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Slide 1 - Lymphoma Presentation and Diagnosis Mark B. Juckett MD Division of Hematology University of Wisconsin June 19, 2003
Slide 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
Slide 3 - Normal B cell Development Travel
Slide 4 - B cell finds “meaning” Germinal Center Formation
Slide 5 - Germinal Center Activity
Slide 6 - Plasma Cells travel back to bone marrow Plasmacytoid Cell IgM
Slide 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
Slide 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
Slide 9 - Causes of LAD (cont) Storage diseases Gaucher’s, Neimann-Pick disease Amyloidosis Endocrinopathies Hyperthyroidism, adrenal insufficiency Cancer “Immune system” cancers Metastatic carcinoma
Slide 10 - Most Frequent Causes Unexplained (?) Infection Immune system disorders Immune system malignancies (Lymphoma) Metastatic carcinoma Other
Slide 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.
Slide 12 - Mortality Rate by Cancer1970 - 1994 Males Age 50 - 74
Slide 13 - Mortality Rate by State1970 - 1994 NHL Males Age 50 - 74
Slide 14 - Mortality Rate by Year1950 - 1994 NHL All ages
Slide 15 - Incidence Rate by Year1973 - 2000 NHL All ages
Slide 16 - Incidence Rate by Age1996 - 2000 NHL M/F
Slide 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.
Slide 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
Slide 19 - 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
Slide 20 - 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
Slide 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
Slide 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
Slide 23 - Prognosis of DLCL by IPI NEJM 329:987, 1993
Slide 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)
Slide 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
Slide 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)
Slide 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
Slide 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)
Slide 29 - High-dose Chemotherapy with Stem Cell Rescue Philip et al NEJM 333:1540, 1995
Slide 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
Slide 31 - 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
Slide 32 - Mechanisms of Activity for IgG1 Antibodies Complement Dendritic Cell NK Cell
Slide 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
Slide 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?)