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The pathologic evaluation of lung adenocarcinoma, because of greater understanding of disease progression and prognosis, has become more complex. It is clear that histologic growth patterns reflect indolent and aggressive disease, resulting in clearer morphologic groups that can be the underpinning of a grading system. In addition, the progression of adenocarcinoma from a tumor that preserves alveolar architecture to one that remodels and effaces lung structure has led to criteria that reflect invasive rather than in-situ growth. While some of these are based on tumor cell growth pattern, aspects of this remodeling from desmoplasia to artifacts of lung collapse and sectioning, can lead to difficult to interpret patterns with lower reproducibility between observers. Such scenarios are examined to provide updates on new histologic concepts and to highlight ongoing problem areas.

Severe acute respiratory syndrome-associated coronavirus-2 (SARS-CoV-2) is the causal agent of coronavirus disease-2019 (COVID-19), a systemic illness characterized by variably severe pulmonary symptoms, cardiac conduction abnormalities, diarrhea, and gastrointestinal bleeding, as well as neurologic deficits, renal insufficiency, myalgias, endocrine abnormalities, and other perturbations that reflect widespread microvascular injury and a pro-inflammatory state. The mechanisms underlying the various manifestations of viral infection are incompletely understood but most data suggest that severe COVID-19 results from virus-driven perturbations in the immune system and resultant tissue injury. Aberrant interferon-related responses lead to alterations in cytokine elaboration that deplete resident immune cells while simultaneously recruiting hyperactive macrophages and functionally altered neutrophils, thereby tipping the balance from adaptive immunity to innate immunity. Disproportionate activation of these macrophages and neutrophils further depletes normal activity of B-cells, T-cells, and natural killer (NK) cells. In addition, this pro-inflammatory state stimulates uncontrolled complement activation and development of neutrophil extracellular traps (NETS), both of which promote the coagulation cascade and induce a state of “thrombo-inflammation”. These perturbations have similar manifestations in multiple organ systems, which frequently show pathologic findings related to microvascular injury and thrombosis of large and small vessels. However, the pulmonary findings in patients with severe COVID-19 are generally more pronounced than those of other organs. Not only do they feature inflammatory thromboses and endothelial injury, but much of the parenchymal damage stems from failed maturation of alveolar pneumocytes, interactions between type 2 pneumocytes and non-resident macrophages, and a greater degree of NET formation. The purpose of this review is to discuss the pathogenesis underlying organ damage that can occur in patients with SARS-CoV-2 infection. Understanding these mechanisms of injury is important to development of future therapies for patients with COVID-19, many of which will likely target specific components of the immune system, particularly NET induction, pro-inflammatory cytokines, and subpopulations of immune cells.

Despite tremendous progress in the last decade, lung adenocarcinoma still represents a tumor with unfavorable prognosis when detected at advanced clinical stage. High-stage tumors are not amenable to surgical resection, and therefore systemic therapies are needed to control these tumors to prolong patient survival. In the era of molecular and personalized therapeutics, the discovery of mutations in epidermal growth factor receptor (EGFR) in 15–20% of lung adenocarcinomas and the associated response to EGFR-targeting tyrosine kinase (TK) inhibitors have provided a successful avenue of attack in high-stage adenocarcinomas. In this review, we will provide an overview of the EGFR pathway, review the significant somatic EGFR alterations in lung adenocarcinoma and highlight their implications for treatment. In addition, we will examine pathways by which tumors resist EGFR TK therapy, both as primary nonresponders and by acquired resistance. In doing so, we will examine other oncogenic pathways whose status in tumor samples may impact therapeutic responses despite presence of activating EGFR mutations.

Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15–45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab. We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I–IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual. Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8–22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3–71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2–79·6]; p<0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3–4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3–4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported. Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial. AstraZeneca.

Recent studies have provided insights into the pathology of and immune response to COVID-19 1 – 8 . However, a thorough investigation of the interplay between infected cells and the immune system at sites of infection has been lacking. Here we use high-parameter imaging mass cytometry 9 that targets the expression of 36 proteins to investigate the cellular composition and spatial architecture of acute lung injury in humans (including injuries derived from SARS-CoV-2 infection) at single-cell resolution. These spatially resolved single-cell data unravel the disordered structure of the infected and injured lung, alongside the distribution of extensive immune infiltration. Neutrophil and macrophage infiltration are hallmarks of bacterial pneumonia and COVID-19, respectively. We provide evidence that SARS-CoV-2 infects predominantly alveolar epithelial cells and induces a localized hyperinflammatory cell state that is associated with lung damage. We leverage the temporal range of fatal outcomes of COVID-19 in relation to the onset of symptoms, which reveals increased macrophage extravasation and increased numbers of mesenchymal cells and fibroblasts concomitant with increased proximity between these cell types as the disease progresses—possibly as a result of attempts to repair the damaged lung tissue. Our data enable us to develop a biologically interpretable landscape of lung pathology from a structural, immunological and clinical standpoint. We use this landscape to characterize the pathophysiology of the human lung from its macroscopic presentation to the single-cell level, which provides an important basis for understanding COVID-19 and lung pathology in general. Imaging mass cytometry of the human lung reveals the cellular composition and spatial architecture during COVID-19 and other acute injuries, enabling the characterization of lung pathophysiology from structural, immunological and clinical perspectives.

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.

- Lung tumors are histologically heterogeneous, but classification of lung carcinoma has prognostic impact and increasingly, specific molecular correlates. - To update the gross, microscopic, and molecular pathology of unusual lung carcinomas to assure accurate classification. In entities with mixed histology, the recognition of specific features or rare patterns is critical to diagnosis. These diagnoses can identify tumors with aggressive clinical behavior, and diagnostic pitfalls can therefore result in underdiagnosis of these already rare entities. Incorrect classification of more indolent tumors into the more aggressive categories can also occur. In the area of molecular pathology, these unusual tumors have a specific spectrum of molecular alterations. - PubMed searches for lung and sarcomatoid carcinoma, pleomorphic carcinoma, blastoma, carcinosarcoma, and adenosquamous and mucoepidermoid carcinoma were undertaken and this information was integrated with clinical experience of the author. - These uncommon carcinomas have specific clinicopathologic features, and attention to their gross and microscopic pathology leads to classification with important associated molecular findings.

- Diagnosis of malignant mesothelioma is more common in the chest than it is in the abdomen. Most published immunohistochemistry data are more applicable to pleural than to peritoneal mesothelioma. - To clarify the practical utility of 17 immunohistochemistry markers in the differential diagnosis of peritoneal mesothelioma with an emphasis on stains for which there is either contradictory information or a paucity of literature. - Consultation files of peritoneal mesothelioma diagnoses rendered from 1999 to 2014 were reviewed; 244 cases were identified. The results of immunohistochemistry markers performed were tabulated. - Immunohistochemistry markers positive in peritoneal mesothelioma in order of sensitivity were calretinin (244 of 244; 100%), WT1 (205 of 218; 94%), CK5/6 (173 of 194; 89%), mesothelin (132 of 150; 88%), and D2-40 (78 of 97; 80%). Markers used to differentiate carcinoma from mesothelioma showed immunoreactivity in peritoneal mesothelioma: estrogen receptor (2 of 84; 2%), B72.3 (6 of 196; 3%), CK20 (5 of 116; 4%), CD15 (7 of 192; 4%), p63 (3 of 62; 5%), carcinoembryonic antigen (9 of 199; 5%), PAX8 (12 of 191; 6%), progesterone receptor (5 of 71; 7%), Ber-EP4 (17 of 209; 8%), and CD138 (9 of 91; 10%). BAP1 loss, increasingly used in the differential diagnosis of benign versus malignant mesothelial proliferation, occured in 55% (99 of 181) of peritoneal mesothelioma cases. - The results support the experience that there is no definitive marker to rule out malignant mesothelioma, including PAX8, estrogen receptor, progesterone receptor, and p63 immunoreactivity. The high rate of immunoreactivity for mesothelin may have a role as a predictive marker for immune targeting. BAP1 loss of 55% in this cohort of peritoneal mesothelioma confirms published observations, and BAP1 retention is seen in a significant proportion of neoplastic cases.

Background: A novel coronavirus, SARS-CoV-2, was identified in Wuhan, China in late 2019. This virus rapidly spread around the world causing disease ranging from minimal symptoms to severe pneumonia, which was termed coronavirus disease (i.e., COVID). Postmortem examination is a valuable tool for studying the pathobiology of this new infection. Methods: We report the clinicopathologic findings from 32 autopsy studies conducted on patients who died of COVID-19 including routine gross and microscopic examination with applicable special and immunohistochemical staining techniques. Results: SARS-CoV-2 infection was confirmed by nasopharyngeal RT-PCR in 31 cases (97%) and by immunohistochemical staining for SARS-CoV-2 spike-protein in the lung in the remaining 1 case (3%). The ethnically diverse cohort consisted of 22 males and 10 females with a mean age of 68 years (range: 30–100). Patients most commonly presented with cough (17 [55%]), shortness of breath (26 [81%]), and a low-grade fever (17 [55%]). Thirty-one (97%) of the patients had at least 1 comorbidity (mean = 4). Twenty-eight patients (88%) had widespread thromboembolic disease, as well as diffuse alveolar damage (30 [94%]), diabetic nephropathy (17 [57%]) and acute tubular injury. Patterns of liver injury were heterogeneous, featuring 10 (36%) with frequent large basophilic structures in sinusoidal endothelium, and increased immunoblast-like cells in lymph nodes. Conclusion: This series of autopsies from patients with COVID-19 confirms the observation that the majority of severely affected patients have significant pulmonary pathology. However, many patients also have widespread microscopic thromboses, as well as characteristic findings in the liver and lymph nodes.