related
Topoisomerase type II inhibitor-related (some may be lymphoid)
Other types
Acute myeloid leukemia not otherwise categorized
Acute myeloid leukemia minimally differentiated
Acute myeloid leukemia without maturation
Acute myeloid leukemia with maturation
Acute myelomonocytic leukemia
Acute monoblastic and monocytic leukemia
Acute erythroid leukemia
Acute megakaryoblastic leukemia
Acute basophilic leukemia
Acute panmyelosis with myelofibrosis
Myeloid sarcoma
Acute leukemia of ambiguous lineage
 World Health Organization Classification of the Myelodysplastic Syndromes
Classification Peripheral Blood Bone Marrow
Refractory anemia Anemia Erythroid dysplasia only
No or rare blasts <5% blasts
<15% ringed sideroblasts
Refractory anemia with ringed Anemia >15% ringed sideroblasts
sideroblasts
No blasts Erythroid dysplasia only
<5% blasts
Refractory cytopenia with multilineage Cytopenias (bicytopenia Dysplasia in >10% of the cells of
dysplasia or pancytopenia) two or more myeloid lines
No or rare blasts <5% blasts in the marrow
No Auer rods No Auer rods
<1 × 109/L monocytes <15% ringed sideroblasts
Refractory cytopenia with multilineage Cytopenias (bicytopenia Dysplasia in >10% of the cells of
dysplasia and ringed sideroblasts or pancytopenia) two or more myeloid lines
No or rare blasts <5% blasts in the marrow
No Auer rods >15% ringed sideroblasts
<1 × 109/L monocytes No Auer rods
Refractory anemia with excess blasts 1 Cytopenias Unilineage or multilineage
dysplasia
<5% blasts 5–9% blasts
No Auer rods No Auer rods
9
<1 × 10 /L monocytes
Refractory anemia with excess blasts 2 Cytopenias Unilineage or multilineage
dysplasia
5–19% blasts 10–19% blasts
Auer rods present Auer rods present
9
<1 × 10 /L monocytes
Myelodysplastic syndrome, Cytopenias Unilineage dysplasia: one myeloid
unclassified cell line
No or rare blasts <5% blasts
No Auer rods No Auer rods
Anemia Normal to increased
megakaryocytes with hypolobated
nuclei
MDS associated with isolated deletion Usually normal or <5% blasts
5q increased platelet count
<5% blasts Isolated del(5q) cytogenetic
abnormality
No Auer rods
 Diagnostic Criteria for Chronic Myelomonocytic Leukemia According to the World Health
Organization
Persistent peripheral blood monocytosis is >1 × 10 9/L.
Absence of Philadelphia chromosome or BCR/ABL rearrangement.
Blastsa are <20% in peripheral blood or bone marrow.
Dysplasia in one or more myeloid lineages, or, in the absence of dysplasia, CMML can be diagnosed, if
all other criteria are met, together with either of the following:
Presence of a clonal cytogenetic abnormality.
Monocytosis has been persistent for at least 3 months and all other causes of monocytosis have been
excluded.
Subgroups
CMML-1: Blasts <5% in peripheral blood and <10% in bone marrow.
CMML-2: Blasts 5–19% in peripheral blood, 10–19% in bone marrow, or Auer rods are present and
blasts are <20% in peripheral blood or bone marrow.
CMML-1 or CMML-2 with eosinophilia: Criteria for CMML-1 and CMML-2 are present, and the
eosinophil count in peripheral blood is >1.5 × 109/L.

WHO Criteria for Accelerated Phase of Chronic Myelogenous Leukemiaa

Blasts 10–19% in blood or marrow
Peripheral blood basophilia ≥20%
Cytogenetic clonal evolution
Persistent thrombocytopenia <(100 × 109/L)
Persistent thrombocytosis (>1,000 × 109/L) unresponsive to therapy
Increasing splenomegaly and increasing WBC count unresponsive to therapy
WBC, white blood cell; WHO, World Health Organization.
Key Features of the Major Myeloproliferative and Myelodysplastic/Myeloproliferative Disease
Disorder Demographics Laboratory features, Cytogenetics Prognosis
morphology
Chronic phase
∼5 years.
?effect of
WBC > 50 × 103/μL, spectrum Gleevec®.
Middle-aged; of maturation of granulocytic Eventual blast
occasionally any cells, myelocyte peak, t(9:22)(q34;q11) BCR- crisis worse
CML age basophilia, anemia, low NAP ABL prognosis
RBC > 6 × 106/μL, Hb > 18.5
g/dL in males, > 16.5 g/dL in
Middle-aged, females, increased platelet May be present, but may
PV M>F count, moderate neutrophilia not be t(9;22) 10–20 years
CIM Typically over Leukoerythroblastic anemia, +8, +9, del(20q), 5 years median
50 years. moderately increased WBC with del(13q), del(1p) and survival
left shift, normal–decreased others are seen in 80%
platelets with atypical of patients, often herald
morphology. Fibrotic BM with conversion to AML or
atypical megakaryocytes and CML. May not be
RBC and granulocyte precursors t(9;22).
Platelets > × 103, abnormal
5th decade (M = morphology. BM with large, del(13q22), +8, +9 seen Stable for many
F), second peak multilobular, clustered in 5–10% of cases. May years (most
ET in 30 s (F > M) megakaryocytes not be t(9;22). cases)
Monocytosis > 1 × 103/μL for 3 20–30 months
months, cytopenias, dysplasias +8, - 7, 12 p with
in myeloid lineage in BM, < abnormalities in 20– progression to
Median 65–75 20% blasts + promonocytes in 40% of cases. May not AML in 15–
CMML years, M > F BM be t(9;22). 30%
Monocytosis > 1 × 103/μL, WBC Poor. Possible
Under 3 years, > 10 × 103/μL, left shifted Monosomy 7, May not benefit from
JMML M>F granulocytes, increased Hb F be t(9;22). BMT

CML = chronic myeloid leukemia; PV = polycythemia vera; CIM = chronic idiopathic myelofibrosis; ET
= essential thrombocythemia; CMML = chronic myelomonocytic leukemia; JMML = juvenile
myelomonocytic leukemia; BM = bone marrow; NAP = neutrophil alkaline phosphatase; BMT = bone
marrow transplant.
Key Features of the Major Acute Myeloid Leukemias (AML)
Category Cell morphology Cell surface Cytogenetics Prognosis
markers
AML with t(8;21) Large blasts, with CD 13, 33,117, t(8;21)(q22;q22) More
abundant basophilic CD19, CD34 AML1/ETO favorable
cytoplasm, Auer rods, than AML
dysplasia, abnormal without
granules, maturing recurrent
granulocytes genetic
abnormality
AML with inv(16) Blasts with both CD 13, 33, 14, inv(16)(p13;q22) or Superior to
monocytic and 4, 64 t(16;16)(p13;q22) other AML
neutrophilic
differentiation, increased
eosinophils/immature
eosinophils
Acute promyelocytic Promyelocytes with CD 13, 33 t(15;17)(q22;q12) Good if
leukemia azurophilic granules, PML/RARα responsive to
Auer rods ATRA
CD2±, DR- Variants all involve
17q12
AML with 11q23 Variable. Monocytic CD 13, 33, 34, ± t(9;11)(p22;q23), Less
differentiation seen in 56, 57. others favorable
t(9;11) than other
CD 14, 4, 36
AML
with monocytic
differentiation
AML, therapy related Multilineage dysplasia, CD 13, 33, 34, ± 11q23 abnormality Median
RS, increased basophils 56, 57 seen with survival < 3
topoisomerase II years
inhibitor-associated
AML
AML, not otherwise categorized
AML, minimally M0 in FAB. Myeloblasts, CD 13, 33, 117 Nonspecific/not Poor
differentiated < 3% positive for SBB, in ≥ 20% of available
MPO or ANA blasts
AML without M1 in FAB. Myeloblasts CD 13, 33, 117 Nonspecific/not Poor
maturation ≥ 90% of nonerythroids available
in BM, ≥ 3% positive for
SBB or MPO
AML with maturation M2 in FAB. Same as for CD 13, 33, 117 Nonspecific/not Variable.
AML with t(8;21) available Less
favorable
than AML
with t(8;21)
Category Cell morphology Cell surface Cytogenetics Prognosis
markers
Acute myelomonocytic M4 in FAB. Monocytic CD 13, 33, 14, Nonspecific/not Variable.
leukemia cells 20–79%, 4, 11b, 11c, 64, available Less
granulocytic 30–80% of 36, 68 favorable
nonerythroids than AML
with inv(16)
Acute M5 in FAB. ≥ 80% of CD 13, 33, 117, t(8;16)(p1l; p13) Poor
monoblastic/monocytic nonerythroids are 14, 4, 11b, 11c, seen in some acute
monoblasts (M5a) or 64, 68, 36 monocytic
show monocytic diff leukemia cases
(M5b)
Nonspecific/not
available
Erythroleukemia M6 in FAB. ≥ 50% Glycophorin A, Nonspecific Poor
erythroblasts and ≥ 20% Hb A in
myeloblasts in erythroid blasts;
nonerythroids. Pure CD 13, 33, 117
erythroleukemia without in myeloblasts
myeloid blasts is rare
Acute Polymorphic CD 41, 61, 36, Nonspecific in Poor,
megakaryoblastic megakaryoblasts, may often CD 13, 33 adults. Infants may especially
leukemia simulate lymphoblasts. show with t(1;22)
PB may show t(1;22)(p13;q13)
megakaryocytic
fragments
 Select Molecular Genetic, Morphologic, Laboratory, and Clinical Findings in the Common
Myeloproliferative Disorders
Disease Molecular Blood Smear Bone Marrow Fibrosis Splenomegaly Other
Findings
CML BCR/ABL Leukocytosis with Marked myeloid Variable ++
immature hyperplasia with
granulocytes, prominence of
basophilia neutrophils and
myelocytes
PV JAK2 Normo- or Panmyelosis ± Increased ++ Low
V617F hypochromic erythroid in spent EPO
anemia, may have hyperplasia, phase
thrombocytosis and atypical
mild basophilia megakaryocytic
hyperplasia
CIMF JAK2V617F Leukoerythroblastic Panmyelosis with Marked +++
with dacrocytes, atypical in
giant and bizarre megakaryocytic fibrotic
platelets hyperplasia, phase
dysplastic and
bizarre
megakaryocytes
ET JAK2V617F Thrombocytosis, Atypical Minimal -/+
often with abnormal megakaryocytic
platelets and hyperplasia with
megakaryocytic large/ giant forms
nuclei
CIMF, chronic idiopathic myelofibrosis; CML, chronic myelogenous leukemia; EPO, erythropoietin;
ET, essential thrombocythemia; PV, polycythemia vera.
Table adapted with permission from George TI, Arber DA. Pathology of the myeloproliferative
diseases. Hematol Oncol Clin North Am 2003;17:1101–1127, Copyright © Elsevier.
Key Features of the Major Mature B Cell Neoplasms
Cell surface
markers
Lymphoma Demographics, clinical Morphology Positive Negativ Cytogenetics
and laboratory e
presentation
CLL/SLL M > F, over 60 years. Monomorphic, CD5, 19, CD10, +12,
Insidious onset of fatigue, small 20, 23, 79a, 22, Bcl- del(13q14),
lymphadenopathy. WBC lymphocytes with dim sIg 6 del(11q22-23),
> 30K, anemia, slight–moderate Ig
thrombocytopenia, cytoplasm, rearrangement
occasionally AIHA condensed
chromatin
B cell PLL M >> F, mean age 65 Prolymphocytes ≥ CD19, 20, Often del(11q23),
years. Massive 55% with large bright sIg CD5, 23 del(13q14), Ig
splenomegaly, minimal vesicular nucleus, negative rearrangement
lymphadenopathy, WBC condensed
> 100K chromatin,
moderate
cytoplasm
Hairy cell M > F, median age 50 Medium-sized CD 19, 20, CD5, Ig
leukemia years. Insidious onset cells with round– 22, 79a, 10, 23 rearrangement
with splenomegaly, oval nuclei, 103, 25,
monocytopenia reticular 11c
chromatin, frayed
cytoplasmic
borders
Lymphoplasmacy M ≈ F, mean age 63. BM, Plasmacytoid CD19, 20, CD5, t(9;14)(p13;q32
tic lymphoma nodal and splenic lymphocytes and 22, 38, 79a, 10, 23 )
involvement, and frequent plasma cells with bright
IgM paraprotein with PAS-positive sIgM,
hyperviscosity (WM) inclusions cIgM
causing decreased visual (Dutcher bodies)
acuity, risk for CVA,
neuropathies
Alpha heavy Younger adults in Lymphoplasmacy NA NA NA
chain disease poorer tic infiltrate of
intestinal mucosa
Mediterranean
communities with
malabsorption,
diarrhea
 Cell surface
markers
Lymphoma Demographics, clinical Morphology Positive Negativ Cytogenetics
and laboratory e
presentation
MALT lymphoma F > M, median age 61. Lymphoepithelial CD19, 20, CD5, +3,
Indolent course involving lesions with small 22, 79a, 10, 23, t(11;18)(q21;q2
stomach, other GI sites. lymphocytes, sIg, bcl-2 bcl-6 1)
Associated with centrocytes,
antecedent autoimmune monocytoid
disease (SS, Hashimoto's) lymphocytes and
or H. pylori infection reactive germinal
centers
Follicular F > M, median age 59 Follicle-like CD19, 20, CD5, 43 t(14;18)(q32;q2
lymphoma years. Peripheral structures with 22, 23, 79a, 1)
lymphadenopathy small, cleaved 10, bcl-2,
dominates, with central lymphocytes and bcl-6
adenopathy, BM and varying numbers
splenic involvement of larger
frequent centroblasts
which allow for
cytologic grading
Mantle cell M > F, median age 60 Atrophic germinal CD19, 20, CD10, t(11;14)(q13;q3
lymphoma years. Lymphadenopathy, centers, 22, 5, 43, 23, bcl- 2)
marked splenomegaly, prominent mantle bcl-2, 6
BM involvement. zones, cyclin D1
Aggressive course monomorphic
cells with small–
medium nuclei
Diffuse large B M > F, all ages, Diffuse infiltrate CDCd19, CD5 t(14;18) in 20–
cell lymphoma associated with HIV. of variably large 20, 22, 79a, (usually 30%, 3q27
Nodal and extranodal B cells, sIg. ), 23 abnormality in
sites, CNS. Aggressive sometimes with Occasional up to 30%,
course centroblastic or ly CD30 complex
immunoblastic (anaplastic abnormality
morphology variant)
Mediastinal large F > M, young–middle- Sclerotic lesions CD45, 19, CD5, 10 Ig
B cell lymphoma aged adults. Airway with clear, 20 rearrangement
compression, superior multilobated or
vena cava syndrome RS-like cells
Primary effusion Rare, associated with Immunoblastic or CD19, 20, sIg, cIg Ig, occasionally
lymphoma HHV-8 in anaplastic cells 79a, often TCR
immunosuppressed, CD30, 38, rearrangement
younger male 138
homosexuals. Pleural
effusion
 Cell surface
markers
Lymphoma Demographics, clinical Morphology Positive Negativ Cytogenetics
and laboratory e
presentation
Burkitt lymphoma 1. Endemic: Uniform cells CD19, 2, TdT t(8;14)(q24;q32
children in with round–oval 20, 79a, )
Africa, jaw mass, nuclei, multiple sIg, often
M>F nucleoli, high CD10
mitotic rate
2. Sporadic:
children–young
adults,
worldwide, M >
F, abdominal
organs
3. Immunodeficienc
y-associated:
HIV patients

Differences between Hodgkin and Non-Hodgkin Lymphomas

Hodgkin Lymphoma Non-Hodgkin Lymphoma

More often localized to a single axial group of nodes More frequent involvement of multiple
(cervical, mediastinal, para-aortic) peripheral nodes
Orderly spread by contiguity Noncontiguous spread
Mesenteric nodes and Waldeyer ring rarely involved Waldeyer ring and mesenteric nodes
commonly involved
Extra-nodal presentation rare Extra-nodal presentation common
Diagnostic Criteria for Plasma Cell Myeloma and for Monoclonal Gammopathy of Undetermined
Significance (MGUS), Indolent and Smoldering Myeloma
Major criteria for plasma cell myeloma Minor criteria for plasma cell myeloma
A. Marrow plasmacytosis (> 30%) 1. Marrow plasmacytosis (10–30%)
B. Plasmacytoma on biopsy 2. M-component: present but less than for C
C. M-component 3. Lytic bone lesions
Serum: IgG > 3.5 g/dL, IgA > 2 g/dL 4. Reduced normal immunoglobulins (<
Urine: > 1 g/24 h of Bence-Jones 50% normal): IgG < 600 mg/dL, IgA <
(BJ) protein 100 mg/dL, IgM < 50 mg/dL

Myeloma
One major and one minor criterion or three minor criteria which must include 1
and 2, in symptomatic patient
MGUS
M-component present, but less than myeloma levels
Marrow plasmacytosis < 10%
No lytic bone lesions
No myeloma-related symptoms
Smoldering myeloma
Same as MGUS except:
Serum M-component at myelomas levels
Marrow plasmacytosis 10–30%
Indolent myelomas
Same as myeloma except:
M-component: IgG < 7 g/dL, IgA < 5 g/dL
Rare bone lesions (≤ 3 lytic lesions), without compression fractures
Normal hemoglobin, serum calcium and creatinine
No infections
The WHO Classification of the Lymphoid Neoplasms
I. PRECURSOR B-CELL NEOPLASMS
B-cell acute lymphoblastic leukemia/lymphoma (B-ALL)
II. PERIPHERAL B-CELL NEOPLASMS
Chronic lymphocytic leukemia/small lymphocytic lymphoma
B-cell prolymphocytic leukemia
Lymphoplasmacytic lymphoma
Splenic and nodal marginal zone lymphomas
Extranodal marginal zone lymphoma
Mantle cell lymphoma
Follicular lymphoma
Marginal zone lymphoma
Hairy cell leukemia
Plasmacytoma/plasma cell myeloma
Diffuse large B-cell lymphoma
Burkitt lymphoma

III. PRECURSOR T-CELL NEOPLASMS

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL)
IV. PERIPHERAL T-CELL AND NK-CELL NEOPLASMS
T-cell prolymphocytic leukemia
Large granular lymphocytic leukemia
Mycosis fungoides/Sézary syndrome
Peripheral T-cell lymphoma, unspecified
Anaplastic large-cell lymphoma
Angioimmunoblastic T-cell lymphoma
Enteropathy-associated T-cell lymphoma
Panniculitis-like T-cell lymphoma
Hepatosplenic γδ T-cell lymphoma
Adult T-cell leukemia/lymphoma
Extranodal NK/T-cell lymphoma
NK-cell leukemia

V. HODGKIN LYMPHOMA
Subtypes of Hodgkin Lymphoma
Subtype Morphology and Immunophenotype
Nodular Frequent lacunar cells and occasional diagnostic
sclerosis RS cells; background infiltrate composed of T
lymphocytes, eosinophils, macrophages, and
plasma cells; fibrous bands dividing cellular areas
into nodules. RS cells CD15+, CD30+; usually
EBV-
Mixed Frequent mononuclear and diagnostic RS cells;
cellularity background infiltrate rich in T lymphocytes,
eosinophils, macrophages, plasma cells; RS cells
CD15+, CD30+; 70% EBV+
Lymphocyte Frequent mononuclear and diagnostic RS cells;
rich background infiltrate rich in T lymphocytes; RS
cells CD15+, CD30+; 40% EBV+
Lymphocyte Reticular variant: Frequent diagnostic RS cells
depletion and variants and a paucity of background reactive males, HIV-infected individuals, and
cells; RS cells CD15+, CD30+; most EBV+
Lymphocyte Frequent L&H (popcorn cell) variants in a
predominance background of follicular dendritic cells and
reactive B cells; RS cells CD20+, CD15-, C30-;
EBV-
Typical Clinical Features
Most common subtype; usually stage
I or II disease; frequent mediastinal
involvement; equal occurrence in
males and females (F = M), most
patients young adults
More than 50% present as stage III or
IV disease; M greater than F;
biphasic incidence, peaking in young
adults and again in adults older than
55
Uncommon; M greater than F; tends
to be seen in older adults
Uncommon; more common in older
in developing countries; often
presents with advanced disease
Uncommon; young males with
cervical or axillary
lymphadenopathy; mediastinal

Clinical Staging of Hodgkin and Non-Hodgkin Lymphomas (Ann Arbor Classification)

Stage Distribution of Disease
I Involvement of a single lymph node region (I) or a single extra-lymphatic organ or site (IE).
II Involvement of two or more lymph node regions on the same side of the diaphragm alone (II) or
localized involvement of an extra-lymphatic organ or site (IIE).
III Involvement of lymph node regions on both sides of the diaphragm without (III) or with (IIIE)
localized involvement of an extra-lymphatic organ or site.
IV Diffuse involvement of one or more extra-lymphatic organs or sites with or without lymphatic
involvement.
Tyrosine Kinase Mutations in Myeloproliferative Disorders
Disorder Mutation Frequency[¶] Consequences[*]
Chronic myeloid leukemia BCR-ABL fusion gene 100% Constitutive ABL kinase
activation[†]
Polycythemia vera JAK2 point mutations >95% Constitutive JAK2 kinase
activation
Essential thrombocythemia JAK2 point muations 50% to 60% Constitutive JAK2 kinase
activation
MPL point mutations 5% to 10% Constitutive MPL kinase
activation
Primary myelofibrosis JAK2 point mutations 50% to 60% Constitutive JAK2 kinase
activation
MPL point mutations 5% to 10% Constitutive MPL kinase
activation
Systemic mastocytosis c-KIT point mutations >90% Constitutive c-KIT kinase
activation
Chronic eosinophilic FIP1L1-PDGFRα fusion Common Constitutive PDGFRα kinase
leukemia[‖] gene activation
PDE4DIP-PDGFRβ Rare Constitutive PDGFRβ kinase
fusion gene activation[†]
Stem cell leukemia[‡] Various FGFR1 fusion 100% Constitutive FGFR1 kinase
genes activation[§]
Autosomal Dominant Disorders

System Disorder
Nervous Huntington disease
Neurofibromatosis
Myotonic dystrophy
Tuberous sclerosis
Urinary Polycystic kidney disease
Gastrointestinal Familial polyposis coli
Hematopoietic Hereditary spherocytosis von Willebrand disease
Skeletal Marfan syndrome[*]
Ehlers-Danlos syndrome (some variants)[*]
Osteogenesis imperfecta
Achondroplasia
Metabolic Familial hypercholesterolemia[*]
Acute intermittent porphyria
Autosomal Recessive Disorders
System Disorder
Metabolic Cystic fibrosis
Phenylketonuria
Galactosemia
Homocystinuria
Lysosomal storage diseases[*]
α 1 -Antitrypsin deficiency
Wilson disease
Hemochromatosis
Glycogen storage diseases[*]
Hematopoietic Sickle cell anemia
Thalassemias
Endocrine Congenital adrenal hyperplasia
Skeletal Ehlers-Danlos syndrome (some variants)[*]
Alkaptonuria[*]
Nervous Neurogenic muscular atrophies
Friedreich ataxia
Spinal muscular atrophy

X-Linked Recessive Disorders

System Disease
Musculoskeletal Duchenne muscular dystrophy
Blood Hemophilia A and B
Chronic granulomatous disease
Glucose-6-phosphate dehydrogenase deficiency
Immune Agammaglobulinemia
Wiskott-Aldrich syndrome
Metabolic Diabetes insipidus
Lesch-Nyhan syndrome
Nervous Fragile-X syndrome[*]
 Biochemical and Phenotypic Characteristics of Lysosomal Storage Diseases
Disease Enzyme Substance Site Complications
Deficiency Accumulated
Gaucher disease
Type 1 Acid β- Primarily Macrophage- Infiltration of bone
glucosidase glucosylceramide monocyte system marrow, progressive
hepatosplenomegaly,
skeletal complications
Type 2 Acid β- Primarily Macrophage- Infiltration of bone
glucosidase glucosylceramide monocyte marrow, progressive
system, CNS hepatosplenomegaly,
skeletal complications,
neurodegeneration
Type 3 Acid β- Primarily Macrophage- Progressive
glucosidase glucosylceramide monocyte neurodegeneration
system, CNS
Niemann-Pick disease
Type A Acid Sphingomyelin Monocyte- Hepatosplenomegaly,
sphingomyelinase macrophage progressive neuro-
system, CNS degeneration
Type B Acid Sphingomyelin Monocyte- Progressive
sphingomyelinase macrophage hepatosplenomegaly,
system infiltrative lung disease
Type C Abnormal Primarily cholesterol Most cells, Hepatosplenomegaly,
cholesterol especially liver, progressive neuro-
transport CNS degeneration
Fabry α-Galactosidase A Primarily Most cells, Ischemia, infarction
globotriaosylceramide particularly
vascular
endothelial and
smooth muscle
cells
Protein
Type/Function Example Molecular Lesion Disease
ENZYME Phenylalanine Splice-site mutation: reduced Phenylketonuria
hydroxylase amount
Hexosaminidase Splice-site mutation or frameshift Tay-Sachs disease
mutation with stop codon:
reduced amount
Adenosine deaminase Point mutations: abnormal protein Severe combined
with reduced activity immunodeficiency
ENZYME α 1 -Antitrypsin Missense mutations: impaired Emphysema and liver
INHIBITOR secretion from liver to serum disease
RECEPTOR Low-density Deletions, point mutations: Familial
lipoprotein receptor reduction of synthesis, transport hypercholesterolemia
to cell surface, or binding to low-
density lipoprotein
Vitamin D receptor Point mutations: failure of normal Vitamin D–resistant
signaling rickets

Oxygen Hemoglobin Deletions: reduced amount α-Thalassemia

Defective mRNA processing: β-Thalassemia
reduced amount
Point mutations: abnormal Sickle cell anemia
structure
Ions Cystic fibrosis Deletions and other mutations: Cystic fibrosis
transmembrane nonfunctional or misfolded
conductance regulator proteins
STRUCTURAL
Extracellular Collagen Deletions or point mutations Osteogenesis
cause reduced amount of normal imperfecta;
collagen or normal amounts of
Ehlers-Danlos
defective collagen
syndromes
Fibrillin Missense mutations Marfan syndrome
Cell membrane Dystrophin Deletion with reduced synthesis Duchenne/Becker
muscular dystrophy
Spectrin, ankyrin, or Heterogeneous Hereditary
protein 4.1 spherocytosis
HEMOSTASIS Factor VIII Deletions, insertions, nonsense Hemophilia A
mutations, and others: reduced
synthesis or abnormal factor VIII
GROWTH Rb protein Deletions Hereditary
REGULATION retinoblastoma
Neurofibromin Heterogeneous Neurofibromatosis type
Protein
Type/Function Example Molecular Lesion Disease
1
Lysosomal Storage Diseases
Major Accumulating
Disease Enzyme Deficiency Metabolites
GLYCOGENOSIS
Type 2—Pompe disease α-1,4-Glucosidase (lysosomal glucosidase) Glycogen
SPHINGOLIPIDOSES
G M1 gangliosidosis G M1 ganglioside β-galactosidase G M1 ganglioside,
galactose-containing
Type 1—infantile,
oligosaccharides
generalized
Type 2—juvenile
G M2 gangliosidosis
Tay-Sachs disease Hexosaminidase, α subunit G M2 ganglioside
Sandhoff disease Hexosaminidase, β subunit G M2 ganglioside,
globoside
G M2 gangliosidosis variant Ganglioside activator protein G M2 ganglioside
AB
SULFATIDOSES
Metachromatic Arylsulfatase A Sulfatide
leukodystrophy
Multiple sulfatase Arylsulfatase A, B, C; steroid sulfatase; Sulfatide, steroid sulfate,
deficiency iduronate sulfatase; heparan N-sulfatase heparan sulfate, dermatan
sulfate
Krabbe disease Galactosylceramidase Galactocerebroside
Fabry disease α-Galactosidase A Ceramide trihexoside
Gaucher disease Glucocerebrosidase Glucocerebroside
Niemann-Pick disease: Sphingomyelinase Sphingomyelin
types A and B
MUCOPOLYSACCHARIDOSES (MPSS)
MPS I H (Hurler) α-L-Iduronidase Dermatan sulfate, heparan
sulfate
MPS II (Hunter) L-Iduronosulfate sulfatase
MUCOLIPIDOSES (MLS)
I-cell disease (ML II) and Deficiency of phosphorylating enzymes Mucopolysaccharide,
pseudo-Hurler essential for the formation of mannose-6- glycolipid
polydystrophy phosphate recognition marker; acid hydrolases
lacking the recognition marker cannot be
targeted to the lysosomes but are secreted
 Major Accumulating
Disease Enzyme Deficiency Metabolites
extracellularly
OTHER DISEASES OF COMPLEX CARBOHYDRATES
Fucosidosis α-Fucosidase Fucose-containing
sphingolipids and
glycoprotein fragments
Mannosidosis α-Mannosidase Mannose-containing
oligosaccharides
Aspartylglycosaminuria Aspartylglycosamine amide hydrolase Aspartyl-2-deoxy-2-
acetamido-glycosylamine
OTHER LYSOSOMAL STORAGE DISEASES
Wolman disease Acid lipase Cholesterol esters,
triglycerides
Acid phosphate deficiency Lysosomal acid phosphatase Phosphate esters
 Principal Subgroups of Glycogenoses
Clinicopath
ologic Enzyme
Category Specific Type Deficiency Morphologic Changes Clinical Features
Hepatic type Hepatorenal Glucose-6- Hepatomegaly— In untreated patients:
—von Gierke phosphatas intracytoplasmic Failure to thrive, stunted
disease (type e accumulations of growth, hepatomegaly, and
I) glycogen and small renomegaly
amounts of lipid;
Hypoglycemia due to
intranuclear glycogen
failure of glucose
Renomegaly— mobilization, often leading
intracytoplasmic to convulsions
accumulations of
Hyperlipidemia and
glycogen in cortical
hyperuricemia resulting
tubular epithelial
from deranged glucose
cells
metabolism; many patients
develop gout and skin
xanthomas
Bleeding tendency due to
platelet dysfunction
With treatment: Most
survive and develop late
complications (e.g., hepatic
adenomas)

Myopathic McArdle Muscle Skeletal muscle only— Painful cramps associated with
type syndrome phosphoryl accumulations of strenuous exercise;
(type V) ase glycogen predominant in myoglobinuria occurs in 50%
subsarcolemmal location of cases; onset in adulthood
(>20 years); muscular exercise
fails to raise lactate level in
venous blood; serum creatine
kinase always elevated;
compatible with normal
longevity
Miscellaneo Generalized Lysosomal Mild hepatomegaly— Massive cardiomegaly, muscle
us types glycogenosis glucosidase ballooning of hypotonia, and
—Pompe (acid lysosomes with cardiorespiratory failure within
disease (type maltase) glycogen, creating 2 years; a milder adult form
II) lacy cytoplasmic with only skeletal muscle
pattern involvement, presenting with
chronic myopathy
Cardiomegaly—
glycogen within
sarcoplasm as well as
membrane-bound
Skeletal muscle—
similar to heart
Selected Oncogenes, Their Mode of Activation, and Associated Human Tumors
Category Proto-oncogene Mode of Activation Associated Human Tumor
GROWTH FACTORS
PDGF-β chain SIS (official Overexpression Astrocytoma
name PBGFB)
Osteosarcoma
Fibroblast growth HST1 Overexpression Stomach cancer
factors
INT2 (official Amplification Bladder cancer
name FGF3)
Breast cancer
Melanoma
TGF-α TGFA Overexpression Astrocytomas
Hepatocellular carcinomas
HGF HGF Overexpression Thyroid cancer
GROWTH FACTOR RECEPTORS
EGF-receptor family ERBB1 Overexpression Squamous cell carcinoma of lung,
(EGFR), gliomas
ERRB2
FMS-like tyrosine FLT3 Amplification Breast and ovarian cancers
kinase 3
Receptor for RET Point mutation Leukemia
neurotrophic factors
Point mutation Multiple endocrine neoplasia 2A and B,
familial medullary thyroid carcinomas
PDGF receptor PDGFRB Overexpression, Gliomas, leukemias
translocation
Receptor for stem cell KIT Point mutation Gastrointestinal stromal tumors,
(steel) factor seminomas, leukemias
PROTEINS INVOLVED IN SIGNAL TRANSDUCTION
GTP-binding KRAS Point mutation Colon, lung, and pancreatic tumors
HRAS Point mutation Bladder and kidney tumors
NRAS Point mutation Melanomas, hematologic malignancies
Nonreceptor tyrosine ABL Translocation Chronic myeloid leukemia
kinase
Acute lymphoblastic leukemia
RAS signal BRAF Point mutation Melanomas
transduction

WNT signal β-catenin Point mutation Hepatoblastomas, hepatocellular

transduction carcinoma
Overexpression
NUCLEAR-REGULATORY PROTEINS
Category Proto-oncogene Mode of Activation Associated Human Tumor
Transcriptional C-MYC Translocation Burkitt lymphoma
activators
N-MYC Amplification Neuroblastoma, small-cell carcinoma of
lung
L-MYC Amplification Small-cell carcinoma of lung
CELL CYCLE REGULATORS
Cyclins Cyclin D Translocation Mantle cell lymphoma
Amplification Breast and esophageal cancers
Cyclin E Overexpression Breast cancer
Cyclin-dependent CDK4 Amplification or Glioblastoma, melanoma, sarcoma
kinase point mutation
Selected Tumor Suppressor Genes Involved in Human Neoplasms
Tumors Associated
Subcellular with Somatic Tumors Assocated with
Locations Gene Function Mutations Inherited Mutations
Cell surface TGF-β Growth inhibition Carcinomas of colon Unknown
receptor
E-cadherin Cell adhesion Carcinoma of stomach Familial gastric cancer
Inner aspect of NF1 Inhibition of RAS Neuroblastomas Neurofibromatosis type 1
plasma signal transduction and and sarcomas
membrane of p21 cell cycle
inhibitor
Cytoskeleton NF2 Cytoskeletal stability Schwannomas and Neurofibromastosis type
meningiomas 2, acoustic schwannomas,
and meningiomas
Cytosol APC/β- Inhibition of signal Carcinomas of Familial adenomatous
catenin transduction stomach, colon, polyposis coli/colon
pancreas; melanoma cancer
PTEN PI3 kinase signal Endometrial and Cowden syndrome
transduction prostate cancers
SMAD2 and TGF-β signal Colon, pancreas Unknown
SMAD4 transduction tumors
Nucleus RB1 Regulation of cell Retinoblastoma; Retinoblastomas,
cycle osteosarcoma osteosarcoma
carcinomas of breast,
colon, lung
p53 Cell cycle arrest and Most human cancers Li-Fraumeni syndrome;
apoptosis in response multiple carcinomas and
to DNA damage sarcomas
WT1 Nuclear transcription Wilms' tumor Wilms' tumor
P16/INK4a Regulation of cell Pancreatic, breast, and Malignant melanoma
cycle by inhibition of esophageal cancers
cyclindependent
kinases
BRCA1 and DNA repair Unknown Carcinomas of female
BRCA2 breast and ovary;
carcinomas of male breast