CLINICALLY INDOLENT PRIMARY HHV8‐NEGATIVE EFFUSION‐BASED LYMPHOMA IS CHARACTERIZED BY COMPLEX GENOMIC ALTERATIONS WITH AGGRESSIVE FEATURES

Abstract

Human herpesvirus 8-negative effusion-based lymphoma (HHV8-negative EBL) is a distinct lymphoma entity related to fluid overload states caused by underlying medical conditions such as cardiac failure or renal insuffciency. Due to a phenotypical resemblance with secondary effusion of diffuse large B-cell lymphoma (DLBCL), HHV8-negative EBL is easily misdiagnosed. However, in contrast to DLBCL, HHV8-negative EBL follows a mild clinical course that is largely determined by comorbidity and high age at diagnosis, underpinning the importance to differentiate between the two entities. From the files of the Dept of Pathology, AmsterdamUMC/VUMC, we retrospecively identified 11 cases of HHV8-negative EBL. All patients presented with isolated pleural (n=10) or pericardial effusion (n=1). Age at presentation ranged from 60-92 years (median 85 years). All cases, except one, showed a mature B-cell immunophenotype (CD20, CD79a positive), one case showed plasmacytic differentiation (CD138 positive). All were EBER negative, 9/10 showed a non-GCB phenotype and 1/10 a GCB-phenotype (Hans/Tally alogorithms). We performed extensive genomic profiling using a custom-made all-in-one assay (NimbleGen EZ SeqCap) to determine genome wide copy number alterations, mutations (369 genes) and translocations (12 target regions) on 8 HHV8-negative EBL cases. A mean number of 33.6 copy number gains and losses per case were found, with recurrent focal deletions of chromosome 3p14.2 and 6q21 in 6/8 cases, encompassing tumor supressor genes FHIT and PRDM1, respectively. We observed a high rate of mutations across genes frequently involved in DLBCL, including patterns of somatic hypermutation (PIM1, KLHL1, BCL2). The most abundant hotspot mutation was found in MYD88L265P (3/8 cases). In addition, 5/8 cases had one or more translocations, involving MYC (n=2), BCL2 (n=1), BCL6 (n=2), TP63 (n=1), EXOC2 (n=1) and KMT2D (n=1), with Ig and non-Ig partners, of which one MYC/BCL6 double hit context. We conclude that HHV8-negative EBL is characterized by heterogeneous genomic features with frequent mutations, copy number aberrations and translocations, similar to aggressive B-cell lymphomas, but despite this follows an indolent clinical course. Keywords: diffuse large B-cell lymphoma (DLBCL); elderly; molecular genetics.