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CD49d, the α4 chain of the VLA‐4 integrin, is a negative prognosticator in chronic lymphocytic leukemia (CLL) with a key role in CLL cell‐microenvironment interactions mainly occurring via its ligands VCAM‐1 and fibronectin. In the present study, we focused on EMILIN‐1 (Elastin‐MIcrofibriL‐INterfacer‐1), an alternative VLA‐4 ligand whose role has been so far reported only in non‐hematological settings, by investigating: i) the distribution of EMILIN‐1 in CLL‐involved tissues; ii) the capability of EMILIN‐1 to operate, via its globular C1q (gC1q) domain, as additional adhesion ligand in CLL; iii) the functional meaning of EMILIN‐1 gC1q/VLA‐4 interactions in CLL. EMILIN‐1 is widely present in the CLL‐involved areas of bone marrow biopsies (BMBs) without difference between CD49d negative and positive cases, displaying at least three different expression patterns: "fibrillar", "dot‐like" and "mixed". The lack in CLL‐BMB of neutrophil elastase, whose proteolytic activity degrades EMILIN‐1 and impairs EMILIN‐1 function, suggests full functional EMILIN‐1 in CLL independently of its expression pattern. Functionally, EMILIN‐1 gC1q domain promotes adhesion of CLL cells through specific interaction with VLA‐4, and releases pro‐survival signals for CLL cells, as demonstrated by enhanced ERK and AKT phosphorylation and impairment of in‐vitro‐induced apoptosis. EMILIN‐1/VLA‐4 interaction can efficiently contribute to the maintenance of the neoplastic clone in CLL. [ABSTRACT FROM AUTHOR]

Summary: High programmed cell death 1 ligand 1 (PD‐L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin‐ and Reed–Sternberg cells (HRSC) have been shown to be associated with favourable response to anti‐PD‐1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD‐L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti‐PD‐1‐based first‐line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced‐stage or r/r cHL. All but two cases (97%) showed PD‐L1 expression by the tumour cells in variable amounts. While MHC‐I was rarely expressed in >50% of HRSC, MHC‐II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD‐L1 and MHC‐I/II expression on early response to the highly effective anti‐PD‐1‐based NIVAHL first‐line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti‐PD‐1 first‐line cHL treatment. [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]

The association of systemic mastocytosis with another hematologic neoplasia of myeloid or lymphoid origin is recognized as an advanced subvariant of mastocytosis. Here, we report the association of indolent or smoldering systemic mastocytosis with three cases of myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis, a recently recognized disease characterized by SF3B1 mutations. The hierarchical pattern of KIT, SF3B1, JAK2, and additional mutations was studied in whole and fractionated subpopulations of peripheral blood cells and whole bone marrow. In two cases, we could demonstrate a multilineage D816V KIT mutation, involving all myeloid lineages in one patient and also the lymphoid series in the other. Two patients displaying both SF3B1 and V617F JAK2 mutations had a very poor prognosis. Another patient bearing SF3B1, but not V617F JAK2 mutation, had a favorable response to erythropoietin treatment and long survival. [ABSTRACT FROM AUTHOR]

Background: Several viruses have been described as causes of acquired inflammatory myopathies; however, the mechanisms by which they cause muscle disease are still unclear. The aim of this study was to describe the laboratory features of benign acute myositis in a small case series.Methods: A detailed pathological and serological analysis was performed in five African migrants who developed an acute viral myositis complicated by rhabdomyolysis.Results: Muscle biopsies clearly documented an inflammatory myopathy with histological features similar to polymyositis including CD8+ T cells surrounding and invading nonnecrotic muscle fibers, CD68+ macrophages and major histocompatibility complex class I antigen upregulation. In addition, positivity for myositis-specific antibodies (MSA), in particular anti-aminoacyl tRNA synthetases, was found in the serum of two patients.Conclusions: Our study demonstrated that T-cell mediated injury occurs in muscle of patients with acute viral myositis, and that MSA may be present in the serum of these patients. [ABSTRACT FROM AUTHOR]

The authors offer a response to criticisms raised about their study on the role of the endothelin-1 (EDN1) axis as a therapeutic target in multiple myeloma (MM). Topics include recognition of aberrant activation of the EDN1 axis as a common mechanism underlying the progression of several solid and blood malignancies, molecular basis of the aberrant expression of EDN receptor B (EDNRB), and effects of EDNRs blockade.

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]

Key Clinical Message Patients with advanced variants of Systemic Mastocytosis may develop destructive bone lesions when massive mast cell ( MC) infiltrates are present. Finding of large osteolyses in indolent systemic mastocytosis, typically characterized by low MC burden, should prompt investigations for an alternative explanation. [ABSTRACT FROM AUTHOR]

New effective treatments are needed to improve outcomes for multiple myeloma ( MM) patients. Receptors with restricted expression on plasma cells ( PCs) represent attractive new therapeutic targets. The endothelin-1 ( EDN1) axis, consisting of EDN1 acting through EDN-receptor A ( EDNRA) and B ( EDNRB), was previously shown to be overexpressed in several tumours, including MM. However, there is incomplete understanding of how EDN1 axis regulates MM growth and response to therapy. Besides EDNRA, the majority of MM cell lines and primary malignant PCs express high levels of EDNRB and release EDN1. Similarly, bone-marrow microenvironment cells also secrete EDN1. Investigating the extent of epigenetic dysregulation of EDNRB gene in MM, we found that hypermethylation of EDNRB promoter and subsequent down-regulation of EDNRB gene was observed in PCs or B lymphocytes from healthy donors compared to EDNRB-expressing malignant PCs. Pharmacological blockade with the dual EDN1 receptor antagonist bosentan decreased cell viability and MAPK activation of U266 and RPMI-8226 cells. Interestingly, the combination of bosentan and the proteasome inhibitor bortezomib, currently approved for MM treatment, resulted in synergistic cytotoxic effects. Overall, our data has uncovered EDN1-mediated autocrine and paracrine mechanisms that regulate malignant PCs growth and drug response, and support EDN1 receptors as new therapeutic targets in MM. [ABSTRACT FROM AUTHOR]

Aims CD30 expression by bone marrow ( BM) mast cells ( MC) has been reported recently in systemic mastocytosis ( SM) patients. The aim of this study was to investigate the potential diagnostic and prognostic value of CD30 expression in SM as assessed by multiparameter flow cytometry. Methods and results A total of 163 consecutive BM samples corresponding to 142 SM patients and 21 non-mastocytosis cases were studied. CD30 was positive in most SM patients (80%), but in only one non-mastocytosis case (4.8%). When combined with CD25, CD30 contributed to an improved accuracy over that of CD25 alone (98% versus 93%) mainly because most (eight of nine) of the well-differentiated SM ( WDSM), who lacked CD25, were CD30+. Similar levels of expression of CD30 were observed among all different subgroups of SM except mast cell leukaemia; among indolent SM ( ISM) patients, no significant association was observed between the levels of CD30 expression and other clinical and biological features of the disease. Conclusions The increased expression of CD30 associated with absence of CD25 contributes to the diagnosis of WDSM and its distinction from other subtypes of SM. By contrast, CD30 expression did not contribute either to prognostic stratification of ISM or to the differential diagnosis between ISM and aggressive SM cases. [ABSTRACT FROM AUTHOR]