Guidelines for pathologic diagnosis of mesothelioma: 2023 update of the consensus statement from the International Mesothelioma Interest Group

Context.— Mesothelioma is an uncommon tumor that can be difficult to diagnose. Objective.— To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. Data Sources.— Pathologists involved in the International Mesothelioma Interest Group and others with expertise in mesothelioma contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions.— There was consensus opinion regarding guidelines for (1) histomorphologic diagnosis of mesothelial tumors, including distinction of epithelioid, biphasic, and sarcomatoid mesothelioma; recognition of morphologic variants and patterns; and recognition of common morphologic pitfalls; (2) molecular pathogenesis of mesothelioma; (3) application of immunohistochemical markers to establish mesothelial lineage and distinguish mesothelioma from common morphologic differentials; (4) application of ancillary studies to distinguish benign from malignant mesothelial proliferations, including BAP1 and MTAP immunostains; novel immunomarkers such as Merlin and p53; fluorescence in situ hybridization (FISH) for homozygous deletion of CDKN2A; and novel molecular assays; (5) practical recommendations for routine reporting of mesothelioma, including grading epithelioid mesothelioma and other prognostic parameters; (6) diagnosis of mesothelioma in situ; (7) cytologic diagnosis of mesothelioma, including use of immunostains and molecular assays; and (8) features of nonmalignant peritoneal mesothelial lesions

Distribution of genotypes from crossing <i>Hras</i>^<i>+/-</i><i>;Nras</i>^<i>+/-</i> mice.

<p>Distribution of genotypes from crossing <i>Hras</i>^<i>+/-</i><i>;Nras</i>^<i>+/-</i> mice.</p

Isoform-Specific Effects of Wild-Type <i>Ras</i> Genes on Carcinogen-Induced Lung Tumorigenesis in Mice

<div><p>The gene <i>KRAS</i> is commonly mutated in lung cancer to encode a constitutively active and oncogenic protein that is well established to initiate and maintain lung tumorigenesis. However, the remaining wild-type KRAS protein, or the other family members HRAS and NRAS, can still be activated in the presence of oncogenic KRAS. Moreover, loss of any one of these three genes has been shown to increase the sensitivity of mice to the carcinogen urethane, which induces <i>Kras</i> mutation-positive early lung lesions. To determine the contribution of progressively disrupting <i>Hras</i> and <i>Nras</i> genes on urethane lung tumorigenesis, mice with different combinations of wild-type and null alleles of <i>Hras</i> and <i>Nras</i> were exposed with urethane and tumor burden was assessed. As previously reported, loss of one allele of <i>Hras</i> increased the sensitivity of mice to this carcinogen, and this effect was further exacerbated by the loss of the second <i>Hras</i> allele. However, loss of one or both alleles of <i>Nras</i> failed to alter tumor burden, either in the absence or presence of <i>Hras</i>, after exposure to urethane. Additionally, no obvious difference between lung lesions in mice with wild-type versus null alleles was detected, suggesting that wild-type Ras proteins may exert a tumor suppressive effects at the time of initiation, although other interpretations are certainly possible. In summary, these data suggest that in some genetic backgrounds inactivation of different wild-type <i>Ras</i> genes can have different effects on urethane-induced lung tumorigenesis.</p></div

Pulmonary blastomycosis presenting as primary lung cancer

Abstract Background Blastomycosis is an endemic mycosis in North America that is caused by the dimorphic fungus Blastomyces dermatitidis. The illness is a systemic disease with a wide variety of pulmonary and extra-pulmonary manifestations. The initial presentation of blastomycosis may easily be mistaken for other infectious or non-infectious etiologies. Case presentation We present the case of a 52-year-old African-American male and former smoker that presented to his primary care provider with a 2-week history of non-productive cough, night sweats and weight loss. Initially diagnosed with primary lung malignancy, the patient was subsequently found to have pulmonary blastomycosis mimicking lung cancer. The patient underwent a successful course of treatment with posaconazole. Conclusions Chronic blastomycosis can present with clinical and radiographic features indistinguishable from thoracic malignancies. There is no clinical syndrome specific for blastomycosis, thus a high degree of suspicion is required for early diagnosis. In this case report, we review recent evidence in radiographic features, diagnostic considerations and treatment of the disease

Loss of wild-type <i>Hras</i> alone or in combination with loss of wild-type <i>Nras</i> promotes lymphoid infiltration in the lungs of urethane-treated mice.

<p>(<b>A</b>) Representative photograph at 2X (<i>right</i>) and 10X (<i>left</i>) magnification of H&E-stained lung tissue containing lymphoid aggregates (indicated by arrowheads). (<b>B</b>) Quantification of the percentage of sections from mice with the indicated combinations of wild-type (+) or null (-) <i>Hras</i> and <i>Nras</i> alleles in which lymphoid aggregates are binned as no aggregates, 1–5 aggregates, or >5 aggregates. <i>n</i> = 4 to 6 sections from 9 to 14 mice per cohort.</p

Effects of concomitant loss of wild-type <i>Hras</i> and <i>Nras</i> on urethane-induced tumorigenesis.

<p>(<b>A</b>) Number of lesions counted per H&E-stained section of lung tissue from urethane-treated mice with the indicated combinations of wild-type (+) or null (-) <i>Hras</i> and <i>Nras</i> alleles. (<b>B</b>) Number and grade of lesions from H&E-stained lung sections (bar: mean ± S.E.M.). AAH = atypical adenomatous hyperplasia. AD = adenoma. ns: not significant. ***<i>p</i> < 0.0001. <i>n</i> = 4 to 6 sections from 9 to 14 mice per cohort.</p

Immunohistochemical staining in urethane-induced lung lesions.

<p>(<b>A</b>) Cleaved caspase 3 (CC3), (<b>B</b>) Ki67, (<b>C</b>) F480, (<b>D</b>) phosphorylated AKT (pAKT), and (<b>E</b>) phosphorylated ERK (pERK) immunohistochemical staining (<i>left</i> panels, examples) and quantification thereof (<i>right</i>, graphs), based on the percentage of positively-staining tumor area calculated for 6–10 lesions from 3–5 mice with the indicated combinations of wild-type (+) or null (-) <i>Hras</i> and <i>Nras</i> alleles. Bar: mean ± S.E.M. ns: not significant.</p

The 2022 Banff Meeting Lung Report

Abstract: The Lung Session of the 2022 16th Banff Foundation for Allograft Pathology Conference-held in Banff, Alberta-focused on non-rejection lung allograft pathology and novel technologies for the detection of allograft injury. A multidisciplinary panel reviewed the state-of-the-art of current histopathologic entities, serologic studies, and molecular practices, as well as novel applications of digital pathology with artificial intelligence, gene expression analysis, and quantitative image analysis of chest computerized tomography. Current states of need as well as prospective integration of the aforementioned tools and technologies for complete assessment of allograft injury and its impact on lung transplant outcomes were discussed. Key conclusions from the discussion were: specialIntscript recognition of limitations in current standard of care assessment of lung allograft dysfunction; specialIntscript agreement on the need for a consensus regarding the standardized approach to the collection and assessment of pathologic data, inclusive of all lesions associated with graft outcome (eg, non-rejection pathology); and specialIntscript optimism regarding promising novel diag- nostic modalities, especially minimally invasive, which should be integrated into large, prospective multicenter studies to further evaluate their utility in clinical practice for directing personalized therapies to improve graft outcomes