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Published on : Feb 24, 2014
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Slide 1 -

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

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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

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Normal B cell Development Travel

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B cell finds “meaning” Germinal Center Formation

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Germinal Center Activity

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Plasma Cells travel back to bone marrow Plasmacytoid Cell IgM

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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

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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

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

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

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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.

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Mortality Rate by Cancer1970 - 1994 Males Age 50 - 74

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Mortality Rate by State1970 - 1994 NHL Males Age 50 - 74

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Mortality Rate by Year1950 - 1994 NHL All ages

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Incidence Rate by Year1973 - 2000 NHL All ages

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Incidence Rate by Age1996 - 2000 NHL M/F

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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.

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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

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WHO Lymphoma Types 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

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

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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

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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

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Prognosis of DLCL by IPI NEJM 329:987, 1993

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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)

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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

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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)

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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

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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)

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

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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

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

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Mechanisms of Activity for IgG1 Antibodies Complement Dendritic Cell NK Cell

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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

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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?)

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