Abstract
Introduction: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin lymphoma (NHL) with a median survival of 3 to 5 years. MCL is characterized by the translocation t(11;14)(q13;32) which results in the overexpression of cyclin-D1 and ultimately an uninhibited G1/S cell cycle transition. MCL has a distinctive immunophenotype among B-cell NHL, characterized by a strong expression of the pan B-cell markers CD19 and CD20, absence of CD10 and CD23, overexpression of the anti-apoptotic protein BCL2, and aberrant expression of the T-cell marker CD5. However, up to 10% of MCL lack CD5 expression and remain ill-characterized. Whether this absence of CD5 expression impacts MCL biology and clinical course remains unknown. We performed a systematic review of all reported cases of CD5-negative MCL and analyzed their biological and clinical characteristics.
Patients and methods: A systematic literature search was performed and included studies published from 1st June 1994 to 1st June 2016 in PubMed, Embase, and Web of Science. We used the key words CD5 negative, CD5-, mantle cell lymphoma, and MCL. Data was tabulated regarding the following 16 variables: t(11;14)(q13;q32), cyclin-D1, CD5, CD10, CD19, CD20, CD23, BCL2, BCL6, Ki-67 (higher or lower than 30%), IGHV mutation status (mutated IGHV >3% discordance with germline), male to female ratio, light chain expression (kappa or lambda), presence of a leukemic phase, stage, and overall survival (OS). Data was reported as percent and total number of cases with available data of each variable.
Results and discussion: 68 out of 470 screened articles included CD5-negative MCL cases. After exclusion of duplicates, 50 sources (46 full articles and 4 abstracts) were included. Data of 222 cases of CD5-negative MCL were collected.
To a degree, reviewed cases of CD-5 negative MCL shared similarities to classic MCL. Both sub-types had a median age at diagnosis of approximately 65 and presented as stage IV disease 70% of the time. Both subtypes overexpressed cyclin-D1 (100%, 222/222), possessed the t(11;14)(q13;q32) (93%, 49/53: 49 of 53 cases with available data on the translocation), were CD-19 positive (100%,18/18), CD20-positive (100%, 58/58), BCL2-positive (97%, 34/35), CD10-negative (93%, 42/45), and CD23-negative (95%,56/59). Presence or absence of leukemic phase was reported in 16 cases, 8 of those were positive for circulating MCL cells (50%). The proliferation marker Ki-67 was reported in 22 cases, 7 (32%) of which were >30%.
CD5-negative MCL deviated from the classic MCL presentation in a number of clinical and biological variables. Most importantly, the median OS of 47 cases with available follow-up was greater than 16 years (Figure 1), which compared very favorably to the historic survival of 3 to 5 years in classic MCL. Interestingly, the number of affected males was less than expected in the CD5-negative group. Male-to-female ratio was 2:1 (74 males and 36 females of 110 cases with available gender data), which is lower than the expected 3:1 ratio.
From a biological standpoint, the CD5-negative MCL cohort had more kappa than lambda-restricted cases (62%, 13 of 21 available light chain data), and more mutated than unmutated IGHV (61% mutated, 11 of 18 cases with available IGHV data). Classically, lambda-restricted MCL and unmutated IGHV are more commonly seen and were associated with worse clinical outcomes. In addition, we observed BCL6 expression in 23% of CD5-negative MCL cases, which is higher than expected (6 of 26 cases with BCL6 available data).
Conclusions: To our knowledge this is the most comprehensive review of CD5-negative MCL. Lack of CD5 expression was associated with important clinical and biological differences compared to classic MCL. The higher survival observed in our analysis suggest that CD5 can potentially be incorporated in identifying a subset of a more indolent MCL that might benefit from a watch and wait approach. Currently, treatment in MCL can be differed in a subset of patients with an indolent presentation characterized by leukemic-only disease with absence of lymphadenopathy, mutated IGHV, and lack of SOX11 expression. SOX11 data was not available in our cohort, and only 18 patients had available IGHV mutation data. While the exact role of CD5 in MCL remains unknown, our findings highlight the need for a deeper investigation of CD5-negative MCL at the genetic, phenotypic, and clinical levels.
No relevant conflicts of interest to declare.
