CD5-Negative Mantle Cell Leukemia Shows Frequent 17p Deletion and Marrow Involvement Mimicking Marginal Zone Lymphoma

Introduction: Mantle cell lymphoma is characterized by the t(11;14)(q13;q32) and can usually be recognized by its typical CD5+/CD23- immunophenotype. However, phenotypic variations have been observed and such variants can resemble other types of B-cell neoplasms, including chronic lymphocytic leukemia (CLL/SLL) and marginal zone lymphoma. In particular, the CD5- variant is diagnostically challenging. Some CD5- mantle cell lymphomas have been reported to have an indolent clinical course, while others follow an aggressive course similar to typical mantle cell lymphoma. To our knowledge, CD5- mantle cell leukemia has not been fully characterized. To further our understanding of this disease entity for diagnostic workup and risk assessment, we evaluated clinical, morphologic, immunophenotypic, and genetic features in a cohort of CD5- mantle cell leukemia.

Methods: Among 111 cases of mantle cell leukemia identified from our database over a 2-year period, 12 were CD5- with t(11;14) and absolute peripheral lymphocytosis (>5,000/uL). Antigen expression was defined by flow cytometry as positive, dim positive, or negative. Conventional chromosome analysis and FISH were performed on all cases, including probes for 11q22.3 (ATM), 12 (CEP 12), 13q14, 13q34, 17p13 (TP53) and t(11;14) (IGH-CCND1). Other parameters obtained included age, gender, CBC, blood and bone marrow histology, and IgVH mutational status.

Results: Of the 12 patients, 7 were female with a median age of 67 years (range: 55-88 years). Patients presented with marked lymphocytosis (mean: 55 K/uL) and mild normocytic anemia (mean: 11.3 g/dL). The average platelet count was within the low normal range (mean: 173 K/uL). Flow cytometric analysis showed that all cases expressed CD19 and surface light chain restriction (10 kappa and 2 lambda), and lacked CD5 and CD10. All except one case expressed CD20. CD23 was negative in 8 cases and dim positive in 4 cases. Thus, the leukemic phenotype was suggestive of a marginal zone lymphoma. Morphologically, the leukemic cells were small to medium sized with round nuclei and scant to moderately abundant cytoplasm. Bone marrow biopsy was performed in 6 of 12 cases. All 6 cases showed marrow involvement (mean: 45%; range: 25-85%) with interstitial and intrasinusoidal distribution patterns. While the marrow histology was suggestive of involvement by marginal zone lymphoma, immunohistochemical testing for cyclin D1 revealed positive nuclear staining in the leukemic cells. FISH for t(11;14) was positive in all 12 cases. In contrast, conventional chromosome analysis detected t(11;14) in only 6 cases (3 blood and 3 marrow samples). Additional cytogenetic abnormalities were detected in 8 (67%) patients. Five (42%) cases showed 17p deletion. Other abnormalities included 13q- (3/12; 25%), 11q- (2/12; 17%), and trisomy 12 (1/12; 8%). IgVH analysis was performed in 2 cases, and both exhibited IgVH hypermutation.

Conclusions: CD5- mantle cell leukemia comprised approximately 11% of mantle cell leukemia in our series. In addition to t(11;14), other chromosome abnormalities were identified in the majority of the cases (67%). Deletion of 17p was most frequent, likely representing a more aggressive form in contrast to the previously described indolent form. The leukemic immunophenotype and marrow infiltration features resembled marginal zone lymphoma, indicating the importance of detecting t(11;14) for proper classification and clinical management of the disease. We observed that FISH was much more sensitive in detecting t(11;14) than conventional chromosome analysis. Therefore, performing FISH for t(11;14) and 17p- would be useful for diagnostic workup of mature B-cell leukemia regardless of CD5 positivity. Our limited observation of IgVH hypermutation in CD5- mantle cell leukemia would suggest future studies to investigate this potential relationship for prognostic implications.