Non-Hodgkin’s Lymphoma Thomas Kochuparambil 10/20/10

Non-Hodgkin’s Lymphoma 6th most common cause of cancer death in United States. Increasing in incidence and mortality. Since 1970, the incidence of lymphoma has almost doubled.

Types of Lymphoma Indolent (low grade) Intermediate Life expectancy in years, untreated 85-90% present in Stage III or IV Incurable Intermediate Aggressive (high grade) Life expectancy in weeks, untreated Potentially curable

Classification Rappaport Classification Kiel and Lukes & Collins Classification Working Formulation REAL WHO Classification 

WHO- B Cell Precursor B-cell neoplasm Precursor B-lymphoblastic leukemia/lymphoma Mature (peripheral) B-cell neoplasms B-cell chronic lymphocytic leukemia / small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes) Hairy cell leuekmia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type Nodal marginal zone lymphoma (+/- monocytoid B-cells) Follicle center lymphoma, follicular, Mantle cell lymphoma Diffuse large cell B-cell lymphoma • Mediastinal large B-cell lymphoma • Primary effusion lymphoma Burkitt's lymphoma/Burkitt's cell leukemia

WHO-T Cell Precursor T cell neoplasm: Precursor T-lymphoblastic lymphoma/leukemia Anaplastic large cell lymphoma, T/null cell, primary systemic type  Mature (peripheral) T cell and NK-cell neoplasms T cell prolymphocytic leukemia T-cell granular lymphocytic leukemia Aggressive NK-Cell leukemia Adult T cell lymphoma/leukemia (HTLV1+) Extranodal NK/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic gamma-delta T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary's syndrome Anaplastic large cell lymphoma, T/null cell, primary cutaneous type Peripheral T cell lymphoma, not otherwise characterized Angioimmunoblastic T cell lymphoma

Etiology of NHL Immune suppression DNA repair defects congenital (Wiskott-Aldrich) organ transplant (cyclosporine) AIDS increasing age DNA repair defects ataxia telangiectasia xeroderma pigmentosum

Etiology of NHL Chronic inflammation and antigenic stimulation Helicobacter pylori inflammation, stomach Chlamydia psittaci inflammation, ocular adnexal tissues Sjögren’s syndrome Viral causes EBV and Burkitt’s lymphoma HTLV-I and T cell leukemia-lymphoma HTLV-V and cutaneous T cell lymphoma Hepatitis C

Clinical Features Lymphadenopathy Cytopenias Systemic symptoms Hepatosplenomegaly Fever Night sweats

Clinical Features Lymphadenopathy may fluctuate or spontaneously remit, especially in low-grade lymphomas. B symptoms more common in high-grade lymphomas. Hematogenous spread of disease, with no predictable pattern.

Epidemiology Indolent lymphomas are rare in young people and increase in incidence with age. Large cell lymphoma is less age related, and is among most common cancers affecting the young. Burkitt’s and lymphoblastic lymphoma are common in adolescents. AIDS patients develop aggressive, high grade lymphomas.

Clinical Features Classic lymphoma: arises in lymph node or bone marrow. Extranodal primary more common in high-grade lymphoma. Waldeyer’s ring involvement frequent in GI lymphomas.

Staging Workup CBC, chemistries, urinalysis CT scans of chest, abdomen and pelvis Bone marrow biopsy and aspirate (Lumbar puncture) AIDS lymphoma T cell lymphoblastic lymphoma High grade lymphoma with positive marrow

Diagnosis of NHL Chromosome changes 14;18 translocation in follicular lymphoma bcl-2 oncogene t(8;14), t(2;8), t(8;22) in Burkitt’s lymphoma c-myc oncogene t(11;14) in mantle cell lymphoma cyclin D1 gene

Staging Workup CBC, chemistries, urinalysis CT scans of chest, abdomen and pelvis Bone marrow biopsy and aspirate (Lumbar puncture) AIDS lymphoma T cell lymphoblastic lymphoma High grade lymphoma with positive marrow

Diagnosis of NHL Excisional biopsy is preferred to show nodal architecture (follicular vs diffuse). Immunohistochemistry to confirm cells are lymphoid LCA (leukocyte common antigen) Monoclonal staining with Igk or Igl Flow cytometry: CD 19, CD20 for B cell lymphomas CD 3, CD 4, CD8 for T cell lymphomas

Staging: Ann Arbor I. 1 lymph node region or structure II. >1 lymph node region or structure, same side of diaphragm III. Both sides of diaphragm IV. Extranodal sites beyond “E” designation subscripts: A, B, E, S

Treatment Options: Indolent lymphomas Diffuse well-differentiated lymphocytic, Nodular poorly differentiated lymphocytic 10-15% in Stage I or II potentially curable local radiotherapy 85-90% Stage III or IV incurable treatment does not prolong survival

Reasons to Treat in Advanced Indolent Lymphomas Constitutional symptoms Anatomic obstruction Organ dysfunction Cosmetic considerations Painful lymph nodes Cytopenias

Treatment Options in Advanced Indolent Lymphomas Observation only. Radiotherapy to site of problem. Systemic chemotherapy oral agents: chlorambucil and prednisone IV agents: CHOP, COP, fludarabine, 2-CDA. Antibody against CD20: Rituxan, Bexxar, Zevalin. Stem cell or bone marrow transplant.

CHOP Chemotherapy Cyclophosphamide (Cytoxan) Hydroxydaunorubicin (Adriamycin) Oncovin (vincristine) Prednisone

Treatment Options: Aggressive Lymphomas Diffuse large cell lymphoma, large cell anaplastic lymphoma, peripheral T cell lymphoma. Very Aggressive Burkitt’s lymphoma and lymphoblastic lymphoma.

Treatment Options for Early Stage Aggressive Lymphomas Often in Stage I or II potentially curable disseminates through bloodstream early must use systemic chemotherapy CHOP x 6 cycles CHOP x 3 cycles followed by radiotherapy

Treatment Options for Advanced Stage Aggressive Lymphomas Systemic chemotherapy CHOP (± Rituxan for over 70 age group) ± Intrathecal chemotherapy AIDS patients and CNS involvement ± Radiotherapy Spinal cord compression, bulky disease

R-CHOP French group ‘GELA’ Randomized trial 399 pts Elderly (higher risk pts) CHOP x 8 +/- Rituximab Improved results with addition of ‘Rituxaimab’ RR 63% 75% 2yr EFS 38%57% 2 yr OS 57%70% (Coiffier B; N Eng J Med 2002:346:235)

Lymphoblastic Lymphoma T cell malignancy. Male adolescents. Mediastinal mass. T cell variant of T cell acute lymphoblastic leukemia. Prognosis improving with intensive ALL regimens.

Burkitt’s Lymphoma African variety: jaw tumor, strongly linked to Epstein-Barr Virus infection. In U.S., about 50% EBV infection. May present as abdominal mass. Most rapidly growing human tumor. Typical chromosome abnormality: c-myc oncogene linked to one of the immunoglobulin genes.

Treatment CHOP alone is not sufficient CAL GB 9251 CODOX M EPOCH HYPER CVAD with alternating Mx + R Tumorlysis Syndrome -Resburicase:  recombinant version of a urate oxidase enzyme 

Mycosis Fungoides Malignancy of helper T cells. Affinity for skin. Can be treated with electron beam radiation, ultraviolet light, or topical alkylating agents.

Adult T Cell Leukemia-Lymphoma Associated with HTLV-I infection. Caribbean, southeastern U.S. Hepatosplenomegaly, leukocytosis, lymphadenopathy, skin involvement, lytic lesions of bone, hypercalcemia. May respond to AZT and interferon.

AIDS Lymphoma Aggressive lymphomas of B cell origin. Burkitt’s, Burkitt’s-like, and large cell immunoblastic. Treatment often limited by immune compromise of the patient. Prognosis improved with HAART therapy.

MALT Lymphoma Mucosa-Associated Lymphoid Tissue Chronic infection of the stomach by Helicobacter pylori. Localized to the stomach, indolent course. Can be cured in many cases by antibiotics against H. pylori.

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