After reading the summary, try answering the three related multiple-choice questions below.
A previously healthy 62-year-old man presented with massive splenomegaly. Grossly, the spleen was 2,640 g and 27.0 x 19.0 x 7.0 cm and was received with multiple detached lymph nodes and a 1.0 cm in greatest dimension accessory spleen. The cut surface revealed multiple beefy, tan/red, nodules, ranging from 0.1 to 0.3 cm in greatest dimension.
Archive Case and Diagnosis:
This case first appeared as Performance Improvement Program in Surgical Pathology (PIP) 2009, case 26, and is mantle cell lymphoma.
Criteria for Diagnosis and Comments:
The histologic sections demonstrate splenic parenchyma with markedly expanded white pulp. The white pulp consists of variably sized nodules composed of monomorphic, small to medium sized lymphocytes with mature, condensed chromatin, slightly irregular nuclear contours, and scant cytoplasm. Scattered histiocytes and mitotic figures are associated with this infiltrate. The neoplastic cells appear to infiltrate the red pulp. Flow cytometric analysis identified a CD5 –, CD10 –, CD19 +, CD20 +, lambda light chain restricted population of B lymphocytes. Immunohistochemical staining demonstrated strong CD20 and Cyclin D1 positivity. FISH analysis revealed the Cyclin D1-IgH gene fusion. These morphologic and cytogenetic features are diagnostic of mantle cell lymphoma involving the spleen except for the aberrant CD5 – results (ordinarily should be CD5 +).
Splenectomy specimens are uncommonly received as diagnostic specimens today. More commonly, they are removed incidentally as part of another procedure. Spleens removed for diagnostic purposes include those with undiagnosed masses, unexplained splenomegaly, and those requiring further characterization of a hematolymphoid disorder. In some cases, bone marrow and/or peripheral blood findings, in the absence of lymphadenopathy or other tumor masses, may suggest a particular lymphoma diagnosis, which can only be confirmed by histologic examination of the spleen.
In the majority of cases with hematolymphoid processes, the spleen will be involved in one of three patterns: predominately white pulp involvement, a predominately nodular pattern irrespective of white or red pulp, and predominately red pulp involvement. Most of the small B-cell lymphomas, including chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), follicular lymphoma, mantle cell lymphoma (MCL), splenic marginal zone lymphoma (SMZL), and lymphoplasmacytic lymphoma classically involve the white pulp with or without extension into the red pulp. Large cell lymphoma and Hodgkin lymphoma typically have a random, nodular pattern. Predominantly red pulp diseases include hairy cell leukemia (HCL), large granular lymphocytic leukemia, and myeloproliferative disorders, such as chronic myelogenous leukemia and chronic idiopathic myelofibrosis.
MCL is a B-cell neoplasm, accounting for approximately six percent of lymphoid neoplasms worldwide. It is primarily a disease of older adults with male predominance. It most commonly involves lymph nodes but can also involve the spleen, gastrointestinal tract and Waldeyer’s ring. Histologically, MCLs are composed of monotonous, small to medium sized cells with variably irregular nuclear contours, scant cytoplasm, and mature chromatin, arranged in either a vaguely nodular, diffuse, or mantle zone pattern. A key diagnostic finding is the lack of transformed cells, i.e., larger cells with more dispersed and/or vesicular chromatin and prominent nucleoli. Pink histiocytes are another frequently observed finding. Several morphologic variants have been described, including the blastoid variant, which is further divided into the classic and pleomorphic types, those mimicking CLL/SLL with round nuclei and irregularly clumped chromatin, and those mimicking marginal zone lymphoma (MZL) with prominent pale cytoplasm.
The neoplastic lymphocytes of MCL classically express CD5, CD19, CD20, CD43, FMC-7, Bcl-2, and Cyclin D1 and are negative for CD10 and CD23. CD5 is a T-cell marker, which is also co-expressed in CLL/SLL and in a minority of diffuse large B-cell lymphomas (DLBCLs). Cases of MCLs lacking CD5 have been described; however, they all demonstrate Cyclin D1 positivity by immunohistochemistry.
Cyclin D1 is a cell cycle regulator produced by the CCND1/PRAD1/BCL-1 genes. In MCL, a translocation between the immunoglobulin heavy chain on chromosome 14 and the BCL-1 gene on chromosome 11 occurs, resulting in Cyclin D1 overexpression. This translocation is detected by fluorescent in-situ hybridization in the large majority of cases, but is detected by conventional cytogenetics in only approximately three quarters of cases. Cyclin D1 expression is not unique to MCL, as other hematolymphoid neoplasms, including plasma cell myeloma and hairy cell leukemia, can show immunohistochemical positivity. Recently, microarray studies have illustrated rare cases of Cyclin D1 negative MCL, by identifying gene expression profiles identical to those of MCL in cases morphologically compatible with MCL that lacked both Cyclin D1 overexpression and the characteristic translocation, t(11;14)(q13;q32).
MCL is classified as a small, B-cell lymphoma; however, unlike many of its counterparts, it does not have an indolent course. The median survival is 3 – 5 years. Suggested poor prognostic indicators include a high mitotic rate, peripheral blood involvement, and the blastoid variant. When involving the spleen, MCL typically shows expansion of the white pulp and minimal, nodular or diffuse, red pulp involvement. Germinal centers, if present, are usually small and depleted. The neoplastic cells have nuclear irregularity and mature, but less condensed chromatin, compared to CLL/SLL lymphocytes. Most cases contain the characteristic pink histiocytes. As in other sites, transformed cells are not present.
The differential diagnosis includes splenic involvement by CLL/SLL which typically demonstrates both white pulp and red pulp involvement. The white pulp is expanded by a monotonous population of small lymphocytes with round nuclear contours and irregularly, coarsely condensed chromatin, interspersed with prolymphocytes and paraimmunoblasts, which may cluster and form proliferation centers. The neoplastic lymphocytes infiltrate the red pulp in either a nodular or diffuse pattern, though the red pulp involvement is less dramatic than the white pulp involvement. Germinal centers may occasionally be present. Immunohistochemically, CLL/SLL cells are CD5, CD20, CD23 and CD43 positive and CD10 and Cyclin D1 negative.
SMZL is a small B-cell lymphoma typically involving the spleen, splenic hilar lymph nodes, bone marrow, and peripheral blood. Peripheral lymph nodes are usually not involved. Classically, the neoplastic infiltrate imparts a biphasic or triphasic nodular pattern within the white pulp, consisting of a central core of small lymphocytes surrounded by a thick marginal zone of small lymphocytes with abundant pale cytoplasm and irregular contours, with or without a residual central germinal center. The small tumor cells are admixed with variable numbers of transformed cells and infiltrate the red pulp to varying degrees. This is primarily a morphologic and clinical diagnosis as the neoplastic cells do not have a diagnostic immunophenotype, being CD5, CD10, and CD23 negative. Circulating lymphoma cells are usually identifiable in the blood, having the characteristic polar, villous cytoplasmic projections. Morphologically, the current case lacks the marginal zone differentiation seen in SMZL.
HCL, in contrast to the other previously discussed small B-cell lymphomas, has a predilection for the red pulp of the spleen. While tumor cells may be found circulating, the neoplastic infiltrate typically involves the bone marrow and spleen. Tumor cells have widely-spaced nuclei with variably irregular nuclei and moderate amounts of lightly eosinophilic cytoplasm and are often associated with red blood cell lakes. The white pulp is usually atrophic. By flow cytometry, the neoplastic cells brightly co-express CD11c and CD22 and express CD25 and CD103.
DLBCL most commonly involves the spleen in a nodular pattern, with tumor nodules often separate from the uninvolved splenic parenchyma by fibrous bands. It may, though, involve the spleen in several other patterns, including predominant white or red pulp disease. The neoplastic infiltrate consists of large cells with variable cytology, which are usually CD20 positive by immunohistochemistry.
Reactive follicular hyperplasia may be seen in a variety of disease states, including blood cytopenias, such as ITP, thrombotic thrombocytopenic purpura, and hemolytic anemias, hypersplenism, and some infections. Florid follicular hyperplasia may mimic a lymphoma grossly, with prominence of the white pulp. As in lymph nodes, reactive splenic follicles vary in size and shape, are well-spaced and polarized with tingible body macrophages, well-defined mantle zones and exhibit Bcl-2 negativity. Reactive features, such as increased numbers of macrophages and/or plasma cells, are usually also seen within the red pulp in such conditions. The current case does not have follicles, nor the polymorphic appearance of a reactive infiltrate.