lymphomas: the basics brad kahl, md assistant professor of medicine director, uw lymphoma service
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Lymphomas: The Basics
Brad Kahl, MD
Assistant Professor of Medicine
Director, UW Lymphoma Service
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Lymphomas: NHL vs Hodgkin’s
• EPIDEMIOLOGY
• Biology
• Classification
• Approach to the Patient
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Hodgkin’s 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
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Hodgkin’s Disease
• Epidemiology– men > women– whites > blacks > Asians– no clear risk factors, several implicated
• EBV (pathogen or passenger)
• HIV
• woodworking, farming
• rare familial aggregations
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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
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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?
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NHL: Epidemiology
• Other risk factors– immunodeficiency states
• AIDS, post-transplant, genetic
– autoimmune diseases• Sjogrens
• Sprue
– infections• H. pylori, EBV, HHV-8
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Epidemiology
• SEER 5 year survival data
• NHL Hodgkin’s– 1974-76: 47.2 71.1%– 1977-79: 48.1 73.0%– 1980-82: 51.1 74.3%– 1983-90 52.0 78.9%
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Hodgkin’s Disease
• Epidemiology
• BIOLOGY
• Classification
• Approach to the Patient
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Hodgkin’s Disease
• Background– first described in 1832 by Dr. Thomas Hodgkin– characterized by the presence of Reed-
Sternberg cells• multinucleated giant cells
• described by Sternberg in 1898 and Reed in 1902
– classified as an infectious disease until 1950’s
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Reed-Sternberg Cell
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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
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Hodgkin’s Disease
• Epidemiology
• Biology
• CLASSIFICATION
• APPROACH TO THE PATIENT
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Hodgkin Lymphoma Classification
• “Classic” Hodgkin’s 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
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Classic Hodgkin Lymphoma
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Nodular Sclerosing Hodgkin Lymphoma
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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
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Hodgkin’s Disease
• Approach to the Patient– staging evaluation
• 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**
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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
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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.
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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
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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
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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)
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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)
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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
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Hodgkin’s Disease
• Results of Treatment• stage 5 year overall survival
– I 90%– II 90%– III 80%– IV 65%
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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
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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
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NHL
• Epidemiology
• BIOLOGY
• Classification
• Approach to the Patient
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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
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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
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NHL
• Epidemiology
• Biology
• CLASSIFICATION
• Approach to the Patient
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NHL: Classification
• Historically- a mess– 1940s Gail and Mallory– 1950s Rappaport– 1970s Lukes-Collins– 1970s Kiel– 1982 Working– 1994 REAL– 1999 WHO
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NHL: Classification
• Key Points– cell size: small cell vs. large cell– nodal architecture: follicular vs. diffuse
• Principle– More aggressive: diffuse, large cell– More indolent: follicular, small cell
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NHL: Classification
• Terminology (refers to natural history)– low grade = indolent– intermediate grade = aggressive– high grade = aggressive
• Principle– indolent: slow growing, incurable– aggressive: rapidly growing, curable
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NHL
• Epidemiology
• Biology
• Classification
• APPROACH TO THE PATIENT
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NHL: Approach to the Patient
• Approach dictated mainly by histology– reliable hematopathology crucial
• Approach also influenced by:– stage– prognostic factors– co-morbidities
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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…)
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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
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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
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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
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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
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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
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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
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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)
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CR and OS stratified by IPI
# RF’s CR 5 yr OS
0,1 87% 73%
2 67% 51%
3 55% 43%
4,5 44% 26%
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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
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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
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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
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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
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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