Lymphoma Diagnosis and Classification

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1 Lymphoma Diagnosis and Classification By Atef Shrit, MD, Pathology B- and T/NK-cell lymphomas are clonal neoplasms of immature and mature B-lymphocytes, T-lymphocytes or natural killer cells at various stages of differentiation. In general, B- and T-cell lymphomas appear to recapitulate stages of normal B-cell or T-cell differentiation. The classification of lymphoid neoplasms is based on the utilization of all available information to define disease entities (e.g., clinical history, morphology, immunophenotyping and genetic findings). Morphology and immunophenotype are sufficient for the diagnosis of most lymphoid neoplasms; however, no one antigenic marker is specific for any neoplasm and the combination of morphologic features and a panel of antigenic markers are necessary for correct diagnosis. Immune profiling is very helpful in the diagnosis of B-cell lymphoma, but it is somewhat less helpful in the subclassification of T-cell lymphomas. Moreover, while certain antigens are commonly associated with specific disease entities, these associations are not entirely disease-specific. For example, CD3 is a universal feature of anaplastic large cell lymphoma (ALCL), but can be expressed in other T-cell and B-cell lymphomas as well as classical Hodgkin s lymphoma. Genetic features are playing an increasingly important role in the classification of lymphoid malignancies. For many of small B-cell lymphomas and leukemias, recurrent genetic alterations have been identified. Lymphoid malignancies range in their clinical behavior from low grade to high grade. Moreover, histological and clinical progression is often encountered during a patient s clinical course. Therefore, the World Health Organization (WHO) classification does not solidify lymphoid malignancies in terms of grade. Both morphology and immunophenotype often change over time, as the lymphoid neoplasm undergoes clonal evolution with the acquisition of additional genetic features. The fourth edition of WHO classification also recognizes grey zone lymphomas. These lymphomas bridge the gap between various forms of lymphomas. Precursor lymphoid neoplasms, including precursor B-cell acute lymphoblastic leukemia (B-lymphoblastic leukemia/lymphoma) and precursor T-cell acute lymphoblastic leukemia (T-lymphoblastic leukemia/lymphoma), are primarily diseases of children as 75 percent of cases occur in children under six years of age. Mature B-cell neoplasms comprise over 9 percent of lymphoid neoplasms worldwide. They represent approximately 4 percent of all new cancers each year. The most recent survey from the Surveillance, Epidemiology and End Results (SEER) Program in the United States indicated an incidence rate Oncology Services Annual Report 1

2 Reference: WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues, 4th Edition, Lyon, 8. Non- Hodgkin s Lymphoma Incidence by AJCC Stage per 1, persons per year of for all lymphoid neoplasms, for B-cell neoplasms, 1.79 for all T-cell neoplasms and 2.67 for Hodgkin s lymphoma. Infectious agents have been shown to contribute to the development of several types of mature B-cell, T-cell and NK-cell lymphomas: Epstein-Barr virus (EBV) is present in nearly 1 percent of endemic Burkitt s lymphoma and in percent of sporadic and HIVassociated cases. EBV is also involved in the pathogenesis of many B-cell lymphomas arising in immune-suppressed and elderly patients, including post-transplant lymphoproliferative disorders, plasmablastic lymphoma and EBV+ large B-cell lymphoma of the elderly. EBV is also associated with extranodal NK/T-cell lymphoma. Some cases of classical Hodgkin s lymphoma are associated with EBV infection. Human herpesvirus-8 (HHV-8) is found in the primary effusion lymphoma and lymphomas associated with multicentric Castleman s disease commonly seen in HIV-infected patients. Human T-cell lymphotropic virus type 1 (HTLV-1) is a causative agent for adult T-cell lymphoma/leukemia. Hepatitis C virus has been implicated in some cases of lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, nodal marginal zone lymphoma and diffuse large B-cell lymphoma. Immune response to Helicobacter pylori has been implicated in the pathogenesis of gastric MALT (Mucosa-Associated Lymphoid Tissue). In conclusion, the fourth edition of WHO classification emphasizes a multi-parameter approach to classification including clinical history, histology, immunophenotyping and genetic features I II III IV AJCC Stage Non-Hodgkin s Lymphoma Incidence Gender Race Age Range Total M F W B CH Stage I denotes involvement of a single lymph node region (I) or localized involvement of a single extra-lymphatic organ or site (IE). Stage II indicates the involvement of 2 or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single associated extra-lymphatic organ or site and its regional lymph nodes, with or without other lymph node regions on the same side of the diaphragm (IIE). The number of lymph node regions involved may be indicated by a subscript, (e.g., II 3 ). Stage III implies involvement of lymph node regions on both sides of the diaphragm (III) that may also be accompanied by localized involvement of an extra-lymphatic organ or site (IIIE), by involvement of the spleen (IIIS), or both (IIISE). Stage IV is disseminated (multifocal) involvement of 1 or more extra-lymphatic sites with or without associated lymph node involvement or isolated extra-lymphatic organ involvement with distant (non-regional) nodal involvement. Source: emedicine from WebMD, 7 2 Miami Valley Hospital

3 Non-Hodgkin s Lymphoma Histology Indolent Types Cases Follicular lymphoma 42 3.% Small B lymphocytic lymphoma % Marginal zone B-cell lymphoma % Lymphoplasmacytic lymphoma % Subtotal Indolent % Aggressive Types Cases Large B-cell diffuse lymphoma % Mantle cell lymphoma % Large B-cell diffuse immunoblastic lymphoma % Mixed small & large cell diffuse lymphoma % Mediastinal large B-cell lymphoma 1.71% Subtotal Aggressive % Other Type Cases Burkitt s lymphoma % Total 1 1.% Non-Hodgkin s Lymphoma by Clinical Behavior Indolent Aggressive Other Cases Oncology Services Annual Report 3

4 Management of Non-Hodgkin s Lymphoma By Basel Yanes, MD, Medical Oncology Table 1. Lymphomas are a heterogeneous group of malignancies of the lymphoid system. This article explains in detail the treatment of the two most common types and briefly discusses the less common lymphoid malignancies. Advanced Indolent (Slow-Growing) Lymphoma This group is comprised mainly of Grade 1-2 follicular lymphomas, which account for 25-3 percent of non-hodgkin s lymphoma (NHL). The majority of patients present with advanced disease (Stage III-IV). The prognosis is determined by the Follicular Lymphoma International Prognostic Index (FLIPI), Table 1 below. Follicular Lymphoma International Prognostic Index Scoring: one point for each of the following characteristics: Age > 6 Stage III or IV LDH above normal Number of invaded nodal areas > 4 Hgb < 12 Overall Overall FLIPI Score Survival 5 Years Survival 1 Years Low Risk -1 9% 7% Intermediate Risk 2 8% 5% High Risk 3 5% 35% Advanced indolent lymphomas have the paradox of good prognosis and no cure. While there is no curative therapy, the median survival of untreated patients is about 1 years. There are multiple management options. The first option is watchful waiting. Asymptomatic patients with a stable or slowly progressive disease should be considered for watchful waiting where treatment is initiated when the disease becomes symptomatic or rapidly progresses. If patients require treatment, there are multiple chemotherapy options ranging from single alkylating agents to combination chemotherapy. More recently, the monoclonal antibody Rituxan (rituximab) has become a major type of treatment in these lymphomas. It is usually given in combination with chemotherapy or alone in certain patients. Perhaps the most widely used treatment regimens are: 1) Rituxan COP (+/- Adriamycin i.e. CHOP). The use of Adriamycin in these patients is controversial. 2) Fludarabine-Novantron-Rituxan (FNR) These regimens induce remission in approximately 8 percent of patients with about percent complete remission. Rituxan alone induces remission in approximately 5 percent of patients but these patients have shorter remissions. Rituxan maintenance prolongs remission but remains controversial as there is no definite survival benefit reported to date. Diffuse Large B-Cell Lymphoma Diffuse Large B-Cell Lymphoma (DLBCL) comprises approximately 3 percent of NHL. It is an aggressive disease and can be rapidly fatal if untreated. Fortunately, chemotherapy is very effective and often curative. The standard regimen is a combination of Cytoxan, Adriamycin, Vincristine, Prednisone (CHOP). Studies in the last few years showed significant improvement in outcome by adding Rituxan (R-CHOP). Currently the standard treatment is R-CHOP at 3-week intervals, usually given for 6-8 cycles. The treatment induces remission in many patients as shown in the above table; most relapses occur in 4 Miami Valley Hospital

5 2-3 years. A significant number of these patients are cured. The percentage is determined by the International Prognostic Index (IPI), Table 2 below. Table 2. International Prognostic Index Scoring: one point for each of the following characteristics: Age > 6 Number of extra-nodal sites > 1 LDH above normal Performance status > 1 Stage III or IV Complete Overall IPI Score Remission Survival 5 Year Low Risk -1 85% 7% Low-Intermediate Risk 2 7% 5% High-Intermediate Risk 3 55% % High Risk % 25% 5-Year Comparative Observed Survival Rates Comparative Data source: Elekta IMPAC Systems National Oncology Data Alliance (NODA) Idolent Type Lymphoma (N=68) Less Common Lymphomas Mantle Cell NHL This is one of the most challenging lymphomas as it has a relatively aggressive behavior but can t be cured with chemotherapy. It comprises approximately 7 percent of NHL. There is no standard approach and treatment ranges from R-CHOP to high dose chemotherapy with bone marrow transplant. Marginal Zone B-Cell Lymphomas This is an indolent type with multiple variants. The most known is gastric MALT (Mucosa-Associated Lymphoid Tissue). These patients often benefit from local treatment and have a good prognosis. Systemic therapy includes Rituxan and a variety of chemotherapy agents and combinations. Small Lymphocytic Lymphomas This is the tissue variant of chronic lymphocytic leukemia and is managed in a similar fashion. In general it has a good prognosis and often can be managed with watchful waiting. Lymphoplasmacytic Lymphoma Formally known as Waldenstrom s macroglobulinemia, this entity has an indolent course. It can often be managed with watchful waiting. When treatment is needed, a variety of chemotherapy agents and combinations as well as Rituxan can be effective At Dx Years Aggressive Type Lymphoma (N=64) At Dx Years Other Type Lymphoma (N=8) At Dx Years MVH NODA Oncology Services Annual Report 5

6 Radiation Therapy and Lymphoma By Douglas W. Ditzel, DO, Radiation Oncology Radiation therapy continues to play an important role in the treatment of lymphomas. As the classification of lymphomas continues to evolve and systemic treatments become more effective, the specific use of radiation is being refined. The larger fields used in the past are being replaced by more local-regional targets. In addition, doses will vary depending on the lymphoma subtype. Typically, involved field radiation will be used as primary treatment in Stage I-II follicular lymphomas, Stage I or II H. pylori negative gastric and non-gastric MALT lymphomas, and early stage primary cutaneous marginal zone or follicular center B-cell lymphomas. Limited field radiation therapy is also used in combination with chemotherapy in diffuse large cell lymphomas and mantle cell lymphomas. Total skin electron beam therapy is an aggressive, highly technical treatment utilized in generalized stage IIB mycosis fungoides. Radiation doses range from -3 Gy with low grade lymphoma to Gy with more resistant aggressive lymphomas. An emerging technology is radioimmunotherapy. Antibodies directed at specific lymphoma cell antigens are tagged with radioactive yttrium or iodine, resulting in eradication of the tumor. Radiation therapy is also effective for palliation of advanced lymphoma. Doses as low as 4 Gy can provide symptomatic relief. In summary, radiation therapy remains an important tool in fighting non-hodgkin s lymphoma. Doses and targets, however, are changing as we improve our understanding of this diverse disease. First Course of Therapy Non-Hodgkin s Lymphoma Number of Cases Stage I Stage II Stage III Stage IV No treatment Chemotherapy and Immunotherapy* Radiation Therapy and Chemotherapy Surgery, Radiation Therapy and Chemotherapy Hormone**, Chemotherapy and Other Total * Transplant or biological response modifier ** Prednisone coded as hormone when given with chemotherapy 6 Miami Valley Hospital