SYMPOSIUM ON ONCOLOGY PRACTICE: HEMATOLOGICAL MALIGNANCIES NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT

Non-Hodgkin Lymphoma: Diagnosis and Treatment STEPHEN M. ANSELL, MD, PHD, AND JAMES ARMITAGE, MD Non-Hodgkin lymphomas are a heterogeneous group of malignancies of the lymphoid system. Based on the World Health Organization classification of hematological and lymphoid tumors, these diseases have been classified as B-cell and T-cell neoplasms. Bcell lymphomas account for approximately 90% of all lymphomas, and the 2 most common histological disease entities are follicular lymphoma and diffuse large B-cell lymphoma. Approximately 55,000 to 60,000 new cases of non-Hodgkin lymphoma are diagnosed annually in the United States, a number that has nearly doubled during the past 3 decades. The Ann Arbor Staging Classification is used routinely to classify the extent of disease, and the International Prognostic Index has been used to define prognostic subgroups. Also, recent data have identified molecular and genetic markers of prognosis that may be used in the future to further refine treatment decisions. Treatment of these diseases is based on the histology and extent of disease. Patients with follicular lymphomas with early-stage disease generally are treated with radiation therapy, whereas those with stage III and IV disease requiring treatment usually are treated with chemotherapy, immunotherapy, or radioimmunotherapy. These patients generally experience long survival, but only a minority are cured. For patients with diffuse large B-cell lymphoma, treatment of limited-stage disease generally includes doxorubicin-based chemotherapy combined with rituximab followed by involved field radiation therapy. Those with extensive disease are treated with rituximab combined with chemotherapy alone. Disease relapse is a problem, and high-dose therapy with stem cell support is the treatment of choice for chemosensitive relapsed aggressive lymphomas. Patients with chemoresistant disease or whose disease relapses subsequently should be treated with novel experimental therapies.

Mayo Clin Proc. 2005;80(8):1087-1097 ACVBP = doxorubicin (Adriamycin), cyclophosphamide, vindesine, bleomycin, and prednisone; CHOP = cyclophosphamide, hydroxydaunomycin (doxorubicin), vincristine (Oncovin), and prednisone; CNS = central nervous system; CVP = cyclophosphamide, vincristine, and prednisone; FDG-PET = positron emission tomography with fluorodeoxyglucose F 18; GI = gastrointestinal; HIV = human immunodeficiency virus; IPI = International Prognostic Index; LDH = lactate dehydrogenase; MALT = mucosa-associated lymphoid tissue; NHL = non-Hodgkin lymphoma; PET = positron emission tomography; R-CHOP = CHOP chemotherapy in combination with rituximab

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n estimated 55,000 to 60,000 new cases of nonHodgkin lymphoma (NHL) are diagnosed in the United States annually.1 Data from the National Cancer Institute have shown that the incidence of NHL increased by 3% annually in the United States in the past 3 decades but seems to have stabilized in the 1990s, with some variation in the rates according to age, ethnicity, and sex.2-4 Non-Hodgkin lymphoma is known to be associated with chronic inflammatory diseases such as Sjögren syndrome, celiac disease, and rheumatoid arthritis. Chronic infection also is associated with lymphoma pathogenesis Mayo Clin Proc.

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as shown by the association between mucosa-associated lymphoid tissue (MALT) lymphomas and Helicobacter pylori infection.5 Human T-lymphotropic virus 1 is associated with adult T-cell leukemia/lymphoma; Epstein-Barr virus is associated with Burkitt lymphoma; and primary effusion lymphomas have been associated with human herpesvirus 8. Also, an association has been shown between Chlamydia psittaci and ocular adenexal lymphomas.6 Furthermore, there is also evidence of an association between hepatitis C infections and splenic or large cell lymphomas.7 Immune suppression also has been associated with an increased risk of NHL. In patients who undergo solid organ transplantation,8 the risk of lymphoma has been associated specifically with the duration of immunosuppression and with the drugs and doses used. Furthermore, human immunodeficiency virus (HIV) infections have been associated with a substantially elevated risk of NHL compared with the risk in the general population.9 DIAGNOSIS Patients with indolent lymphomas, such as follicular, marginal zone, and lymphoplasmacytic lymphoma, commonly present with slowly progressive and usually painless peripheral lymphadenopathy. Patients sometimes report a history of the involved lymph nodes getting larger and then smaller before a diagnosis is made. Spontaneous regression of some of these lymph nodes can occur, which may delay the diagnostic biopsy while patients receive therapy for a presumed infectious condition. Primary extranodal involvement or systemic symptoms are less common at presentation but are seen more commonly as the disease advances. Systemic B-symptoms, such as fever, night sweats, and weight loss, may develop and may be associated with more advanced or aggressive disease. Bone marrow involvement in indolent lymphomas is frequent and From the Division of Hematology, Mayo Clinic College of Medicine, Rochester, Minn (S.M.A.); and Department of Medical Oncology, University of Nebraska, Omaha (J.A.). Address correspondence to Stephen M. Ansell, MD, PhD, Division of Hematology, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Individual reprints of this article and a bound booklet of the entire Symposium on Oncology Practice: Hematological Malignancies will be available for purchase from our Web site www.mayoclinicproceedings.com. © 2005 Mayo Foundation for Medical Education and Research

August 2005;80(8):1087-1097

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NON-HODGKIN LYMPHOMA: DIAGNOSIS AND TREATMENT

TABLE 1. World Health Organization Classification of Lymphoid Malignancies11* Percentage of total cases

Classification I Peripheral B-cell neoplasms Precursor B lymphoblastic leukemia/lymphoma Mature B-cell neoplasms Chronic lymphocytic leukemia/small lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone lymphoma Extranodal marginal zone B-cell lymphoma of MALT (MALT lymphoma) Nodal marginal zone lymphoma Follicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphoma Mediastinal (thymic) large B-cell lymphoma Intravascular large B-cell lymphoma Primary effusion lymphoma Burkitt lymphoma/leukemia Hairy cell leukemia Plasma cell myeloma Solitary plasmacytoma of bone B-cell proliferation of uncertain malignant potential Lymphomatoid granulomatosis Posttransplantation lymphoproliferative disorder, polymorphic

6.7 1.2