Background: The important diagnostic challenge facing the cytopathologist is whether a mesothelial proliferation on effusions represents a malignant mesothelioma (MM) or a benign mesothelial hyperplasia (MH). Here, we evaluated the diagnostic utility of BAP1 immunohistochemistry (IHC) in distinguishing between reactive and neoplastic mesothelial cells. Methods:In pleural and peritoneal effusions from 147 patients with diagnosed MM or with a differential diagnosis of MM and MH, the expression of BAP1 was examined by IHC on paraffinembedded cell blocks (n 5 121) and biopsies (n 5 44). Included were also synchronous and methacronous cytology/biopsy pair samples. BAP1 IHC was evaluated for nuclear staining as positive or negative on target mesothelial cells, with appropriate internal control.Results: In MM cases, loss of BAP1 nuclear staining was observed in 76.5% of the cell blocks and 47.5% of the biopsies. All BAP1-negative cases with a differential diagnosis of benign and malignant mesothelial proliferations were MM at follow-up. All MH cases, the 29% of epithelial MM and the 90% of nonepithelial MM, retained BAP1 expression. Synchronous and methacronous biopsy/cytology pairs showed matching BAP1 results. Conclusion:In effusions with mesotheliomatous cells or atypical mesothelial cells of uncertain significance, negative BAP1 IHC strongly supports a diagnosis of MM. With prudence in interpreting immunostaining, BAP1 may be included in IHC panels for MM cytodiagnosis, given its high specificity and sensitivity. 1 An effusion is the only available sample in specific settings, as in the elderly or in patients with co-morbidities. Based on cytomorphology alone, the differential diagnosis between MM, mesothelial hyperplasia (MH), and metastatic carcinoma may be difficult. It is necessary to use ancillary techniques, primarily immunohistochemistry (IHC). 1 IHC markers to distinguish epithelioid MM from metastatic carcinoma are well-defined, 2,3 whereas those to distinguish epithelioid MM from MH are less definite, except for GLUT-1, IMP-3, Desmin, and EMA. Regarding the practical utility of the latter two markers, Desmin shows low sensitivity 4 and EMA shows low specificity. 5-7Recently, a new marker has been proposed to aid in distinguishing MM from MH, namely BRCA1-associated protein 1 (BAP1 The aim of this study was to evaluate the utility of BAP1 IHC in the diagnosis of MM in effusions. To do this, we investigated the BAP1 protein expression on a large series of cell blocks from pleural/peritoneal effusions, with a definite diagnosis of MM or an uncertain diagnosis between MM and MH, and benign effusions. BAP1 immunostaining was also performed on biopsy samples with the same diagnoses to evaluate the differences between effusion and tissue samples. | M A TE RI A L S A ND M E TH ODSThis study was designated as exempt by the ethics committee due to its retrospective nature; moreover, no protected health information The following formulae of BAP1 testing for the outcome MM were calculated: sensitivity, defined as ...

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BACKGROUND Primary effusion lymphoma (PEL) is a very rare non‐Hodgkin lymphoma caused by human herpesvirus‐8 (HHV8) that grows in liquid phase within body cavities. The diagnosis of PEL is based on cytology but requires confirmatory ancillary tests. PEL occurs mainly in association with HIV infection. This study describes 9 cases of PEL in HIV‐negative patients and compares their characteristics with 10 HIV‐associated cases of PEL diagnosed at a single institution in Italy between 1995 and 2019. METHODS Clinical records were reviewed for demographic data, comorbidities, laboratory abnormalities, and outcome. PEL samples were evaluated for cytomorphology, immunophenotype, immunoglobulin (IG)/T cell receptor (TR) rearrangements, and HHV8 and Epstein‐Barr virus (EBV) viral loads in effusion supernatants. RESULTS HIV‐unrelated PEL occurred in 8 elderly patients (7 men, 1 woman) and 1 young adult with primary antibody deficiency. Cytology revealed HHV8‐positive lymphoma cells lacking B/T cell antigens and exhibiting 2 cell patterns (polymorphous or monotonous). IG was clonally rearranged in all cases; aberrant TRG occurred in 2 cases. Effusion supernatants had more than 106 HHV8 DNA copies per mL and variable loads of EBV DNA. Compared with HIV‐associated PEL, the HIV‐negative cohort was characterized by older age, less frequent association with Kaposi sarcoma and/or multicentric Castleman disease, comparable but less abnormal laboratory parameters, and a nonsignificant survival benefit. PEL cases with low apoptosis were associated with better prognosis. CONCLUSION To the best of our knowledge, our case series of HIV‐unrelated PEL is the largest thus far, expands the spectrum of cytological findings, and supports the need for a multidisciplinary approach in the diagnostic workup.

We report a family with domestic exposure to asbestos and multiple cancers, including eight pleural malignant mesotheliomas and several other lung/pleural tumors. DNA sequence analysis revealed no evidence for an inherited mutation of BAP1. Sequence analysis of other potentially relevant genes, including TP53, CDKN2A and BARD1, also revealed no mutations. DNA microarray analysis of two mesotheliomas revealed multiple genomic imbalances including consistent losses of overlappping segments in 2q, 6q, 9p, 14q, 15q and 22q, but no losses of chromosome 3 harboring the BAP1 locus. However, immunohistochemistry demonstrated loss of nuclear BAP1 staining in 3 of 6 mesotheliomas tested, suggesting that somatic alterations of BAP1 occurred in a subset of tumors from this family. Since mesothelioma could be confirmed in only a single generation, domestic exposure to asbestos may be the predominant cause of mesothelioma in this family. Given the existence of unspecified malignant pleural tumors and lung cancers in a prior generation, the possibility that some other tumor susceptibility or modifier gene(s) may contribute to the high incidence of mesothelioma in this family is discussed. Because the incidence of mesothelioma in this family is higher than expected even in heavily exposed asbestos workers, we conclude that both asbestos and genetic factors have played a role in the high rate of mesothelioma and potentially other pleural/lung cancers seen in this family.

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (n=1), and unknown (n=1). These family units without inheritance of a BAP1 predisposing mutation expand the number of unmutated germline BAP1 families with multiple mesothelioma cases. This suggests that besides the exposure to asbestos other currently unknown genetic or epigenetic factors may be responsible for the high incidence of mesothelioma in BAP1-unmutated families.

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Purpose Diffuse large B‐cell lymphoma (DLBCL) is an aggressive lymphoma often refractory to currently available treatments (immuno‐chemotherapy/autologous‐stem‐cell‐transplantation‐ASCT). Recently, new cell therapies have been approved for patients failing two conventional treatments, CAR‐T (Chimeric‐Antigen‐Receptor‐T‐cell), committing payers in planning and implementing their use. We aim to define, using Real World Data (RWD), a reproducible procedure that allows identification of CAR‐T target population for DLBCL. Methods Through the linking of electronic healthcare datasets (EHD), we identified patients with non‐Hodgkin's Lymphoma (NHL), resident in Lazio region (2010–2015), aged ≥20 years. DLBCL patients were followed using pathological anatomy (PA) reports, up to 3 years. To be defined as relapsed after two treatment lines, patients must have had new chemotherapy and/or NHL hospitalization after ASCT or at the end of the second chemotherapy. The incident rate of second relapse (R2‐rate) was extended to the population without PA reports. Result NHL incident patients were 7384, 68% presented a PA report and, 29% of these had DLBCL codes. Patients who relapsed after two treatment lines were 47 (39%) in the subgroup of patients who received ASCT and 138 (41%) in that with second chemotherapy treatment. Patients in the two subgroups were very different in terms of age and comorbidity. The annual incident number of DLBCL was estimated to be 329 which multiplied by R2‐rate (13.7%) gives 45 patients per year eligible for CAR‐T. Discussion This study shows how RWD allows the identification of a target population with new advanced therapies. This approach is rigorous, transparent and verifiable over time.