Lymphomas: The Basics

Brad Kahl, MD
Assistant Professor of Medicine
Director, UW Lymphoma Service

Lymphomas: NHL vs Hodgkins

EPIDEMIOLOGY
Biology
Classification
Approach to the Patient

Hodgkins Disease
Epidemiology

14% of malignant lymphomas

0.5% of all malignancies
approximately 8000 new cases/yr in US
approximately 1500 deaths/yr
over past 30 years
age adjusted incidence rates declined appreciably
mortality rates declined substantially

Hodgkins Disease
Epidemiology
men > women
whites > blacks > Asians
no clear risk factors, several implicated

EBV (pathogen or passenger)

HIV
woodworking, farming
rare familial aggregations

NHL: Epidemiology

Most common hematologic malignancy

60,000 new cases annually
6th leading cause of cancer death
incidence rising
overall incidence up by 73% since 1973
epidemic
2nd most rapidly rising malignancy

NHL: Epidemiology
Why the increase?
Increase noted mostly in farming states
MN #1, WI #7 NHL incidence
possible role of herbicides, insecticides, etc.

Other environmental factors?

NHL: Epidemiology
Other risk factors
immunodeficiency states
AIDS, post-transplant, genetic

autoimmune diseases
Sjogrens
Sprue

infections
H. pylori, EBV, HHV-8

Epidemiology
SEER 5 year survival data

NHL
Hodgkins

1974-76:
1977-79:
1980-82:
1983-90

47.2
48.1
51.1
52.0

71.1%
73.0%
74.3%
78.9%

Hodgkins Disease

Epidemiology
BIOLOGY
Classification
Approach to the Patient

Hodgkins Disease
Background
first described in 1832 by Dr. Thomas Hodgkin
characterized by the presence of ReedSternberg cells
multinucleated giant cells
described by Sternberg in 1898 and Reed in 1902

classified as an infectious disease until 1950s

Reed-Sternberg Cell

Hodgkin Biology
RS is a crippled germinal center B cell
does not have normal B cell surface antigens
micromanipulation of single RS followed by PCR
demonstrates clonally rearranged, but non functional
immunoglobulin genes
somatic mutations result in stop codon (no sIg)
no apoptotic death
malignant transformation

unclear how this occurs; ? EBV

unclear how cells end up with RS phenotype

Hodgkins Disease

Epidemiology
Biology
CLASSIFICATION
APPROACH TO THE PATIENT

Hodgkin Lymphoma Classification

Classic Hodgkins Disease

nodular sclerosis
mixed cellularity
lymphocyte depleted (very rare)
classical lymphocyte rich

HRS cells CD30 and CD15 positive

nodular lymphocyte predominant

HRS cells (L&H cells) have B cell markers
CD 20 and surface Immunoglobulin

Classic Hodgkin Lymphoma

Nodular Sclerosing
Hodgkin Lymphoma

Approach to the Patient

Hodgkins Disease
approach dictated mainly by where the disease
is located rather (results of staging) than the
exact histologic subtype

NHL
approach is dictated mainly by the histologic
subtype rather than the results of staging

Hodgkins Disease
Approach to the Patient
staging evaluation

H&P
CBC, diff, plts
ESR, LDH, albumin, LFTs, Cr
CT scans chest/abd/pelvis
bone marrow evaluation
**PET or gallium scan**
**lymphangiogram or laparotomy**

Ann Arbor Staging System

Stage I:
single lymph node region (I) or single
extralymphatic organ or site (I E)
Stage II: > 2 lymph node regions on same side of
diaphragm (II) or with limited, contiguous
extra lymphatic
tissue involvement (IIE)
Stage III: both sides of diaphragm involved, may include
spleen (IIIS) or local tissue involvement (III E)
Stage IV: multiple/disseminated foci involved with > 1
extralymphatic organs (i.e. bone marrow)

(A) or (B) designates absence/presence of B symptoms

Ann Arbor Staging System for Hodgkin's

Disease and Non-Hodgkin's Lymphoma

Stage I

Stage II

Stage III

Stage IV

Reprinted with permission. Adapted from Skarin.

Dana-Farber Cancer Institute Atlas of
Diagnostic Oncology. 1991.

Modified Ann Arbor Staging

E designation for extranodal disease
B symptoms
recurrent drenching night sweats during previous month
unexplained, persistent, or recurrent fever with temps above 38
C during the previous month
unexplained weight loss of more than 10% of the body weight
during the previous 6 months

Criteria for bulk

10 cm nodal mass
mediastinal mass > 1/3 thorax diameter

Hodgkin Lymphoma
Treatment
approach depends upon stage, prognostic factors,
and co-morbidities
Stage I-II
consider XRT, chemotherapy, or combined therapy

Bulky stage I-II

combined modality therapy

Stage III-IV
ABVD x 6-8 cycles gold standard

Hodgkin Lymphoma
Adverse prognostic features for stage I & II (EORTC data)

more than 3 nodal sites

bulky adenopathy
ESR > 50
B symptoms
invasion into critical organs
male
age > 40
MC or LD subtype

should probably not receive XRT alone if any of the above

present (excessive relapse rate)

Hodgkin Lymphoma
Independent adverse prognostic factors
advanced stage (III-IV)

male sex
age > 45
albumin < 4 gm/dl
HgB < 10.5 mg/dl
stage IV disease
WBC count > 15,000/mm3
lymphocyte count < 600/mm3
(Hasenclever et al, NEJM 339,1506-1514;1998)

Hodgkins Disease
Role for Stem Cell Transplantation
clinical trials show benefit for patients who
receive high dose chemotherapy followed by
SCT for patients who have relapsed after initial
therapy or for patients are primary refractory

Hodgkins Disease
Results of Treatment
stage
I
II
III
IV

5 year overall survival

90%
90%
80%
65%

Hodgkin Lymphoma
Late Complications
depends upon treatment modality utilized
XRT vs. MOPP vs. ABVD vs. CMT
issues depends upon the age of patient
relative risks higher in younger patients
absolute risks higher in older patients

major focus of current clinical trials to to maintain high cure

rate while minimizing late complication
shorter courses of chemotherapy with lower radiation doses in
smaller fields
elimination of radiotherapy

Hodgkins: future directions

Limited stage and good prognosis advanced stage
cure rate high
current goal is to minimize late complications
trials looking at CMT with less chemotherapy and less
radiation

Advanced stage
cure rate around 50-70%
trial comparing ABVD to Stanford V

Clinical Trials

NHL

Epidemiology
BIOLOGY
Classification
Approach to the Patient

Lymphoma Biology
Indolent vs. Aggressive NHL
key principle in understanding biology, and approach to the
patient
Indolent = incurable
Aggressive = curable
WHY?

Chromosomal Abnormalities in NHL

frequent chromosomal translocations into Ig gene loci
t(8;14), t(2;8), t(8;22) Burkitts
t(14;18) follicular NHL

Lymphoma Biology
Aggressive NHL
short natural history (patients die within months
if untreated)
disease of rapid cellular proliferation

Indolent NHL
long natural history (patients can live for many
years untreated)
disease of slow cellular accumulation

NHL

Epidemiology
Biology
CLASSIFICATION
Approach to the Patient

NHL: Classification
Historically- a mess

1940s Gail and Mallory

1950s Rappaport
1970s Lukes-Collins
1970s Kiel
1982 Working
1994 REAL
1999 WHO

NHL: Classification
Key Points
cell size: small cell vs. large cell
nodal architecture: follicular vs. diffuse

Principle
More aggressive:
More indolent:

diffuse, large cell

follicular, small cell

NHL: Classification
Terminology (refers to natural history)
low grade = indolent
intermediate grade = aggressive
high grade = aggressive

Principle
indolent:
aggressive:

slow growing, incurable

rapidly growing, curable

NHL

Epidemiology
Biology
Classification
APPROACH TO THE PATIENT

NHL: Approach to the Patient

Approach dictated mainly by histology
reliable hematopathology crucial

Approach also influenced by:

stage
prognostic factors
co-morbidities

NHL: Approach to the Patient

Staging evaluation
History and PE
Routine blood work
CBC, diff, plts, electrolytes, BUN, Cr, LFTs, uric acid,
LDH, B2M

CT scans chest/abd/pelvis
Bone marrow evaluation
Other studies as indicated (lumbar puncture,
gallium, etc)

NHL: Approach to the Patient

Indolent NHL: typical scenario

patient presents with painless adenopathy

otherwise asymptomatic
follicular small cell histology
average age 59
usually stage III-IV at diagnosis

NHL: Approach to the Patient

Indolent NHL: guiding treatment principle
early treatment does not prolong overall survival

When to treat?
constitutional symptoms
compromise of a vital organ by compression or
infiltration, particularly the bone marrow
bulky adenopathy
rapid progression
evidence of transformation

NHL: Approach to the Patient

Indolent NHL: typical scenario

watchful waiting: 2-4 years

first remission length: 3-4 years
second remission: 2-3 years
third remission: 1-2 years
each subsequent remission shorter than prior
median survival 8-12 years for FLSC

NHL: Approach to the Patient

Indolent NHL: treatment options
watchful waiting
radiation to involved fields
single agent chemotherapy
chlorambucil + prednisone, fludarabine

combination chemotherapy
CVP, CF, FND, CHOP

chemotherapy + interferon
chemotherapy + monoclonal antibodies
monoclonal antibodies
radiolabeled monoclonal antibodies
stem cell transplantation

NHL: Approach to the Patient

Aggressive NHL: typical scenario
patients notes B symptoms of several weeks
duration
work-up reveals pathologic adenopathy
histology: diffuse large cell lymphoma
about 50% patients stage I-II, 50% stage III-IV
average age 64
IPI score

NHL: Approach to the Patient

Aggressive NHL: treatment approach
Stage I-II: combined modality therapy
CHOP chemotherapy x 3 + IF radiotherapy
cure rate around 70%

Stage III-IV (also bulky stage II)

(R)CHOP chemotherapy x 6-8 cycles
cure rate around 40%

(R)CHOP is the standard

NHL: Approach to the Patient

International Prognostic Index
Risk Factors (0-5)

age > 60
two or more extranodal sites
performance status > 2
elevated LDH
stage III-IV

Age adjusted IPI (0-3)

CR and OS stratified by IPI

# RFs

CR

5 yr OS

0,1

87%

73%

67%

51%

55%

43%

4,5

44%

26%

NHL: Approach to the Patient

Is CHOP the best we can do?
R-CHOP may be better
National Trials opening looking at alternative
strategies in poor prognosis DLCL
age adjusted IPI > 2
CHOP vs. CHOP + SCT

Risk stratification is the current trend in NHL

Sorting out role for stem cell transplantation
Sorting out role for innovative combinations

NHL: Approach to the Patient

Role for Autologous Stem Cell Transplantation

Aggressive NHL
clear benefit when used for aggressive NHL in
first relapse in appropriately selected patients
1/3 of these patients can be cured by SCT

Indolent NHL
no indication that patients are cured
no indication that OS is prolonged

NHL: future directions

Indolent

monoclonal antibodies (Rituximab)

radiolabeled monoclonal antibodies
chemotherapy combined with antibodies
antibodies combined with immunomodulators

Aggressive
risk stratification
CHOP vs. CHOP plus SCT
chemotherapy plus antibodies

Clinical Trials

Summary
NHL incidence increasing, Hodgkins decreasing
Hodgkins cure rate quite high
approach is dictated mainly by disease stage

NHL cure rate mediocre

approach is dictated mainly by histologic subtype
indolent vs. aggressive
indolent: watchful waiting perfectly acceptable for
asymptomatic patients
aggressive: require aggressive treatment ASAP to achieve cure

Lymphoma Clinic
Multidisciplinary
radiotherapy-Dr. Scott Tannehill
hematopathology-Dr. Catherine Leith

Emphasis on clinical trials

formal testing of promising new therapies

Every Wednesday
Clinic phone #: 608-263-7022