Leukemic non-nodal mantle cell lymphomas have a distinct phenotype and are associated with deletion of PARP1 and 13q14

Abstract

Leukemic non-nodal mantle cell lymphoma (lMCL) is a particular subtype of mantle cell lymphoma (MCL), characterized by leukemic non-nodal disease and slow progression. Recognition of this entity is relevant to avoid overtreatment. Despite indolent clinical behaviour, lMCL might transform to a more aggressive disease. The purpose of this study was to compare lMCL with classical MCL (cMCL) and aggressive MCL (aMCL) using immunohistochemistry, interphase fluorescence in situ hybridization (FISH), and array-based comparative genomic hybridization, in order to identify biomarkers for lMCL diagnosis and prognosis. Seven lMCL patients were included. All had bone marrow involvement without lymphadenopathy. An lMCL phenotype was distinct from that of cMCL and aMCL: SOX11-, ATM+, PARP1+/-, and low KI67 (average 2 %). Beyond the t(11;14) translocation, fewer secondary cytogenetic alterations were found in lMCL compared to cMCL and aMCL, including deletion of PARP1 and 13q14. At last follow-up, one patient with lMCL had died of disease and another had progressive disease. These patients were respectively 13q14 deletion- and PARP1-positive. One other case of lMCL harbored a 13q14 deletion associated with PARP1 deletion. This patient had indolent disease. lMCL has a particular phenotype and fewer secondary cytogenetic alterations than cMCL and aMCL. PARP1 protein expression and 13q14 deletion are associated with a progressive clinical course of lMCL and should be included in initial diagnostic studies as predictors of unfavorable outcome. PARP1 deletion is involved in lMCL pathogenesis and might confer advantage.

CD200 expression in mantle cell lymphoma identifies a unique subgroup of patients with frequent IGHV mutations, absence of SOX11 expression, and an indolent clinical course

“…All 6 of these patients did not require high dose chemotherapy. It is noteworthy that over the course of the disease of mantle cell lymphoma, including non-nodal leukemic variant indolent mantle cell lymphoma, additional molecular/cytogenetic abnormalities can be acquired and lead to more aggressive forms of mantle cell lymphoma, 32,33 which might account for some aggressive disease in this cohort of patients. One of the two blastoid variant mantle cell lymphoma tested was positive for p53 by immunohistochemistry.…”

Progress in molecular feature of smoldering mantle cell lymphoma

“…Using Ki-67 positivity cutoffs of < 10%, 10-30% and > 30% of cells, Determann et al demonstrated 3-year OS rates of 93%, 74% and 66% in MCL patients [6]. Moreover, Gallo et al reported that the Ki-67 index was lower in leukemic non-nodal MCL (average 2%) than in classical MCL (40%) and aggressive MCL (76%), conferring a better prognosis [20]. Therefore, the proliferative activity reflected by the Ki-67 index has become a strong and independent variable for predicting survival in MCL patients.…”

“…Importantly, poly(ADP-ribose) polymerase 1 (PARP1) protein expression is related to a progressive course of indolent MCL and shortened OS. Gallo and colleagues indicated that PARP1 should be included in initial diagnostic studies as a negative predictor [ 20 ]. PARP1 is a nuclear protein involved in DNA repair and the maintenance of genomic stability and is overexpressed in a number of aggressive cancers.…”

Inconsistency associated with SOX11 immunohistochemistry in mantle cell lymphoma: a meta-analysis

“…Among the studies with mouse monoclonal antibodies, clone MRQ-58 was used on 10 study populations [5, 10-12, 14-16, 18, 19, 22]. MCLs with indolent traits (leukemic non-nodal MCL, small cell variant MCL, and MCL with indolent clinical course) were included in 10 study populations [7,9,11,13,16,20,24]. Aggressive variant MCLs (pleomorphic and blastoid variants) were included in 14 study populations [5, 8, 10-14, 16, 19, 20].…”

“…The first covariate was the proportion of cases with indolent traits. 10 study populations with specified cases of indolent traits were included in the meta-regression [7,9,11,13,16,20,24]. Results showed that the proportion of cases with indolent traits was a statistically significant covariate (intercept = 1.51, 95% CI = [0.71, 2.31], p = 0.0002, slope = − 2.87, 95% CI = [− 4.60, − 1.14], p = 0.0012).…”