Lymphoma Presentation and Diagnosis

1. Lymphoma Presentation and Diagnosis Mark B. Juckett MD Division of Hematology University of Wisconsin June 19, 2003

2. Approach to Lymphadenopathy • Palpable LAD in children – “the rule” • LAD in adults • < 1cm considered “normal” (< 2cm in groin) • LAD is normal response to foreign antigens • May include infections, allergens, autoimmune targets • Pathologic LAD due to proliferation or infiltration

3. Pre B cell IgM B cell Follicles Bone Marrow Lymph Node Normal B cell Development Travel

4. “meaning” B cell activation B cell finds “meaning” Germinal Center Formation

5. Proliferation Signals “Never die” Signals Mutation Signals Survival Signals Germinal Center Germinal Center Activity

6. Memory B cell “Activated B cell” Plasma Cells travel back to bone marrow Plasmacytoid Cell IgM

7. Causes of LAD • Infections • Bacterial – pyogenic, cat-scratch, syphilis, tularemia, plague • Mycobacterial – tuberculosis, leprosy, MAI • Fungal – histoplasmosis, coccidioidiomycosis • Chlamydial – lymphogranuloma venereum • Parasitic – toxo, trypanosomiasis, filariasis • Viral – EBV, CMV, rubella, HIV, hepatitis C

8. Causes of LAD (cont) • Inflammatory disorders • Autoimmune - Rheumatoid arthritis, SLE • Drugs – serum sickness, phenytoin • Castleman’s disease • Histiocytic diseases (SHML, LH) • Kawasaki syndrome • Kimura’s disease • Sarcoidosis

9. Causes of LAD (cont) • Storage diseases • Gaucher’s, Neimann-Pick disease • Amyloidosis • Endocrinopathies • Hyperthyroidism, adrenal insufficiency • Cancer • “Immune system” cancers • Metastatic carcinoma

10. Most Frequent Causes • Unexplained (?) • Infection • Immune system disorders • Immune system malignancies (Lymphoma) • Metastatic carcinoma • Other

11. Approach to patient with LAD • Does the patient have a known illness that causes LAD? Treat and monitor • Is there infection? Treat and monitor. • Is the LAD large (> 3cm) or have unusual characteristic (i.e. hard)? Biopsy. • If none are true, monitor 2 to 6 weeks, if persistent or large, biopsy.

12. Mortality Rate by Cancer1970 - 1994 • Males • Age 50 - 74

13. Mortality Rate by State1970 - 1994 • NHL • Males • Age 50 - 74

14. Mortality Rate by Year1950 - 1994 • NHL • All ages

15. Incidence Rate by Year1973 - 2000 • NHL • All ages

16. Incidence Rate by Age1996 - 2000 • NHL • M/F

17. Classification of Lymphoma • Past schemes: Rappaport, Kiel, Working formulation, “R.E.A.L.”, others • World Health Organization involved to develop uniform classification • Focus on defining distinct disease entities • Classification defined 23 separate NHL and 5 Hodgkins lymphoma diagnoses.

18. General Comments on Diagnosis • Initial diagnosis depends on tissue biopsy • FNA rarely useful • Fresh tissue important for path studies • Flow cytometry and cytogenetics helpful • Best imaging techniques: CT, PET scan • Important labs: LDH, CBC • Also LFT’s, Alb, Cr, uric acid, lytes

19. Precursor B-lymphoblastic leukemia/lymphoma CLL / SLL Prolymphocytic leukemia Lymphoplasmacytic lymphoma Marginal zone B-cell lymphoma Hairy cell leuekmia Follicle center lymphoma Mantle cell lymphoma Diffuse large cell B-cell lymphoma Burkitt's lymphoma/Burkitt's cell leukemia Precursor T-lymphoblastic leukemia/lymphoma T cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-Cell leukemia Adult T cell lymphoma/leukemia Extranodal NK/T-cell nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma Subcutaneous panniculitis-like T-cell Mycosis fungoides/Sézary's syndrome Anaplastic large cell lymphoma Peripheral T cell lymphoma Angioimmunoblastic T cell lymphoma WHO Lymphoma Types

20. Many lymphomas are curable Even after relapse The incurable NHL can be indolent International Prognostic Index Most important for most NHL General Comments on Prognosis • Age over 60 • Stage 3 or 4 disease • More than one extranodal site • Elevated LDH • Poor general health

21. Most Common NHL Diagnoses • Diffuse Large B-cell Lymphoma • Follicular Lymphoma • Small Lymphocytic Lymphoma • Mantle Cell Lymphoma • Peripheral T-cell Lymphoma Armitage JCO 16:2780, 1998

22. Diffuse Large B-cell Lymphoma • Present with symptoms from focal disease • Most common lymphoma (30 – 40%) • Aggressive behavior • Median Age: 64 yo • IPI predictive of response and survival • Standard treatment: CHOP ± rituximab • Curable with chemotherapy

23. Prognosis of DLCL by IPI NEJM 329:987, 1993

24. Follicular Lymphoma • Asymptomatic LAD • Median age: 59 yo • Indolent behavior • Median survival 10 years • Stage III – IV disease 67% • IPI predictive, few high risk • Incurable with chemo • Stage I curable with XRT • Treatment based on symptoms • No need to treat at diagnosis • Characteristic t(14:18)

25. Small Lymphocytic Lymphoma • Asymptomatic LAD • Median Age 65 • “Solid” counterpart to CLL • Indolent behavior • Median survival 4 – 5 years • Stage III – IV disease 91% • Incurable with chemo • Treatment based on symptoms • No need to treat at diagnosis • Treatment as for CLL

26. Mantle Cell Lymphoma • Few symptoms at diagnosis • Indolent behavior at diagnosis • Relentless progression • Median survival 2 yrs • Male predominance 3:1 • Stage III – IV 80% • GI/blood involvement common • Poor overall response & survival • Aggressive regimens may help • Characteristic t(11:14)

27. Peripheral T-cell Lymphoma • Present with symptoms from focal disease • Aggressive behavior • Median Age: 61 yo • IPI not predictive of response and survival • Survival short: median 1 year • Standard treatment (?) CHOP • Few are cured with chemotherapy • Novel approaches needed

28. Treatment of NHL • Most aggressive lymphomas • CHOP – cyclophosphamide, vincristine, doxorubicin, and prednisone • Most indolent lymphomas • Many need no treatment – only for symptoms • Oral alkylators, CVP, CHOP, fludarabine, rituximab (antibiotics for MALT) • Relapse – many patients will benefit from high dose chemotherapy (transplant)

29. High-dose Chemotherapy with Stem Cell Rescue Philip et al NEJM 333:1540, 1995

30. Rituximab (Rituxan®) • FDA Approved Indication • “RITUXAN is indicated for the treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive B-cell non-Hodgkin’s lymphoma” • IgG1 kappa chimeric murine/human monoclonal antibody against CD20 • Application in B-cell malignancy and autoimmunity

31. Making Chimeric Antibody Murine Anti-CD20 Ig gene Human IgG1 gene Clone Variable Region gene Clone Constant Region gene Mouse Human Chimeric Gene Cellular Producer

32. Mechanisms of Activity for IgG1 Antibodies Dendritic Cell Complement NK Cell

33. New Agents/Approaches • Rituximab • Most commonly prescribed cancer drug • Ibritumomab Tiuxetan (Zevalin®) • Yittrium 90 labeled rituximab • Iodine 131 Tositumomab (Bexxar®) • Alemtuzumab (Campath 1H®) • Pentostatin, Fludarabine, Cladribine

34. Conclusion • Persistent LAD in older pts needs biopsy • Many with aggressive lymphoma will be cured • Many with indolent lymphoma will live many years with disease • Our ability to define NHL has outpaced our knowledge of how to best treat • Many new agents available (how to use?)