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The World Health Organization (WHO) highlights a greater susceptibility of males to tuberculosis (TB), a vulnerability attributed to sex-specific variations in body fat and dietary factors. Our study delves into the unexplored terrain of how alterations in body fat influence Mycobacterium tuberculosis ( Mtb ) burden, lung pathology, immune responses, and gene expression, with a focus on sex-specific dynamics. Utilizing a low-dose Mtb -HN878 clinical strain infection model, we employ transgenic FAT-ATTAC mice with modulable body fat to explore the impact of fat loss (via fat ablation) and fat gain (via a medium-fat diet, MFD). Firstly, our investigation unveils that Mtb infection triggers severe pulmonary pathology in males, marked by shifts in metabolic signaling involving heightened lipid hydrolysis and proinflammatory signaling driven by IL-6 and localized pro-inflammatory CD8 + cells. This stands in stark contrast to females on a control regular diet (RD). Secondly, our findings indicate that both fat loss and fat gain in males lead to significantly elevated (1.6-fold ( p ≤ 0.01) and 1.7-fold ( p ≤ 0.001), respectively) Mtb burden in the lungs compared to females during Mtb infection (where fat loss and gain did not alter Mtb load in the lungs). This upsurge is associated with impaired lung lipid metabolism and intensified mitochondrial oxidative phosphorylation-regulated activity in lung CD8 + cells during Mtb infection. Additionally, our research brings to light that females exhibit a more robust systemic IFNγ ( p ≤ 0.001) response than males during Mtb infection. This heightened response may either prevent active disease or contribute to latency in females during Mtb infection. In summary, our comprehensive analysis of the interplay between body fat changes and sex bias in Mtb infection reveals that alterations in body fat critically impact pulmonary pathology in males. Specifically, these changes significantly reduce the levels of pulmonary CD8 + T-cells and increase the Mtb burden in the lungs compared to females. The reduction in CD8 + cells in males is linked to an increase in mitochondrial oxidative phosphorylation and a decrease in TNFα, which are essential for CD8 + cell activation.

The curriculum vitae of Dr. Mark R. Wick contains 57 peer-reviewed publications, 3 editorials, 6 book chapters and a whole book dedicated to diseases of the lung and pleura. It is remarkable that such productivity should represent only a small portion of the overall output of Dr. Wick, which includes (at last count) 341 original peer-review publications, 119 invited review articles, 93 book chapters, 42 editorials, 3 society-related position papers, 18 books and 2 interactive video disks. Yet, his contributions to the literature in pulmonary and pleural pathology have been significant and influential and have established for him a national and international reputation as one of the leading experts in pulmonary pathology. Herein, it is my privilege to recount the various publications contributed by Dr. Wick to this topic, which span the gamut from transplant pathology to neoplastic diseases of the lung and pleura., Competing Interests: Declaration of competing interest There is no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a viral pneumonia characterized by acute interstitial pneumonia and diffuse alveolar damage in humans. Non-human primates (NHPs) are widely used as preclinical animal models for vaccine development against SARS-CoV-2. However, the pathological changes in NHPs have been described only in selected facets and inconsistent nomenclature is used, making it difficult to interpret and compare the outcomes between studies. Here, we present a standardized methodology for histopathological evaluation of experimental infection outcomes in rhesus (Macaca mulatta) and cynomolgus (Macaca fascicularis) macaques. Evaluation criteria for vascular and epithelial changes in the early (3 days post infection [dpi]) and late (21 dpi) phases of the infection were developed, and a four-grade classification encompassing all the histopathological lung lesions was established. The grades of histopathological lung lesions were higher at 3 dpi compared with 21 dpi in both species of macaques, and there were no statistically significant differences in the grades between the two species at 3 dpi and 21 dpi. This study contextualized the pathological SARS-CoV-2 presentation and standardized the terminology and grading scale for lesion severity to facilitate histopathological examination in the macaque model. By referring to the standardized histopathological criteria and grades proposed here, comparable results with high reproducibility can be obtained in future studies of pathogenicity., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Minimally invasive autopsies (MIAs) allow the collection of tissue samples for diagnostic and research purposes in special situations, e.g., when there is a high risk of infection which is the case in the context of COVID-19 or restrictions due to legal or personal reasons. We performed MIA to analyze lung tissue from 92 COVID-19 patients (mean age 78 years; range 48-98; 35 women, 57 men), representing 44% of all patients who died from the disease between October 2020 and April 2021. An intercostal approach was used with removal of a 5-cm rib section followed by manual collection of four lung tissue samples (5-8 cm in size). Diffuse alveolar damage (DAD) was found in 89 (97%) patients at various stages. Exudative DAD (eDAD) predominated in 18 (20%) patients, proliferative DAD (pDAD) in 43 (47%) patients, and mixed DAD (mDAD) in 31 (34%) patients. There were no significant differences in the predominant DAD pattern between tissue samples from the same patient. Additional purulent components were present in 46 (50%) cases. Fungi were detected in 11 (12%) patients. The pDAD pattern was associated with longer hospital stay including intensive care unit (p=0.026 and p<0.001) and younger age (p=0.019). Positive bronchoalveolar lavage and blood cultures were observed more frequently in pDAD patterns (p<0.001; p=0.018). In contrast, there was no significant association between intravital positive microbiological results and superimposed bronchopneumonia or fungal infection at autopsy. Having demonstrated the characteristic lung changes in a large longitudinal autopsy series, we conclude that the presented MIA approach can be considered a reliable and safe method for performing post mortem lung diagnostics in COVID-19 and other high-risk situations. The lack of correlation between histological changes indicative of bacterial or fungal superinfection and microbiology could have clinical implications for disease and treatment surveillance., (© 2023. The Author(s).)

Background: Non-thrombotic pulmonary embolism, an uncommon entity, is defined as the embolization of tissues, microorganisms, air, or foreign material. One subset in this non-thrombotic category is septic pulmonary embolism (SPE) that refers to embolism of microorganisms with or without a thrombotic mantle into the pulmonary vasculature. This condition is often recognized on the basis of imaging with a clinical correlation. Unfortunately, data regarding the pathological features are meager. This has prompted to review such cases at autopsy., Aims: To study the pathological features of SPE at autopsy., Materials and Methods: Ten-year (2012 to 2021) autopsy records of the hospital were retrospectively reviewed. The diagnosis was based on the identification of acute necrotizing pulmonary arteritis with peri-bronchoarterial consolidation. These cases were analyzed with reference to the demographics, clinical characteristics, and pulmonary/extrapulmonary findings at autopsy., Statistical Analysis: Nil., Results: According to the inclusion criterion, 19 cases demonstrated the presence of SPE. There were 11 men and 8 women with a mean age of 32.1 years. The major source of infection included infection arising from skin and musculo-skeletal system (11 patients, 59.7%). The common clinical presentation included fever, dyspnea, chest pain, hemoptysis, and altered sensorium. The cause of death was mainly due to septicemia and/or confluent lung consolidations. A large number of bacterial colonies were seen in all; Candida species were also identified in two cases. Other lung findings included diffuse alveolar damage, fresh arterial thrombosis, infarction, arterial pseudo-aneurysms, abscess formation, and pyogenic pleuritis., Conclusion: Presence of an extrapulmonary infection with persistent fever, bacteremia, and pulmonary complaints should raise suspicion for this entity, particularly in resource-poor settings, to prevent grave pulmonary complications.

Objectives: Mesothelioma is a lethal disease that arises from the serosal lining of organ cavities. Several recurrent alterations have been observed in pleural and peritoneal -mesotheliomas, including in BAP1, NF2, and CDKN2A. Although specific histopathologic parameters have been correlated with prognosis, it is not as well known whether genetic alterations correlate with histologic findings., Methods: We reviewed 131 mesotheliomas that had undergone next-generation sequencing (NGS) at our institutions after pathologic diagnosis. There were 109 epithelioid mesotheliomas, 18 biphasic mesotheliomas, and 4 sarcomatoid mesotheliomas. All our biphasic and sarcomatoid cases arose in the pleura. Of the epithelioid mesotheliomas, 73 were from the pleura and 36 were from the peritoneum. On average, patients were 66 years of age (range, 26-90 years) and predominantly male (92 men, 39 women)., Results: The most common alterations identified were in BAP1, CDKN2A, NF2, and TP53. Twelve mesotheliomas did not show a pathogenic alteration on NGS. For epithelioid mesotheliomas in the pleura, the presence of an alteration in BAP1 correlated with low nuclear grade (P = .04), but no correlation was found in the peritoneum (P = .62). Similarly, there was no correlation between the amount of solid architecture in epithelioid mesotheliomas and any alterations in the pleura (P = .55) or peritoneum (P = .13). For biphasic mesotheliomas, cases with either no alteration detected or with an alteration in BAP1 were more likely to be epithelioid predominant (>50% of the tumor, P = .0001), and biphasic mesotheliomas with other alterations detected and no alteration in BAP1 were more likely to be sarcomatoid predominant (>50% of the tumor, P = .0001)., Conclusions: This study demonstrates a significant association between morphologic features associated with a better prognosis and an alteration in BAP1., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The diagnostic performance of cytology was compared with the frozen results and its usability was evaluated as a rapid diagnosis method in intraoperative thoracic surgery in a single institution (Istanbul, Turkey)., Methods: All 197 subsequent patient specimens (cases) from 158 patients who were sent to our department from the thoracic surgery clinic for an intraoperative diagnosis request between the years 2016 and 2021 were evaluated. Obtained results from frozen and cytology were compared with final paraffin section diagnoses. Lesions were grouped into three different groups as nonneoplastic, benign, and malignant neoplasms., Results: Diagnostic accuracy values of cytology and frozen sections in intraoperative consultation were 98.8% and 99.4%, respectively. Sensitivity values of cytology and frozen sections in intraoperative consultation were 96.3% and 98.7%, respectively. Specificity values of cytology and frozen sections in intraoperative consultation were 100% and 100%, respectively. Negative predictive values of cytology and frozen sections in intraoperative consultation were 96.7% and 98.9%, respectively. Positive predictive values of cytology and frozen sections in intraoperative consultation were 100% and 100%, respectively. Kappa statistics between cytology and frozen revealed a very high interrater reliability (Cohen's Kappa value: 0.911; p = .001; p < .01). The difficulty in distinguishing primary and metastatic carcinoma, which is mostly undecided in frozen sections and the definitive diagnosis is left to paraffin sections, seems also be a problem in the cytological examination., Conclusions: Cytological diagnosis can be used in the evaluation of small biopsy specimens that require tissue preservation in intraoperative consultation, especially for immunohistochemical and advanced genetic studies., (© 2022 Wiley Periodicals LLC.)

Epithelioid hemangioendothelioma (EHE) is a rare neoplasm of a vascular origin which can arise in different locations such as the lungs, liver, soft tissue, and rarely, in the bones. In the lungs, pulmonary hemangioendothelioma (PEH) shows a variable clinical behavior, displaying a range from either an asymptomatic course to a highly aggressive progression with metastases. Based on radiological features, PEH differential diagnosis mainly includes primary or metastatic lymphangitic carcinomatosis, granulomatous infections, and diffuse interstitial lung diseases where ground glass pattern predominates. In this case, a transbronchial biopsy and subsequent histological and immunohistochemical analysis allowed for the attribution of the scenario to a pulmonary epithelioid hemangioendothelioma. Clinicians should always consider bronchoscopy as a useful and effective tool to better investigate indeterminate and questionable clinical pictures, sparing patients the morbidity and mortality associated with more invasive techniques such as surgical or thoracoscopic biopsy.

The application of whole-body post-mortem computed tomography (PMCT) in veterinary and wildlife post-mortem research programs is advancing. A high incidence of pulmonary pathology is reported in the harbor porpoise ( Phocoena phocoena ). In this study, the value of PMCT focused on pulmonary assessment is evaluated. The objectives of this study were to describe pulmonary changes as well as autolytic features detected by PMCT examination and to compare those findings with conventional necropsy. Retrospective evaluation of whole-body PMCT images of 46 relatively fresh harbor porpoises and corresponding conventional necropsy reports was carried out, with a special focus on the respiratory tract. Common pulmonary PMCT findings included: moderate (24/46) to severe (19/46) increased pulmonary soft tissue attenuation, severe parasite burden (17/46), bronchial wall thickening (30/46), and mild autolysis (26/46). Compared to conventional necropsy, PMCT more frequently identified pneumothorax (5/46 vs. none), tracheal content (26/46 vs. 7/46), and macroscopic pulmonary mineralization (23/46 vs. 11/46), and provided more information of the distribution of pulmonary changes. These results indicate that PMCT adds information on pulmonary assessment and is a promising complementary technique for necropsy, despite the frequent presence of mild autolytic features.

Background Hypersensitivity pneumonitis (HP) infrequently presents in childhood. Asthma or a pneumonia-like clinical presentation may lead to diagnostic delay, especially in children. Case Report: We present two cases of HP, a 6-year-old (Case 1) male and a 5-year-old (Case 2) female. Both cases had a negative infectious work-up and patchy ground glass lung opacities on chest computed tomography. Lung biopsies demonstrated lymphocytic bronchiolitis with granulomatous interstitial and peribronchial inflammation. Serology demonstrated elevated immunoglobulin precipitins toward Thermoactinomyces and Aspergillus species in Case 1 and Aspergillus fumigatus in Case 2. Both patients received steroid therapy and had symptom resolution. Conclusions: A diagnosis of HP should be considered in pediatric lung biopsies with granulomatous interstitial and peribronchial inflammation, if infectious etiologies are excluded. Integration of clinical, radiological, and laboratory findings can facilitate a timely diagnosis.

Background: Despite the rapidly expanding data on clinical, epidemiological and radiological aspects of coronavirus disease 2019 (COVID-19), little is known about the disease's pathological aspects. The scarcity of pathological data on COVID-19 can be explained by the limited autopsy procedures performed on deceased patients., Aim: This work aims to review and summarize the pulmonary pathological findings observed in COIVD-19 deceased individuals based on recent case series reports published in English up to September 2020., Methods: A search in Google Scholar, PubMed Ò , MEDLINE Ò , and Scopus was performed using the keywords "autopsy and COVID-19," "postmortem and COVID-19," and "pulmonary/lung pathology and COVID-19.", Results: Pulmonary autopsy hallmark findings of COVID-19 cases demonstrate the presence of diffuse alveolar damage. The presence of pulmonary thrombi was reported in the majority of patients. Cellular alterations included type 2 pneumocyte hyperplasia, inflammatory cell infiltrates predominantly by lymphocytes, other mononuclear cells, and neutrophils as evident by their specific immunohistochemical markers. Electron microscopy confirmed the presence of virus particles in different cell types, including types 1 and 2 pneumocytes., Conclusion: The few emerging autopsy reports have substantially contributed towards our understanding of COVID-19 pulmonary histopathological aspects. COVID-19 caused acute severe respiratory manifestations that are the leading cause of morbidity and mortality in infected patients. More studies and research are needed to understand the inflammatory processes and histopathological changes associated with COVID-19 in African populations., Relevance for Patients: Postmortem investigations advance important mechanistic knowledge on COVID-19 pathophysiology and clinical outcomes and could facilitate provisions for targeted therapies., Competing Interests: The authors declare no conflict of interest., (Copyright: © Whioce Publishing Pte. Ltd.)

Coronavirus disease 2019 (COVID-19) has shown the importance of postmortem investigation of deceased patients. For a correct interpretation of the pulmonary findings in this new era, it is, however, crucial to be familiar with pathologic pulmonary conditions observed in postmortem investigations in general. Adequate postmortem histopathological evaluation of the lungs may be affected by suboptimal gross work up, autolysis or poor fixation. Using a standardized preparation approach which consisted in instillation of 4% buffered formaldehyde through the large bronchi for proper fixation and preparing large frontal tissue sections of 1-2 cm thickness after at least 24 h fixation, we comprehensively analyzed postmortem pulmonary findings from consecutive adult autopsies of a two-year period before the occurrence of COVID-19 (2016-2017). In total, significant pathological findings were observed in 97/189 patients (51%), with 28 patients showing more than one pathologic condition. Acute pneumonia was diagnosed 33/128 times (26%), embolism 24 times (19%), primary pulmonary neoplasms 18 times (14%), organizing pneumonia and other fibrosing conditions 14 times (11%), pulmonary metastases 13 times (10%), diffuse alveolar damage 12 times (9%), severe emphysema 9 times (7%) and other pathologies, e.g., amyloidosis 5/128 times (4%). Pulmonary/cardiopulmonary disease was the cause of death in 60 patients (32%). Clinical and pathological diagnoses regarding lung findings correlated completely in 75 patients (40%). Autopsy led to confirmation of a clinically suspected pulmonary diagnosis in 57 patients (39%) and clarification of an unclear clinical lung finding in 16 patients (8%). Major discrepant findings regarding the lungs (N = 31; 16%) comprised cases with clinical suspicions that could not be confirmed or new findings not diagnosed intra vitam . A significant proportion of acute pneumonias (N = 8; 24% of all cases with this diagnosis; p = 0.011) was not diagnosed clinically. We confirmed the frequent occurrence of pulmonary pathologies in autopsies, including inflammatory and neoplastic lesions as the most frequent pathological findings. Acute pneumonia was an important cause for discrepancy between clinical and postmortem diagnostics.

COVID-19 has quickly reached pandemic levels since it was first reported in December 2019. The virus responsible for the disease, named SARS-CoV-2, is enveloped positive-stranded RNA viruses. During its replication in the cytoplasm of host cells, the viral genome is transcribed into proteins, such as the structural protein spike domain S1, which is responsible for binding to the cell receptor of the host cells. Infected patients have initially flu-like symptoms, rapidly evolving to severe acute lung injury, known as acute respiratory distress syndrome (ARDS). ARDS is characterized by an acute and diffuse inflammatory damage into the alveolar-capillary barrier associated with a vascular permeability increase and reduced compliance, compromising gas exchange and causing hypoxemia. Histopathologically, this condition is known as diffuse alveolar damage which consists of permanent damage to the alveoli epithelial cells and capillary endothelial cells, with consequent hyaline membrane formation and eventually intracapillary thrombosis. All of these mechanisms associated with COVID-19 involve the phenotypic expression from different proteins transcription modulated by viral infection in specific pulmonary microenvironments. Therefore, this knowledge is fundamentally important for a better pathophysiological understanding and identification of the main molecular pathways associated with the disease evolution. Evidently, clinical findings, signs and symptoms of a patient are the phenotypic expression of these pathophysiological and molecular mechanisms of SARS-CoV-2 infection. Therefore, no findings alone, whether molecular, clinical, radiological or pathological axis are sufficient for an accurate diagnosis. However, their intersection and/or correlation are extremely critical for clinicians establish the diagnosis and new treatment perspectives., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Diabetes mellitus type 2 (DM) may impede immune responses in tuberculosis (TB) and thus contribute to enhanced disease severity. In this study, we aimed to evaluate DM-mediated alterations in clinical, radiological and immunological outcomes in TB disease., Methods: Newly diagnosed pulmonary TB patients with or without DM (TB n = 40; TB-DM n = 40) were recruited in Dhaka, Bangladesh. Clinical symptoms, sputum smear and culture conversion as well as chest radiography were assessed. Peripheral blood and sputum samples were collected at the time of diagnosis (baseline) and after 1, 2 and 6 months of standard anti-TB treatment. Blood samples were also obtained from healthy controls (n = 20). mRNA expression of inflammatory markers in blood and sputum samples were quantified using real-time PCR., Results: The majority of TB-DM patients had poor glycemic control (HbA1c > 8%) and displayed elevated pulmonary pathology (P = 0.039) particularly in the middle (P < 0.004) and lower lung zones (P < 0.02) throughout the treatment period. However, reduction of clinical symptoms and time to sputum smear and culture conversion did not differ between the groups. Transcripts levels of the pro-inflammatory cytokines IL-1β (P = 0.003 at month-1 and P = 0.045 at month-2) and TNF-α (P = 0.005 at month-1) and the anti-inflammatory cytokine IL-10 (P = 0.005 at month-2) were higher in peripheral blood after anti-TB treatment in TB-DM compared to TB patients. Conversely in sputum, TB-DM patients had reduced CD4 (P < 0.009 at month-1) and IL-10 (P = 0.005 at month-1 and P = 0.006 at month-2) transcripts, whereas CD8 was elevated (P = 0.016 at month-2). At 1- and 2-month post-treatment, sputum IL-10 transcripts were inversely correlated with fasting blood glucose and HbA1c levels in all patients., Conclusion: Insufficient up-regulation of IL-10 in the lung may fuel persistent local inflammation thereby promoting lung pathology in TB-DM patients with poorly controlled DM.

Competing Interests: Competing interests: None declared.

Objectives: Although diffuse alveolar damage, a subtype of acute lung injury (ALI), is the most common microscopic pattern in coronavirus disease 2019 (COVID-19), other pathologic patterns have been described. The aim of the study was to review autopsies from COVID-19 decedents to evaluate the spectrum of pathology and correlate the results with clinical, laboratory, and radiologic findings., Methods: A comprehensive and quantitative review from 40 postmortem examinations was performed. The microscopic patterns were categorized as follows: "major" when present in more than 50% of cases and "novel" if rarely or not previously described and unexpected clinically., Results: Three major pulmonary patterns were identified: ALI in 29 (73%) of 40, intravascular fibrin or platelet-rich aggregates (IFPAs) in 36 (90%) of 40, and vascular congestion and hemangiomatosis-like change (VCHL) in 20 (50%) of 40. The absence of ALI (non-ALI) was novel and seen in 11 (27%) of 40. Compared with ALI decedents, those with non-ALI had a shorter hospitalization course (P = .02), chest radiographs with no or minimal consolidation (P = .01), and no pathologically confirmed cause of death (9/11). All non-ALI had VCHL and IFPAs, and clinically most had cardiac arrest., Conclusions: Two distinct pulmonary phenotypic patterns-ALI and non-ALI-were noted. Non-ALI represents a rarely described phenotype. The cause of death in non-ALI is most likely COVID-19 related but requires additional corroboration., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

During the COVID-19 pandemic, many deaths occurred especially among the old patients with cardiovascular comorbidities. Many questions have been asked and few simple answers have been given. The autopsy data are few and the aspects often observed are pulmonary diffuse alveolar damage (DAD), myocarditis, acute myocardial infarction (AMI), and disseminated intravascular coagulation (DIC); these aspects are not only in COVID-19 but also in other viral infections and in sepsis. It should be considered that coronavirus with its pathological organ changes have already been described in the years preceding the pandemic., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

Sclerosing pneumocytoma (SP) is a rare benign low-grade tumour of the lung, and typically presents as single discrete coin lesions on imaging. Multiple SP is an exceedingly rare entity and thus reported sparingly. We review the literature on multiple SP, their clinical presentations, histopathology, relevant differential diagnoses and molecular histogenesis of this entity. SP has a predilection for East Asian origin females who have never smoked. Patients are either asymptomatic or have symptoms such as cough, haemoptysis that may be persistent, chest pain if involving the pleura and presents as discrete coin lesion on chest X-ray. Histologically, they are papillary, solid, angiomatoid or sclerotic, or combinations of these four basic patterns. Multiple lesions have the same or slightly different histological patterns. They can be distributed in either lung, in any lobe and can even be bilateral. AKT-1 molecular pathways are pivotal in their molecular pathogenesis. In this review, we further propose a classification based on five types of distribution of multiple SP., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Investigate the impact of interlaboratory- and interobserver variability of immunohistochemistry on the assessment of programmed death ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC)., Methods: Two tissue microarrays (TMAs) were constructed from 50 (TMA-A) and 51 (TMA-B) resected NSCLC cases, and distributed among eight centres. Immunostaining for PD-L1 was performed using Agilent's 22C3 pharmDx Assay (pharmDx) and/or a 22C3 laboratory developed test (LDT). The interlaboratory variability of staining- and interobserver variability of scoring for PD-L1 were assessed in selected critical samples (samples at the cut-off of positivity) and non-critical samples. Also, PD-L1 epitope deterioration in time in stored unstained slides was analysed. Krippendorff's alpha values (0=maximal, 1=no variability) were calculated as measure for variability., Results: For interlaboratory variability of immunostaining, the percentage of PD-L1 positive cases among centres ranged 40%-51% (1% cut-off) and 23%-30% (50% cut-off). Alpha values at 1% cut-off were 0.88 (pharmDx) and 0.87 (LDT) and at 50% cut-off 0.82 (pharmDx) and 0.95 (LDT). Interobserver variability of scoring resulted in PD-L1 positive cases ranging 29%-55% (1% cut-off) and 14%-30% (50% cut-off) among pathologists. Alpha values were at 1% cut-off 0.83 (TMA-A) and 0.66 (TMA-B), and at 50% cut-off 0.77 (TMA-A) and 0.78 (TMA-B). Interlaboratory variability of staining was higher (p<0.001) in critical samples than in non-critical samples at 50% cut-off. Furthermore, PD-L1 epitope deterioration in unstained slides was observed after 12 weeks., Conclusions: The results provide insight in factors contributing to variability of immunohistochemical assessment of PD-L1, and contribute to more reliable predictive testing for PD-L1., Competing Interests: Competing interests: RB: none. N‘tH: MSD (unrestricted grant), Pfizer (personal fee). KM: Roche (research grant, personal fee), MSD (research grant, personal fee), Astra Zeneca (research grant, personal fee), Pfizer (personal fee), Benecke (personal fee), BMS (personal fee), Abbvie (personal fee), Diaceutics (personal fee). E-JS: MSD (research grant, personal fee), BMS (research grant, personal fee), Novartis (research grant), AstraZeneca (research grant), AbbVie (personal fee), Bayer (personal fee), Roche (personal fee). ET: HistoGeneX (personal fee), Roche Diagnostics (personal fee). JHVdT: Astellas (research grant), BMS (research grant, personal fee), AbbVie (personal fee), Astra Zeneca (personal fee), Boehringer-Ingelheim (personal fee), BMS (personal fee), Eli Lilly (personal fee), MSD (personal fee), Pfizer (personal fee), Roche (personal fee). WT: MSD (personal fee), Roche-Ventana (personal fee), Pfizer (personal fee), Astra Zeneca (personal fee), GSK (personal fee), Chiesi (personal fee), Dutch Asthma Fund (research grant), Biotest (personal fee), Novartis (personal fee), Lilly Oncology (personal fee), Boehringer Ingelheim (personal fee). MJvdV: MSD (research grant), Roche (personal fee)., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To report the methods and findings of two complete autopsies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive individuals who died in Oklahoma (United States) in March 2020., Methods: Complete postmortem examinations were performed according to standard procedures in a negative-pressure autopsy suite/isolation room using personal protective equipment, including N95 masks, eye protection, and gowns. The diagnosis of coronavirus disease 2019 (COVID-19) was confirmed by real-time reverse transcriptase polymerase chain reaction testing on postmortem swabs., Results: A 77-year-old obese man with a history of hypertension, splenectomy, and 6 days of fever and chills died while being transported for medical care. He tested positive for SARS-CoV-2 on postmortem nasopharyngeal and lung parenchymal swabs. Autopsy revealed diffuse alveolar damage and chronic inflammation and edema in the bronchial mucosa. A 42-year-old obese man with a history of myotonic dystrophy developed abdominal pain followed by fever, shortness of breath, and cough. Postmortem nasopharyngeal swab was positive for SARS-CoV-2; lung parenchymal swabs were negative. Autopsy showed acute bronchopneumonia with evidence of aspiration. Neither autopsy revealed viral inclusions, mucus plugging in airways, eosinophils, or myocarditis., Conclusions: SARS-CoV-2 testing can be performed at autopsy. Autopsy findings such as diffuse alveolar damage and airway inflammation reflect true virus-related pathology; other findings represent superimposed or unrelated processes., (© American Society for Clinical Pathology, 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Enterovirus 71 (EV71) is a major pathogen that causes hand, foot and mouth disease (HFMD), which is a life threatening disease in certain children. The pathogenesis of EV71-caused HFMD is poorly defined due to the lack of simple and robust animal models with severe phenotypes that recapitulate symptoms observed in humans. Here, we generated the infectious clone of a clinical isolate from a severe HFMD patient. Virus rescued from the cDNA clone was infectious in cell lines. When administrated intraperitoneally to neonatal ICR, BALB/c and C57 immune competent mice at a dosage of1.4 × 10 4  pfu per mouse, the virus caused weight loss, paralysis and death in the infected mice after 4-5 days of infection. In the infected mice, detectable viral replication was detected in various tissues such as heart, liver, brain, lung, kidney, small intestine, leg skeletal muscle and medulla oblongata. The histology of the infected mice included massive myolysis, glomerular atrophy, villous blunting in small intestine, widened alveolar septum, diminished alveolar spaces and lymphocytes infiltration into the lung. By using the UV-inactivated virus as a control, we elucidated that the virus first amplified in the leg skeletal muscle tissue and the muscle tissue served as a primary viral replication site. In summary, we generated a stable EV71 infectious clone that is capable of infecting neonatal immune competent mice without adaptive mutations and provide a simple, valuable animal model for the studies of EV71pathogenesis and therapy.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1 ., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2019.)

Objectives: We compared minimally invasive tissue sampling (MITS) with conventional autopsy (CA) in detection of respiratory pathology/pathogens among Kenyan children younger than 5 years who were hospitalized with respiratory disease and died during hospitalization., Methods: Pulmonary MITS guided by anatomic landmarks was followed by CA. Lung tissues were triaged for histology and molecular testing using TaqMan Array Cards (TACs). MITS and CA results were compared for adequacy and concordance., Results: Adequate pulmonary tissue was obtained by MITS from 54 (84%) of 64 respiratory deaths. Comparing MITS to CA, full histologic diagnostic concordance was present in 23 (36%) cases and partial concordance in 19 (30%), an overall 66% concordance rate. Pathogen detection using TACs had full concordance in 27 (42%) and partial concordance in 24 (38%) cases investigated, an overall 80% concordance rate., Conclusions: MITS is a viable alternative to CA in respiratory deaths in resource-limited settings, especially if combined with ancillary tests to optimize diagnostic accuracy., (© American Society for Clinical Pathology, 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The mechanism of oxaliplatin (OXA) induced pulmonary toxicity is not fully understood., Aim of the Study: The present study was designed to investigate the pulmonary toxicity of OXA that has been reported in previous studies. Study design: animal experiments., Material and Methods: A total of 40 female Wistar rats were divided into 5 groups. In group 1, 5% glucose was injected intra-peritoneally; then the rats were sacrificed on day 14. OXA was administered in groups 2, 3, 4, and 5; then the animals were sacrificed on day 7 in group 2, day 14 in group 3, day 28 in group 4 and day 48 in group 5. The groups were further categorized as short-term administration and long-term administration groups. Furthermore, tissue glutathione peroxidase (GPX) activity was measured in all rats., Results: The mean GPX activities were 0.66 U/mg in the sham group, 0.74 U/mg in the short-term groups, and 0.74 U/mg in the long-term groups. We found that long-term OXA administration causes pulmonary toxicity resulting in increased intra-alveolar/interstitial macrophages and interstitial pneumonia. Similarly, we found reduced and permanent tissue GPX activity in rats that received OXA in higher doses and for a long term., Conclusions: Long-term OXA therapy causes toxic changes in the lung tissue., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2019 Termedia Sp. z o. o.)

Tuberculosis remains a threat to public health. The major problem for curing this disease is latent infection, of which the underlying mechanisms are still not fully understood. Previous studies indicate that natural killer (NK) cells do not play a role in inhibiting the growth of Mycobacterium tuberculosis in the lung, and recent studies have revealed that NK cells regulate the adaptive immunity during mycobacterial infection. By using a mouse model of direct lung infection with Mycobacterium bovis bacillus Calmette-Guerin (BCG), we found that the presence of NK cells postponed the priming and activation of T cells after BCG infection. In addition, depletion of NK cells before infection alleviated pulmonary pathology. Further studies showed that NK cells lysed BCG-infected macrophages in an NKG2D dependent manner. Thus, NK cells did not play a direct role in control BCG, but aggravated the pulmonary inflammation and impaired anti-BCG T cell immunity, likely through killing BCG-infected macrophages. Our results may have important implications for the design of immune therapy to treat tuberculosis., (© 2018 John Wiley & Sons Ltd.)

Nestin is considered to be a cancer stem cell marker. Nestin expression in neuroendocrine tumours might be useful to predict prognosis and facilitate treatment planning. 88 patients with neuroendocrine lung tumours operated in the Department of Thoracic Surgery from 2007 to 2015 were included into the study. Immunohistochemical staining for nestin was performed. Clinicopathological and survival data were retrospectively analyzed. Nestin expression was detected in 15 (17%) specimens. Multivariate analysis showed that lymph node metastases (p = 0.0001; hazard ratio (HR) = 3.93; confidence interval (CI) 95%: 1.96-7.87), nestin expression (p = 0.034; HR = 2.30; CI 95%: 1.06-4.99) and patient's age (p = 0.024; HR = 1.04; CI 95%: 1.00-1.09) were independent negative prognostic factors. Nestin expression was significantly higher in large cell neuroendocrine carcinoma when compared with carcinoids (p = 0.001). Collected data support the thesis that nestin can be regarded as a biomarker in patients with neuroendocrine lung tumours.

Background: Light chain deposition disease (LCDD) is usually a systemic disorder characterised by non-amyloid monoclonal immunoglobulin light chain deposition in tissues. Localised nodular pulmonary (NP) LCDD is a rare and poorly characterised entity and, owing to the difficulties in diagnosis, limited data are available., Methods: We investigated the clinical, radiological and pathological characteristics of a series of six confidently diagnosed cases of NPLCDD., Results: There were three men and three women with ages ranging from 33 to 74 years. In all cases there were single or multiple pulmonary nodules, in one case associated with cysts. Two patients had no previous history of a lymphoproliferative or autoimmune disorder, two had Sjögren syndrome (SS) and two had extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Lung biopsies led to diagnoses of MALT lymphoma in four patients, including both of those with a previous history of lymphoma and one with SS. In five cases the diagnosis was confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and in one by electron microscopy. There was no evidence of systemic LCDD in any of the cases. Five patients had an indolent course in spite of limited therapeutic intervention while, in the patient who died, the cause of death was related to the spread of the lymphoma and was not due to the pulmonary lesions., Conclusions: NPLCDD is an indolent disease, in most cases associated with MALT lymphoma or autoimmune disease., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Small cell carcinoma of the lung (SCLC) is a well characterized form of lung cancer that is frequently already metastatic at diagnosis. Thus, patients with SCLC are usually treated with chemotherapy, and therefore emphasis has been placed on distinguishing that tumor from squamous cell carcinomas, large cell carcinomas and other pulmonary neoplasms that can more often be managed surgically. SCLC can be readily and accurately diagnosed in biopsy specimens or cytological preparations, but in selected cases, it can pose difficult diagnostic dilemmas. This review discusses selected problems encountered during the pathologic diagnosis of SCLC, including its distinction from other neuroendocrine lesions such as large cell neuroendocrine carcinoma and "carcinoid" tumors." The role of immunohistology is also considered in this context., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Bronchiolitis obliterans (BO) is a serious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Lung biopsy is the gold standard for diagnosis. This study describes the course of BO and assesses the congruity between biopsy-verified BO and a modified version of the National Institutes of Health's consensus criteria for BO syndrome (BOS) based exclusively on noninvasive measures. We included 44 patients transplanted between 2000 and 2010 who underwent lung biopsy for suspected BO. Of those, 23 were diagnosed with BO and 21 presented other noninfectious pulmonary pathologies, such as cryptogenic organizing pneumonia, diffuse alveolar damage, interstitial pneumonia, and nonspecific interstitial fibrosis. Compared with patients with other noninfectious pulmonary pathologies, BO patients had significantly lower values of forced expiratory volume in 1 second (FEV1), FEV1/forced vital capacity, and maximal mid-expiratory flow throughout follow-up, but there was no difference in the change in pulmonary function from the time of lung biopsy. The BO diagnosis was not associated with poorer overall survival. Fifty-two percent of patients with biopsy-verified BO and 24% of patients with other noninfectious pulmonary pathology fulfilled the BOS criteria. Pathological BO diagnosis was not superior to BOS criteria in predicting decrease in pulmonary function beyond the time of biopsy. A lung biopsy may provide a characterization of pathological patterns that can extend our knowledge on the pathophysiology of HSCT-related lung diseases., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Aims: Pulmonary hypertension (PH) in asymptomatic patients is a rare cause of sudden death. This study aims to determine the incidence of this entity and raise awareness among pathologists., Methods: We retrospectively investigated 44 cases of sudden unexpected death in relation to PH in patients not on antihypertensive therapy. This is the largest pathological study reported., Results: We report 44 cases of sudden death due to PH in which 28 (63.63%) were female and 16 (36.36%) were male, and the age range was from 5 days to 93 years old (mean age: 24±20). The majority had no clinical evidence of PH prior to death with none on therapy. The majority died at rest, 18 cases (40.90%), while 7 patients (15.90%) died following cardiac surgery and 7 patients (15.90%) during pregnancy or postpartum, 6 of whom had congenital heart disease. The cause of PH was recognised as congenital heart disease in 27 patients (61.36%), 14 of whom had simple congenital heart disease, such as atrial or ventricular septal defect,and 13 had complex congenital heart disease with associated atrial septal defect or ventricular septal defect. The remaining 17 patients (29.55%) suffered from primary PH due to plexiform arteriopathy, veno-occlusive disease and thromboembolic disease. Extensive sampling of the lungs is required to detect the lesions microscopically in these conditions., Conclusions: It is important that clinicians and pathologists be aware of the risk of sudden unexpected death in asymptomatic patients with PH, especially in those with congenital heart disease, after cardiac surgery or pregnancy., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

The current report describes granulomatous pneumonia due to Spirocerca lupi in 2 free-ranging maned wolves (Chrysocyon brachyurus). Both wolves had multiple, white, 1-1.5 cm in diameter, soft, encapsulated granulomas in the caudal lung lobes, which contained centrally placed parasites on cut sections. Microscopically, there was granulomatous inflammation with numerous intralesional sections of spirurid nematodes. Representative complete adult specimens of nematodes derived from these lesions were submitted for parasitological exam and identified as the spirurid S. lupi. To the authors' knowledge, there have been no published reports of S. lupi in maned wolves., (© 2014 The Author(s).)

Smoking-related interstitial fibrosis (SRIF) is a common, histologically striking finding in smokers that must be distinguished from the idiopathic interstitial pneumonias and other chronic interstitial fibrosing lesions. It is characterised by marked thickening of alveolar septa by fibrosis composed of thick collagen bundles that have a distinctive hyalinised quality and often are admixed with variable numbers of hyperplastic smooth muscle fibres. There is minimal accompanying inflammation. This fibrosis is usually most prominent in subpleural and centrilobular parenchyma, but can be present elsewhere as well. It is accompanied by emphysema and respiratory bronchiolitis. Most patients are asymptomatic or only mildly symptomatic, and the clinical course is stable in most. This paper reviews the pathologic features of SRIF in detail, its differentiation from more ominous interstitial fibrosing processes, and the clinical implications of its diagnosis., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Dectin-1, the innate immune receptor that recognizes β-glucan, plays an important role in immunity against fungal pathogens. Paracoccidioides brasiliensis, the etiological agent of paracoccidioidomycosis, has a sugar-rich cell wall mainly composed of mannans and glucans. This fact motivated us to use dectin-1-sufficient and -deficient mice to investigate the role of β-glucan recognition in the immunity against pulmonary paracoccidioidomycosis. Initially, we verified that P. brasiliensis infection reinforced the tendency of dectin-1-deficient macrophages to express an M2 phenotype. This prevalent antiinflammatory activity of dectin-1(-/-) macrophages resulted in impaired fungicidal ability, low nitric oxide production, and elevated synthesis of interleukin 10 (IL-10). Compared with dectin-1-sufficient mice, the fungal infection of dectin-1(-/-) mice was more severe and resulted in enhanced tissue pathology and mortality rates. The absence of dectin-1 has also impaired the production of T-helper type 1 (Th1), Th2, and Th17 cytokines and the activation and migration of T cells to the site of infection. Remarkably, dectin-1 deficiency increased the expansion of regulatory T cells and reduced the differentiation of T cells to the IL-17(+) phenotype, impairing the migration of IL-17(+)CD8(+) T cells and polymorphonuclear cells to infected tissues. In conclusion, dectin-1 exerts an important protective role in pulmonary paracoccidioidomycosis by controlling the innate and adaptive phases of antifungal immunity., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: To describe the demographics, clinical characteristics, diagnostic findings, underlying etiologies, treatment, and outcome associated with secondary spontaneous pneumothorax (SSP) in cats; and to identify clinical feature differences among cats with asthma associated secondary spontaneous pneumothorax (AASSP) versus nonasthma-associated secondary spontaneous pneumothorax (NAASSP)., Design: Retrospective case series., Setting: University teaching hospital., Animals: Sixteen client-owned cats with secondary spontaneous pneumothorax., Interventions: None., Measurements and Main Results: Domestic short hair was the predominant breed in this study (n = 15). The median age was 8 years old (range: 7 weeks to 17 years) with no sex predilection. Fourteen cats were affected by multi-lobar pulmonary pathology of infectious, inflammatory, or neoplastic causes. Asthma was the most common cause of spontaneous pneumothorax (25%). Ten of 12 treated cats survived the initial episode of spontaneous pneumothorax to discharge with medical management, including all 4 cats with AASSP. Reoccurrence was documented in 4 cats. Pulmonary lobectomy was curative for 1 cat with congenital accessory lung lobe emphysema. No difference in clinical presentation was identified between cats with AASSP and cats with NAASSP., Conclusions: Feline SSP is frequently associated with extensive pulmonary pathology. Supportive medical management is most appropriate, except in rare cases with focal congenital abnormalities that may benefit from surgical intervention. AASSP appears to carry a good prognosis for short-term outcome (survival to discharge). Clinical assessment, imaging, and invasive diagnostics were required to differentiate between AASSP and NAASSP., (© Veterinary Emergency and Critical Care Society 2014.)

Aims: Pulmonary bone marrow embolism (BME) and pulmonary bone fragment embolism (BFE) are two types of non-thrombotic pulmonary embolism (NTPE). While BME can be found consistently in autopsies, BFE is a rarely observed event. Both these conditions have bone lesions as source of embolism and are not considered to be causative for death., Methods: A retrospective autopsy study was performed and lung whole tissue slides were reviewed for the presence of pulmonary embolism. Clinicopathological data were screened for osseous lesions considered as risk factors for BME and BFE., Results: We reviewed 985 consecutive, unselected autopsies and identified 29 cases of BME (2.9%) and 5 cases of BFE (0.5%). Both conditions were mutually exclusive. While BME showed a significant association with costal fractures, BFE was significantly associated with osteomyelitis and previously performed femur nailing. There were between 1 and 346 bone emboli in BFE with a density ranging from 0.74 to 30.5 emboli/cm(2) with mean embolic diameter of 45.8±37.6 μm. In two patients, BFE contributed significantly to fatal outcome., Conclusions: BME was associated with costal fractures, while BFE was associated with orthopaedic procedures and osteomyelitis. BFE can result in patient death. Both conditions appeared exclusively, indicating that although they originate from osseous lesions their underlying pathogenesis may likely be different.

Clot load scores have previously been developed with the goal of improving prognosis in acute pulmonary embolism (PE). These scores provide a simple estimate of pulmonary vascular bed obstruction, however they have not been adopted clinically as they have poor correlation with mortality and right ventricular (RV) dysfunction. This study performed a quantitative analysis of blood flow and gas exchange in 12 patient-specific models of PE, to understand the limitations of current clot load scores and how their prognostic value could be improved. Prediction of hypoxemia in the models when using estimated baseline (non-occluded) minute ventilation and cardiac output correlated closely with clinical metrics for RV dysfunction, whereas the clot load score had only a weak correlation. The model predicts that large central clots have a greater impact on function than smaller distributed clots with the same total clot load, and that the partial occlusion of a vessel only has a significant impact on pulmonary function when the vessel is close to completely occluded. The effect of clot distribution on the redistribution of blood from its normal pattern - and hence the magnitude of the potential effect on gas exchange - is represented in the model but is not included in current clot load scores. Improved scoring systems need to account for the expected normal distribution of blood in the lung, and the impact of clot on redistributing the blood flow., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Introduction: Despite the advent of PET scanning and endoscopic minimally invasive methods of sampling mediastinal lymph nodes, surgical assessment, particularly by mediastinoscopy, remains an important tool for staging non-small cell lung cancer., Methods: We carried out a retrospective review of mediastinoscopic lymph node biopsies taken at The Royal Infirmary of Edinburgh between 1996 and 2006 and performed additional histological investigations on select cases., Results: In total, 89/802 (11%) patients had a negative mediastinoscopy but final resection stage of N2/N3. Within this group, 41/89 (46%) patients had positive resection lymph nodes in stations potentially accessible to biopsy at mediastinoscopy. Of these, 30 (34%) patients had had the metastatic station sampled at mediastinoscopy. Further histopathological examination (multiple levels and pancytokeratin immunohistochemistry) of these original biopsies detected micrometastases in two cases, one of which, in retrospect, had been missed on the original section at the time of reporting. Isolated tumour cells were detected by immunohistochemistry in another two cases., Conclusions: Routine examination of additional levels and immunohistochemical staining of mediastinal lymph nodes biopsies is not required and would not improve the overall negative predictive value of the procedure.

Smoking-related interstitial fibrosis (SRIF) is a common, histologically striking finding in smokers that must be distinguished from the idiopathic interstitial pneumonias and other chronic interstitial fibrosing lesions. It is characterised by marked thickening of alveolar septa by fibrosis composed of thick collagen bundles that have a distinctive hyalinised quality and often are admixed with variable numbers of hyperplastic smooth muscle fibres. There is minimal accompanying inflammation. This fibrosis is usually most prominent in subpleural and centrilobular parenchyma, but can be present elsewhere as well. It is accompanied by emphysema and respiratory bronchiolitis. Most patients are asymptomatic or only mildly symptomatic, and the clinical course is stable in most. This paper reviews the pathologic features of SRIF in detail, its differentiation from more ominous interstitial fibrosing processes, and the clinical implications of its diagnosis.

Pulmonary fibrosis in surgical lung biopsies is said to have a 'usual interstitial pneumonia-pattern' (UIP-pattern) of disease when scarring of the parenchyma is present in a patchy, 'temporally heterogeneous' distribution. These biopsies are one of the more common non-neoplastic specimens surgical pathologists encounter and often pose a number of challenges. UIP is the expected histopathological pattern in patients with clinical idiopathic pulmonary fibrosis (IPF), but the UIP-pattern can be seen in other conditions on occasion. Most important among these are the rheumatic interstitial lung diseases (RILD) and chronic hypersensitivity pneumonitis (CHrHP). Because theses entities have different mechanisms of injury, approach to therapy, and expected clinical progression, it is imperative for the surgical pathologist to correctly classify them. Taken in isolation, the UIP-pattern seen in patients with IPF may appear to overlap with that of RILD and CHrHP, at least when using the broadest definition of this term (patchy fibrosis). However, important distinguishing features are nearly always present in our experience, and the addition of a multidisciplinary approach will often resolve the critical differences between these diseases. In this manuscript, we review the distinguishing clinical, radiologic and histopathological features of UIP of IPF, RILD and CHrHP, based, in part, on the existing literature, but also lessons learned from a busy lung biopsy consultation practice.

This review addresses the pathology of lung disease in which the predominant finding is diffuse cystic change. Although cysts may be found radiologically in a wide variety of disease states, the entities discussed are those most likely to be encountered in biopsies where the underlying aetiology is unclear. These include Langerhans cell histiocytosis, lymphangioleiomyomatosis and Birt-Hogg-Dubé syndrome, and recent advances in the molecular pathology of these entities are reviewed. Conditions in which cyst formation may occur but does not represent the predominant pathology are also considered, including alveolar septal amyloidosis, light chain disease, follicular bronchiolitis and lymphocytic interstitial pneumonia. Cystic metastases may present a differential diagnostic dilemma.