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Diagnosing any of the more than 30 types of T-cell lymphomas is considered a challenging task for many pathologists and currently requires morphological expertise as well as the integration of clinical data, immunophenotype, flow cytometry and clonality analyses. Even considering all available information, some margin of doubt might remain using the current diagnostic procedures. In recent times, the genetic landscape of most T-cell lymphomas has been elucidated, showing a number of diagnostically relevant mutations. In addition, recent data indicate that some of these genetic alterations might bear prognostic and predictive value. Extensive genetic analyses, such as whole exome or large panel sequencing are still expensive and time consuming, therefore limiting their application in routine diagnostic. We therefore devoted our effort to develop a lean approach for genetic analysis of T-cell lymphomas, focusing on maximum efficiency rather than exhaustively covering all possible targets. Here we report the results generated with our small amplicon-based panel that could be used routinely on paraffin-embedded and even decalcified samples, on a single sample basis in parallel with other NGS-panels used in our routine diagnostic lab, in a relatively short time and with limited costs. We tested 128 available samples from two German reference centers as part of our routine work up (among which 116 T-cell lymphomas), which is the largest routine diagnostic series reported to date. Our results showed that this assay had a very high rate of technical success (97%) and could detect mutations in the majority (79%) of tested T-cell lymphoma samples. [ABSTRACT FROM AUTHOR]

Primary pancreatic lymphoma (PPL) is a rare disease representing 0.1% of malignant lymphomas, which lacks well‐defined diagnostic and therapeutic protocols. Objectives: To describe PPL clinical, diagnostic and histological characteristics, together with therapy and outcome, in a relatively large series of patients. Methods: The study includes 39 PPL patients, aged ≥15 years, observed from January 2005 to December 2018, in 8 Italian Institutions. Results: The main symptoms were abdominal pain (58%) and jaundice (47%). Lactate dehydrogenase serum levels were elevated in 43% of patients. Histological specimens were mostly obtained by percutaneous (41%) or endoscopic (36%) biopsy, with diffuse large B‐cell lymphoma being the most frequent (69%) histological diagnosis. Chemotherapy was administered alone in 65% of patients, with radiotherapy in 17%, or after surgery in 9%. The 2‐year overall survival (OS) was 62%, the 2‐year progression‐free survival (PFS) 44%. Debulking surgery (with or without chemotherapy) was associated with a significant worse OS. Three (9.4%) of 32 high‐grade patients experienced a central nervous system (CNS) relapse. Conclusions: PPL is rare, often high‐grade, with symptoms and localization similar to other pancreatic malignancies. Biopsy should be the preferred diagnostic method. High‐grade PPL should undergo CNS prophylaxis. [ABSTRACT FROM AUTHOR]

Aggressive B‐cell lymphomas present as a heterogeneous spectrum of disease. A primary diagnosis in the bone marrow (BM) may be challenging in terms of diagnostic classification and clinical handling, owing to limited architectural information. Aggressive B‐cell lymphomas can be subdivided into entities that typically present primarily in the BM, and cases with BM involvement in which the bulk of disease is present in other organs. One main topic at the 2018 BM workshop of the European Association of Haematopathology/Society of Hematopathology was therefore aggressive B‐cell lymphomas with a primary BM presentation. The spectrum of cases submitted to this topic gave a good overview of commonly encountered problems, as well as unusual manifestations, and highlighted areas of imprecise disease definitions and diagnostic grey zones. The categories submitted to the workshop included cases of Burkitt lymphoma (BL) with unusual features, high‐grade B‐cell lymphomas (HG‐BCLs) with and without so‐called double/triple‐hit, and diffuse large B‐cell lymphomas (DLBCLs) with a primary BM presentation. Areas of difficulties included the morphological boundaries of HG‐BCL not otherwise specified, cases with MYC and bcl‐2 or bcl‐6 translocations and terminal deoxynucleotidyl transferase (TdT) expression, which were categorised as B‐cell lymphoblastic leukaemia/lymphoma if most cells showed TdT positivity, and the clinicopathological overlap between intravascular large B‐cell lymphoma, CD5‐positive DLBCL, and DLBCL with primary presentations in the BM, spleen, and liver. This review summarises our understanding of the main aggressive B‐cell lymphoma categories with a common primary BM presentation and potential problem areas, and makes suggestions for the immunophenotypic and genetic work‐up, illustrated by the interesting and challenging cases submitted to the workshop. [ABSTRACT FROM AUTHOR]

I Sir: i The 3rd session of the bone marrow (BM) workshop of the 19th meeting of the European Association for Haematopathology (EAHP)/Society of Hematopathology (SH) in Edinburgh in 2018 was dedicated to T-cell and natural killer (NK)/T-cell lymphomas/lymphoproliferations. In this article we discuss cases submitted to the 3rd session of the EAHP/SH BM workshop and focus on diagnostic challenges, including the difficulties in clarifying borders between overlapping primary BM T-cell and NK/T-cell lymphoproliferations, and the limitations of applying existing diagnostic criteria related to nodal-type T-cell lymphomas or extranodal NK/T-cell (ENKT) lymphoproliferations to rare cases of isolated involvement or initial presentation in the BM. GLO:EW1/01jul20:his14093-fig-0003.jpg PHOTO (COLOR): 3 Angioimmunoblastic T-cell lymphoma with bone marrow (BM) involvement that was obscured by a dense polytypic plasmacytic infiltrate, and a case of primary BM involvement by peripheral T-cell lymphoma expressing T follicular helper cell (TFH) markers. A,B, Bone marrow (BM) examination of case no. 21/217 showed dense infiltration by two topographically and morphologically distinct lymphoid infiltrates: confluent nodules of small lymphoid cells [A, haematoxylin and eosin (H&E)], and (B) many large bizarre atypical lymphoid cells in a fibrotic background of small lymphoid cells and histiocytes (B, H&E). [Extracted from the article]

Summary: Predominantly diffuse t(14;18) negative follicular lymphoma (FL) with 1p36 deletion shows distinctive clinical, morphological and molecular features that distinguish it from classical FL. In order to investigate whether it possesses a unique mutation profile, we performed whole exome sequencing of six well‐characterised cases. Our analysis showed that the mutational landscape of this subtype is largely distinct from classical FL. It appears to harbour several recurrent mutations, affecting STAT6, CREBBP and basal membrane protein genes with high frequency. Our data support the view that this FL subtype should be considered a separate entity from classical FL. [ABSTRACT FROM AUTHOR]

Background: Mantle cell lymphoma (MCL) is currently an incurable entity, and new therapeutic approaches are needed. We have applied a high-throughput phospho-proteomic technique to MCL cell lines to identify activated pathways and we have then validated our data in both cell lines and tumor tissues. Methods: PhosphoScan analysis was performed on MCL cell lines. Results were validated by flow cytometry and western blotting. Functional validation was performed by blocking the most active pathway in MCL cell lines. Results: PhosphoScan identified more than 300 tyrosine-phosporylated proteins, among which many protein kinases. The most abundant peptides belonged to proteins connected with B-cell receptor (BCR) signaling. Active BCR signaling was demonstrated by flow cytometry in MCL cells and by western blotting in MCL tumor tissues. Blocking BCR signaling by Syk inhibitor piceatannol induced dose/time-dependent apoptosis in MCL cell lines, as well as several modifications in the phosphorylation status of BCR pathway members and a collapse of cyclin D1 protein levels. Conclusion: Our data support a pro-survival role of BCR signaling in MCL and suggest that this pathway might be a candidate for therapy. Our findings also suggest that Syk activation patterns might be different in MCL compared to other lymphoma subtypes. [ABSTRACT FROM AUTHOR]

Splenic marginal zone lymphoma Is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted: therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples Identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High M phenotype was confirmed in an Independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of N0TCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvlval lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF-1) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to ademethylating agent caused partial reversion of the High-M phenotype and Inhibition of proliferation. [ABSTRACT FROM AUTHOR]