Lymphomas: The Basics

1. Lymphomas: The Basics Brad Kahl, MD Assistant Professor of Medicine Director, UW Lymphoma Service

2. Lymphomas: NHL vs Hodgkin’s • EPIDEMIOLOGY • Biology • Classification • Approach to the Patient

3. 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

4. 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

5. 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

6. 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?

7. NHL: Epidemiology • Other risk factors • immunodeficiency states • AIDS, post-transplant, genetic • autoimmune diseases • Sjogrens • Sprue • infections • H. pylori, EBV, HHV-8

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%

9. Hodgkin’s Disease • Epidemiology • BIOLOGY • Classification • Approach to the Patient

10. 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

11. Reed-Sternberg Cell

12. 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

13. Hodgkin’s Disease • Epidemiology • Biology • CLASSIFICATION • APPROACH TO THE PATIENT

14. 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

15. Classic Hodgkin Lymphoma

16. Nodular Sclerosing Hodgkin Lymphoma

17. 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

18. 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**

19. 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

20. 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.

21. 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

23. 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

24. 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)

25. 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)

26. 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

27. Hodgkin’s Disease • Results of Treatment • stage5 year overall survival • I 90% • II 90% • III 80% • IV 65%

28. 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

29. 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

30. NHL • Epidemiology • BIOLOGY • Classification • Approach to the Patient

31. 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

32. 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

33. NHL • Epidemiology • Biology • CLASSIFICATION • Approach to the Patient

34. NHL: Classification • Historically- a mess • 1940s Gail and Mallory • 1950s Rappaport • 1970s Lukes-Collins • 1970s Kiel • 1982 Working • 1994 REAL • 1999 WHO

36. 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

37. 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

38. NHL • Epidemiology • Biology • Classification • APPROACH TO THE PATIENT

39. NHL: Approach to the Patient • Approach dictated mainly by histology • reliable hematopathology crucial • Approach also influenced by: • stage • prognostic factors • co-morbidities

40. 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…)

42. 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

45. 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

46. 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

47. 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

48. 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