Lymphomas: The Basics
Brad Kahl, MD
Assistant Professor of Medicine
Director, UW Lymphoma Service
Lymphomas: NHL vs Hodgkin’s
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EPIDEMIOLOGY
Biology
Classification
Approach to the Patient
Hodgkin’s Disease
• Epidemiology
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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
Hodgkin’s Disease
• Epidemiology
– men > women
– whites > blacks > Asians
– no clear risk factors, several implicated
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EBV (pathogen or passenger)
HIV
woodworking, farming
rare familial aggregations
NHL: Epidemiology
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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
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NHL
Hodgkin’s
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1974-76:
1977-79:
1980-82:
1983-90
47.2
48.1
51.1
52.0
71.1%
73.0%
74.3%
78.9%
Hodgkin’s Disease
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Epidemiology
BIOLOGY
Classification
Approach to the Patient
Hodgkin’s 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 1950’s
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
Hodgkin’s Disease
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Epidemiology
Biology
CLASSIFICATION
APPROACH TO THE PATIENT
Hodgkin Lymphoma Classification
• “Classic” Hodgkin’s Disease
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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
• Hodgkin’s 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
Hodgkin’s Disease
• Approach to the Patient
– staging evaluation
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H&P
CBC, diff, plts
ESR, LDH, albumin, LFT’s, 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 (IE)
• 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 (IIIE)
• 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)
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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)
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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)
Hodgkin’s 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
Hodgkin’s 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
Hodgkin’s: 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
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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) Burkitt’s
• 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
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Epidemiology
Biology
CLASSIFICATION
Approach to the Patient
NHL: Classification
• Historically- a mess
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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
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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, LFT’s, 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
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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
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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
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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)
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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
# RF’s
CR
5 yr OS
0,1
87%
73%
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67%
51%
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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
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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, Hodgkin’s decreasing
• Hodgkin’s 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
