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U-M CCC - Michigan Oncology Journal Fall 2000

New Small Lymphocytic Lymphomas

Increased understanding of clinical, hematologic, immunophenotypic and molecular aspects of small lymphocytic disorders has allowed for more accurate delineation of several lymphoma entities. This knowledge has been incorporated into the Revised European-American Lymphoma (REAL) (1) and more recently World Health Organization (WHO) (2) classifications for lymphoma. Several of the newer lymphoma entities are less common, but their separation from follicular small cleaved cell lymphoma (Working Formulation) allows for more uniform groups of lymphoma that differ in treatment options and prognosis.

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) represents approximately 8% of non-Hodgkin's lymphoma (NHL) and results from the transformation of a naive pre-germinal center B-cell (3). MCL cells express CD5, CD20 and moderately strong surface immunoglobulin. Over-expression of cyclin D1 results from a t(11;14)(q13;q32) translocation and is a specific abnormality of MCL that can be used to differentiate it from other small lymphocytic lymphomas (4). In typical MCL, the tumor is composed of uniformly small- or medium-sized cells surrounding residual germinal centers (mantle zone pattern). Blastic MCL, a more aggressive cytologic variant, shows a spectrum of morphologic appearances with cells that resemble lymphoblasts to those that are larger and pleomorphic.

At presentation, MCL involves the bone marrow in 50 to 82% of the patients (5), however, bone marrow involvement by itself has not been associated with a poor prognosis. MCL frequently involves other extranodal sites (75%) including the spleen, gastrointestinal tract, Waldeyer's ring, liver and central nervous system (3, 5). An extranodal site is the primary site of involvement at presentation in 25% of patients.

Several characteristics have been associated with poor survival: age > 60 years, advanced stage disease, poor performance status, an elevated LDH, involvement of more than two extra nodal sites, splenomegaly, peripheral blood involvement, anemia and elevated b2 microglobulin. The International Lymphoma Prognostic Index, which includes several of these features, has been found to be of prognostic value (6).

Conventional chemotherapy treatment with cyclophosphamide, vincristine, prednisone (CVP) or with the addition of doxorubicin (CHOP) results in an overall response rate of approximately 85% and a complete response rate of 45%. Unfortunately, conventional chemotherapy does not result in durable responses and is thus not considered curative (7). The median progression-free survival is 20 months with an overall median survival of 36 months.

Other treatment strategies have also been studied in small trials. Purine analogues, alone or in combination therapy, have not shown convincing superior efficacy to conventional therapy. Clinical activity with anti-CD20 monoclonal chimeric antibody (Rituximab) is modest in MCL but can be active in chemotherapy- resistant disease. Intensive chemo/radiotherapy with autologous stem cell transplant is a promising treatment strategy but remains plagued by recurrent disease. Allogeneic transplant for MCL results in excellent complete response rates and may have an associated graft vs. lymphoma (GVL) activity but treatment-related toxicity remains high.

Novel treatment approaches are also being developed. Anti-bcl-1 (cyclin D1) antisense oligonucleotides are being used to inhibit the expression of cyclin D1. Non-myeloablative chemotherapy with allogeneic stem cell ± lymphocyte infusions is being used to decrease the chemotherapy-related toxicities while augmenting GVL activity. Tumor vaccines targeting the tumor's idiotype immunoglobulin are also being studied as adjuvant therapy after chemotherapy to prolong clinical responses.

Marginal-Zone Lymphoma (MZL)
The term MZL came from the supposed but controversial common origin of the lymphoma cells. These lymphomas involve the marginal B-cell compartment of lymphoid tissue outside the follicle mantle zone with a peculiar growth pattern reminiscent of the marginal zone. The cellular composition of these lymphomas shows considerable variations but consists mostly of clear cells with relatively abundant pale cytoplasm called monocytoid B-cells or centrocytic-like cells, with a small percentage of larger cells and plasmacytic cells. The cells have a virtually identical immunophenotype, with the presence of surface immunoglobulin, CD19, CD20 and CD22, and absence of CD5, CD10, CD23 and cyclin D1. The WHO classification (2) denotes three subtypes of MZL: extranodal MALT, nodal MZL and splenic MZL.

Extranodal MALT Lymphoma
Extranodal marginal zone lymphoma develops in mucosal-associated lymphoid tissue (MALT) (8) with the most common site being in the stomach (60 to 70%). The current model for the pathogenesis of MALT lymphoma suggests that an infection or site of inflammation recruits and activates B and T lymphocytes followed by a clonal outgrowth of B-cells that give rise to the MALT lymphoma. The genetic abnormality that allows for the development of MALT lymphoma is unknown, but karyotype analysis of MALT lymphomas frequently detect a t(11;18)(q21;q21) translocation, which may result in a cell survival advantage. Most MALT lymphomas have been associated with H pylori infections (especially GI MALT lymphoma), but it can also be found in the setting of celiac disease, Sjogren's Syndrome and autoimmune thyroid disease.

The most common presenting symptoms of low-grade gastric MALT lymphomas are dyspepsia and epigastric pain. Constitutional B symptoms are uncommon as most patients (88%) present with Stage I disease (limited to the GI tract as single or multiple noncontiguous lessons). Initial treatment of early stage gastric MALT lymphoma is directed at eradi-cating the H pylori infection with a regimen of antibiotics and a stomach acid-reducing drug. This treatment results in complete responses occurring in 60 to 85% of patients. Tumor response to the antibiotics can be slow with maximal response occurring between six weeks and 18 months after treatment. Patients that fail antibiotic therapy can be treated with locoregional radiation or chemotherapy (single agent or combination chemotherapy). Patients with high-grade or diffuse disease should be treated with combination chemotherapy. Overall prognosis is very good with >80% 5-year survival.

Nodal Marginal-Zone B-Cell Lymphoma
Nodal MZL account for ~2% of NHL and has been thought to be a nodal variety of MALT lymphoma (9). Clinically, however, nodal MZL is a more aggressive disease. Patients with nodal MZL present with more advance disease (71%) and BM involvement (28%), and have a corresponding poor prognosis with a 5-year overall survival rate of 56% and a failure-free survival rate of only 28%. Histologic transformation to a higher-grade lymphoma occurs in more than 20% of cases. In ~70% of nodal MZL, there is no involvement of spleen or extranodal sites.

Because conventional chemotherapy is not curative, patients are managed with expectant observation followed by combined chemotherapy.

Splenic Marginal-Zone Lymphoma/Splenic Lymphoma with Villous Lymphocytes (SLVL)
Patients with splenic MZL present with splenic enlargement and often circulating lymphocytes that have fine villous projections (10). The lymphocytosis can be variable with levels usually ranging from 10 to 40 x 109/L. The nucleo/cytoplasmic ratio is higher than in Hairy Cell leukemia and closer to that in CLL, but the overall size is slightly larger than CLL cells. In one-third of splenic MZL patients, the villous lymphocytes constitute <25% of the lymphocytes and are not easily identified on peripheral blood smears. Immunophenotype analysis of blood lymphocytes can be used to detect small numbers of circulating MZL cells. The degree of splenomegaly can vary from barely palpable to massive such that it hangs below the umbilicus. In general, splenic MZL is a slow progressive chronic lymphoproliferative malignancy. Patients are usually managed with expectant observation and therapy initiated when the disease progression warrants intervention. Often the hypersplenism is the reason for treatment and splenectomy is the recommended intervention. Close to 50% of splenic MZL patients will require splenectomy, which will correct the abnormalities associated with hypersplenism in 90% of the cases. When there are significant surgical risks, splenic irradiation can also be used. Chemotherapy is usually reserved for patients who progress after splenectomy and induces useful responses but seldom-complete remission. Alkalating agents are often used in the initial chemotherapy, but nucleoside analogs appear to have clinical activity as well.

References

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Continue reading:

Antibody Therapy for Non-Hodgkin's Lymphoma

Treatment of Intermediate and High-Grade Non-Hodgkin's Lymphoma

The Revised European-American Classification of Lymphoid Neoplasms (REAL Classification)

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