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Lymphomas: The Basics. Brad Kahl, MD Assistant Professor of Medicine Director, UW Lymphoma Service. Lymphomas: NHL vs Hodgkin’s. EPIDEMIOLOGY Biology Classification Approach to the Patient. Hodgkin’s Disease. Epidemiology 14% of malignant lymphomas 0.5% of all malignancies
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Lymphomas: The Basics Brad Kahl, MD Assistant Professor of Medicine Director, UW Lymphoma Service
Lymphomas: NHL vs Hodgkin’s • EPIDEMIOLOGY • Biology • Classification • Approach to the Patient
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
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
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 • NHLHodgkin’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%
Hodgkin’s Disease • Epidemiology • BIOLOGY • Classification • Approach to the Patient
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
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 • Epidemiology • Biology • CLASSIFICATION • APPROACH TO THE PATIENT
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
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 • 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) • 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)
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 • stage5 year overall survival • I 90% • II 90% • III 80% • IV 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 • 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 • 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: diffuse, large cell • More indolent: follicular, small cell
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
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, 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 • 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