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SARS-CoV-2, the etiologic agent of COVID-19, is a global pandemic with substantial mortality dominated by acute respiratory distress syndrome. We systematically evaluated lungs of 68 autopsies from 3 institutions in heavily hit areas (2 USA, 1 Italy). Detailed evaluation of several compartments (airways, alveolar walls, airspaces, and vasculature) was performed to determine the range of histologic features. The cohort consisted of 47 males and 21 females with a median age of 73 years (range 30–96). Co-morbidities were present in most patients with 60% reporting at least three conditions. Tracheobronchitis was frequently present, independent from intubation or superimposed pneumonia. Diffuse alveolar damage (DAD) was seen in 87% of cases. Later phases of DAD were less frequent and correlated with longer duration of disease. Large vessel thrombi were seen in 42% of cases but platelet (CD61 positive) and/or fibrin microthrombi were present at least focally in 84%. Ultrastructurally, small vessels showed basal membrane reduplication and significant endothelial swelling with cytoplasmic vacuolization. In a subset of cases, virus was detected using different tools (immunohistochemistry for SARS-CoV-2 viral spike protein, RNA in situ hybridization, lung viral culture, and electron microscopy). Virus was seen in airway epithelium and type 2 pneumocytes. IHC or in situ detection, as well as viable form (lung culture positive) was associated with the presence of hyaline membranes, usually within 2 weeks but up to 4 weeks after initial diagnosis. COVID-19 pneumonia is a heterogeneous disease (tracheobronchitis, DAD, and vascular injury), but with consistent features in three centers. The pulmonary vasculature, with capillary microthrombi and inflammation, as well as macrothrombi, is commonly involved. Viral infection in areas of ongoing active injury contributes to persistent and temporally heterogeneous lung damage.

Context—Traditionally, lung cancer has been viewed as an aggressive, relentlessly progressive disease with few treatment options and poor survival. The traditional role of the pathologist has been primarily to differentiate small cell carcinoma from non–small cell carcinoma on biopsy and cytology specimens and to stage non–small cell carcinomas that underwent resection. In recent years, our concepts of lung cancer have undergone a revolution, including (1) the advent of successful, new, molecular-targeted therapies for lung cancer, many of which are associated with specific histologic cell types and subtypes; (2) new observations on the natural history of lung cancer derived from ongoing high-resolution computed tomography screening studies and recent histologic findings; and (3) proposals to revise the classification of lung cancers, particularly adenocarcinomas, in part because of the first 2 developments. Objective—To summarize the important, new developments in lung cancer, emphasizing the role of the surgical pathologist in personalized care for patients with lung cancer. Data Sources—Information about the new developments in lung cancer was obtained from the peer-review medical literature and the authors' experiences. Conclusions—For decades, we have perceived lung cancer as a relentlessly aggressive and mostly incurable disease for which the surgical pathologist had a limited role. Today, surgical pathologists have an important and expanding role in the diagnosis and treatment of lung cancer, and it is essential to keep informed of new advances.

Context. —Acute lung injury and acute respiratory distress syndrome are significant causes of pulmonary morbidity and are frequently fatal. These 2 entities have precise definitions from a clinical standpoint. Histologically, cases from patients with clinical acute lung injury typically exhibit diffuse alveolar damage, but other histologic patterns may occasionally be encountered such as acute fibrinous and organizing pneumonia, acute eosinophilic pneumonia, and diffuse hemorrhage with capillaritis. Objective. —To review the diagnostic criteria for various histologic patterns associated with a clinical presentation of acute lung injury and to provide diagnostic aids and discuss the differential diagnosis. Data sources. —The review is drawn from pertinent peer-reviewed literature and the author's personal experience. Conclusions. —Acute lung injury remains a significant cause of morbidity and mortality. The pathologist should be aware of histologic patterns of lung disease other than diffuse alveolar damage, which are associated with a clinical presentation of acute lung injury. Identification of these alternative histologic findings, as well as identification of potential etiologic agents, especially infection, may impact patient treatment and disease outcome.

- Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. - To provide updated, practical guidelines for the pathologic diagnosis of MM. - Pathologists involved in the International Mesothelioma Interest Group and others with an interest and expertise in the field contributed to this update. Reference material included up-to-date, peer-reviewed publications and textbooks. - There was discussion and consensus opinion regarding guidelines for (1) distinguishing benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) recognition of the key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiating epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid MM, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels employed is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Depending on the morphology, immunohistochemical panels should contain both positive and negative markers for mesothelial differentiation and for lesions considered in the differential diagnosis. Immunohistochemical markers should have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic and membranous markers). Selected molecular markers are now being used to distinguish benign from malignant mesothelial proliferations. These guidelines are meant to be a practical diagnostic reference for the pathologist; however, some new pathologic predictors of prognosis and response to therapy are also included.

Objective.—To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR - and ALK -directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed. Participants .—Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies. Evidence .—Three unbiased literature searches of electronic databases were performed to capture articles published from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. Evidence was formally graded for each recommendation. Consensus Process .—Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4). Conclusions .—The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines.

Cystic fibrosis (CF) lung disease is characterized by the presence of marked, neutrophil-dominant inflammation that contributes to tissue injury and the development of irreversible structural lung disease. Here, we describe a dysregulated, neutrophil-dominant inflammation and an accompanying pro-inflammatory airway epithelium in the pediatric CF lung through the application of single-cell RNA sequencing (scRNA-seq) to minimally invasive respiratory specimens collected during flexible bronchoscopy. These findings were present in both an infant and an adolescent with CF, the latter on cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy, suggesting a common pathological program that starts early in life and may be challenging to reverse once structural lung disease is established. Intercellular communication network analysis further revealed potential mechanisms whereby airway epithelial cells modulate the ongoing, destructive airway inflammation present in the CF lung. Importantly, the scRNA-seq workflow leveraged in this study provides a unique opportunity to investigate and monitor disease-related changes in the composition, function, and interaction of the immune and airway epithelial cell populations in CF and other respiratory diseases across the life course.

- Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as a very useful tool in the field of diagnostic respiratory cytology. Rapid on-site evaluation (ROSE) of EBUS-TBNA not only has the potential to improve diagnostic yield of the procedure but also to triage samples for predictive molecular testing to guide personalized treatments for lung cancer. - To provide an overview of the current status of the literature regarding ROSE of EBUS-TBNA in the diagnosis of lung cancer. - An electronic literature search in PubMed and Google databases was performed using the following key words: cytology, lung cancer, on-site evaluation, rapid on-site evaluation, and ROSE EBUS-TBNA. Only articles published in English were included in this review. - Rapid on-site evaluation can ensure that the targeted lesion is being sampled and can enable appropriate specimen triage. If available, it should be used with EBUS-TBNA in the diagnosis of lung cancer because it can minimize repeat procedures for additional desired testing (ie, molecular studies). Some studies have shown that ROSE does not adversely affect the number of aspirations, total procedure time of EBUS-TBNA, or the rate of postprocedure complications; it is also helpful in providing a preliminary diagnosis that can reduce the number of additional invasive procedures, such as mediastinoscopy. As EBUS technology continues to evolve, our knowledge of the role of ROSE in EBUS-TBNA for the diagnosis of lung cancer will also continue to grow and evolve.

Mesothelioma is an uncommon tumor that can be difficult to diagnose. To provide updated, practical guidelines for the pathologic diagnosis of mesothelioma. 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. 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.

Context .—Malignant mesothelioma (MM) is an uncommon tumor that can be difficult to diagnose. Objective .—To provide updated practical guidelines for the pathologic diagnosis of MM. Data Sources .—Pathologists involved in the International Mesothelioma Interest Group and others with an interest in the field contributed to this update. Reference material includes peer-reviewed publications and textbooks. Conclusions .—There was consensus opinion regarding (1) distinction of benign from malignant mesothelial proliferations (both epithelioid and spindle cell lesions), (2) cytologic diagnosis of MM, (3) key histologic features of pleural and peritoneal MM, (4) use of histochemical and immunohistochemical stains in the diagnosis and differential diagnosis of MM, (5) differentiation of epithelioid MM from various carcinomas (lung, breast, ovarian, and colonic adenocarcinomas, and squamous cell and renal cell carcinomas), (6) diagnosis of sarcomatoid mesothelioma, (7) use of molecular markers in the diagnosis of MM, (8) electron microscopy in the diagnosis of MM, and (9) some caveats and pitfalls in the diagnosis of MM. Immunohistochemical panels are integral to the diagnosis of MM, but the exact makeup of panels used is dependent on the differential diagnosis and on the antibodies available in a given laboratory. Immunohistochemical panels should contain both positive and negative markers. It is recommended that immunohistochemical markers have either sensitivity or specificity greater than 80% for the lesions in question. Interpretation of positivity generally should take into account the localization of the stain (eg, nuclear versus cytoplasmic) and the percentage of cells staining (>10% is suggested for cytoplasmic membranous markers). These guidelines are meant to be a practical reference for the pathologist.

The binding of programmed death ligand-1 and ligand-2 (PD-L1 and PD-L2) to PD-1 blocks T-cell–mediated immune response to tumor. Antibodies that target programmed death receptor-1 (PD-1) will block the ligand-receptor interface, thereby allowing T cells to attack the tumor and increase antitumor immune response. In clinical trials, PD-1 inhibitors have been associated with an approximately 20% overall response rate in unselected patients with non–small cell lung cancer, with sustained tumor response in a subset of patients treated by these immune checkpoint inhibitors. Facing a proliferation of PD-L1 immunohistochemistry clones, staining platforms, and scoring criteria, the pathologist must decide on the feasibility of introducing a newly approved companion diagnostic assay that may require purchase not only of a specific antibody kit but of a particular staining platform. Given the likely reality that clinical practice may, in the near future, demand access to 4 different PD-L1 antibodies coupled with different immunohistochemistry platforms, laboratories will be challenged with deciding among this variety of testing methods, each with its own potential benefits. Another immediate challenge to PD-L1 testing in lung cancer patients is that of access to adequate tumor tissue, given that non–small cell lung cancer samples are often extremely limited in size. With PD-L1 testing it has become clear that the historically used US regulatory approach of one assay–one drug will not be sustainable. One evolving concept is that of complementary diagnostics, a novel regulatory pathway initiated by the US Food and Drug Administration, which is distinct from companion diagnostics in that it may present additional flexibility. Although pathologists need to face the practical reality that oncologists will be asking regularly for the PD-L1 immunohistochemistry status of their patients' tumors, we should also keep in mind that there may be room for improvement of biomarkers for immunotherapy response. The field is rich with opportunities for investigation into biomarkers of immunotherapy response, particularly in the form of collaborative, multidisciplinary studies that incorporate oncologists, pathologists, and basic scientists. Pathologists must take the lead in the rational incorporation of these biomarkers into clinical practice.