There are at least six pathologic classification systems for non-Hodgkin's lymphoma (NHL) in use throughout the world.[1] Some systems place major emphasis on the overall nodal architecture; others emphasize the morphology of the cells themselves. All cla ssification systems can distinguish indolent lymphomas from rapidly progressive forms of NHL. Whenever possible, a pathologist should be consulted prior to biopsy, and tissue should be frozen for special studies. Knowledge of cell surface markers and immu noglobulin and T-cell receptor gene rearrangements may help with diagnostic and therapeutic decisions. The clonal excess of light-chain immunoglobulin may differentiate malignant from reactive cells. Since the prognosis and the approach to treatment are i nfluenced by histopathology, obtaining a careful review of biopsy specimens by a hematopathologist who is experienced in diagnosing lymphomas is extremely important. A pathologist should be consulted prior to the biopsy because special studies require spe cial preparation of tissue.

The working formulation contains explicit translation to the other six classifications of NHL. As an example, the following table provides the modified Rappaport classification for the working formulation categories.

Working Formulation--[1]
Rappaport Classification


A. small lymphocytic, consistent with diffuse lymphocytic, chronic lymphocytic leukemia (SL) well-differentiated (DLWD)

B. follicular, predominantly small nodular lymphocytic, poorly cleaved cell (FSC) differentiated (NLPD)

C. follicular, mixed small cleaved and nodular mixed, lymphocytic and large cell (FM) histiocytic (NM)


D. follicular, predominantly large cell nodular histiocytic (FL) (NH)

E. diffuse, small cleaved cell* diffuse lymphocytic, poorly (DSC) differentiated (DLDP)

F. diffuse mixed, small and large cell diffuse mixed, lymphocytic and (DM) histiocytic (DM) G. diffuse, large cell cleaved or diffuse histiocytic (DH) noncleaved cell (DL)

* Although included here in the working formulation as an intermediate-grade lymphoma, its natural history is more typical of low-grade lymphomas and it is frequently managed as a low-grade lymphoma.


H. immunoblastic, large cell (IBL)** diffuse histiocytic (DH)

I. lymphoblastic, convoluted or diffuse lymphoblastic nonconvoluted cell (LL) (DL)

J. small noncleaved cell, Burkitt's or diffuse undifferentiated, non-Burkitt's (SNC) Burkitt's or non-Burkitt's (DU)

** Although included here in the working formulation as a high-grade lymphoma, its natural history is more typical of an intermediate-grade lymphoma and it is frequently managed as a diffuse, large-cell (DL) lymphoma. This type includes Ki-1 antigen-positive anaplastic large-cell lymphoma, which is generally treated the same as diffuse, large-cell lymphoma.[2]

Several subsets of NHL have been recognized that are not identified in the working formulation

Lymphoplasmacytoid lymphoma is usually associated with a monoclonal serum paraprotein of immunoglobulin M type (Waldenstrom's macroglobulinemia).[4] Most patients have bone marrow, lymph node, and splenic involvement, and some patients may develop hypervi scosity syndrome. Other lymphomas may also be associated with serum paraproteins. The management of lymphoplasmacytoid lymphoma is discussed in the PDQ statement on plasma cell neoplasm, but the treatment is similar to that of other low-grade lymphomas.

Mantle cell lymphoma is found in lymph nodes, the spleen, bone marrow, blood, and sometimes the gastrointestinal system (lymphomatous polyposis).[3,5-7] Like the low-grade lymphomas, mantle cell lymphoma appears incurable with anthracycline-based chemothe rapy. However, the median survival is significantly shorter (3-5 years) than that of other low-grade lymphomas. A blastoid variant of mantle cell lymphoma may be better characterized as an intermediate- or high-grade form, but the curability is not known. It is unclear which chemotherapeutic approach offers the best long-term survival in this clinicopathologic entity.

Mucosa-associated lymphoid tissue lymphomas and monocytoid B-cell lymphoma represent another family of low-grade lymphomas.[3,9-11] These lymphomas typically involve extranodal tissue (gastrointestinal tract, thyroid, breast, and skin). Many patients have a history of autoimmune disease, such as Hashimoto's thyroiditis or Sjogren's syndrome, or of Helicobacter gastritis. Most patients present with stage I or II extranodal disease, which is most often in the stomach. Treatment of Helicobacter pylori infect ion may resolve many cases of localized gastric involvement.[12-14] Localized involvement of other sites can be treated with radiation or surgery. When disseminated to lymph nodes, bone marrow, or blood, this entity behaves like other low-grade lymphomas.

Splenic marginal zone lymphoma is an indolent lymphoma that is marked by massive splenomegaly and peripheral blood and bone marrow involvement, usually without adenopathy.[15,16] This type of lymphoma is biologically similar to splenic lymphoma with villo us lymphocytes, an uncommon variant of B-cell chronic lymphocytic leukemia. Splenectomy may result in prolonged remission. Management is similar to that of other low-grade lymphomas.

Anaplastic large-cell lymphomas may be confused with carcinomas and are associated with the Ki-1 (CD30) antigen. These lymphomas are usually of T-cell origin and often present with extranodal disease, especially the skin. These are generally treated with the same strategy and have the same outcome as diffuse, large-cell lymphomas.[2,17-19]

Other NHLs that do not fit well into the working formulation include cutaneous T-cell lymphomas, or mycosis fungoides, which are tumors of CD4 helper lymphocytes and have a prolonged clinical course.[20] (A separate statement containing information on cut aneous T-cell lymphoma is available in PDQ.) Adult T-cell lymphoma or leukemia is caused by infection with the retrovirus human T-cell lymphotropic virus type I and is frequently associated with hypercalcemia, a rapidly progressive course, and poor respon se to therapy.[21] The combination of zidovudine and interferon alfa has activity against adult T-cell leukemia/lymphoma, even for patients who failed prior cytotoxic therapy.[22,23] Intravascular lymphomatosis is characterized by large-cell lymphoma conf ined to the intravascular lumen; with the use of aggressive combination chemotherapy, the prognosis is similar to more conventional presentations.[24]

The natural history of follicular large-cell lymphoma remains controversial.[25] While there is agreement about the significant number of long-term disease-free survivors with early-stage disease, the curability of patients with advanced disease (stage II I or IV) remains uncertain. Some groups report a continuous relapse rate similar to the other follicular lymphomas (a pattern of indolent lymphoma).[26] Other investigators report a plateau in freedom from progression at levels expected for an aggressive lymphoma (40% at 10 years).[27] This discrepancy may be due to variations in histologic classification between institutions and to the rarity of patients with follicular large-cell lymphoma.


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