Epstein–Barr virus (EBV)-associated diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS) constitute a distinct clinicopathological entity in the current World Health Organization (WHO) classification. However, its genomic features remain sparsely characterized. Here, we combine whole-genome sequencing (WGS), targeted amplicon sequencing (tNGS), and fluorescence in situ hybridization (FISH) from 47 EBV + DLBCL (NOS) cases to delineate the genomic landscape of this rare disease. Integrated WGS and tNGS analysis clearly distinguished this tumor type from EBV-negative DLBCL due to frequent mutations in ARID1A (45%), KMT2A/KMT2D (32/30%), ANKRD11 (32%), or NOTCH2 (32%). WGS uncovered structural aberrations including 6q deletions (5/8 patients), which were subsequently validated by FISH (14/32 cases). Expanding on previous reports, we identified recurrent alterations in CCR6 (15%), DAPK1 (15%), TNFRSF21 (13%), CCR7 (11%), and YY1 (6%). Lastly, functional annotation of the mutational landscape by sequential gene set enrichment and network propagation predicted an effect on the nuclear factor κB (NFκB) pathway (CSNK2A2, CARD10), IL6/JAK/STAT (SOCS1/3, STAT3), and WNT signaling (FRAT1, SFRP5) alongside aberrations in immunological processes, such as interferon response. This first comprehensive description of EBV + DLBCL (NOS) tumors substantiates the evidence of its pathobiological independence and helps stratify the molecular taxonomy of aggressive lymphomas in the effort for future therapeutic strategies.

Background: Malignant neoplasms of the salivary glands are rare, and therapeutic options are limited. Results from recently published studies indicate a possible use for checkpoint inhibition in a subset of patients, but there are no established criteria for programme cell death ligand 1 (PD-L1) scoring in salivary gland carcinomas (SGCs). Methods: In this retrospective study, we present a cohort of 94 SGC patients with full clinical follow-up. We included 41 adenoid cystic carcinomas (AdCC), 21 mucoepidermoid carcinomas (MEC), 16 acinic cell carcinomas (ACC), 12 adenocarcinomas, not otherwise specified (AC, NOS), 2 epithelial-myoepithelial carcinomas (EMC), one salivary duct carcinoma (SDC), and one carcinoma ex pleomorphic adenoma (CA ex PA). Subsequent histopathological analysis was performed with special emphasis on the composition of the immune cell infiltrate (B-/T-lymphocytes). We assessed PD-L1 (SP263) on full slides by established scoring criteria: tumor proportion score (TPS), combined positivity score (CPS) and immune cell (IC) score. Results: We identified significantly elevated CD3+, TP, CP, and IC scores in AC, NOS compared to AdCC, MEC, and ACC. CPS correlated with node-positive disease. Moreover, AC, NOS displayed IC scores of 2 or 3 in the majority (67%) of cases (p = 0.0031), and was associated with poor prognosis regarding progression-free (PFS) (p < 0.0001) and overall survival (OS) (p < 0.0001). CPS correlated with strong nuclear or null p53 staining in AC, NOS but not in other SGCs. Long-lasting partial remission could be achieved in one AC, NOS patient who received Pembrolizumab as third-line therapy. Conclusions: The current study is the first to investigate the use of established scoring criteria for PD-L1 expression in malignant salivary gland tumors. Our findings identify unique characteristics for AC, NOS among the family of SGCs, as it is associated with poor prognosis and might represent a valuable target for immune checkpoint inhibition.

Plasmablastic lymphoma (PBL) represents a clinically heterogeneous subtype of aggressive B-cell non-Hodgkin lymphoma. Targeted-sequencing studies and a single-center whole-exome sequencing (WES) study in HIV-positive patients recently revealed several genes associated with PBL pathogenesis; however, the global mutational landscape and transcriptional profile of PBL remain elusive. To inform on disease-associated mutational drivers, mutational patterns, and perturbed pathways in HIV-positive and HIV-negative PBL, we performed WES and transcriptome sequencing (RNA-sequencing) of 33 PBL tumors. Integrative analysis of somatic mutations and gene expression profiles was performed to acquire insights into the divergent genotype–phenotype correlation in Epstein-Barr virus–positive (EBV+) and EBV– PBL. We describe a significant accumulation of mutations in the JAK signal transducer and transcription activator (OSMR, STAT3, PIM1, and SOCS1), as well as receptor tyrosine-kinase RAS (ERBB3, NRAS, PDGFRB, and NTRK) pathways. We provide further evidence of frequent perturbances of NF-κB signaling (NFKB2 and BTK). Induced pathways, identified by RNA-sequencing, closely resemble the mutational profile regarding alterations accentuated in interleukin-6/JAK/STAT signaling, NF-κB activity, and MYC signaling. Moreover, class I major histocompatibility complex–mediated antigen processing and cell cycle regulation were significantly affected by EBV status. An almost exclusive upregulation of phosphatidylinositol 3-kinase/AKT/mTOR signaling in EBV+ PBL and a significantly induced expression of NTRK3 in concert with recurrent oncogenic mutations in EBV– PBL hint at a specific therapeutically targetable mechanism in PBL subgroups. Our characterization of a mutational and transcriptomic landscape in PBL, distinct from that of diffuse large B-cell lymphoma and multiple myeloma, substantiates the pathobiological independence of PBL in the spectrum of B-cell malignancies and thereby refines the taxonomy for aggressive lymphomas.

Background: Immunity and inflammatory response affect the tumour microenvironment and the progression of malignancies. Metabolic and inflammatory parameters and ratios of the peripheral blood correlate with outcome in cancer patients. There exist several established and validated inflammation-based scores of prognostic significances including the Glasgow Prognostic Score (GPS). Methods: In this retrospective, multicentre study, we investigated the prognostic capabilities of baseline GPS in patients with multiple myeloma (MM) undergoing autologous stem cell transplantation as a complementary resource for risk stratification. For GPS calculation, a C-reactive-protein (CRP) value of >10 mg/dL counts as one point and an albumin value of <35 g/L connotes another point, resulting in three different subgroups (group I: 0 points; group II: 1 point; and group III: 2 points). Patients with MM admitted to the participating institutions between January 2010 and July 2018 were screened, and established prognostic scores and ratios were assessed. Characteristics significantly associated with overall survival (OS) or progression-free survival (PFS), upon univariate analysis, were included in a Cox proportional hazards model. Results: Following initial assessment, we identified 224 fully evaluable patients who underwent autologous haematopoietic stem cell transplantation for multiple myeloma. A centralised review of pathology and cytogenetic reports was conducted, and a central hematopathology assessment was performed in 175 of 224 cases (78.1%). Proceeding to high-dose chemotherapy and subsequent autologous stem cell transplantation was the main inclusion criterion for all transplant-eligible patients in the study. The median age at diagnosis was 59 years (range: 35–76 years) with a median follow-up of 76 months. Multivariate analysis revealed neutrophil–platelet score (NPS) (HR = 0.528, 95% CI = 0.284–0.984) and B symptoms at primary diagnosis (HR = 1.838, 95% CI = 1.232–2.740) to be independent predictors of PFS while high-risk cytogenetic changes (HR = 2.358, 95% CI = 1.413–3.934, p = 0.001) could be identified as an independent predictor of OS, and GPS to be the only independent predictor of both OS and PFS (OS: HR = 2.127, 95% CI = 1.431–3.162, p < 0.0001 and PFS: HR = 1.405; 95% CI = 1.058–1.867, p = 0.019). Conclusions: Our data show that baseline GPS correlates with rates of relapse and refractory disease in MM patients undergoing autologous transplantation. In a multivariate analysis, these effects were proven to hold prognostic capabilities beyond and independent from established prognosticators. These results require further validation in a prospective setting.