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 lymphoma of mucosa-associated lymphoid tissue, nodal marginal zone lymphoma, and splenic marginal zone lymphoma. Besides these diffuse processes, additional low grade B-cell lymphomas with follicular differentiation are discussed in a subsequent section.
Small Lymphocytic Lymphoma / Chronic Lymphocytic Leukemia
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. A diagnosis of CLL requires the presence in the blood of at least 5 x 109/L monoclonal lymphocytes with a CLL immunophenotype. The normal counterpart of these diseases is a small subset of resting lymphocytes that in some cases are antigen-naive and in others not.
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 (PC) (image) surrounded by a sea of the smaller lymphoma cells. PCs must not be mistaken for follicles. Recent studies show that PCs may express cyclin D1 or MYC proteins. When large or confluent or highly proliferative, they are a significant and independent adverse prognostic indicator.
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. The immunophenotype that distinguishes SLL/CLL from mantle cell lymphoma (a more aggressive CD5+ B-cell lymphoma) consists of:
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).
Recently the disease has been divided into 2 prognostic groups depending on whether or not the immunoglobulin variable region gene shows somatic mutations, and thus whether the lymphoma cell is a memory cell or a antigen-naive cell. Such mutations are evidence of exposure to antigen and passage through the germinal center stage of development. Post-germinal center cases of SLL/CLL, which have somatic mutations, have a better prognosis than pre-germinal center cases, which lack them. Because sequencing the gene to assay for mutations is an expensive research procedure not suitable for clinical application, efforts have been made to find substitute markers for the absence or presence of such mutations. Expression of CD38 or ZAP-70 (a T cell-related molecule) correlates with unmutated variable region genes and a worse prognosis. Of the 2, ZAP-70 expresion is probably more signficant.
A related entity is monoclonal B-cell lymphocytosis (MBL): the presence in the blood of a clonal B-cell population of up to 5 x 109/L without other evidence for lymphoma. Immunophenotypically MBLs may resemble CLL or atypical CLL or may be CD5-. Although it occurs in up to 12% of healthy individuals, it is a precursor of virtually all cases of CLL. The 2016 WHO lymphoma classification divides MBL into:
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", although this phenomenon may be present in other types of lymphomas as well. 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 usually 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 sinuses. A distinction from marginal zone lymphomas with plasmacytic differentiation may be difficult and, in some cases, impossible.
Immunophenotypically this lymphoma expresses the usual pan-B-cell antigens. Unlike SLL/CLL it is usually negative for CD5 and CD23, and surface immunoglobulin expression is usually much stronger. Almost half the cases have an alteration of the PAX-5 gene due to a t(9;14)(p13;q32) translocation.
Marginal Zone Lymphomas (Nodal, Extra-Nodal, and Splenic)