V. PATHOPHYSIOLOGY

The following information will help you understand lymphoma and decide the proper treatment for this patient.

Polyclonal (reactive) vs. monoclonal (neoplastic) Lymphomas
Lymphomas are neoplasms arising from the lymphoid hematopoietic tissue. They are fundamentally characterized by their clonal derivation, in contrast to any reactive lymphoproliferation which will be comprised of a diverse lymphocyte population. Lymphocytes have the unique property of undergoing physiologic gene rearrangements of their immunoglobulin (B-cells) or T-cell receptor (T-cell) gene loci. Gene rearrangement studies can be used to assay whether a tumor population is derived from a single clone (only one band for each allele of a single clone), or multiple clones (many bands).

Lymphoma Classification
Reflecting the complexities of lymphocyte development, there are a bewildering assortment of lymphoma sub-types that can broadly be divided into 1) B-cell neoplasms, 2) T- and NK- cell neoplasms, and 3) Hodgkin’s Disease. In the past, there have been many competing lymphoma classification systems, but recently the Revised European/American Lymphoma/World Health Organization (R.E.A.L./WHO) classification has become the accepted standard. The key insights underlying this classification are that 1) there is no single test that is the “gold standard” for sub-type classification, and 2) a broad, international consensus, as opposed to single groups of investigators, is required to form a reproducible classification system. DBLCL is the most common subtype of Non-Hodgkin’s Lymphoma (NHL).

Hodgkin’s Disease (HD) vs. Non-Hodgkin's Lymphoma (NHL)
The B-cell and T- and NK- cell lymphomas are called NHL. Recently, it has been determined that Hodgkin’s Disease, also called Hodgkin’s Lymphoma, is most commonly a form of B-cell neoplasm, but for historical and clinical reasons, HD is kept as a separate entity. HD is characterized by tumors that are predominantly comprised of reactive lymphoproliferation and a small population of malignant "Reed-Sternberg cells." HD is also highly curable.

Another method of categorizing lymphomas, favored by clinicians, is by their clinical acuity. In general, Non-Hodgkin's Lymphomas are classified as 1) indolent (low grade) or 2) aggressive (high grade), based on features of the lymph node biopsy.

1. Indolent lymphomas include:
• Follicular Center Cell Lymphomas - Grade I (mainly small cells, the most common type of indolent NHL) and Grade II (mixed small and large cells),
• Small Lymphocytic Lymphoma (the tissue counterpart of Chronic Lymphocytic Leukemia (CLL)),
• Lymphoplasmacytoid Lymphoma (Waldenström's Macroglobulinemia), associated with a monoclonal IgM paraprotein),
• Mycosis Fungoides (a cutaneous T cell lymphoma), and
• Marginal Zone Lymphoma (called Mucous-Associated Lymphoid Tissue (MALT) when they involve extranodal tissues).
Indolent lymphomas tend to progress slowly but are usually not curable with standard treatment approaches. A small percentage of patients with indolent lymphoma present with localized disease and may have long-term disease-free survival after local radiation therapy. However, most patients with indolent lymphoma present with Stage III or Stage IV disease. Many patients live 7 to 10 years after the diagnosis of indolent lymphoma. The treatment approach must be individualized and depends in part on the specific type of indolent lymphoma.

The most common indolent lymphoma is Follicular Center Cell Lymphoma.
• If the patient with Follicular Center Cell Lymphoma is asymptomatic, a "watchful waiting" approach is reasonable, deferring treatment until s/he develops symptoms or marked progression of disease.
• If the patient has "B" symptoms (fever, drenching night sweats, or significant weight loss), pancytopenia due to marrow replacement with lymphoma, or bulky, obstructing adenopathy, it is reasonable to proceed with treatment. Patients who develop an elevated serum LDH level or who develop B symptoms should be investigated for the possibility of transformation of an indolent lymphoma into an aggressive lymphoma, which can occur in 20-40% of cases. Initial therapeutic options, depending on clinical presentation, include:
• Oral chemotherapy with chlorambucil or cyclophosphamide
• Intravenous chemotherapy with cyclophosphamide/vincristine/prednisone (CVP), cyclophosphamide/doxorubicin/vincristine/prednisone (CHOP), or fludarabine
• Intravenous immunotherapy with the anti-CD20 antibody rituximab
• Combinations of these approaches
• Most patients will obtain a remission, which may last many years. Eventually patients again develop symptoms and require treatment. A second remission is achieved in a smaller proportion of patients and lasts a shorter period of time. Treatment approaches for patients with relapsed low grade lymphoma include autologous stem cell transplantation or radiation treatment delivered by infusion of an I¹³¹- or Y⁹⁰-conjugated monoclonal antibody that recognizes an antigen present on the malignant cells.
2. Aggressive lymphomas include:
• Diffuse Large B-Cell Lymphoma (the most common type of aggressive Non-Hodgkin's Lymphoma),
• Anaplastic Large Cell Lymphoma (often T-cell, express CD30 antigen),
• Follicular Center Cell Lymphomas – Grade III (predominately large cells),
• Mantle Cell Lymphoma,
• Lymphoblastic Lymphoma and
• Burkitt's Lymphoma