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Summary: The DNA damage response (DDR) is the cellular process of preserving an intact genome and is often deregulated in lymphoma cells. The ataxia telangiectasia and Rad3‐related (ATR) kinase is a crucial factor of DDR in the response to DNA single‐strand breaks. ATR inhibitors are agents that have shown considerable clinical potential in this context. We characterized the activity of the ATR inhibitor elimusertib (BAY 1895344) in a large panel of lymphoma cell lines. Furthermore, we evaluated its activity combined with the clinically approved PI3K inhibitor copanlisib in vitro and in vivo. Elimusertib exhibits potent anti‐tumour activity across various lymphoma subtypes, which is associated with the expression of genes related to replication stress, cell cycle regulation and, as also sustained by CRISPR Cas9 experiments, CDKN2A loss. In several tumour models, elimusertib demonstrated widespread anti‐tumour activity stronger than ceralasertib, another ATR inhibitor. This activity is present in both DDR‐proficient and DDR‐deficient lymphoma models. Furthermore, a combination of ATR and PI3K inhibition by treatment with elimusertib and copanlisib has in vitro and in vivo anti‐tumour activity, providing a potential new treatment option for lymphoma patients. [ABSTRACT FROM AUTHOR]

Primary cutaneous B‐cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence‐based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple‐step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners. [ABSTRACT FROM AUTHOR]

Session 3 of the 2021 European Association for Haematopathology/Society for Hematopathology Workshop focused on mediastinal large B cell lymphomas and surrounding gray areas. One half of the session was dedicated to primary mediastinal large B cell lymphoma (PMBL) and included cases with classic clinicopathologic features, as well as cases with either morphologic or immunophenotypic variation, and PMBL-like cases with primary extramediastinal disease. The role of additional immunophenotyping and/or molecular testing to aid in the diagnosis of PMBL was discussed. The second half of the session focused on mediastinal and non-mediastinal gray zone lymphomas (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (CHL). Several cases illustrating the current challenges in separating this entity from PMBL/DLBCL and CHL were presented. There was discussion regarding the clinical and genetic differences between mediastinal and non-mediastinal GZLs. Rare cases of PMBL and GZL associated with EBV or follicular lymphoma were reviewed. Finally, several cases included in the session highlighted composite or sequential CHL and PMBL/DLBCL and/or GZL, highlighting challenges in separating such cases from GZL. [ABSTRACT FROM AUTHOR]

Summary: Since the publication in 2017 of the revised 4th Edition of the World Health Organization (WHO) classification of haematolymphoid tumours, here referred to as WHO‐HAEM4, significant clinicopathological, immunophenotypic and molecular advances have been made in the field of lymphomas, contributing to refining the diagnostic criteria of several diseases, upgrading entities previously defined as provisional and identifying new entities. This process has resulted in two recent classification proposals of lymphoid neoplasms: the International Consensus Classification (ICC) and the 5th edition of the WHO classification (WHO‐HAEM5). In this paper, we review and compare the two classifications in terms of diagnostic criteria and entity definition, focusing on T‐cell lymphomas and histiocytic/dendritic cell tumours. Moreover, we update the genetic data of the various pathological entities. The main goal is to provide a tool to facilitate the work of the pathologists, haematologists and researchers involved in the diagnosis and treatment of these haematological malignancies. [ABSTRACT FROM AUTHOR]

To evaluate the association between radiomic features (RFs) extracted from 18F‐FDG PET/CT (18F‐FDG‐PET) with progression‐free survival (PFS) and overall survival (OS) in diffuse large‐B‐cell lymphoma (DLBCL) patients eligible to first‐line chemotherapy. DLBCL patients who underwent 18F‐FDG‐PET prior to first‐line chemotherapy were retrospectively analyzed. RFs were extracted from the lesion showing the highest uptake. A radiomic score to predict PFS and OS was obtained by multivariable Elastic Net Cox model. Radiomic univariate model, clinical and combined clinical‐radiomic multivariable models to predict PFS and OS were obtained. 112 patients were analyzed. Median follow‐up was 34.7 months (Inter‐Quartile Range (IQR) 11.3–66.3 months) for PFS and 41.1 (IQR 18.4–68.9) for OS. Radiomic score resulted associated with PFS and OS (p < 0.001), outperforming conventional PET parameters. C‐index (95% CI) for PFS prediction were 0.67 (0.58–0.76), 0.81 (0.75–0.88) and 0.84 (0.77–0.91) for clinical, radiomic and combined clinical‐radiomic model, respectively. C‐index for OS were 0.77 (0.66–0.89), 0.84 (0.76–0.91) and 0.90 (0.81–0.98). In the Kaplan‐Meier analysis (low‐IPI vs. high‐IPI), the radiomic score was significant predictor of PFS (p < 0.001). The radiomic score was an independent prognostic biomarker of survival in DLBCL patients. The extraction of RFs from baseline 18F‐FDG‐PET might be proposed in DLBCL to stratify high‐risk versus low‐risk patients of relapse after first‐line therapy, especially in low‐IPI patients. [ABSTRACT FROM AUTHOR]

The concept of gray-zone lymphoma (GZL) has been progressively refined since its introduction in the literature in 1998. For several years, it was applied to a rather broad spectrum of conditions, posing the problem of the differential diagnosis between any type of Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma, with special reference to primary mediastinal forms (PMBL). Officially recognised as a provisional entity in the 4th and revised 4th editions of the WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues with the term "B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma", it was limited to tumours showing either morphologic features reminiscent of classic HL (CHL) but carrying a complete B-cell phenotype or conversely provided with a PMBL morphology yet revealing CHL phenotypic characteristics. The definition of GZL has been further revised in the recently published International Lymphoma Classification and 5th edition of the WHO Classification of Haematolymphoid Tumours, which have limited it to mediastinal neoplasms (MGZL) based on emerging molecular evidence. The aim of this review is to critically discuss the issue of MGZL, as well as in light of the suboptimal response to current therapies. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is the most common cutaneous lymphoma characterized by an indolent course. Prognosis is stage-based but this approach does not reflect the different outcomes within stages. Considering that tumor microenvironment is known to be involved in MF pathogenesis and progression, we decided to investigate 99 MF cases by using the PanCancer Immune Profiling Panel. We identified and validated a signature of 9 genes able to predict MF survival and distinguish a high-risk group with a worse outcome from a low-risk group of cases with a better outcome. At the molecular level, low-risk vs. high-risk cases reported a global upregulation of immune genes, enriched in cytokines, and a higher density of dendritic cells and mast cells, possibly associated with a more favorable clinical course. [ABSTRACT FROM AUTHOR]

Although chemotherapy (CHT) exposure is an established cause of telomere attrition, determinants of telomere length (TL) dynamics after chemotherapy are poorly defined. In this study, we analyzed granulocyte telomere dynamics in 34 adult lymphoma patients undergoing first‐line CHT. TL was measured by southern blot at each CHT cycle and after 1 year from CHT completion. Median age was 59 yrs (range 22–77). Median number of CHT cycles was 6 (range 3–6). The majority of patients (79%, n = 27) experienced TL shortening following CHT exposure. Mean telomere loss was 673 base pairs (bp) by cycle 6. Telomere shortening was an early event as 87% of the total telomere loss (mean 586 bp) occurred by the end of cycle 3, with no significant recovery after 1 year. A significant correlation was observed between baseline TL and total or fractional telomere loss (p < 0.001), with telomere shortening by cycle 3 observed predominantly in male patients with long telomeres at pre‐treatment evaluation. Stratifying the analysis by gender and age only young women (<51 years of age) did not show significant telomere shortening following chemotherapy exposure. These findings indicate that gender and baseline TL are major determinants of TL dynamics following chemotherapy exposure in lymphoma patients. [ABSTRACT FROM AUTHOR]

Extranodal T-lymphoproliferative disorders or T-cell lymphomas (TLPD) are classified according to the WHO Classification (4th and upcoming 5th editions) (Swerdlow et al., IARC Press 1; Alaggio et al., Leukemia 36(7):1720–1748, 2) and to the International Consensus Classification Update (Campo et al., Blood 140(11):1229–1253, 3) upon several morphologic, phenotypic, and genetic features. None of those at present included has been characterized by primary pulmonary onset. We herein present two such cases which, to the best of our knowledge, have not been previously reported and that might represent another variant of T-cell proliferation at mucosal sites. The two cases share similar histological and phenotypic features, suggesting an origin from CD4 + effector memory T cells with the expression of a CD279/PD-1 antigen. They are both monoclonal, harbor few mutations, and show no disease progression outside the lung. They only differ concerning the local extension of the process and clinical setting. The two cases are examples of so far unreported primary pulmonary TLDP, with limited stage and low proliferative index. A possible relationship with a local yet unknown inflammatory trigger that might have favored the development of the T-cell clone cannot be ruled out. [ABSTRACT FROM AUTHOR]

Background: The immune response to breast implants after COVID-19 disease or COVID-19 vaccine administration includes acute inflammatory manifestations, capsular contracture and seroma. Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare tumor in which numerous up-regulated pro-inflammatory immunological pathways activate a T cell lymphoproliferative disorder. Methods: The first reported case of a BIA-ALCL hidden mass clinically manifesting with inflammatory signs after SARS-CoV-2 infection and vaccinations is here described. Results: Complete capsulectomy and adjuvant chemotherapy were performed and immediately after the surgical procedure local inflammatory signs disappeared; no evidence of disease was present 1 year later. Conclusions: Immunological stimulation by COVID-19 disease and vaccines may highlight some rare clinical manifestations of BIA-ALCL; persistent inflammatory symptomatology over breast implants should be investigated using second-level imaging. Level of Evidence V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. [ABSTRACT FROM AUTHOR]

A five-gene signature may associate with central nervous system dissemination in adult acute lymphoblastic leukemia Five genes were found differentially expressed between the two groups: 2 genes - I CENPV i and I E2F8 i - were down-regulated and 3 genes - I RNF157 i , I LGMN i , and I RIPOR2 i -were up-regulated in CNS-positive versus CNS-negative cases ( I Pval i <=0.01, |Log2 (FC)|>=1) (Figure 1). Keywords: ALL; CNS; dissemination; gene expression; leukemia; NanoString; therapy EN ALL CNS dissemination gene expression leukemia NanoString therapy 789 791 3 10/10/23 20231001 NES 231001 PEER REVIEW The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1002/hon.3136. [Extracted from the article]

Richter's Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases. Richter's Transformation is a treatment-resistant and fatal progression from Chronic Lymphocytic Leukemia (CLL) to an aggressive lymphoma. Here, the authors show that PRMT5 is upregulated months prior to and after transformation, PRMT5 overexpression in a CLL mouse model leads to increased risk of transformation, and that targeted PRMT5 inhibition prolongs survival and delays disease development. [ABSTRACT FROM AUTHOR]

Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen, and liver. Their nomenclature refers to their usual clinical presentation and predilection for specific anatomic sites—i.e. extranodal NK/T-cell lymphoma, nasal-type, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas, indolent lymphoproliferative disorders of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma. Extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities range from indolent to highly aggressive diseases. Here, we will review the clinicopathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on the changes introduced in the 2022 International Consensus Classification of lymphoid neoplasms, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is an aggressive and heterogenous group of diseases and the most common subtype of non-Hodgkin lymphoma. In the past decade, there has been an explosion in molecular profiling that has helped to identify subgroups and shared oncogenic driving mechanisms. Since the 2017 World Health Organization (WHO) classification, additional studies investigating these genomic abnormalities and phenotypic findings have been reported. Here we review these findings in DLBCL and address the proposed changes by the 2022 International Consensus Classification. [ABSTRACT FROM AUTHOR]

Lymphoproliferative neoplasms of uncertain biological significance are increasingly encountered due to widespread usage of immunophenotypic and molecular techniques. Considering that clearer biological criteria and patient management have been established for B-cell lymphoproliferative diseases of undetermined significance occurring in the peripheral blood, many issues are still obscure for early lesions detected in lymphoid tissues. Regardless that some categories of lymphoproliferative neoplasms of uncertain biological significance have been recognized by the 4th edition of the WHO, other anecdotal early lymphoproliferative lesions still remain fully undefined. Some early lesions frequently originate from the germinal center, including atypical germinal centers BCL2-negative, an early pattern of large B-cell lymphoma with IRF4 rearrangement, and "in situ" high-grade B lymphomas. Moreover, other early lymphoproliferative lesions arise outside the germinal center and include those developing within the setting of monocytoid B-cell hyperplasia, but they also can be directly or indirectly associated with chronic inflammations. This review aims to summarize the concepts discussed during the IV Workshop organized by the Italian Group of Hematopathology, focus on the state-of-the-art on B-cell lymphoproliferative neoplasms of uncertain biological significance, and offer operative insights to pathologists and clinicians in routine diagnostics. [ABSTRACT FROM AUTHOR]

The T‐cell Lymphoma Project is an international registry prospective study that enrolled patients with newly diagnosed peripheral T‐cell and NK‐cell lymphomas (PTCL). The main objective was to define the clinical features and outcomes, establishing a robust benchmark for future clinical trials. Seventy‐four institutions from 14 countries in North America, South America, Europe, and Asia collected data on patients diagnosed and treated at their respective centers between September 2006 and February 2018. Among 1553 PTCL patients, 131 (8.4% of the total cohort) were confirmed to have anaplastic large cell lymphoma ‐ kinase positive (ALCL, ALK+). The median age of the patients was 39 years (18–84). Sixty‐five patients (66%) had advanced‐stage disease, although majority (45 patients, 54%) had a low‐risk International Prognostic Index (IPI) score (0–1). Of 97 patients treated with chemotherapy, 97% received anthracycline‐containing regimens. The overall response rate was 81%, with 69 patients (70%) achieving complete remission. Estimated OS and PFS at 3 years were 77% (95% CI: 54%–99%) and 68% (95% CI: 46%–90%), respectively, and at 5 years were very similar, 77% of OS (95% CI: 62%–92%) and 64% of PFS (95% CI: 34%–94%). Multivariate analysis for PFS showed advanced stage (hazard ratios [HR]: 4.72, 95% CI: 1.43–23.9, p = 0.015), elevated lactate dehidrogenade (LDH) (HR 4.85; 95% CI: 1.73–13.60, p = 0.001), and Eastern Cooperative Oncology Group Performance Status scale (ECOG‐PS) ≥2 (HR: 5.25; 95% CI: 1.68–16.4, p = 0.024). For OS, elevated LDH (HR: 3.77; 95% CI: 1.98–14.17, p = 0.014) and ECOG‐PS ≥2 (HR: 4.59; 95% CI: 1.46–14.39, p = 0.004) were identified. In summary, although the outcome of ALK+ ALCL is superior to that of other PTCLs, it remains sufficiently favorable, given the young median age of the patients. Our results confirm the usefulness of both IPI and Prognostic Index for T‐cell Lymphoma (PIT) in identifying groups of patients with different outcomes. Clinical Trials ID: NCT01142674. [ABSTRACT FROM AUTHOR]

This document is a correction notice for an article titled "Mediastinal large B cell lymphoma and surrounding gray areas: a report of the lymphoma workshop of the 20th meeting of the European Association for Haematopathology." The correction addresses an error in the author's name, which was incorrectly written as "Stefan Docjinov" instead of "Stefan Dojcinov." The original article has been corrected. The publisher, Springer Nature, remains neutral regarding jurisdictional claims and institutional affiliations. The article was authored by Sarah E. Gibson, Stefan Dojcinov, Snjezana Dotlic, Sylvia Hartmann, Eric D. Hsi, Monika Klimkowska, Federica Melle, Stefano A. Pileri, Colleen A. Ramsower, Karen Rech, Lisa M. Rimsza, Socorro Maria Rodriguez‑Pinilla, Thomas A. Tousseyn, Daphne de Jong, and Elena Sabattini. [Extracted from the article]

Summary: The prognostic role of TP53 disruption has been established in diffuse large B‐cell lymphoma (DLBCL). Aim of this analysis was to correlate TP53 mutations by Sanger sequencing, cell of origin (COO) profile by Lymph2Cx panel on the NanoString platform and MYC, BCL2 and BCL6 overexpression or re‐arrangements by immunohistochemistry (IHC) and fluorescent in‐situ hybridization (FISH), with outcome in DLBCL patients enrolled into the FIL‐DLCL04 trial (NCT00499018). One hundred and twenty‐five DLBCL patients with tumour block available were analyzed. TP53 was mutated in 11/125 (9%) cases; 60/125 patients received high‐dose chemoimmunotherapy up‐front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B‐cell like, 25 activated B‐cell like and 17 unclassified; 26 patients were double expressors in IHC and 11 double hit in FISH. After a median follow‐up of 72 months, five‐year failure‐free survival (FFS) for TP53 mutated versus wild‐type was 24% and 72%, and five‐year overall survival (OS) was 34% and 83%, respectively. Adjusted hazard ratio (HR) was 2·28 [95% confidence interval (CI) 0·89–5·86, p = 0·086] and 4·05 (95% CI 1·37–11·97, p = 0·011) for FFS and OS, respectively. In this series of young DLBCL patients, TP53 gene mutation identified a poor prognosis subgroup, regardless of treatment and other biological markers. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent type of non-Hodgkin lymphoma. Globally, DLBCL is an aggressive disease, requiring an accurate diagnosis and prompt treatment. The diagnosis is often made on biopsy samples of a nodal mass, however, approximately 40% of DLBCL cases arise at extranodal sites. The most common extranodal site is the gastrointestinal tract, however any extranodal area may be primarily involved. Primary urinary bladder lymphoma represents only 0.2% of extranodal non-Hodgkin lymphomas, whereas secondary involvement of the urinary bladder by a systemic lymphoma is a more common event. Despite being rare, DLBCL is considered to represent the predominant primary urinary bladder lymphoma. The majority of cases reported in the bladder belong to the DLBCL, NOS group, and there are only rare cases of EBV-positive DLBCL, NOS. In this review, we summarize the current knowledge on DLBCL primarily occurring in the urinary bladder, with the aim of increasing clinician and pathologist awareness on this aggressive lymphoma rarely arising in the urinary bladder. Additionally, we focus on those entities which should be taken into consideration in the differential diagnosis, highlighting potential diagnostic pitfalls. [ABSTRACT FROM AUTHOR]

Motivation Accurate classification of somatic variants in a tumor sample is often accomplished by utilizing a paired normal tissue sample from the same patient to enable the separation of private germline mutations from somatic variants. However, a paired normal sample is not always available, making a reliable somatic variant calling more challenging. In silico screening of variants against public or private databases and other filtering approaches are often used in absence of a paired normal sample. Nevertheless, difficulties in performing a tumor-only calling with sufficient accuracy and lack of open-source software have limited their applications in clinical research. Results To address these limitations, we developed TOSCA, the first automated tumor-only somatic calling workflow in whole-exome sequencing and targeted panel sequencing data which performs an end-to-end analysis from raw read files, via quality checks, alignment and variant calling to functional annotation, databases filtering, tumor purity and ploidy estimation and variant classification. Application of our workflow to tumor-only data provides estimates of somatic and germline variants that are consistent with results from paired analyses. Availability and implementation TOSCA is a Snakemake-based workflow and freely available at https://github.com/mdelcorvo/TOSCA. Supplementary information Supplementary data are available at Bioinformatics Advances online. [ABSTRACT FROM AUTHOR]

Patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL) have a poor prognosis, with an expected survival of less than 1 year using standard salvage therapies. Recent advances in our understanding of the biology of PTCL have led to identifying B-Cell Lymphoma 2 (BCL2) protein as a potential therapeutic target. BLC2 inhibitor venetoclax was investigated in a prospective phase II trial in patients with BCL2-positive R/R PTCL after at least one previous standard line of treatment (NCT03552692). Venetoclax given alone at a dosage of 800 mg/day resulted in one complete response (CR) and two stable diseases (SDs) among 17 enrolled patients. The majority of patients (88.2%) interrupted the treatment due to disease progression. No relationship with BCL2 expression was documented. At a median follow-up of 8 months, two patients are currently still on treatment (one CR and one SD). No case of tumor lysis syndrome was registered. Therefore, venetoclax monotherapy shows activity in a minority of patients whose biological characteristics have not yet been identified. Clinical Trial Registration: www.clinicaltrials.gov (NCT03552692, EudraCT number 2017-004630-29). [ABSTRACT FROM AUTHOR]

Mantle cell lymphoma (MCL) shows a clinical aggressiveness that varies from patient to patient. Despite major advances in outcomes with current immunochemotherapy, the future development of therapies requires risk stratification to tailor therapy intensity. Within the group of reference pathologists for the ongoing trials of the European MCL Network, we performed a round robin test on a tissue microarray to evaluate the reproducibility in assessing the biomarkers of outcome in MCL. Cytological subtype, Ki67-index and expression of p53 and SOX11 were evaluated on 20 diagnostic tumour samples by eight participating labs independently. We demonstrate that the assessment of the proliferation index by counting the Ki67 positive cells as well as assessment of SOX11 and p53 expression status is reproducible between labs. For the most established prognostic biomarker, Ki67, the intra-class correlation coefficient was very good when assessed as a continuous parameter (0.87). The agreement was lower when the values were analysed in a dichotomized way applying the commonly used cutoff of 30% (kappa = 0.65, complete concordance of all labs in 13/20 (65%)). Cases with discrepant results between labs in the dichotomized analysis showed mean values close to the cutoff of 30%. Centralised scoring and digital image analysis revealed results in line with the scores from individual labs. All cases in our cohort were additionally assessed for gene expression signatures and of TP53 gene alterations. Given the good reproducibility when guidelines of assessment are applied, the biomarker studied in this inter-laboratory test presents potential candidates to be enhanced for risk-stratification in the future clinical trials. [ABSTRACT FROM AUTHOR]

A percentage of celiac disease (CD) patients develop refractory type-2 disease (RCD2), a condition associated with increased risk of enteropathy-associated T-cell-lymphoma (EATL) and without therapeutic option. Therefore, we profiled the miRNome in series of peripheral T-cell lymphomas (PTCLs), CD, RCD1 or 2 and in the murine interleukin-15 (IL15)-transgenic (TG) model of RCD. The transcriptome was analyzed in 18 intestinal T-cell lymphomas (ITLs). Bioinformatics pipelines provided significant microRNA (miRNA) lists and predicted targets that were confirmed in a second set of patients. Our data show that ITLs have a unique miRNA profile with respect to other PTCLs. The c-MYC regulated miR-17/92 cluster distinguishes monomorphic epitheliotropic ITL (MEITL) from EATL and prognosticates EATL outcome. These miRNAs are decreased in IL15-TG mice upon Janus kinase (JAK) inhibition. The random forest algorithm identified a signature of 38 classifier miRNAs, among which, themiR-200 and miR-192/215 families were progressively lost in RCD2 and ITL-CD, whereas miR-17/92 and C19MCmiRNAs were up-regulated. Accordingly, SMAD3, MDM2, c-Myc and activated-STAT3 were increased in RCD2 and EATL tissues while JAK inhibition in IL15-TG mice restored their levels to baseline. Our data suggest that miRNAs circuit supports activation of STAT3 and c-Myc oncogenic signaling in RCD2, thus contributing to lymphomagenesis. This novel understanding might pave the way to personalized medicine approaches for RCD and EATL. [ABSTRACT FROM AUTHOR]

Among classical exemplifications of tumor microenvironment (TME) in lymphoma pathogenesis, the "effacement model" resembled by diffuse large B cell lymphoma (DLBCL) implies strong cell autonomous survival and paucity of non-malignant elements. Nonetheless, the magnitude of TME exploration is increasing as novel technologies allow the high-resolution discrimination of cellular and extra-cellular determinants at the functional, more than morphological, level. Results from genomic-scale studies and recent clinical trials revitalized the interest in this field, prompting the use of new tools to dissect DLBCL composition and reveal novel prognostic association. Here we revisited major controversies related to TME in DLBCL, focusing on the use of bioinformatics to mine transcriptomic data and provide new insights to be translated into the clinical setting. [ABSTRACT FROM AUTHOR]

The aim of this study was to review the histopathological, phenotypic, and molecular characteristics of pediatric-type follicular lymphoma (PTFL) and to assess the diagnostic value of novel immunohistochemical markers in distinguishing PTFL from follicular hyperplasia (FH). A total of 13 nodal PTFLs were investigated using immunohistochemistry, fluorescence in situ hybridization (FISH), and PCR and were compared with a further 20 reactive lymph nodes showing FH. Morphologically, PTFL cases exhibited a follicular growth pattern with irregular lymphoid follicles in which the germinal centers were composed of numerous blastoid cells showing a starry-sky appearance. Immunohistochemistry highlighted preserved CD10 (13/13) and BCL6 (13/13) staining, CD20 (13/13) positivity, a K light chain predominance (7/13), and partial BCL2 expression in 6/13 cases (using antibodies 124, E17, and SP66). The germinal center (GC)-associated markers stathmin and LLT-1 were positive in most of the cases (12/13 and 12/13, respectively). Interestingly, FOXP-1 was uniformly positive in PTFL (12/13 cases) in contrast to reactive GCs in FH, where only a few isolated positive cells were observed. FISH revealed no evidence of BCL2, BCL6, or MYC rearrangements in the examined cases. By PCR, clonal immunoglobulin gene rearrangements were detected in 100% of the tested PTFL cases. Our study confirmed the unique morphological and immunophenotypic features of PTFL and suggests that FOXP-1 can represent a novel useful diagnostic marker in the differential diagnosis between PTFL and FH. [ABSTRACT FROM AUTHOR]

Tumors derived from histiocytic and dendritic cells encompass a large and heterogeneous group of neoplastic and reactive conditions, and their diagnosis is challenging both for pathologists and clinicians. Diagnosis is based on morphological and phenotypical findings, but hybrid features are not uncommon. Furthermore, recent studies uncovered the molecular mechanisms driving some of these tumors, improving diagnostic adequacy, and providing the basis for effective therapeutic breakthroughs.Sixty-seven cases were submitted to the accessory cell and histiocytic neoplasms session at the European Association of Haematopathology/Society for Hematopathology workshop 2016 held in Basel, Switzerland. The cases included histiocytic sarcomas (HS), Langerhans cell tumors (LCT), Erdheim-Chester disease, interdigitating dendritic cell sarcomas (IDCS), indeterminate dendritic cell tumors (IND-DCT), follicular dendritic cell sarcomas, and blastic plasmacytoid dendritic cell neoplasms. Rosai-Dorfman disease and, more rare, conditions such as ALK-positive histiocytosis were also submitted. These cases illustrated classical and unexpected features at morphological, phenotypical, and molecular levels, providing a valuable compendium for pathologists confronting with these tumors.The paper summarizes the most notable features of every single group of diseases, with comments about the most challenging issues, in the attempt to provide practical indications for their recognition. [ABSTRACT FROM AUTHOR]

Mycosis fungoides (MF) is characterized by a switch from indolent behaviour in the early stages to a worse clinical outcome in the advanced ones. Recently, various studies have investigated the role the microenvironment might play in such a switch. We have analysed the distribution of Langerhans cells, plasmacytoid dendritic cells and myeloid-derived suppressor cells in 46 MF cases in various stages, aiming to assess whether changes occur from early to advanced stage. We have investigated the number of langerin, CD303 and arginase-1 positive cells and their distribution at high power. Data were analysed using t test for continuous variables, χ 2 tests or Fisher's exact test for categorical variables, as well as analysis of covariance. In comparing stages IA/B to IIB, we observed a significant decrease in Langerhans cells (p value 0.03) and a significant increase in CD303 and arginase-1 positive cells (p value <0.01 for both markers). Furthermore, a significant increase in Langerhans cells only was observed in stage IIB in comparison to stage III (p = 0.02), while in stage IV, a significant decrease in Langerhans cells was noted in comparison to stage III (p = 0.02). Our data suggest that changes in the microenvironment might influence disease progression, especially from stages IA/B to IIB, opening new scenarios in MF therapy. [ABSTRACT FROM AUTHOR]

The article offers information on analysing public datasets containing whole exome sequencing data from multiple studies on mature lymphoid B cell malignancies using the cBioportal website analysis tool, focusing on genomic alterations of ribosomal protein genes and the TP53 gene; and mentions that genomic alterations of ribosomal proteins (RPs) occurred at low frequency in 4 percent of analysed samples.

Granulysin is a cytolytic protein expressed in cytotoxic T and natural killer (NK) cells. Abnormal serum levels of granulysin in lymphomas with NK and cytotoxic phenotype have been shown to correlate with tumour progression. In this study, we investigated the expression pattern of granulysin in routine sections of normal and reactive lymphoid tissues as well as in a large series of lymphomas. In normal tissues, granulysin labelled a small population of cells that double immunostaining revealed to belong to the pool of cytotoxic T/NK cells. Among lymphoid neoplasms, the highest expression of granulysin (71%) was found in extranodal NK/T cell lymphomas of nasal type (ENKTL). To note is that 29% of ENKTLs, which were negative for one or more of classical cytotoxic markers strongly expressed granulysin. Furthermore, expression of granulysin was observed in rare cases of T cell lymphomas with a cytotoxic phenotype (i.e. ALK-negative anaplastic large cell lymphoma (26%), enteropathy-associated T cell lymphoma (12%) and peripheral T cell lymphoma, NOS (4%)). None of the investigated non-Hodgkin B cell lymphomas, Hodgkin lymphoma and plasma cell myeloma were granulysin positive. The results suggest granulysin as a novel marker for a subset of cytotoxic NK cell derived malignancies and its usefulness is highlighted in those ENKTLs that lack expression of other cytotoxic markers but retain granulysin expression. [ABSTRACT FROM AUTHOR]

We investigated panobinostat 40 mg three times weekly in 35 adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Overall response rate and complete response were 17.1% and 11.4%, respectively. Median progression-free survival (PFS) and overall survival were 2.4 and 7.6 months, respectively. Calculated 12, 24 and 36 months PFS were 26%, 11% and 11%, respectively. Four patients who achieved a sustained CR, continued receiving panobinostat for an overall period of 44, 48, 50, 62 months. Thrombocytopenia grade 3 (5 patients) and 4 (24 patients) represented the main toxic effect, causing dose reduction or treatment suspension in 19 patients. Genomic analysis was unable to identify any relationship between mutations and response; TP53 mutation appeared not to impact the clinical outcome. Overall, panobinostat has a modest activity in R/R DLBCL patients, however it can induce very long lasting responses in some cases. Thrombocytopenia frequently limits the use of this agent. [ABSTRACT FROM AUTHOR]

Identify a subset of early-stage HL children (GR1) curable with limited chemotherapy+/-radiotherapy; improve outcome of intermediate (GR2) and high-risk (GR3) patients; establish impact of response to chemotherapy evaluated with conventional imaging (CI). One hundred and sixty GR1-patients received 3ABVD + involved-field (IF) low-dose (LD) (20 Gy) irradiation if mediastinal mass or partial response (PR) after chemotherapy. Eighty-five GR2- and 315 GR3-patients received 4 and 6 COPP/ABV + IFRT, respectively. The 63 GR1 patients spared from radiotherapy had 15-year survival and EFS of 100 and 84.5%, respectively. The GR2 and GR3 15-year FFP were 84.7 and 78.6%, respectively. No different prognosis for patients in CR or PR evaluated during and after chemotherapy was observed. In conclusion, low-risk patients in CR may be successfully treated with radiation-free, low-intensity chemotherapy. Good, but less satisfactory, results were registered in GR2 and GR3. Response evaluated with CI is not a prognostic factor, but permits identification of low-risk patients who can avoid radiotherapy. [ABSTRACT FROM AUTHOR]

Keywords: BPDCN; discriminant analysis; miRNAs; MS EN BPDCN discriminant analysis miRNAs MS 831 833 3 12/31/20 20201201 NES 201201 Blastic plasmacytoid dendritic cell neoplasm (BPDCN) and myeloid sarcoma (MS) are two rare hematological neoplasms, both stemming from a myeloid precursor undergoing divergent malignant transformation.1 They can primarily present in the skin, with or without extramedullary organ involvement and leukemic dissemination, and are characterized by a highly aggressive clinical course with dismal prognosis (overall survival 12-14 months).1 Possibly due to their rareness, BPDCN and MS still show unexplored biological facets and lack a standardized therapeutic approach, thus justifying their inclusion among orphan tumors. To evaluate the impact of these differentially expressed miRNAs on the BPDCN transcriptional program and determine miRNA-genes regulatory pathways potentially contributing to BPDCN pathogenesis, we performed a functional network analysis. Interestingly, we found that in BPDCN respect to MS the I TP53 i signaling may be inhibited by miRNAs upregulated while the dysregulation of the intrinsic apoptotic pathway may be due to lower miRNAs expression level. [Extracted from the article]

Germinotropic lymphoproliferative disorders were previously described as localized disorders associated with coinfection by human herpes virus 8 and Epstein-Barr virus and characterized by good clinical outcome. We report the clinical, morphological, phenotypical, and molecular features of three cases of a hitherto unreported variant of Epstein-Barr virus (EBV)-positive, human herpes virus 8 (HHV8)-negative large B cell lymphoma with exclusive intrafollicular localization. All cases occurred in elderly individuals (63, 77, and 65 years old; one male, two females) without obvious immunedeficiency, who presented with high stage disease. Lymph nodes showed an effaced nodular architecture with abnormal B follicles colonized by EBV+ large, pleomorphic atypical cells, including Reed-Sternberg-like cells, showing an activated B cell phenotype (CD10-FOXP1-Bcl6-IRF4+ or CD10-FOXP1+Bcl6+IRF4+) and intense expression of CD30. No monoclonal light-chain restriction was detected by immunohistochemistry or in situ hybridization, and IGH rearrangement was polyclonal; notably, EBV clonality was detectable in one case. Lymphoma cells in all cases showed diffuse expression of the c-Myc protein, while Bcl2 was dim or negative; moreover, the strong expression of phosphorylated-STAT3 in tumor cell nuclei suggested activation of the JAK-STAT pathway. FISH analysis was performed in two cases and showed no translocations of BCL2, BCL6, MYC, and PAX5 genes. Response to treatment was poor in 2/3 patients: one died after 18 months, one is alive with disease after 12 months. The intrafollicular EBV-positive large B cell lymphoma expands the spectrum of EBV-associated lymphoproliferative disorders in immunocompetent individuals. [ABSTRACT FROM AUTHOR]

Summary: Different models to investigate the prognosis of peripheral T cell lymphoma not otherwise specified (PTCL‐NOS) have been developed by means of retrospective analyses. Here we report on a new model designed on data from the prospective T Cell Project. Twelve covariates collected by the T Cell Project were analysed and a new model (T cell score), based on four covariates (serum albumin, performance status, stage and absolute neutrophil count) that maintained their prognostic value in multiple Cox proportional hazards regression analysis was proposed. Among patients registered in the T Cell Project, 311 PTCL‐NOS were retained for study. At a median follow‐up of 46 months, the median overall survival (OS) and progression‐free survival (PFS) was 20 and 10 months, respectively. Three groups were identified at low risk (LR, 48 patients, 15%, score 0), intermediate risk (IR, 189 patients, 61%, score 1–2), and high risk (HiR, 74 patients, 24%, score 3–4), having a 3‐year OS of 76% [95% confidence interval 61–88], 43% [35–51], and 11% [4–21], respectively (P < 0·001). Comparing the performance of the T cell score on OS to that of each of the previously developed models, it emerged that the new score had the best discriminant power. The new T cell score, based on clinical variables, identifies a group with very unfavourable outcomes. [ABSTRACT FROM AUTHOR]

Summary: In the mantle cell lymphoma (MCL)‐002 study, lenalidomide demonstrated significantly improved median progression‐free survival (PFS) compared with investigator's choice (IC) in patients with relapsed/refractory MCL. Here we present the long‐term follow‐up data and results of preplanned subgroup exploratory analyses from MCL‐002 to evaluate the potential impact of demographic factors, baseline clinical characteristics and prior therapies on PFS. In MCL‐002, patients with relapsed/refractory MCL were randomized 2:1 to receive lenalidomide (25 mg/day orally on days 1–21; 28‐day cycles) or single‐agent IC therapy (rituximab, gemcitabine, fludarabine, chlorambucil or cytarabine). The intent‐to‐treat population comprised 254 patients (lenalidomide, n = 170; IC, n = 84). Subgroup analyses of PFS favoured lenalidomide over IC across most characteristics, including risk factors, such as high MCL International Prognostic Index score, age ≥65 years, high lactate dehydrogenase (LDH), stage III/IV disease, high tumour burden, and refractoriness to last prior therapy. By multivariate Cox regression analysis, factors associated with significantly longer PFS (other than lenalidomide treatment) included normal LDH levels (P < 0·001), nonbulky disease (P = 0·045), <3 prior antilymphoma treatments (P = 0·005), and ≥6 months since last prior treatment (P = 0·032). Overall, lenalidomide improved PFS versus single‐agent IC therapy in patients with relapsed/refractory MCL, irrespective of many demographic factors, disease characteristics and prior treatment history. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post-thymic lymphoid cells at different stages of differentiation with different morphological patterns, phenotypes and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub-classified using World Health Organization (WHO) 2008 criteria. In 2006 the International T-Cell Lymphoma Project launched the T-Cell Project, building on the retrospective study previously carried on by the network, with the aim to prospectively collect accurate data to improve knowledge on this group of lymphomas. Based on previously published reports from International Study Groups it emerged that rendering a correct classification of PTCLs is quite difficult because the relatively low prevalence of these diseases results in a lack of confidence by most pathologists. This is the reason why the T-Cell Project requested the availability of diagnostic material from the initial biopsy of each patient registered in the study in order to have the initial diagnosis centrally reviewed by expert hematopathologists. In the present report the results of the review process performed on 573 cases are presented. Overall, an incorrect diagnosis was centrally recorded in 13.1% cases, including 8.5% cases centrally reclassified with a subtype eligible for the project and 4.6% cases misclassified and found to be disorders other than T-cell lymphomas; 2.1% cases were centrally classified as T-Cell disorders not included in the study population. Thus, the T-Cell Project confirmed the difficulties in providing an accurate classification when a diagnosis of PTCLs is suspected, singled out the major pitfalls that can bias a correct histologic categorization and confirmed that a centralized expert review with the application of adequate diagnostic algorithms is mandatory when dealing with these tumours. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

B-cell lymphomas encompass a large number of disease entities clinically ranging from indolent to aggressive. The defining pathological features usually predict clinical course, with small and large B-cell lymphomas correlating to low-grade vs high-grade features, but discordant situations may be encountered. Two sessions of the workshop of the XVIII meeting of the European Association for Haematopathology (EAHP) held in Basel in 2016 addressed this topic. One session illustrated various facets of 'aggressiveness' in indolent lymphomas, either peculiar clinical manifestations, cytological variants, or unusual genetic features, as well as several examples of progression or transformation to a more aggressive disease. Another session exemplified large B-cell lymphomas with unexpected indolent behavior including cases arising in well-defined body compartments or in sanctuary sites. This paper describes the features of the cases presented in both groups, highlights the most salient points of discussion raised by the submitters and the panel, and summarizes current knowledge and recommendations relevant to diagnostic pathology practice. [ABSTRACT FROM AUTHOR]

Our understanding of mature aggressive B cell lymphomas has evolved significantly in the last years as reflected in the 2016 update of the WHO lymphoma classification. A main topic of the 2016 European Association for Haematopathology/Society of Hematopathology lymphoma workshop in Basel therefore was the clinicopathological spectrum of mature aggressive B cell lymphomas with the exception of conventional diffuse large B cell lymphoma. In this review, we summarize two sessions dedicated to "high-grade B cell lymphomas, with MYC and BCL2 and/or BCL6 rearrangements (so-called double/triple-hit lymphomas)" and "high-grade B cell lymphomas, NOS" as defined in the 2016 update of the WHO lymphoma classification, Burkitt lymphoma and related neoplasms, and terminally differentiated aggressive B cell lymphomas. One focus was on cases of Burkitt lymphoma with unusual clinical features such as spontaneous regression or association with immunosuppression, and the new provisional category of Burkitt-like lymphoma with 11q aberration. The large numbers of cases submitted for the new high-grade categories with or without genetic "double/triple hit" demonstrated the broad clinical and pathological spectrum of this group and gave ample opportunity for discussion. In this review, current definitions and our understanding of the main high-grade categories, potential problem areas, and suggestions for the immunophenotypic and genetic work-up of these neoplasms are discussed and illustrated by many interesting and challenging cases submitted to the workshop. [ABSTRACT FROM AUTHOR]

Aims Glycogen synthase kinase-3 beta ( GSK-3β) is a serine/threonine kinase involved in glycogen metabolism, cell cycle progression, differentiation, embryogenesis, migration, metabolism, survival and cellular senescence. Its main biological function is to inhibit β-catenin by sequestration and promotion of its proteasomal degradation in the Wnt canonical pathway; however, GSK-3β interacts with multiple signalling pathways, and aberrant expression of the enzyme was reported in many solid neoplasms. This study aimed to investigate the biological relevance of GSK-3β in classical Hodgkin lymphomas (cHL). Methods and results We analysed the functional status of GSK-3β enzyme in cHL by using antibodies raised against fixation-resistant epitopes of phospho Y216 GSK-3β (active form), phospho S9 GSK-3β (inactive form) and β-catenin protein. We first detected the pY216 GSK-3β active form of the enzyme in 100 of 100 (100%) of the cases, and in line with the latter expression profile, the β-catenin protein was found in only 12 of 100 (12%) of the samples. As reported previously in bladder cancer, pancreatic adenocarcinoma and chronic lymphocytic leukaemia, we showed an aberrant nuclear localization in the neoplastic clone of active pY216 GSK-3β in 78 of 100 (78%) of cHL cases. Conclusions We demonstrated the activation of GSK-3β in cHL resulting in inhibition of the Wnt/β-catenin signal cascade and the aberrant accumulation of its activated form in nuclei of Hodgkin Reed-Sternberg and Hodgkin cells. These findings may be relevant for future clinical studies, identifying GSK-3β as a potential therapeutic target for cHL. [ABSTRACT FROM AUTHOR]

Aims A new subtype of granzyme B (GrB)-producing regulatory B cells (Bregs) has been described recently; these peculiar cytotoxic B cells are increased significantly in interleukin ( IL)-21-rich settings, and in particular during HIV and Epstein-Barr virus ( EBV) infection. Our aim is to report a unique case of an EBV-positive diffuse large B cell lymphoma ( DLBCL) with cytotoxic features arisen in an HIV+ patient, and to understand if this lesion may represent a proliferation of neoplastic cytotoxic Bregs. Methods and results We describe a 66-year-old male patient who presented with cervical lymph node enlargement and B symptoms; subsequently, HIV infection was diagnosed. Histopathological, immunohistochemical and molecular studies were performed, and revealed an EBV-positive DLBCL with cytotoxic features. Considering the immunological setting and unconventional phenotype observed, we tried to evaluate further the expression of GrB and IL-21 in another 150 aggressive B cell lymphomas (17 of 150 EBV+, two of 150 EBV+/ HIV+). Minimal dot-like expression of GrB was found in seven lymphomas (in fewer than 1% of tumour cells), three of which were EBV-positive. Conclusions Breg origin has never been reported in B cell lymphomas. We describe an exceptional case of EBV-positive DLBCL with aberrant expression of cytotoxic markers in a patient with a previously unknown HIV infection. We propose cytotoxic Bregs as a possible normal counterpart for this unusual tumour. [ABSTRACT FROM AUTHOR]

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non--catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support a driver oncogenic role for VAV1 signaling in the pathogenesis of PTCL. [ABSTRACT FROM AUTHOR]