Immunophenotype

MCL is thought to arise from naive pregerminal center B cells in the primary follicles or mantle zone of secondary follicles. It has an immunophenotype of a mature B cell,151618-21 expressing CD19, CD20, CD22, CD79A, IgM, and/or IgD. MCL express lambda light chain more often than kappa light chain. Additionally, these malignant cells are CD5+, CD43+, but CD23", and CD10", which differentiates them from chronic lymphocytic leukemia. Most cases display an unmutated immunoglobulin chain locus.22,23 Recent studies have now shown that 25-30% of MCL carry mutations in the IgVH, a feature of postgerminal center cells.22,24,25

Some patients may present with peripheral lymphocytosis with a t(11;14) translocation, extra-nodal disease, and may have a different clinical course than that for classical MCL. In a study that looked at the clinical course in 80 MCL patients with circulating t(11;14) lymphocytes, IgVH genes were unmutated in 90% of nodal MCL patients, while only 44% of the extra-nodal patients had unmutated IgVH genes.26 Interestingly, long-term survivors in this study were all found in the extra-nodal group with IgVH gene mutation. The authors suggested that mutated IgVH genes found in the extra-nodal asymptomatic MCL group may be of use to identify patients who have more indolent disease and for whom early intensive treatment is not indicated. Further studies are warranted before adopting this management approach for extra-nodal MCL.

GENETICS/CYTOGENETICS

MCL is associated with the t(11;14)(q13;q32) the ataxia telangiectasia mutation and the 11q deletion. The t(11;14) juxtaposes the Cyclin D1 gene to the B-cell immunoglobulin transcription enhancer, which results in the overexpression of Cyclin D1.16 This results in deregulation of the G1 phase of the cell cycle. While Cyclin D1 overexpression is a hallmark of MCL, it is also observed in a variety of other hematologic and nonhematologic malignancies, and the precise role that Cyclin D1 overexpression plays in the development of MCL is not understood. This translocation is found in more than 95% of MCL cases. Up to 50% of the breakpoints on 11q13 occur within a restricted area called the major translocation cluster, and this region is used to amplify genomic DNA by PCR as a diagnostic method. Using the PCR assay as a molecular diagnostic tool for MCL detects the rearrangement in only 35%of patients.16 New PCR methods are being investigated that examine the Cyclin D1/Cyclin D3 ratio by realtime PCR, and these have shown improved specificity for the diagnosis of MCL.27 PCR has also been used for molecular follow-up studies of MCL1628

Fluorescence in situ hybridization (FISH) can show the t(11;14) translocation with a greater sensitivity of >95%. Another benefit of FISH is that it can be performed on archival cytologic material.29

Additional diagnostic approaches for MCL are under investigation. Microarray data suggests that there may be a disease-specific signature, including signatures for apoptosis, cell cycle, and cell signaling 30. Transgenic animal studies have shown that CCND1 gene overexpression alone cannot induce lymphoma and that other oncogenic factors, such as c-myc, are needed.31 Cyclin D1 overexpression is the only one mechanism responsible for deregulating the G1 phase of the cell cycle in MCL. Other mechanisms include hypermethylation and inactivation of p16INK4a, TP53 mutations, and loss of p27Kip1.32-35 Microarray analysis has shown that MCL exhibits alterations in the expression of apoptosis-related molecules, with an overall pattern of antiapoptosis36 and a low MCL apoptotic rate.37 In addition, MCL cells have been shown to express low or absent levels of Fas and thus may have prolonged survival.38 Additionally, the myeloid cell leukemia 1 (Mcl-1) gene, a member of the BCL-2 gene family, and its protein product promotes cell survival and Mcl-1-positive MCL tumors have been shown to have a higher frequency of blastoid/large-cell morphology, and higher Ki67 immunolabelling.39 Using RNA expression profiling, Rosenwald et al. have identified a set of 48 genes that stratify MCL patients into subsets that differ by more than 5 years in median sur-vival.5 These recent elucidations in the biology of this disease, we hope, will in turn result in better diagnostics, prognostics, and treatments for MCL.

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