Testicular large b‐cell lymphoma is genetically similar to primary central nervous system lymphoma and distinct from nodal diffuse large b‐cell lymphoma

Introduction: Testicular large B-cell lymphoma (TLBCL) is an infrequent and aggressive lymphoma presenting in an immune-privileged site, recently recognized as a distinct entity from diffuse large B-cell lymphoma (DLBCL). Here, we performed the genetic characterization of TLBCL and compare it with a published series of nodal DLBCL and primary central nervous system lymphoma (PCNSL). Patients and Methods: We collected 61 patients with TLBCL diagnosed between 2002 and 2021. Cell-of-origin was determined by immunochemistry and Lymph2Cx assay. To characterize the genomic profile of TLBCL we performed targeted next-generation sequencing, copy number arrays, and fluorescent in situ hybridization, and compared them to those of DLBCL and PCNSL. Results: The median age was 70 years and 30% of the patients had disseminated disease at diagnosis, including six cases with CNS involvement. Using Hans' algorithm, 83% (44/53) were identified as a non-germinal center while the Lymph2Cx assay categorized 71% (30/42) as activated B-cell phenotype and 12% (5/42) as unclassified. BCL6 rearrangements were detected in 36% (17/47) of cases, and no concomitant BCL2 and MYC rearrangements were found. Integrative analysis of 40 cases with single nucleotide variants, indels, and copy number alterations (CNA) data showed that the most frequent alterations (>50%) in TLBCL were PRDM1, CDKN2A/B, TNFAIP3, SGK1, ARID1B, MYD88L265P, SPIB, PIM1, and CD79B (Figure). Concomitant variants in MYD88L265P, CD79B, and PIM1 were detected in twelve (29%) cases. Using the LymphGen tool, 71% (30/42) of the cases could be classified into a molecular subgroup, with MCD being the most frequent group (66%, 20/30). Interestingly, patients with localized or disseminated disease displayed similar genomic complexity based on the number of CNAs and the number of mutated genes. Compared with nodal DLBCL, localized and disseminated TLBCL have less CNA complexity (P = 0.01 and P < 0.04, respectively) but showed a higher number of variants (P = 0.01 and P < 0.001, respectively). TLBCL also presented more frequently 18q21.32-q23 (BCL2) gains and 6q and 9p21.3 (CDKN2A/B) deletions. PIM1, MYD88L265P, CD79B, TBL1XR1, MEF2B, CIITA, EP300, and ETV6 variants were enriched in TLBCL, and BCL10 mutations in nodal DLBCL. There were no genetic differences between TLBCL and PCNSL. Encore Abstract - previously submitted to regional or national meetings (up to <1’000 attendees). The research was funded by: Asociación Española Contra el Cancer AECC/CIBER: PROYE18020BEA (SB); Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III Instituto de Salud Carlos III, “Cofinanciado por la Unión Europea” and Fondos FEDER: European Regional Development Fund “Una manera de hacer Europa”: PI17/01061 (SB), PI19/00887 (ALG and EG), and INT20/00050 (ALG); Marató TV3 TV3-Cancer/ 201904-30 (SB). ARD is supported by a grant from Sociedad Española de Hematología y Hemoterapia. CL is supported by postdoctoral Beatriu de Pinós grant from Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement de la Generalitat de Catalunya and by Marie Sklodowska-Curie COFUND program from H2020 (2018-BP-00055). Keywords: Extranodal non-Hodgkin lymphoma, Pathology and Classification of Lymphomas Conflicts of interests pertinent to the abstract. F. Nadeu Honoraria: Janssen, AbbVie E. Campo Consultant or advisory role: Takeda, NanoString, AbbVie, Illumina Honoraria: Janssen, EUSPharma, Roche Research funding: AstraZeneca A. López-Guillermo Consultant or advisory role: Roche, Gilead, Kite Pharma, Celgene, Bristol Myers Squibb, Incyte, Takeda, Kern Pharma, Pfizer, Janssen Honoraria: Janssen, Roche, Kite Research funding: Gilead, Janssen, Celgene, Bristol Myers Squibb Educational grants: Roche, Kite/Gilead