Case 4 -

Splenic Marginal Zone Lymphoma Marsha C. Kinney and Steven H. Swerdlow

Clinical History 70 year old female with questionable history of lymphoma in marrow. Chest and abdominal CT scans remarkable only for splenomegaly. Splenectomy performed and revealed a 930 gm spleen. Diagnosis: Splenic Marginal Zone Lymphoma Case 4 - Figure 1 - Splenic marginal zone lymphoma in spleen. There are prominent biphasic white pulp nodules with a core of smaller darker appearing lymphoid cells surrounded by a paler marginal zone. In addition, there are small nodules in the red pulp. Case 4 - Figure 2 - Splenic marginal zone lymphoma in spleen. See the biphasic nature of one of the white pulp nodules. Case 4 - Figure 3 - Splenic marginal zone lymphoma in spleen. The smaller lymphocytes with little cytoplasm that comprise the core of the white pulp nodules are seen on the left. Most of the figure depicts the marginal zone that includes larger cells with more cytoplasm and more dispersed chromatin. Occasional transformed cells are also present. Discussion of Case 4 What are splenic marginal zone lymphomas? Difficult question as some do not believe that these are actually related to splenic marginal zone cells. How do we make the diagnosis? How are they distinguished from other splenic lymphomas that are in the differential diagnosis? What is their genotypic fingerprint? What does the diagnosis mean? The WHO classification recognizes three distinct marginal zone lymphomas. Splenic marginal zone lymphoma Extranodal marginal zone B-cell lymphoma of MALT type Nodal marginal zone B-cell lymphoma Splenic histology Normal splenic histology is best seen with a PAS stain. The white pulp includes lymphoid nodules with a central follicle with or without a germinal center and a peripheral paler marginal zone composed of intermediate sized lymphoid cells with somewhat dispersed chromatin, often small nucleoli and more abundant cytoplasm than the adjacent mantle zone cells. [2] Ultrastructural study shows characteristic serpentine endoplasmic reticulum. [173] The marginal zone cells are IgM+ CD5- CD10- B-cells. The PAS stain also highlights the cords and sinuses of the red pulp. The latter are surrounded by "ring" fibers. Histopathology of splenic marginal zone lymphoma As defined in the WHO classification, splenic marginal zone lymphoma is a biphasic lymphoma that causes expansion of the white pulp with nodules that have dark central cores of small lymphocytes and a peripheral paler marginal zone. [174, 175, 176, 177, 178] The marginal zones are composed of cells resembling normal marginal zone cells. Scattered transformed cells are present. The white pulp nodules may have residual follicular centers, usually without a reactive mantle zone. A minority of cases have plasmacytic differentiation; however, perhaps depending on the diagnostic criteria, plasmacytic differentiation may be more common. [177] Red pulp involvement often with the paler marginal zone cells is also seen. Others describe cases with a more homogeneous population of cells closely resembling splenic marginal zone cells. [173] A more aggressive subset of splenic marginal zone lymphoma has been reported with an increased number/conspicuous component of larger lymphoid cells. [50] A type with a predominant red pulp growth pattern and some distinctive clinical features has also been described. [179] Case 4: Histopathologic appearance shows a typical biphasic growth pattern. Immunophenotype of splenic marginal zone lymphoma [10, 173, 174, 176, 177, 178, 180] CD20 positive CD5-, CD10-, CD23-, CD43- cases studied by FCIPS are more often reported to be CD5 or CD10+ (but are these really SMZL?) IgM positive often with IgD Some cases have monoclonal plasma cells At least vast majority, if not all "authentic" cases, cyclin D1- (not completely resolved). Case 4: Flow cytometric immunophenotypic studies demonstrated CD5-, CD10- B-cell population with a kappa predominance (difficult from these studies to call monoclonal). Paraffin section immunostains highlighted some residual bcl-6+ reactive germinal centers. Unlike the most typical cases, IgD was not identified in the paraffin section immunostains that showed IgM. Genotypic studies confirmed B-cell monoclonality. Lymph node involvement in splenic marginal zone lymphomas Involved lymph nodes demonstrate a vaguely nodular or more diffuse proliferation composed of an admix of the different cell types seen in the spleen generally without the zonation found in other marginal zone lymphomas. [173, 181] The lymphoma may surround reactive germinal centers usually without a distinct residual mantle zone. Hilar lymph nodes often demonstrate intact sinuses. The hilar lymph nodes in case 4 showed typical involvement by the lymphoma. Major diagnostic pitfalls & how to deal with them Hyperplastic splenic marginal zones Nonclonal by immunophenotypic and genotypic studies Pale appearing marginal zone involvement by other types of non-Hodgkin lymphomas – follicular lymphoma, mantle cell lymphoma, other marginal zone lymphomas [182, 183] Morphologic features: central small lymphoid cells do not suggest a follicular or mantle cell lymphoma, other marginal zone lymphomas are more likely to be associated with a distinct normal mantle zone surrounding any reactive germinal centers. Phenotypic features: CD5-, CD10-, CD23-, CD43-, cyclin D1- phenotype argues against a follicular or mantle cell lymphoma (beware of exceptions). IgD positivity is typical but not a specific finding and not always found. Genotypic features (see below) Cytogenetic/genotypic studies Not usually necessary for diagnosis. Clonal immunoglobulin gene rearrangement. Absence of t(14;18)/bcl-2, t(11;14)(q13;q32)/cyclin D1, t(11;18)/API2 translocations. Frequency of trisomy 3 controversial [60, 184, 185, 186] Significant minority have deletions of 7q31-32 (present in case 4) 40% vs 7.7% of other B-cell neoplasms [187] Some have translocations involving 7q21-q22 with an associated dysregulation/over-expression of cyclin dependent kinase 6 [188] p53 mutations/deletion not uncommon in some series and may be associated with an adverse prognosis [180, 186, 189] t(11;14) (p11;q32) reported (NOT a cyclin D1 rearrangement) and associated with a "high grade" component. [190] As with CLL, SMZL can be divided into those with mutated and unmutated immunoglobulin genes. [191, 192] The unmutated cases may be associated with an adverse prognosis. [191] Clinical features at presentation [50, 173, 176, 177, 178, 180, 193, 194, 195, 196, 197, 198, 199] Older adults (median age 60s) who present with marked splenomegaly (although sometimes spleens are of normal size). 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