Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. 103 O-DLBCL patients were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin (COO) was determined by immunohistochemistry and gene-expression-profiling (GEP) using (extended)-NanoString/Lymph2Cx. Mutational profiles were identified with targeted next-generation deep-sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCL, were predominantly classified as GCB-phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx demonstrated significantly different GEP-clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P<0.001). Expression levels of 23 genes of two different targeted GEP-panels, indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB showed a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes, i.e. B2M, EZH2, IRF8, and TNFRSF14, compared to NO-DLBCL-GCB (P=0.031, P=0.010, P=0.047, and P=0.003). PB-DLBCL with its corresponding specific mutational profile were significantly associated with a superior overall survival compared to equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P=0.011). This study is the first to demonstrate that PB-DLBCL is characterized by a GCB-phenotype, with a centrocyte-like GEP-pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity and its specific mutational landscape holds potential for targeted therapies (e.g. EZH2-inhibitors).

A 68-year-old man who presented with periodic fever and generalized weakness was diagnosed with Enterococcus faecalis bacteraemia from an infected abdominal aneurysm. The aneurysm was new: aortic dilatation was absent a year before. In such patients the diagnosis "microbial aortitis" is more appropriate than "mycotic aneurysm". We discuss the pathophysiology, epidemiology, prognosis and treatment of this condition.

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This case highlights the use of lymphoscintigraphy with SPECT/CT in patients with previous chest and/or axillary surgery. A 67-year-old woman with a history of left breast carcinoma treated with lumpectomy and radiotherapy, and a second lumpectomy of the ipsilateral breast for a second breast carcinoma, underwent a lymphoscintigraphy for a new left breast lesion. Planar images visualized an alternative lymphatic drainage to the contralateral axilla and to the left paravertebral area. SPECT/CT confirmed sentinel nodes in both stations.

Background:Primary bone diffuse large B‐cell lymphoma (PB‐DLBCL) is a rare extranodal lymphoma comprising 1–2% of all malignant lymphomas. Large next‐generation sequencing (NGS) studies identified genetic drivers in nodal diffuse large B‐cell lymphomas (DLBCLs), resulting in novel targeted therapeutic opportunities. However, the genetic constitution of PB‐DLBCL is still unclear and extensive sequencing studies have yet been performed.Aims:We aim to determine mutational profiles in a unique large cohort of PB‐DLBCL patients in correlation with clinicopathological characteristics.Methods:This retrospective cohort study consisted of 38 patients with bone localization of DLBCL, of which pretreatment fresh frozen or formalin‐fixed paraffin‐embedded bone tissue samples were available. Patients were diagnosed between 2003 and 2019 at Leiden University Medical Center (LUMC), a center of expertise for bone tumors, and affiliated hospitals in the Netherlands. Strict definitions, based on radiological assessment of anatomical disease localizations at diagnosis were applied, categorizing 3 different subgroups (figure 1A): patients with osseous involvement only (single or multiple bone lesions) (PB‐DLBCL), patients with osseous involvement and locoregional lymphadenopathy (locoregional disease), and patients with osseous and multiple extraosseous localizations (disseminated disease). An in‐house developed and validated targeted NGS panel comprising 52 B‐cell lymphoma‐specific genes was used for sequencing with the Ion S5TM System.Results:Our cohort contained 38 patients, 22 (58%) were male, and the median age at diagnosis was 61 years (range 13–92). Twenty patients had PB‐DLBCL (53%), 4 had locoregional disease (10%), and 14 had disseminated disease (37%). NGS analysis identified 32 genes with ‘pathogenic’ mutations, with on average 2.3 mutated genes per patient (figure 1B). No mutations were detected in 4 patients with disseminated disease. Overall, in patients with bone localization of DLBCL, high mutation frequencies were observed for EZH2 (31.6%), TP53 (21.1%), B2 M (15.8%), and TNFRSF14 (15.8%), belonging to epigenetic (63.2%), DNA damage response (21.1%), and immunity (26.3%) pathways, respectively. In PB‐DLBCL, EZH2 (35%) and TP53 (25%) mutations were considerably more frequently detected compared to disseminated disease (21% and 14%, respectively). In context, previous studies reported substantial lower incidences of mutated EZH2 (11–22%) and TP53 (12–20%) in DLBCLs with germinal center B‐cell (GCB) subtype (Reddy A. et al. 2017; Karube K. et al. 2018; Schmitz R. et al. 2018; and Chapuy B. et al. 2018). Although a small patient group, locoregional disease also demonstrated frequent mutations in EZH2 (50%, 2/4), TNFRSF14 (50%, 2/4), B2 M (50%, 2/4), and TP53 (25%, 1/4).Taken together, these findings demonstrate that the epigenetic pathway is affected most commonly in PB‐DLBCL and locoregional disease (75%), with a substantial lower frequency in disseminated disease (43%) (figure 1C). Correlation of genetic aberrations with gene‐expression profiling and clinicopathological characteristics will follow shortly.Summary/Conclusion:To our knowledge, this is the first study reporting a higher frequency of epigenetic mutations in patients with bone localization of DLBCL, thereby strengthening the concept that DLBCLs with bone location belong to the GCB subtype. Furthermore, the high incidence of mutated EZH2 in PB‐DLBCL patients provides a rationale for exploration of novel targeted treatment with EZH2 inhibitors to improve survival outcomes in these patients.image