Contributed by Yan Peng MD, PhD, and Lydia C Contis MDFINAL DIAGNOSIS:
LYMPH NODE, RIGHT AXILLA, BIOPSY,
CD5 NEGATIVE MANTLE CELL LYMPHOMA
DISCUSSION:
Mantle cell lymphoma (MCL) is an aggressive and untreatable B cell neoplasm, and comprises approximately 3-10% of non-Hodgkin lymphomas. It occurs in middle aged to older individuals with a median age of approximately 60 years with a marked male predominance. Lymph nodes are the most commonly involved site; the spleen and bone marrow are other important sites of involvement (1).
MCL can demonstrate either a vaguely nodular or a diffuse growth pattern, with or without residual germinal centers. Nodular growth patterns with residual germinal centers are considered to have a mantle zone growth pattern (1). The neoplastic cells are small to intermediate in size with irregular nuclear contours, dispersed chromatin, small inconspicuous nucleoli and scant cytoplasm. Hyalinized small blood vessels can also be seen. Morphologically, MCL can resemble a variety of B-cell lymphoid neoplasms. These include nodal marginal zone B cell lymphoma and B-cell chronic lymphocytic leukemia/ small lymphocytic lymphoma. A follicular growth pattern can rarely been seen in MCL and can suggest a diagnosis of a follicular lymphoma.
Immunophenotypically, the neoplastic cells are monoclonal B-cells with strong surface IgM and IgD expression. MCL is typically CD5 positive, CD10 negative and CD23 negative. The T-cell marker CD43 may also be positive. These markers are useful in distinguishing MCL from small lymphocytic lymphoma/B-cell chronic lymphocytic leukemia, which is also CD5 positive, CD10 negative but CD23 positive and with dim surface immunoglobulin expression; or from follicular lymphoma, which is typically CD5 negative, CD10 positive and CD23 negative. Nodal marginal zone B-cell lymphoma and hairy cell leukemia are typically CD5 negative, CD10 negative and CD23 negative. Virtually all MCLs express cyclin D1 by immunohistochemistry with a nuclear staining pattern, including CD5 negative cases.
The molecular pathogenesis of MCL involves a translocation between the long arm of chromosomes 11 and 14, t (11; 14)(q13; q32). This translocation results in rearrangement of the bcl-1 locus and overexpression of the cyclin D1 oncogene at the messenger RNA and protein levels. The fluorescence in situ hybridization (FISH) technique has shown that the 11; 14 translocations are present in virtually all MCLs (2-4), although positive only in approximately 70% of cases by Southern blot. In addition, many MCL cases also have point mutations and /or deletion of the ataxia telangiectasia mutated (ATM) gene (5-7). Recent studies support the t(11; 14) and cyclin D1 overexpression as the initial or very early transforming events in MCL, with ATM mutations also occurring as frequent early events. The presence of cyclin D1 overexpression and the t(11; 14)(q13; q 32) translocation is characteristic of MCL, but not specific for MCL. Other B cell neoplasms have been shown to demonstrate t(11; 14) translocation and cyclin D1 overexpression at molecular levels, including splenic marginal zone lymphoma, prolymphocytic leukemia and multiple myeloma. Therefore, it is very important to combine histopathology, immunophenotypic, molecular and cytogenetic studies for making an accurate diagnosis of MCL.
Although CD5 expression is characteristic in MCL, CD5 negative cases do exist and must be distinguished from other CD5 negative B cell lymphomas, such as nodal marginal zone B cell lymphoma, follicular lymphoma, hairy cell leukemia and splenic marginal zone lymphoma, which all have a more indolent clinical course. Therefore, the distinction of CD5 negative MCL from these entities has clinical implications and prognostic significance. There are only 8 cases of CD5 negative MCL reported in the world literature (8, 9). In these cases, CD5 negativity was confirmed by immunohistochemistry and flow cytometric immunophenotypic studies. All of the cases expressed nuclear staining for cyclin D1 protein. In addition, cytogenetic analysis demonstrated the presence of t(11; 14) in these cases. CD5 negative MCLs showed similar clinical features to their CD5 positive counterparts; however, they experienced longer survivals. These rare cases of CD5 negative MCL exemplify the importance of combined molecular, cytogenetic, immunohistochemical and morphologic evaluation when confronted with a lymphoma having an atypical phenotype. Absence of the CD5 antigen does not preclude a diagnosis of MCL. Cytogenetic evaluation for t(11; 14) and the overexpression of cyclin D1 gene are essential to define and confirm this entity.
MCL has one of the poorest overall prognoses of the non-Hodgkin lymphomas and is incurable (1). The median survival of MCL is 3-5 years (1). However, recent reports of the induction chemotherapy regimen hyperCVAD followed by autologous or allogeneic stem cell transplantation have shown promise (10, 11). In addition, other novel approaches under consideration include the development of specific agents targeting the overexpressed cyclin D1, such as cyclin D1 antisense therapy (12).
Unfortunately, as this case was sent for consultation, neither flow cytometric, molecular or cytogenetic studies were performed on this case. However, the typical morphologic features along with the cyclin D1 expression by immunohistochemistry supported the diagnosis of CD5 negative MCL.
REFERENCES
Contributed by Yan Peng MD, PhD, and Lydia C Contis MD
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