Citations

Context.— Studies of lungs in patients with COVID-19 have focused on early findings. Objective.— To systematically study histopathologic and imaging features and presence of SARS-CoV-2 RNA in lung tissue from patients in later stages of COVID-19. Design.— Autopsies, explants, surgical lung biopsies, transbronchial biopsies, cryobiopsies, and needle biopsies from patients with COVID-19 whose onset of symptoms/confirmed diagnosis was more than 28 days before the procedure were studied. Available images were reviewed. Reverse transcription droplet digital polymerase chain reaction for SARS-CoV-2 RNA was performed on lung tissue. Results.— Of 44 specimens (43 patients; median age, 59.3 years; 26 [60.5%] male) features of acute lung injury (ALI) were seen in 39 (88.6%), predominantly organizing pneumonia and diffuse alveolar damage, up to 298 days after onset of COVID-19. Fibrotic changes were found in 33 specimens (75%), most commonly fibrotic diffuse alveolar damage (n = 22) and cicatricial organizing pneumonia (n = 12). Time between acquiring COVID-19 and specimen was shorter in patients with diffuse ALI (median, 61.5 days) compared with patients with focal (140 days) or no ALI (130 days) (P = .009). Sixteen (of 20; 80%) SARS-CoV-2 reverse transcription droplet digital polymerase chain reaction tests were positive, up to 174 days after COVID-19 onset. Time between COVID-19 onset and most recent computed tomography in patients with consolidation on imaging was shorter (median, 43.0 days) versus in patients without consolidation (87.5 days; P = .02). Reticulations were associated with longer time to computed tomography after COVID-19 onset (median, 82 versus 23.5 days; P = .006). Conclusions.— ALI and SARS-CoV-2 RNA can be detected in patients with COVID-19 for many months. ALI may evolve into fibrotic interstitial lung disease.

AbstractKallikrein related peptidase 6 (Klk6) is a secreted serine protease highly expressed in oligodendrocytes and implicated in demyelinating conditions. To gain insights into the significance of Klk6 to oligodendrocyte biology, we investigated the impact of global Klk6 gene knockout on CNS developmental myelination using the spinal cord of male and female mice as a model. Results demonstrate that constitutive loss of Klk6 expression accelerates oligodendrocyte differentiation developmentally, including increases in the expression of myelin proteins such as MBP, PLP and CNPase, in the number of CC‐1+ mature oligodendrocytes, and myelin thickness by the end of the first postnatal week. Co‐ordinate elevations in the pro‐myelinating signaling pathways ERK and AKT, expression of fatty acid 2‐hydroxylase, and myelin regulatory transcription factor were also observed in the spinal cord of 7d Klk6 knockouts. LC/MS/MS quantification of spinal cord lipids showed sphingosine and sphingomyelins to be elevated in Klk6 knockouts at the peak of myelination. Oligodendrocyte progenitor cells (OPCs)‐derived from Klk6 knockouts, or wild type OPCs‐treated with a Klk6 inhibitor (DFKZ‐251), also showed increased MBP and PLP. Moreover, inhibition of Klk6 in OPC cultures enhanced brain derived neurotrophic factor‐driven differentiation. Altogether, these findings suggest that oligodendrocyte‐derived Klk6 may operate as an autocrine or paracrine rheostat, or brake, on pro‐myelinating signaling serving to regulate myelin homeostasis developmentally and in the adult. These findings document for the first time that inhibition of Klk6 globally, or specifically in oligodendrocyte progenitors, is a strategy to increase early stages of oligodendrocyte differentiation and myelin production in the CNS.

Abstract Objectives Differentiating malignant pleural mesothelioma from benign reactive mesothelial processes can be quite challenging. Ancillary tests such as BRCA1-associated protein 1 (BAP1) immunohistochemistry and p16 fluorescence in situ hybridization (FISH) are helpful tools to aid in this distinction. Immunohistochemistry for methylthioadenosine phosphorylase (MTAP) has recently been proposed as an effective surrogate marker for p16 FISH and is an attractive alternative test due to shorter turnaround time. There are little data regarding the specificity of MTAP loss for mesothelioma or whether it may be useful to distinguish mesothelioma from the most common entity in the differential diagnosis, sarcomatoid carcinoma. Methods We studied well-characterized cases of sarcomatoid carcinoma (n = 34) and sarcomatoid mesothelioma (n = 62), which were stained for MTAP (clone 2G4) and BAP1 (clone C-4). Results Loss of MTAP expression was observed in 17 (50%) of 34 pulmonary sarcomatoid carcinomas; BAP1 expression was retained in all of the cases in which it was performed (n = 31). MTAP expression was lost in 38 (61%) of 62 sarcomatoid mesotheliomas; BAP1 was lost in 6 (10%) of 62. In the six cases with BAP1 loss, five also had loss of MTAP, while MTAP expression was retained in one. Conclusions Loss of MTAP expression by immunohistochemistry is common in pulmonary sarcomatoid carcinoma, as it is present in half of cases. This rate is similar to what is observed in sarcomatoid mesothelioma (61%). Therefore, this stain is not useful to distinguish between these two malignancies. MTAP loss is more common than BAP1 loss in the setting of sarcomatoid mesothelioma (61% vs 10%, respectively).

Abstract B-cell activation is increasingly linked to numerous fibrotic lung diseases, and it is well known that aggregates of lymphocytes form in the lung of many of these patients. Activation of B-cells by pattern recognition receptors (PRRs) drives the release of inflammatory cytokines, chemokines, and metalloproteases important in the pathophysiology of pulmonary fibrosis. However, the specific mechanisms of B-cell activation in patients with idiopathic pulmonary fibrosis (IPF) are poorly understood. Herein, we have demonstrated that B-cell activation by microbial antigens contributes to the inflammatory and profibrotic milieu seen in patients with IPF. B-cell stimulation by CpG and β-glucan via PRRs resulted in activation of mTOR-dependent and independent pathways. Moreover, we showed that the B-cell–secreted inflammatory milieu is specific to the inducing antigen and causes differential fibroblast migration and activation. B-cell responses to infectious agents and subsequent B-cell–mediated fibroblast activation are modifiable by antifibrotics, but each seems to exert a specific and different effect. These results suggest that, upon PRR activation by microbial antigens, B-cells can contribute to the inflammatory and fibrotic changes seen in patients with IPF, and antifibrotics are able to at least partially reverse these responses.

Abstract Context. —Not uncommonly, a surgical pathologist will be requested to review excised material, with a clinical diagnosis of cancer, in which no malignancy can be identified. Often, sampling may be the issue. However, different nonneoplastic processes may mimic cancer clinically and not be recognized histologically. These are commonly referred to as pseudoneoplasms and can involve the lung, pleura, and mediastinum. Objective. —To review the most commonly encountered pseudoneoplasms of the thoracic cavity in surgical pathology and discuss the main differential diagnosis. Data Sources. —Literature and personal review of cases with focus on inflammatory pseudotumors of the lung, organizing pneumonia, nodular lymphoid hyperplasia, apical cap, round atelectasis, and sclerosing mediastinitis with its pulmonary counterpart, hyalinizing granuloma. Conclusions. —When reviewing specimens that appear nondiagnostic for malignancy, it is important to consider one of these pseudoneoplasms in the differential diagnosis as they may explain the clinical and radiologic information.

Abstract Context. —Diffuse pulmonary hemorrhage is an uncommon presenting manifestation of angiosarcoma. Objective. —To review the clinical, radiologic, and pathologic findings of patients with metastatic angiosarcoma who presented with diffuse pulmonary hemorrhage. Design. —Patients fulfilling inclusion criteria were identified from the consultation files. Clinical and radiologic data were obtained from referring pathologists. Histologic slides were reviewed in all patients. Results. —Our patients included 6 men and 1 woman, aged 31 to 73 years; 4 patients were younger than 40 years. Six patients presented with hemoptysis, and all had diffuse abnormalities on radiographic studies. Clinical considerations prior to biopsy included pulmonary hemorrhage syndrome (n = 2), acute respiratory failure (n = 1), and infection (n = 1). Metastatic disease was included in the differential diagnosis in only 1 patient. None had a diagnosis of malignancy prior to lung biopsy. All biopsies showed hemorrhage associated with atypical epithelioid and spindle cells, forming anastomosing vascular channels, distributed along and within lymphatics and arteries. Neoplastic cells were immunoreactive for factor VIII–related protein or CD31 in all cases for which special stains were available. Three patients with complete follow-up died of their disease. Primary sites were discovered in all 3 patients who underwent autopsy examination. Two tumors arose in the heart and 1 in the pelvic soft tissues. One additional patient had a likely primary site identified in the right atrium by cardiac ultrasound and was subsequently lost to follow-up. Conclusion. —Angiosarcoma should be included in the differential diagnosis of diffuse pulmonary hemorrhage, especially in young adults.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its resultant clinical presentation, coronavirus disease 2019 (COVID-19), is an emergent cause of mortality worldwide. Cardiac complications secondary to this infection are common; however, the underlying mechanisms of such remain unclear. A detailed cardiac evaluation of a series of individuals with COVID-19 undergoing postmortem evaluation is provided, with 4 aims: (1) describe the pathological spectrum of the myocardium; (2) compare with an alternate viral illness; (3) investigate angiotensin-converting enzyme 2 expression; and (4) provide the first description of the cardiac findings in patients with cleared infection. Methods: Study cases were identified from institutional files and included COVID-19 (n=15: 12 active, 3 cleared), influenza A/B (n=6), and nonvirally mediated deaths (n=6). Salient information was abstracted from the medical record. Light microscopic findings were recorded. An angiotensin-converting enzyme 2 immunohistochemical H-score was compared across cases. Viral detection encompassed SARS-CoV-2 immunohistochemistry, ultrastructural examination, and droplet digital polymerase chain reaction. Results: Male sex was more common in the COVID-19 group ( P =0.05). Nonocclusive fibrin microthrombi (without ischemic injury) were identified in 16 cases (12 COVID-19, 2 influenza, and 2 controls) and were more common in the active COVID-19 cohort ( P =0.006). Four active COVID-19 cases showed focal myocarditis, whereas 1 case of cleared COVID-19 showed extensive disease. Arteriolar angiotensin-converting enzyme 2 endothelial expression was lower in COVID-19 cases than in controls ( P =0.004). Angiotensin-converting enzyme 2 myocardial expression did not differ by disease category, sex, age, or number of patient comorbidities ( P =0.69, P =1.00, P =0.46, P =0.65, respectively). SARS-CoV-2 immunohistochemistry showed nonspecific staining, whereas ultrastructural examination and droplet digital polymerase chain reaction were negative for viral presence. Four patients (26.7%) with COVID-19 had underlying cardiac amyloidosis. Cases with cleared infection had variable presentations. Conclusions: This detailed histopathologic, immunohistochemical, ultrastructural, and molecular cardiac series showed no definitive evidence of direct myocardial infection. COVID-19 cases frequently have cardiac fibrin microthrombi, without universal acute ischemic injury. Moreover, myocarditis is present in 33.3% of patients with active and cleared COVID-19 but is usually limited in extent. Histological features of resolved infection are variable. Cardiac amyloidosis may be an additional risk factor for severe disease.

Context.— Respiratory failure appears to be the ultimate mechanism of death in most patients with severe coronavirus disease 2019 (COVID-19) infection. Studies of postmortem COVID-19 lungs largely report diffuse alveolar damage and capillary fibrin thrombi, but we have also observed other patterns. Objective.— To report demographic and radiographic features along with macroscopic, microscopic, and microbiologic postmortem lung findings in patients with COVID-19 infections. Design.— Patients with confirmed COVID-19 infection and postmortem examination (March 2020–May 2020) were included. Clinical findings were abstracted from medical records. Lungs were microscopically reviewed independently by 4 thoracic pathologists. Imaging studies were reviewed by a thoracic radiologist. Results.— Eight patients (7 men, 87.5%; median age, 79 years; range, 69–96 years) died within a median of 17 days (range, 6–100 days) from onset of symptoms. The median lung weight was 1220 g (range, 960–1760 g); consolidations were found in 5 patients (62.5%) and gross thromboemboli were noted in 1 patient (12.5%). Histologically, all patients had acute bronchopneumonia; 6 patients (75%) also had diffuse alveolar damage. Two patients (25%) had aspiration pneumonia in addition. Thromboemboli, usually scattered and rare, were identified in 5 patients (62.5%) in small vessels and in 2 of these patients also in pulmonary arteries. Four patients (50%) had perivascular chronic inflammation. Postmortem bacterial lung cultures were positive in 4 patients (50%). Imaging studies (available in 4 patients) were typical (n = 2, 50%), indeterminate (n = 1, 25%), or negative (n = 1, 25%) for COVID-19 infection. Conclusions.— Our study shows that patients infected with COVID-19 not only have diffuse alveolar damage but also commonly have acute bronchopneumonia and aspiration pneumonia. These findings are important for management of these patients.

Abstract Aims Coronavirus disease 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been associated with cardiovascular features of myocardial involvement including elevated serum troponin levels and acute heart failure with reduced ejection fraction. The cardiac pathological changes in these patients with COVID-19 have yet to be well described. Methods and results In an international multicentre study, cardiac tissue from the autopsies of 21 consecutive COVID-19 patients was assessed by cardiovascular pathologists. The presence of myocarditis, as defined by the presence of multiple foci of inflammation with associated myocyte injury, was determined, and the inflammatory cell composition analysed by immunohistochemistry. Other forms of acute myocyte injury and inflammation were also described, as well as coronary artery, endocardium, and pericardium involvement. Lymphocytic myocarditis was present in 3 (14%) of the cases. In two of these cases, the T lymphocytes were CD4 predominant and in one case the T lymphocytes were CD8 predominant. Increased interstitial macrophage infiltration was present in 18 (86%) of the cases. A mild pericarditis was present in four cases. Acute myocyte injury in the right ventricle, most probably due to strain/overload, was present in four cases. There was a non-significant trend toward higher serum troponin levels in the patients with myocarditis compared with those without myocarditis. Disrupted coronary artery plaques, coronary artery aneurysms, and large pulmonary emboli were not identified. Conclusions In SARS-CoV-2 there are increased interstitial macrophages in a majority of the cases and multifocal lymphocytic myocarditis in a small fraction of the cases. Other forms of myocardial injury are also present in these patients. The macrophage infiltration may reflect underlying diseases rather than COVID-19.

Context.— Distinguishing pulmonary sarcomatoid carcinoma from pleural sarcomatoid mesothelioma is challenging because of overlapping histology, immunophenotype, and clinical features. Reliable immunohistochemical markers to aid in this distinction would be very valuable. Recent studies have proposed that MUC4 expression is common in sarcomatoid carcinoma but not in sarcomatoid mesothelioma, with the converse pattern reported for GATA3. Objective.— To further explore the utility of MUC4 and GATA3 in distinguishing pulmonary sarcomatoid carcinoma from sarcomatoid mesothelioma. Design.— Well-characterized cases of sarcomatoid carcinoma (n = 32) and sarcomatoid mesothelioma (n = 64) were included. Diagnoses were confirmed by thoracic pathologists with incorporation of immunophenotype, clinical, and radiographic features. Whole-tissue sections were stained for GATA3 and MUC4. Results.— Patients with sarcomatoid carcinoma and sarcomatoid mesothelioma had similar mean age and male predominance. GATA3 was positive in 63 of 64 sarcomatoid mesotheliomas (98%; 42 diffuse, 16 patchy, 5 focal), and 15 of 32 sarcomatoid carcinomas (47%; 3 diffuse, 8 patchy, 4 focal). MUC4 was positive in 2 of 64 sarcomatoid mesotheliomas (3%; 1 patchy, 1 focal), and in 12 of 32 sarcomatoid carcinomas (38%; 5 diffuse, 6 patchy, 1 focal). Conclusions.— Diffuse GATA3 expression favors sarcomatoid mesothelioma over sarcomatoid carcinoma, which rarely shows diffuse expression (sensitivity and specificity of diffuse staining 66% and 94%, respectively). Focal and patchy GATA3 expression is observed in both tumor types, and therefore is not helpful in this distinction. Sensitivity of MUC4 for sarcomatoid carcinoma was low in our cohort, positive in only 38% with frequent patchy staining, but it was quite specific.