The concomitant evaluation of cell of origin along with tumor microenvironment components identifies patients with DLBCL treated with R-CHOP chemotherapy portraying a worse prognosis.

Survival following anthracycline-based chemotherapy remains poor among patients with most T-cell lymphoproliferative disorders. This may be attributed, at least in part, to cell-autonomous mechanisms of chemotherapy resistance observed in these lymphomas, including the loss of important tumor suppressors and the activation of signaling cascades that culminate in the expression and activation of transcription factors promoting cell growth and survival. Therefore, the identification of novel therapeutic targets is needed. In an effort to identify novel tumor dependencies, we performed a loss-of-function screen targeting ≈500 kinases and identified polo-like kinase 1 (PLK-1). This kinase has been implicated in the molecular cross-talk with important oncogenes, including c-Myc, which is itself an attractive therapeutic target in subsets of T-cell lymphomas and in high-grade (“double hit”) diffuse large B-cell lymphomas. We demonstrate that PLK-1 expression is prevalent among these aggressive lymphomas and associated with c-myc expression. Importantly, PLK-1 inhibtion with the PLK-1 inhibitor volasertib significantly reduced downstream c-myc phosphorylation and impaired BRD4 binding to the c-myc gene, thus inhibiting c-myc transcription. Therefore, volasertib led to a nearly complete loss of c-myc expression in cell lines and tumor xenografts, induced apoptosis, and thus warrants further investigation in these aggressive lymphomas.

Large atypical cells with morphologic and immunophenotypic features resembling Reed-Sternberg cells can be seen in the background of reactive lymphadenopathies as well as non-Hodgkin lymphomas. The presence of these cells is an important diagnostic pitfall that must be recognized by pathologists who regularly interpret lymph node biopsies. A thorough evaluation of the morphologic and immunophenotypic features of these cells and the cellular milieu is crucial in achieving the correct diagnosis. In this review, examples of lymphomas presenting with Reed-Sternberg–like cells will be provided. Additionally, a detailed description of the common morphologic and immunophenotypic features of these cells, as well as strategies that can be used to distinguish them from the Reed-Sternberg cells of classical Hodgkin lymphoma, will be emphasized.

Gene fusion characterisation of rare aggressive prostate cancer variants-adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma: an analysis of 19 cases Aims: To evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma. Methods and results: We retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next-generation sequencing assay targeting recurrent gene fusions, and fluorescence insitu hybridisation (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant-cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in nine (47%, seven via sequencing, showing TMPRSS2-ERG fusions and one GRHL2-ERG fusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false-positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harboured BRAF fusions (FAM131A-BRAF and SND1-BRAF).