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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 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.
       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 / Chronic Lymphocytic Leukemia Small lymphocytic lymphoma (SLL) (image) is almost identical to chronic lymphocytic leukemia SLL (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.
      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.
      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:

  1. the expression of CD23
  2. dim as opposed to bright expression of CD20 and surface immunoglobulin
  3. lack of expression of FMC-7
        Characteristic cytogenetic lesions of small lympocytic lymphoma include:
  • trisomy 12 (20% of cases, poor prognosis and likely to occur in atypical cases)
  • deletion 13q14 (up to 50% of cases, better prognosis, involving a nontranscribed gene and two micro-RNA genes)
  • deletion 11q22-q23 (20% of cases, poor prognosis, involving the ATM gene)
  • deletion 17p13 (5-10% of cases, poor prognosis, involving the p53 gene)
        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 (or any case of ambiguous CD5+ B-cell lymphoma) from mantle cell lymphoma, it is necessary to demonstrate the absence of the genetic lesion of mantle cell lymphoma, a translocation involving the cyclin D1 gene on chromosome 11 and the immunoglobulin gene on chromosome 14, either by cytogenetics or FISH or immunologically by staining for the protein product cyclin D1.
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).
       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:
  • Low count MBL, which shows less than 0.5 x 109/L and does not require routine follow-up.
  • High count MBL, which shows more than 0.5 x 109/L and does require routine or yearly follow-up.
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", 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)
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. Characteristic genetic findings include trisomy 3 and t(11;18).
       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 for very early tumors 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 they present at lower stages than other diffuse, low-grade B-cell lymphomas.
       Splenic marginal zone lymphomas are characterized by a proliferation of small lymphocytes and slightly larger marginal-zone type cells that surround, colonize, and eventually obliterate the white pulp germinal centers and also spill over into the red pulp. The cells may circulate in the blood as villous lymphocytes, whose cytoplasmic projections tend to be polar rather than circumferential as in hairy cell leukemia. Although a relatively rare lymphoma, it may be responsible for most cases of low-grade B cell lymphoproliferative disorders involving the blood that are negative for CD5 and CD10. Cytogenetically splenic marginal zone lymphomas usually lack the lesions seen in MALT-lymphomas, but del(7q21-32) is common.
       Immunophenotypically the 3 types of marginal zone lymphomas have subtle differences (CD43 is often positive in MALT-lymphomas but not the other 2 types), but they all express monoclonal surface immunoglobulin and pan-B-cell antigens and are usually negative for CD5, CD10, and CD23.

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