Mesothelioma in situ of the peritoneum: report of three cases and review of the literature.

AIM: Diagnosis of mesothelioma in situ (MIS) is historically controversial and, until recently, specific features defining the entity have not been well characterized. Most reported cases of MIS occurred in the pleura; peritoneal MIS is very rare. This study investigates the morphologic features and results of ancillary testing in peritoneal MIS. METHODS: We present three patients with peritoneal MIS, as defined by a single layer of mesothelial cells with loss of nuclear BRCA-1-associated protein-1 (BAP1) immunostaining and without evidence of invasive tumour by microscopic evaluation, imaging, or direct examination of the peritoneum. Histology and immunostains were reviewed by three expert thoracic pathologists with multidisciplinary input. Next-generation sequencing (NGS) was performed in all three cases. A literature review was conducted to characterize this rare precursor lesion. RESULTS: BAP1 was lost in all three lesions, while methylthioadenosine phosphorylase (MTAP) was retained in two (not performed in the third). NGS revealed BAP1 pathogenic alterations in all three cases as well as mutations of SMO, ERCC3, TET2, and U2AF1. Progression to invasive mesothelioma occurred in one patient at 13 months postdiagnosis (case 1). One patient was diagnosed at age 24 and was later found to harbour a BAP1 germline mutation (case 3). CONCLUSION: This work describes the histologic features and clinicopathologic characteristics of peritoneal MIS in three cases, highlights BAP1 somatic and germline mutations in peritoneal MIS, and strengthens the importance of ancillary studies (including immunohistochemical and molecular studies) in the diagnosis of MIS.

Usual interstitial pneumonia is the predominant histopathology in patients with systemic sclerosis receiving a lung transplant.

OBJECTIVES: Studies identifying nonspecific interstitial pneumonia (NSIP) as the predominant histopathology in systemic sclerosis-associated interstitial lung disease (SSc-ILD) have primarily utilised surgical lung biopsies in early disease. These case series may only reflect the histopathology of early disease and differ from the histopathology of advanced disease in those with respiratory failure. METHODS: Patients receiving a lung transplant for a diagnosis of SSc at a single centre from 2000-2021 were included for retrospective analysis. All explanted lungs underwent histopathology review as part of routine care. RESULTS: 127 patients with SSc received a native lung transplant during the study period. Usual interstitial pneumonia (UIP) was identified in 111 explants (87.4%), NSIP in 45 (35.4%) explants, organising pneumonia in 11 explants (8.7%), and lymphocytic bronchitis in 2 explants (1.6%). Areas of both UIP and NSIP were identified in 37 explants (29.1%), with only 9 explants (7.1%) showing neither UIP nor NSIP. Aspiration was identified on histology in 49 (38.6%) explants. Pathology results were available from a prior surgical lung biopsy for 19 patients, with 11 patients maintaining the same primary pathology on biopsy and explant (2 NSIP, 9 UIP) and 8 patients showing different pathology at the timepoints, all of whom had UIP on explant. Most patients (101, 79.5%) had evidence of pulmonary hypertension and vasculopathy on explant. CONCLUSIONS: UIP is the predominant histopathology in patients with SSc receiving a lung transplant, with many patients concurrently having both NSIP and UIP or showing progression from NSIP to UIP over time before transplant.

Preservation of Circumferential and Radial Left Ventricular Function as a Mitigating Mechanism for Impaired Longitudinal Strain in Early Cardiac Amyloidosis.

BACKGROUND: In patients with cardiac amyloidosis (CA), left ventricular ejection fraction (LVEF) is frequently preserved, despite commonly reduced global longitudinal strain (GLS). We hypothesized that nonlongitudinal contraction may initially serve as a mitigating mechanism to maintain cardiac output and studied the relationship between global circumferential (GCS) and radial (GRS) strain with LVEF and extracellular volume (ECV), a marker of amyloid burden. METHODS: Patients with CA who underwent cardiac magnetic resonance (CMR; n = 140, 70.7 ± 11.5 years, 66% male) or echocardiography (n = 67, 71 ± 13 years, 66% male) and normal controls (CMR, n = 20; echocardiography, n = 45) were retrospectively identified, and GCS, GLS, and GRS were quantified using feature-tracking CMR or speckle-tracking echocardiography and compared between CA patients with preserved and reduced LVEF (CAHFpEF, CAHFrEF) and controls. The prevalence of impaired strain (magnitudes <2.5th percentile of the controls) was compared between CAHFpEF and CAHFrEF and between ECV quartiles. RESULTS: While echocardiography-derived GLS was impaired in both CAHFpEF (-13.4% ± 3.1%, P < .003) and CAHFrEF (-9.1% ± 3.2%, P < .003), compared with controls (-20.8% ± 2.4%), GCS was more impaired in CAHFrEF compared with both controls (-15.6% ± 5.0% vs -32.3% ± 3.3%, P < .003) and CAHFpEF (-30.4% ± 5.7%, P < .003) and did not differ between CAHFpEF and controls (P = .24). The prevalence of abnormal CMR-derived GCS (P < .0001) and GRS (P < .0001) but not GLS (P = .054) varied significantly across ECV quartiles. CONCLUSIONS: Among CA patients with preserved LVEF, preserved GCS and GRS, despite near-universally impaired GLS, may be explained by an initial predominantly subendocardial involvement, where mostly longitudinal fibers are located. If confirmed in future studies, these findings may facilitate identification of patients with early stages of CA, when treatments may be most effective.

Updated Imaging Classification of Hypersensitivity Pneumonitis.

Hypersensitivity pneumonia (HP) refers to a heterogeneous group of interstitial lung diseases resulting from a non-IgE immune-mediated reaction to inhaled pathogens in susceptible and sensitized hosts. Environmental and genetic factors are important substrates of disease pathogenesis. A recurrent or ongoing airborne exposure results in activation of humoral and cellular immune responses. This article discusses key clinical, radiologic, and histopathologic features of HP and reviews current recommendations.

Uncertainty-informed deep learning models enable high-confidence predictions for digital histopathology.

A model's ability to express its own predictive uncertainty is an essential attribute for maintaining clinical user confidence as computational biomarkers are deployed into real-world medical settings. In the domain of cancer digital histopathology, we describe a clinically-oriented approach to uncertainty quantification for whole-slide images, estimating uncertainty using dropout and calculating thresholds on training data to establish cutoffs for low- and high-confidence predictions. We train models to identify lung adenocarcinoma vs. squamous cell carcinoma and show that high-confidence predictions outperform predictions without uncertainty, in both cross-validation and testing on two large external datasets spanning multiple institutions. Our testing strategy closely approximates real-world application, with predictions generated on unsupervised, unannotated slides using predetermined thresholds. Furthermore, we show that uncertainty thresholding remains reliable in the setting of domain shift, with accurate high-confidence predictions of adenocarcinoma vs. squamous cell carcinoma for out-of-distribution, non-lung cancer cohorts.

Highly aneuploid non-small cell lung cancer shows enhanced responsiveness to concurrent radiation and immune checkpoint blockade.

Over 500 clinical trials are investigating combination radiotherapy and immune checkpoint blockade (ICB) as cancer treatments; however, the majority of trials have found no positive interaction. Here we perform a comprehensive molecular analysis of a randomized phase I clinical trial of patients with non-small cell lung cancer (NSCLC) treated with concurrent or sequential ablative radiotherapy and ICB. We show that concurrent treatment is superior to sequential treatment in augmenting local and distant tumor responses and in improving overall survival in a subset of patients with immunologically cold, highly aneuploid tumors, but not in those with less aneuploid tumors. In addition, radiotherapy alone decreases intratumoral cytotoxic T cell and adaptive immune signatures, whereas radiotherapy and ICB upregulates key immune pathways. Our findings challenge the prevailing paradigm that local ablative radiotherapy beneficially stimulates the immune response. We propose the use of tumor aneuploidy as a biomarker and therapeutic target in personalizing treatment approaches for patients with NSCLC treated with radiotherapy and ICB.

Biphenotypic sinonasal sarcoma: Report of 3 cases with a review of literature.

Biphenotypic sinonasal sarcoma (BSNS) is a rare recently described distinct spindle cell sarcoma which arises exclusively in the sinonasal region and is characterized by concomitant neural and myogenic differentiation. Before this neoplasm was characterized, most were classified as other entities including adult fibrosarcoma, monophasic synovial sarcoma and malignant peripheral nerve sheath tumor. By immunohistochemistry, these tumors characteristically express S100 and smooth muscle actin (SMA) and/or muscle specific actin (MSA). Most cases harbor rearrangements of PAX3 (paired box gene 3), and the most frequent translocation partner is MAML3 (mastermind like transcriptional coactivator 3). Herein, we described three cases of BSNS involving the nasal cavity with or without paranasal sinus involvement. We also did a literature review of the clinical features, histologic and immunophenotypic findings, cytogenetics, pathogenesis and behavior of this rare entity.