MCL is a very well characterized entity of peripheral B-cell lymphoma with aggressive clinical behavior. Morphologically, the lymphoma cells are small to medium in size with scant cytoplasm and slightly irregular nuclear contours, similar to the centrocytes seen in low-grade follicle center cell lymphoma. Rare or no admixed large cells are present. The majority of MCL display a diffuse proliferation pattern, though nodular as well as mantle zone pattern have also be observed. Immunophenotypically, the lymphoma cells are characteristically positive for CD5, CD20, FMC7 and Cyclin D1without expression of germinal center cell markers, such as CD10. The demonstration of t(11;14) involving BCL1
gene is diagnostic of MCL with the appropriate morphology and immunophenotype. Most MCLs lack significant somatic hypermutation of the immunoglobulin genes, consistent with the notion that MCL is derived from naïve pregerminal center or mantle zone B lymphocytes [25
Despite the usual uniformity, cases of MCL with morphologic, immunophenotypic, genetic and clinical heterogeneity have been documented. Pleomorphic or blastoid variants of MCL usually have additional genetic changes and are more aggressive than the classical form [28
]. Morphologically, the neoplastic cells may be confused with diffuse large cell lymphoma or other blastic hematolymphoid neoplasms. MCL with plasmacytic differentiation or marginal zone pattern has also been recognized [29
]. The lymphoma cells in these cases have relatively more abundant cytoplasm compared to the classical form, mimicking small lymphocytic lymphoma/ chronic lymphocytic leukemia, lymphoplasmacytic lymphoma or marginal zone lymphoma. In addition, MCL with an indolent course as well as MCL with somatic mutations of the immunoglobulin heavy chain genes have also been described, suggesting that the neoplastic cells have been exposed to the germinal center microenvironment and the neoplastic cells may be derived from germinal center or even post-germinal center B lymphocytes.
The mainstay to diagnose MCL is immunophenotypic profiling by flow cytometry and/or immunohistochemical stain. The lymphoma cells are typically positive for CD5, pan-B cell markers including CD20 and FMC7 with surface immunoglobulin light chain restriction. With appropriate morphology and phenotype, positive immu-nohistochemical staining for Cyclin D1 essentially confirms the diagnosis of MCL. Cytogenetic or FISH studies, if performed, demonstrate the presence of chromosomal translocation t (11; 14) involving BCL1 and IGH in the majority of MCL cases.
The characteristic immunophenotypic profile is not always seen in MCL. Chronic lymphocytic leukemia/small lymphocytic lymphoma may have an immunophenotypic profile identical to MCL [13
]. Lack of CD5 expression has been observed in about 10% of MCLs [19
]. Markers associated with germinal and post-germinal center B cell differentiation, such as CD10, BCL6 and MUM1 have all been reported in MCL [14
]. These variations from the typical immunophenotypic profile could be misleading and cause diagnostic difficulties, particularly when the morphological features are not classical or the biopsy specimen is small.
CD10 is a zinc metalopeptidase expressed in many normal tissue cell types, including early lymphoid progenitors and normal germinal center B cells. CD10 expression has been used as a diagnostic marker of germinal center-derived B cell lymphomas, including follicular lymphoma, germinal center B-cell-like DLBL and Burkitt lymphoma. Aberrant expression of CD10 has also been observed in a variety of non-germinal center B-cell lymphomas, such as hairy cell leukemia, chronic lymphocytic leukemia/small lymphocytic lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, and MCL.
The first case of MCL with aberrant expression of CD10 was reported by Xu et al
in their multi-parameter flow cytometric study of small B-cell lymphomas [20
]. Except for expression of CD10, this case has a morphology and immunophenotypic profile characteristic of MCL. To date, a total of 38 MCLs with aberrant expression of CD10 have been reported in the literature. The majority of these cases express CD5 and other markers typically seen in MCL [15
]. Most of them are also of classical morphology. Among the 13 MCLs with a CD10+
phenotype, 6 of them represent pleomorphic blastoid MCL transformed from a preexistent classical MCL [14
]. The remaining 6 cases plus the one reported here are de novo
MCL (Table 1) [16
]. Interestingly, all de novo
cases have a classical morphology.
Kostopoulos et al
reported the first case of de novo
]. The lymphoma cells demonstrated a classical cytomorphology arranged in a nodular proliferation pattern with residual follicular dendritic network, closely mimicking low-grade follicular lymphoma. In addition, the neoplastic cells were also focally positive for Bcl6. FISH studies demonstrated the presence of t(11;14) involving BCL1
, but not t(14;18) translocations involving BCL2
characteristic of follicular lymphoma. More than 50% of the cells were positive for MIB1. The patient was in remission for 1 year before relapse. In the largest series of MCL with aberrant expression of CD10, Zanetto et al
described 2 cases of de novo
]. Both were weakly positive for BCL6. Molecular studies demonstrated gain of BCL6
gene copy number in addition to the t(11;14). One patient was in remission 1 year after treatment and the other patient died of intracranial hemorrhage before initiation of treatment. Gao et al
described 3 cases of de novo
MCL in their study with multiparameter flow cytometric immunophenotyping [16
]. The lymphoma cells in all 3 cases demonstrated low proliferation rate. No follow-up information was available. Our case has features similar to those reported by Zanetto et al
]. But repeated staining for BCL6 was negative and we did not study the chromosomal change or copy number gain of BCL6
gene. The likelihood that our case may represent transformation from a preexistent typical MCL with acquisition of CD10 and loss of CD5 expression is very low since all transformed CD10+
MCLs have a pleomorphic blastoid morphology. Though repeated immunohisto-chemical stains for CD5 was negative, we cannot completely rule out very low level CD5 expression detectable only by more sensitive multiparameter flow cytometric immunophenotyping.
The mechanism of aberrant CD10 expression in MCL is unclear, but it does not appear to be related to the germinal center cell ontogeny of the lymphoma cells since most CD10-positive MCL analyzed do not show somatic hypermutation of the immunoglobulin heavy chain genes. The clinical significance is also unknown and remains to be determined because the number of reported cases is small and aberrant expression of CD10 has been seen in MCL with both classical and pleomorphic blastoid morphology.
In conclusion, de novo CD10+CD5- MCL is extremely rare. Pathologists, however, should be aware of its existence to avoid misdiagnosis and inappropriate treatment. In cases with atypical phenotype, but morphologically suspicious for MCL, a simple immunostain for Cyclin D1 will be helpful in the final diagnosis. FISH or molecular genetic studies might be needed to confirm or exclude the diagnosis of de novo CD10+CD5-MCL