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Since its initial recognition in December 2019, Coronavirus disease 19 (COVID-19) has quickly spread to a pandemic infectious disease. The causative agent has been recognized as a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily affecting the respiratory tract. To date, no vaccines are available nor any specific treatment. To limit the number of infections, strict directives have been issued by governments that have been translated into equally rigorous guidelines notably for post-mortem examinations by international and national scientific societies. The recommendations for biosafety control required during specimen collection and handling have strongly limited the practice of autopsies of the COVID-19 patients to a few adequate laboratories. A full pathological examination has always been considered an important tool to better understand the pathophysiology of diseases, especially when the knowledge of an emerging disorder is limited and the impact on the healthcare system is significant. The first evidence of diffuse alveolar damage in the context of an acute respiratory distress syndrome has now been joined by the latest findings that report a more complex scenario in COVID-19, including a vascular involvement and a wide spectrum of associated pathologies. Ancillary tools such as electron microscopy and molecular biology used on autoptic tissue samples from autopsy are also significantly contributing to confirm and/or identify new aspects useful for a deeper knowledge of the pathogenetic mechanisms. This article will review and summarize the pathological findings described in COVID-19 until now, chiefly focusing on the respiratory tract, highlighting the importance of autopsy towards a better knowledge of this disease.

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.

Recent literature has shown the presence of B cells and autoantibodies in idiopathic pulmonary fibrosis (IPF) which would imply the presence of tertiary lymphoid structures (TLS, sites where the immune response is triggered), yet TLS are not considered features of the histological characteristics of IPF. This study aims to quantify the presence, size, and degree of activation of TLS in biopsied and explanted lungs from patients with early- and late-IPF, never treated with antifibrotics, and relate their presence and activity to the clinical course, disease progression, and lung inflammation. Immunohistochestry for B cells and CD4, CD8, and CD45 cells was performed in lung tissue from IPF patients: 18 at diagnosis (early), 39 explanted (end-stage), and 12 smoking controls. TLS activation was assessed by CD40 expression. Spirometry along 31 (12-72) months of follow-up was used to characterize end-stage IPF as slow progressors or rapid progressors. B cells, along with other inflammatory cells, were higher in early- and end-stage IPF than in controls ( < 0.001). In rapid progressors, all inflammatory cells were higher than in slow progressors ( < 0.05). TLS were present in 100% of early- and end-stage IPF and in 50% of controls. In end-stage IPF, the TLS area and activation score were higher than in early IPF ( < 0.0001; = 0.005) and controls ( < 0.04; < 0.002). TLS activation score correlated with FVC decline during follow-up in rapid progressors ( = 0.73; = 0.007) but not in slow progressors. A prominent B-cell infiltration, along with the presence of TLS, the activity of which correlates with FVC decline, is an important component of IPF from the beginning of the disease, likely playing an important role on its mechanism and progression.

Plasma donor-derived cell-free DNA (dd-cfDNA) is an emerging potential tool for diagnosing lung graft injury. This study explored the relevance of dd-cfDNA levels in different graft injuries thoroughly characterized after a well-established multidisciplinary team approach. The usefulness of bronchoalveolar lavage (BAL) dd-cfDNA in complementing detection of allograft injury was also investigated. Plasma dd-cfDNA was measured by next generation sequence on 127 samples from patients visited consecutively, contemporaneously with a systematic analysis of surveillance transbronchial biopsy by LASHA template, BAL analysis and immunological monitoring. Patients with immunological injury exhibited the highest plasma dd-cfDNA levels (median 2.67%), with a sensitivity of 100% while patients with non-immunological insults showed a sensitivity of 28%. The combination of BAL with plasma dd-cfDNA improved the sensitivity for detecting non-immunological injury from 28% to 71%. Random forest analysis showed that plasma dd-cfDNA >1% was among the most important variables in predicting death and chronic lung allograft dysfunction. Our data suggests that plasma dd-cfDNA is a useful tool for immunological graft injury assessment. The performance of BAL dd-cf DNA needs to be validated on larger case series. The integration of plasma dd-cfDNA with other post-transplant follow-up investigations may allow more sensitive diagnoses and appropriate graft injury management.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by irreversible scarring of the distal lung. IPF is best described by its histopathological pattern of usual interstitial pneumonia (UIP), characterized by spatial heterogeneity with alternating interstitial fibrosis and areas of normal lung, and temporal heterogeneity of fibrosis characterized by scattered fibroblastic foci (FF), dense acellular collagen and honeycomb changes. FF, comprising aggregated fibroblasts/myofibroblasts surrounded by metaplastic epithelial cells (EC), are the cardinal pathological lesion and their presence strongly correlates with disease progression and mortality. We hypothesized that the EC/FF sandwich from patients with UIP/IPF has a distinct molecular signature which could offer new insights into the crosstalk of these two crucial actors in the disease. Laser capture microdissection with RNAseq was used to investigate the transcriptome of the EC/FF sandwich from IPF patients versus controls (primary spontaneous pneumothorax). Differentially expressed gene analysis identified 23 up-regulated genes mainly related to epithelial dysfunction. Gene ontology analysis highlighted the activation of different pathways, mainly related to EC, immune response and programmed cell death. This study provides novel insights into the IPF pathogenetic pathways and suggests that targeting some of these up-regulated pathways (particularly those related to secreto-protein/mucin dysfunction) may be beneficial in IPF. Further studies in a larger number of lung samples, ideally from patients with early and advanced disease, are needed to validate these findings.

COVID-19-related acute respiratory distress syndrome (CARDS) is associated with high mortality rates. We still have limited knowledge of the complex alterations developing in the lung microenvironment. The goal of the present study was to comprehensively analyze the cellular components, inflammatory signature, and respiratory pathogens in bronchoalveolar lavage (BAL) of CARDS patients (16) in comparison to those of other invasively mechanically ventilated patients (24). In CARDS patients, BAL analysis revealed: SARS-CoV-2 infection frequently associated with other respiratory pathogens, significantly higher neutrophil granulocyte percentage, remarkably low interferon-gamma expression, and high levels of interleukins (IL)-1β and IL-9. The most important predictive variables for worse outcomes were age, IL-18 expression, and BAL neutrophilia. To the best of our knowledge, this is the first study that was able to identify, through a comprehensive analysis of BAL, several aspects relevant to the complex pathophysiology of CARDS.

The term progressive pulmonary fibrosis (PPF) refers to a specific disorder that becomes worse despite optimal treatment. The pathogenic explanation of this progressive worsening is still to be found. In this study, we explored whether any histological, molecular, radiological, or clinical features could predict a progressive phenotype in patients with fibrotic interstitial lung diseases. Two hundred and fifteen patients with PPF other than idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated ILD (CTD-ILD) were followed in our ILD clinic between January 2016 and May 2023. Based on tissue block availability, 48 patients were definitively enrolled. Progression was defined according to the most recent guidelines. Clinical, radiological, and functional data were also collected retrospectively and correlated with tissue morphological and molecular cytokine profiles. Fifteen patients were classified as progressors (PPF) and 33 as non-progressors (nPPF) with similar age at diagnosis and gender. PPF showed a higher prevalence of traction bronchiectasis (80% vs. 27%; p=<0.001) at CT scan and lower functional parameters [FVC: 2.42 L vs. 3.37 L; p=0.004; TLC: 3.83 L vs. 4.65 L; p=0.027] at diagnosis. Lung specimens revealed a significant overexpression of IL9 in the PPF compared to the nPPF group (p=0.049). Boruta algorithm analysis showed that lymphoid aggregates and traction bronchiectasis at diagnosis are the most important variables in determining the PPF status. The present results increase the understanding of the pathological mechanisms of PPF, offering potential avenues for improved prognostication and therapeutic intervention.

PRAME (Preferentially Expressed Antigen in Melanoma) is increasingly used as an immunohistochemical marker in the evaluation of melanocytic lesions; however, its expression in benign melanocytic proliferations remains incompletely characterized. This study investigated PRAME expression in melanoacanthomas, with particular emphasis on its relationship with ultraviolet exposure and chronic solar damage. A consecutive series of melanoacanthomas was retrospectively analyzed. Melanocytes were identified and quantified using SOX10 immunohistochemistry, while PRAME-positive melanocytes were counted and graded semiquantitatively according to nuclear staining intensity. PRAME expression was correlated with lesion site (photoexposed versus non-photoexposed skin) and with the degree of solar elastosis. Eighty-four cases were evaluated, of which 25 (29.8%) showed at least focal PRAME positivity in melanocytes. Overall melanocytic density assessed by SOX10 did not differ significantly between photoexposed and non-photoexposed lesions. Similarly, stratification based on total PRAME-positive melanocyte counts, irrespective of staining intensity, revealed no significant association with photoexposure. In contrast, analysis restricted to melanocytes with strong nuclear PRAME expression demonstrated a significant enrichment in photoexposed lesions compared with non-photoexposed sites (p < 0.01). Moreover, high-intensity PRAME expression showed a positive association with increasing grades of solar elastosis. These findings indicate that strong PRAME expression in melanoacanthoma could be associated with chronic sun damage and may reflect non-specific, ultraviolet-related modulation rather than malignant transformation, underscoring the importance of contextual interpretation of PRAME immunohistochemistry in diagnostic practice.

Bronchial carcinoids are uncommon neuroendocrine tumors. According to their pathological differentiation, they are divided into typical and atypical forms, with diverse biological behavior and aggressiveness. Bronchial carcinoids may be associated with familial neuroendocrine syndromes, such as MEN‐1. They can also present initially as diffuse hyperplastic proliferation of neuroendocrine foci throughout the pulmonary parenchyma (DIPNECH). Metachronous and bilateral forms are sporadic in the literature. We describe a case of a 68‐year‐old man with metachronous bilateral typical‐atypical carcinoid neoplasms. The patient was treated with a two‐stage mini‐invasive pulmonary surgery in a time frame of 5 years. This case may be unique because it features two rare and distinct pathological entities in the same patient, not associated with any known genetic mutation. Carcinoid tumors require multidisciplinary care and a collaborative approach due to their pleomorphic behavior, ensuring comprehensive management and maximizing therapeutic efficacy.

Pulmonary nodules detected in patients with a history of malignancy are often clinically presumed to represent metastatic disease until proven otherwise. Granular cell tumor (GCT) is an uncommon, usually benign neoplasm of presumed Schwannian origin, which rarely occurs in the lung. Our aim is to emphasize the diagnostic challenges and the crucial role of histopathology in preventing overtreatment in oncology patients. Herein, we report the case of a 56-year-old woman with a previous history of papillary renal cell carcinoma diagnosed one year earlier, staged as pT1, WHO/ISUP grade 2, and treated with partial nephrectomy, with no evidence of residual disease or distant metastases at follow-up. During routine surveillance, she developed a solitary pulmonary nodule. Chest computed tomography (CT) showed a 12 mm solid nodule in the left upper lobe which was then further investigated with a positron emission tomography with 2-[18F] fluoro-2-deoxy-D-glucose [(18F)-FDG PET/CT, revealing a low glucidic uptake (SUVmax 4 and SUV mean 1.4). Endobronchial ultrasound-guided biopsy was non-diagnostic. Given the patient’s oncological history, the solid appearance on CT, and the mild FDG uptake, metastatic disease could not be excluded, and a parenchyma-sparing diagnostic wedge resection was performed. Histology showed a well-circumscribed proliferation of epithelioid cells with abundant granular eosinophilic cytoplasm and bland nuclei. Immunohistochemistry demonstrated diffuse S100 and CD68 positivity, supporting the diagnosis of primary pulmonary granular cell tumor. This case underscores the critical role of histopathological evaluation in the assessment of solitary pulmonary nodules, emphasizing that lesions identified during oncologic surveillance are not invariably indicative of malignancy.