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Low Grade Diffuse B-Cell Lymphomas: Small Lymphocytic and Others

Small lymphocytic | Lymphoplasmacytic | Marginal zone

THIS is a diverse group of lymphomas. The most common and the prototypical type is small lymphocytic lymphoma (SLL). When this disease presents primarily with blood and bone marrow involvement, it has another another name: chronic lymphocytic leukemia (CLL). The other types discussed here include lymphoplasmacytic lymphoma and various types of marginal zone lymphomas including lymphomas of mucosa-associated lymphoid tissue. Besides these diffuse processes, additional low grade B-cell lymphomas with follicular differentiation are discussed in a subsequent section.
       Taken as a whole, low grade lymphomas (diffuse and follicular, B-cell and T-cell) make up from 20-45% of lymphomas and have a median survival of 5 years or more. Patients are often left untreated until morbidity occurs. While combination chemotherapy usually secures a complete or partial response, the relapse rate is 10-15% per year thereafter.

Small Lymphocytic Lymphoma SLL
Small lymphocytic lymphoma (SLL) (image) is almost identical to chronic lymphocytic leukemia (CLL) both morphologically and clinically. A somewhat arbitrary distinction is drawn between them based on the relative degree of marrow and nodal involvement and the numbers of circulating lymphoma cells. The normal counterpart of this lymphoma is a small subset of resting lymphocytes that are antigen-naive.
      As a lymphoma, SLL acounts for about 4% of non-Hodgkin's lymphoma. As a leukemia, CLL accounts for about 30% of adult leukemias in Western countries. In SLL the patients are elderly (median age 60 years) and usually present with diffuse lymphadenopathy and some degree of marrow and peripheral blood involvement (Stage IV disease). Mild to moderate splenomegaly is common. Constitutional ("B") symptoms are seen in 15%. Many patients have decreased normal antibodies (hypogammaglobulinemia) leading to infections. Patients may also have anemia or thrombocytopenia from marrow infiltration or more rarely from immune hemolysis. With the most sensitive techniques, a monoclonal serum immunoglobulin (M-component) can be identified in almost half the cases.

The larger cells are prolymphocytes / paraimmunoblasts
      In the lymph nodes, SLL shows sheets of small lymphoid cells that tend to flood the lymph node and its sinuses without destroying them and that usually respect the capsule. The cells have scant cytoplasm, rounded nuclei, darkly clumped chromatin, and inconspicuous nuclei. In isolation they are almost indistinguishable from benign small lymphocytes (Can you tell them apart?) Almost all cases of SLL include intermingled larger lymphoma cells with more open chromatin and more prominent nucleoli. These cells, called prolymphocytes or paraimmunoblasts, often occur in small islands called proliferation centers (image) surrounded by a sea of the smaller lymphoma cells. Proliferation centers must not be mistaken for follicles.
      Because SLL/CLL cells have an unassuming appearance, minimal disease may be hard to detect, especially in the marrow. Immunophenotyping may help to identify it because the malignant cells usually express clonal kappa or lambda light chains. They also aberrantly express T-cell antigens CD5 and CD43, in addition to another characteristic antigen, CD23. Cytogenetically some cases show trisomy 12.
        A variant of SLL called "atypical SLL" fails to express CD23; and like mantle cell lymphoma it expresses bright CD20 and surface light chain and FMC7. Often these are the cases with trisomy 12. This variant may follow a slightly more aggressive course. To distinguish it from mantle cell lymphoma, it is necessary to provide evidence that the genetic lesion of mantle cell lymphoma is not present, either cytogenetically by testing for t(11;14) or immunologically by staining for cyclinD1.
SLL in marrow       In the marrow, SLL/CLL (images) may be interstitial (scattered among normal marrow cells), diffuse, or nodular. The nodules are usually non-paratrabecular as opposed to deposits of follicular lymphoma, which love tightly to embrace the bony trabeculae.
       This lymphoma is very indolent but relentless, with median survivals of almost a decade. Although the slowly proliferating cells are sensitive to chemotherapeutic agents, chemotherapy is almost never curative and relapse inevitably follows. Most studies find no benefit in treating patients until they develop symptoms. Therapy tends to be low-intensity: single alkylator therapy such as chlorambucil or combination therapy with cyclophosphamide/vincristine/prednisone. A new and promising drug is fludarabine, but it has not been shown to prolong survival either. About 30% of cases of SLL progress to a higher grade process such as prolymphocytic lymphoma or diffuse large cell lymphoma (Richter's syndrome).

Lymphoplasmacytic Lymphoma

Note the 2 plasma cells in the upper half.

Lymphoplasmacytic lymphoma, sometimes called "immunocytoma", is an uncommon lymphoma affecting elderly patients. The patients often present with Stage IV disease; in fact initial involvement of the marrow, spleen, or liver is even more common than in SLL. Generalized lymphadenopathy is frequent, and the neoplastic cells circulate in the blood in about one-third of the cases.
      Often the cells secrete IgM, and the condition is called "Waldenstrom's macroglobulinemia." Bone involvement is almost always seen (images). The presence of quantities of this large protein in the blood may produce hyperviscosity symptoms such as bleeding, confusion, fatigue, and oncotic plasma volume expansion. For this and other reasons, survival is shorter than in SLL. About one-third of patients show evidence of hepatitis C infection. Though intriguing, this association has not been explained.
       Against a background of neoplastic small lymphocytes, variable numbers of the lymphoma cells show differentiation toward plasma cells, either resembling them in appearance or like them containing monoclonal cytoplasmic immunoglobulin. It is this trait that distinguishes the lymphoma from SLL, in which the cells have surface immunoglobulin and may secrete it, but their cytoplasm does not harbor enough immunoglobulin to detect with routine immunohistochemistry. The plasmacytoid cells may be sparse or numerous. In lymphoplasmacytic lymphoma some nuclei may contain PAS-positive inclusions called "Dutcher bodies". Other possible features include epithelioid histiocytes and in some cases residual normal germinal centers and open sinusoids.
       Immunophenotypically this lymphoma resembles SLL. It is, however, more likely to be CD5 (-) and CD25 (+).

Marginal Zone Lymphomas (Nodal, Extra-Nodal, and Splenic)
In the WHO classification, there are separate categories for each of these 3 types of marginal zone lymphomas. Most extra-nodal marginal zone lymphomas are epithelium-associated and called marginal zone lymphomas of mucosa-associate lymphoid tissue (or more loosely MALT lymphomas).
       All these various lymphomas usually display a variety of cell types, including small lymphocytes, centrocyte-like cells, monoctyoid B-cells, marginal zone cells, plasma cells, and infrequent larger cells. Occasionally a vaguely nodal pattern can be discerned, most often produced by residual benign germinal centers either surrounded or infiltrated by lymphoma cells. When the lymphomas occur near epithelium, they tend to invade it destructively to produce characteristic lympho-epithelial lesions.
       The most interesting and probably most common entity in this category is the MALT lymphoma. These lymphomas (images) occur in many organs equipped with mucosa-associated lymphoid tissue either as a normal component or as the result of chronic inflammation. Because the lymphoid cells have receptors that cause them to home selectively to their particular epithelial milieu, MALT lymphomas have a remarkable tendency to remain localized without spreading to the marrow, liver, spleen, or blood. The patients, usually in their 50s and 60s, tend to present with localized, Stage I disease and have an excellent 80%-100% 5-year survival.
      The most common site for MALT lymphomas is the stomach, where they are associated with H pylori infection and a predominantly male population. Other MALT lymphomass occurring in the lung, salivary gland, thryoid, breast and other organs are often associated with auto-immune disease (especially Sjorgren's syndrome)and a female population, but not with H pylori.
       Treatment of gastric MALT lymphomas in particular is a fascinating subject, because patients have apparently been cured by eradicating the H pylori infection with antibiotics. Such treatment may be acceptable first-line therapy as long as rapid tumor regression is not needed. Surgery (which is almost never used for the more systemic lymphomas unless the tumor mass is urgently symptomatic) and low-intensity chemotherapy have also been used satisfactorily.
       Nodal marginal zone lymphomas are slightly more aggressive diseases compared to MALT lymphomas, tending to present at a higher stage and having a 5-year survival rate of 50%. On the other hand, if compared to other diffuse, low-grade B-cell lymphomas, they present at lower stages.
       Immunophenotypically marginal zone lymphoma cells express monoclonal surface immunoglobulin and pan-B-cell antigens. They are usually negative for CD5, CD10, CD23, and CD43. No chromosomal translocations are characteristic.

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