Differential diagnosis of IgG4-positive plasma cells in the lung.

The recognition of immunoglobulin G4-related disease (IgG4-RD) as an entity in the pancreaticobiliary tract was followed by a slew of papers describing inflammation and fibrosis containing IgG4-positive plasma cells in a variety of sites including the respiratory tract, leading to the hypothesis that these abnormalities were attributable to IgG4-RD. Predictably, pathologists began to see requests from clinicians to perform IgG4 immunohistochemistry in lung biopsies "to rule out IgG4-RD". Several years later, the notion that IgG4-RD would prove to be the underlying cause of a wide array of fibroinflammatory lesions in the lung has not panned out as promised. To the contrary, it has become clear that IgG4-positive plasma cells are not specific for IgG4-RD, and that large numbers of IgG4-positive plasma cells can be encountered in other well-defined entities, including inflammatory myofibroblastic tumor and nodular lymphoid hyperplasia, as well as in lymphoplasmacytic infiltrates in other entities, including connective tissue disease and idiopathic forms of interstitial lung disease. It has also become clear that raised serum IgG4 levels can occur in settings other than IgG4-RD. These observations suggest that true IgG4-RD of the lung is far less common than previously surmised. Pathologists must familiarize themselves with mimics of IgG4-RD in the lung and exercise caution before attributing lymphoplasmacytic infiltrates in the lung to IgG4-RD.

Targeting Doublecortin-Like Kinase 1 (DCLK1)-Regulated SARS-CoV-2 Pathogenesis in COVID-19.

Host factors play critical roles in SARS-CoV-2 infection-associated pathology and the severity of COVID-19. In this study, we systematically analyzed the roles of SARS-CoV-2-induced host factors, doublecortin-like kinase 1 (DCLK1), and S100A9 in viral pathogenesis. In autopsied subjects with COVID-19 and pre-existing chronic liver disease, we observed high levels of DCLK1 and S100A9 expression and immunosuppressive (DCLK1+S100A9+CD206+) M2-like macrophages and N2-like neutrophils in lungs and livers. DCLK1 and S100A9 expression were rarely observed in normal controls, COVID-19-negative subjects with chronic lung disease, or COVID-19 subjects without chronic liver disease. In hospitalized patients with COVID-19, we detected 2 to 3-fold increased levels of circulating DCLK1+S100A9+ mononuclear cells that correlated with disease severity. We validated the SARS-CoV-2-dependent generation of these double-positive immune cells in coculture. SARS-CoV-2-induced DCLK1 expression correlated with the activation of ß-catenin, a known regulator of the DCLK1 promoter. Gain and loss of function studies showed that DCLK1 kinase amplified live virus production and promoted cytokine, chemokine, and growth factor secretion by peripheral blood mononuclear cells. Inhibition of DCLK1 kinase blocked pro-inflammatory caspase-1/interleukin-1ß signaling in infected cells. Treatment of SARS-CoV-2-infected cells with inhibitors of DCLK1 kinase and S100A9 normalized cytokine/chemokine profiles and attenuated DCLK1 expression and ß-catenin activation. In conclusion, we report previously unidentified roles of DCLK1 in augmenting SARS-CoV-2 viremia, inflammatory cytokine expression, and dysregulation of immune cells involved in innate immunity. DCLK1 could be a potential therapeutic target for COVID-19, especially in patients with underlying comorbid diseases associated with DCLK1 expression. IMPORTANCE High mortality in COVID-19 is associated with underlying comorbidities such as chronic liver diseases. Successful treatment of severe/critical COVID-19 remains challenging. Herein, we report a targetable host factor, DCLK1, that amplifies SARS-CoV-2 production, cytokine secretion, and inflammatory pathways via activation of ß-catenin(p65)/DCLK1/S100A9/NF-κB signaling. Furthermore, we observed in the lung, liver, and blood an increased prevalence of immune cells coexpressing DCLK1 and S100A9, a myeloid-derived proinflammatory protein. These cells were associated with increased disease severity in COVID-19 patients. Finally, we used a novel small-molecule inhibitor of DCLK1 kinase (DCLK1-IN-1) and S100A9 inhibitor (tasquinimod) to decrease virus production in vitro and normalize hyperinflammatory responses known to contribute to disease severity in COVID-19.

Airway Injury Caused by Aspiration of Iron Sulfate Pills: A Series of 11 Cases.

It is not widely recognized that iron (ferrous sulfate) pill aspiration causes airway damage. Clinical diagnosis is challenging because patients are often unaware that they have aspirated a pill. The literature on this entity consists mainly of case reports. The aim of this study is to describe the clinical and pathologic features of iron pill aspiration in a series of 11 patients. A retrospective review of our pathology archives was performed to identify cases of iron pill aspiration (2013-2023). All available histologic and cytologic material was rereviewed. Clinical information was collected from the electronic medical record, and imaging studies were rereviewed. Eighteen endobronchial biopsies were identified from 11 patients (7 women and 4 men; mean age, 70 years; range, 44-82 years). Eight patients had corresponding cytology (20 specimens). Medication history was available in 9 of 11 patients, all of whom were taking iron sulfate pills. Two patients reported possible aspiration episodes; 4 had risk factors for aspiration. The diagnosis of iron pill aspiration was suspected prior to biopsy in only 1 case. Histologically, iron pill particles were yellow, golden brown, or gray, were elongated and crystal or fiber like, and stained strongly with an iron stain. Common histologic findings included mucosal ulceration, acute and/or chronic inflammation, fibrosis, and squamous metaplasia. Iron pill particles were also identified in 11 cytology specimens from 6 patients. On Papanicolaou staining, iron pill particles were yellow to golden, fiber like, refractile, and crystalline. Reactive epithelial cells, squamous metaplasia, and acute inflammation were common. The combination of iron pill intake and discolored mucosa on bronchoscopy is a potential clue to the diagnosis of iron pill aspiration. Pathologists should familiarize themselves with the appearance of iron pill particles in endobronchial biopsies and cytology specimens from the respiratory tract as this diagnosis is seldom suspected on clinical grounds, and most patients lack a history of aspiration.

The state of the art for artificial intelligence in lung digital pathology.

Lung diseases carry a significant burden of morbidity and mortality worldwide. The advent of digital pathology (DP) and an increase in computational power have led to the development of artificial intelligence (AI)-based tools that can assist pathologists and pulmonologists in improving clinical workflow and patient management. While previous works have explored the advances in computational approaches for breast, prostate, and head and neck cancers, there has been a growing interest in applying these technologies to lung diseases as well. The application of AI tools on radiology images for better characterization of indeterminate lung nodules, fibrotic lung disease, and lung cancer risk stratification has been well documented. In this article, we discuss methodologies used to build AI tools in lung DP, describing the various hand-crafted and deep learning-based unsupervised feature approaches. Next, we review AI tools across a wide spectrum of lung diseases including cancer, tuberculosis, idiopathic pulmonary fibrosis, and COVID-19. We discuss the utility of novel imaging biomarkers for different types of clinical problems including quantification of biomarkers like PD-L1, lung disease diagnosis, risk stratification, and prediction of response to treatments such as immune checkpoint inhibitors. We also look briefly at some emerging applications of AI tools in lung DP such as multimodal data analysis, 3D pathology, and transplant rejection. Lastly, we discuss the future of DP-based AI tools, describing the challenges with regulatory approval, developing reimbursement models, planning clinical deployment, and addressing AI biases. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pericardial mesothelioma presenting as constrictive pericarditis.

A 46-year-old woman underwent pericardiocentesis and pericardial window for recurrent pericardial effusion. She presented 17 months later with signs and symptoms consistent with constrictive pericarditis. Cardiac magnetic resonance imaging revealed an infiltrative mass surrounding the pericardium. A transcutaneous core needle biopsy of the pericardium confirmed the diagnosis of pericardial mesothelioma.

Usual interstitial pneumonia (UIP): a clinically significant pathologic diagnosis.

This editorial focuses on common issues that surround the diagnosis of usual interstitial pneumonia (UIP), a clinically significant pathologic diagnosis. Most of these issues stem from conflation of the pathologically defined entity UIP with the clinically defined entity IPF. A pathologic or radiologic diagnosis of UIP is required for the clinical/multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF) but it has also been described in several other clinical settings. I offer my viewpoint on 5 important questions. 1. Is UIP a diagnosis or a "pattern"? ANSWER: UIP is a pathologic diagnosis and is better conceptualized as a "pattern" than as a specific clinical entity. Since all cases of UIP require pattern recognition, adding the word "pattern" to UIP is redundant. 2. Is pathology the gold standard for UIP? ANSWER: Yes. 3. How do you "prove" etiology of a given case of UIP? ANSWER: "Soft" histologic features can raise the possibility of certain etiologies but the final determination of etiology comes from the multidisciplinary team. With few exceptions, there are no findings pathognomonic for any etiology in UIP. 4. Does UIP imply IPF? ANSWER: No. 5. What should we do when pathology and HRCT are discordant? ANSWER: This depends on the specifics of the discrepancy. When HRCT suggests a non-UIP diagnosis such as NSIP and histology shows UIP, histology has been shown to predict prognosis in multiple studies. In other settings, the radiologic impression based on HRCT is often proven to be incorrect by the histologic findings.

Prospective cohort of cryobiopsy in interstitial lung diseases: a single center experience.

RATIONALE: Transbronchial cryobiopsy has been increasingly used to diagnose interstitial lung diseases. However, there is uncertainty regarding its accuracy and risks, mainly due to a paucity of prospective or randomized trials comparing cryobiopsy to surgical biopsy. OBJECTIVES: To evaluate the diagnostic yield and complications of cryobiopsy in patients selected by multidisciplinary discussion. METHODS: This was a prospective cohort from 2017 to 2019. We included consecutive patients with suspected interstitial lung diseases being considered for lung biopsy presented at our multidisciplinary meeting. MEASUREMENTS AND MAIN RESULTS: Of 112 patients, we recommended no biopsy in 31, transbronchial forceps biopsy in 16, cryobiopsy in 54 and surgical biopsy in 11. By the end of the study, 34 patients had had cryobiopsy and 24 patients, surgical biopsy. Overall pathologic and multidisciplinary diagnostic yield of cryobiopsy was 47.1% and 61.8%, respectively. The yield increased over time for both pathologic (year 1: 28.6%, year 2: 54.5%, year 3: 66.7%, p = 0.161) and multidisciplinary (year 1: 50%, year 2: 63.6%, year 3: 77.8%, p = 0.412) diagnosis. Overall rate of grade 4 bleeding after cryobiopsy was 11.8%. Cryobiopsy required less chest tube placement (11.8% vs 100%, p < 0.001) and less hospitalizations compared to surgical biopsy (26.5% vs 95.7%, p < 0.001), but hospitalized patients had a longer median hospital stay (2 days vs 1 day, p = 0.004). CONCLUSIONS: Diagnostic yield of cryobiopsy increased over time but the overall grade 4 bleeding rate was 11.8%.

Endotracheal Tube Obstruction Among Patients Mechanically Ventilated for ARDS Due to COVID-19: A Case Series.

BACKGROUND: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing endotracheal tube (ETT) obstruction that has not been previously described in patients with ARDS due to other causes. The purpose of this report is to describe a case series of patients with COVID-19 and ARDS in which ETT occlusion resulted in significant clinical consequences and to define the pathology of the obstructing material. METHODS: Incidents of ETT occlusion during mechanical ventilation of COVID-19 patients were reported by clinicians and retrospective chart review was conducted. Statistical analysis was performed comparing event rates between COVID-19 and non-COVID 19 patients on mechanical ventilation over the predefined period. Specimens were collected and submitted for pathological examination. FINDINGS: Eleven COVID-19 patients experienced endotracheal tube occlusion over a period of 2 months. Average age was 69 (14.3, range 33-85) years. Mean APACHE III score was 73.6 (17.3). All patients had AKI and cytokine storm. Nine exhibited biomarkers for hypercoagulability. Average days on mechanical ventilation before intervention for ETT occlusion was 14 (5.18) days (range of 9 to 23 days). Five patients were discharged from the ICU, and 4 expired. Average documented airway resistance on admission was 14.2 (3.0) cm H2O/L/sec. Airway resistance before tube exchange was 28.1 (8.0) cm H2O /L/sec. No similar events of endotracheal tube occlusion were identified in non-COVID patients on mechanical ventilation during the same time period. Microscopically, the material consisted of mucin admixed with necrotic cell debris, variable numbers of degenerated inflammatory cells, oral contaminants and red blood cells. INTERPRETATION: Patients with COVID-19 and ARDS on prolonged mechanical ventilation are at risk for developing ETT obstruction due to deposition of a thick, tenacious material within the tube that consists primarily of mucin and cellular debris. Clinicians should be aware of this dangerous but treatable complication.

Detection of SARS-CoV-2 in formalin-fixed paraffin-embedded tissue sections using commercially available reagents.

Coronavirus Disease-19 (COVID-19), caused by the coronavirus SARS-CoV-2, was initially recognized in Wuhan, China and subsequently spread to all continents. The disease primarily affects the lower respiratory system, but may involve other organs and systems. Histopathologic evaluation of tissue from affected patients is crucial for diagnostic purposes, but also for advancing our understanding of the disease. For that reason, we developed immunohistochemical (IHC) and in situ hybridization (ISH) assays for detection of the. virus. A total of eight autopsy lungs, one placenta, and ten kidney biopsies from COVID-19 patients were stained with a panel of commercially available antibodies for IHC and commercially available RNA probes for ISH. Similarly, autopsy lungs, placentas and renal biopsies from non-COVID-19 patients were stained with the same antibodies and probes. All eight lungs and the placenta from COVID-19 patients stained positive by IHC and ISH, while the kidney biopsies stained negative by both methodologies. As expected, all specimens from non-COVID-19 patients were IHC and ISH negative. These two assays represent a sensitive and specific method for detecting the virus in tissue samples. We provide the protocols and the list of commercially available antibodies and probes for these assays, so they can be readily implemented in pathology laboratories and medical examiner offices for diagnostic and research purposes.

Interpretable multimodal deep learning for real-time pan-tissue pan-disease pathology search on social media.

Pathologists are responsible for rapidly providing a diagnosis on critical health issues. Challenging cases benefit from additional opinions of pathologist colleagues. In addition to on-site colleagues, there is an active worldwide community of pathologists on social media for complementary opinions. Such access to pathologists worldwide has the capacity to improve diagnostic accuracy and generate broader consensus on next steps in patient care. From Twitter we curate 13,626 images from 6,351 tweets from 25 pathologists from 13 countries. We supplement the Twitter data with 113,161 images from 1,074,484 PubMed articles. We develop machine learning and deep learning models to (i) accurately identify histopathology stains, (ii) discriminate between tissues, and (iii) differentiate disease states. Area Under Receiver Operating Characteristic (AUROC) is 0.805-0.996 for these tasks. We repurpose the disease classifier to search for similar disease states given an image and clinical covariates. We report precision@k = 1 = 0.7618 ± 0.0018 (chance 0.397 ± 0.004, mean ±stdev ). The classifiers find that texture and tissue are important clinico-visual features of disease. Deep features trained only on natural images (e.g., cats and dogs) substantially improved search performance, while pathology-specific deep features and cell nuclei features further improved search to a lesser extent. We implement a social media bot (@pathobot on Twitter) to use the trained classifiers to aid pathologists in obtaining real-time feedback on challenging cases. If a social media post containing pathology text and images mentions the bot, the bot generates quantitative predictions of disease state (normal/artifact/infection/injury/nontumor, preneoplastic/benign/low-grade-malignant-potential, or malignant) and lists similar cases across social media and PubMed. Our project has become a globally distributed expert system that facilitates pathological diagnosis and brings expertise to underserved regions or hospitals with less expertise in a particular disease. This is the first pan-tissue pan-disease (i.e., from infection to malignancy) method for prediction and search on social media, and the first pathology study prospectively tested in public on social media. We will share data through http://pathobotology.org . We expect our project to cultivate a more connected world of physicians and improve patient care worldwide.

Expanding the spectrum of chronic necrotising (semi-invasive) aspergillosis: a series of eight cases presenting as radiologically solid lung nodules mimicking malignancy.

AIM: To clinicopathologically characterise a subset of aspergillosis cases characterised by radiologically solid lung nodules. METHODS AND RESULTS: We reviewed our archives for lung biopsies/resections with fungal hyphae on histology. Cases classifiable as a well-established form of aspergillosis were excluded. Unclassifiable cases with radiologically solid lung nodules and histological evidence of fungal hyphae consistent with Aspergillus were analysed in detail. Of 134 lung biopsies/resections with fungal hyphae, eight presented as a solid lung nodule on imaging and could not be classified as a well-recognised form of aspergillosis. All patients were non-immunocompromised/minimally immunocompromised adult smokers. Imaging showed solid, predominantly solitary, spiculated, subpleural, hypermetabolic upper lobe nodules in emphysematous lungs. Malignancy was suspected clinically in all cases. Histologically, the nodules were necrotising granulomas containing fungal hyphae consistent with Aspergillus. On follow-up, none of the nodules recurred or progressed to invasive disease. CONCLUSIONS: Aspergillosis can present as a radiologically solid, spiculated lung nodule suspicious for malignancy.

Social media in academics and research: 21st-century tools to turbocharge education, collaboration, and dissemination of research findings.

The near-ubiquitous use of smartphones and the rapid emergence of free, widely used, social media platforms have combined to turbocharge the dissemination of information at a scale and speed that would have been unimaginable just a few years ago. Increasingly, internet-savvy pathologists of all ages from every corner of the world are flipping the paradigm of traditional academia by posting educational content online free of charge, unencumbered by the limitations of traditional print media and educational conferences. These platforms are being used in innovative ways, not just to disseminate research findings, but also to create new knowledge through using them to empower research collaborations. In this review, we outline ways in which social media platforms, such as Twitter, Facebook, and YouTube, are being used by pathologists to enhance academic work and facilitate the dissemination of research. We outline key differences between the various platforms with respect to pathology academics and research, and describe key areas in which these platforms have already made an impact. These include rapid dissemination of research findings to a worldwide audience, live transnational discussion of journal articles and conference proceedings, intercontinental networking between pathologists for academic purposes, free education on a global scale at minimal or no cost, and research collaborations initiated on and facilitated by social media platforms. Finally, we provide practical tips for pathologists who wish to adopt these novel 21st-century technologies to enhance their academic endeavours.

Disseminated Metacestode Versteria Species Infection in Woman, Pennsylvania, USA1.

A patient in Pennsylvania, USA, with common variable immunodeficiency sought care for fever, cough, and abdominal pain. Imaging revealed lesions involving multiple organs. Liver resection demonstrated necrotizing granulomas, recognizable tegument, and calcareous corpuscles indicative of an invasive cestode infection. Sequencing revealed 98% identity to a Versteria species of cestode found in mink.

Insulinoma-associated protein 1 (INSM1) is a sensitive and highly specific marker of neuroendocrine differentiation in primary lung neoplasms: an immunohistochemical study of 345 cases, including 292 whole-tissue sections.

Recent evidence suggests a role for the nuclear marker INSM1 in the diagnosis of neuroendocrine lung neoplasms. The aim of this study was to determine the utility of INSM1 as a marker of neuroendocrine differentiation using a large series of whole-tissue sections of primary lung neoplasms. We stained 345 primary lung neoplasms with INSM1, including 292 whole-tissue sections. Most cases were also stained with synaptophysin, chromogranin, and CD56. The tumors included 64 small cell lung carcinomas, 24 large cell neuroendocrine carcinomas, 64 carcinoid tumors (48 typical, 16 atypical), 130 adenocarcinomas, and 33 squamous cell carcinomas. For small cell lung carcinoma, the sensitivity of INSM1 (98%) was similar to synaptophysin (100%) and CD56 (95%) but considerably higher than chromogranin (83%). For large cell neuroendocrine carcinoma, CD56 (92%) and synaptophysin (88%) were more sensitive than INSM1 (75%), while chromogranin was less sensitive (46%). All markers stained 100% of carcinoid tumors, except one atypical carcinoid tumor, which was negative for INSM1. The sensitivity of INSM1 for neuroendocrine lung neoplasms as a group (95%) was similar to synaptophysin (98%) and CD56 (97%), but higher than chromogranin (84%). The specificity of INSM1 for neuroendocrine lung neoplasms (97%) was similar to chromogranin (98%) but higher than synaptophysin (90%) and CD56 (87%). INSM1 staining was concordant in primary tumors and matched metastases. In conclusion, INSM1 is a reliable marker of neuroendocrine differentiation in primary lung neoplasms, with sensitivity similar to synaptophysin and CD56, and specificity similar to chromogranin.

Pathology of pulmonary tuberculosis and non-tuberculous mycobacterial lung disease: Facts, misconceptions, and practical tips for pathologists.

Most pathologists are familiar with the microscopic features of tuberculosis and the need to examine special stains for acid-fast bacteria (AFB) in cases of granulomatous lung disease. However, misconceptions do exist, including the concept that finding AFB in "caseating granulomas" confirms the diagnosis of tuberculosis. This dogma is attributable to the high prevalence of tuberculosis in many countries, as well as unfamiliarity with the microscopic spectrum of non-tuberculous mycobacterial lung disease. This review aims to provide surgical pathologists with practical tips to identify AFB, illustrate the histologic overlap between pulmonary tuberculosis and non-tuberculous mycobacterial lung disease, and highlight the importance of cultures in this setting. M. tuberculosis and non-tuberculous mycobacteria cannot be reliably differentiated either on the basis of the tissue reaction or by bacterial morphology on acid-fast stains. Although a presumptive clinical diagnosis of tuberculosis can be made without culture-confirmation, the only definitive means to determine the true identity of AFB is by cultures or molecular methods. Making this distinction is most critical when AFB are found in incidentally detected lung nodules in geographic locations where the incidence of tuberculosis is low, because in such settings AFB in necrotizing granulomas of the lung are more likely to be non-tuberculous mycobacteria than M. tuberculosis.

Thoracic Frozen Section Pitfalls: Lung Adenocarcinoma Versus Selected Mimics.

CONTEXT.­: Intraoperative (frozen section) analysis of lung lesions (nodules, masses, ground-glass opacities) can occasionally be diagnostically challenging. OBJECTIVE.­: To describe selected pitfalls in thoracic frozen sections with a focus on the differential diagnosis between adenocarcinoma and its mimics, and to provide tips to prevent misinterpretation. DATA SOURCES.­: Peer-reviewed literature and the author's experience. CONCLUSIONS.­: A common challenge in thoracic frozen sections is the differential diagnosis between lung adenocarcinoma and its mimics. Diagnostic difficulties arise because mimics of adenocarcinoma often entrap reactive lung epithelium that can appear atypical on frozen section slides. Entities that can be misinterpreted as adenocarcinoma include ciliated muconodular papillary tumor/bronchiolar adenoma, hamartoma, inflammatory myofibroblastic tumor, and pulmonary Langerhans cell histiocytosis. Knowledge of the key clinical, radiologic, and histologic features of these entities can help prevent overdiagnosis of adenocarcinoma. Pathologic findings that facilitate the distinction between adenocarcinoma and its mimics at frozen section include the appearance and contour of the lesion at low magnification, growth patterns, cilia, stromal features, shape of the epithelial cells (cuboidal versus columnar), nuclear features of malignancy (crowding, hyperchromasia, irregular contours), and abruptness of the junction between the lesion and adjacent uninvolved lung. Knowledge of the clinical context, imaging findings, and the surgical consequence of the intraoperative diagnosis can also prevent diagnostic errors. Finally, since adenocarcinomas of the lung are often relatively bland and lack the stromal desmoplasia seen in adenocarcinomas of other organs, familiarity with the morphologic spectrum of lung adenocarcinomas at frozen section analysis is important.

Smoking-Related Interstitial Lung Disease: Historical Perspective and Advances in the Twenty-first Century.

In the twenty- first century, there is widespread agreement that in addition to lung cancer, emphysema, and chronic bronchitis, cigarette smoking causes accumulation of pigmented macrophages, interstitial fibrosis, and Langerhans cell proliferation in various permutations. These histologic changes remain subclinical in some patients and produce clinical manifestations and imaging abnormalities in others. Debate surrounds terminology of these lesions, which are often grouped together under the umbrella of "smoking-related interstitial lung disease." This review summarizes modern concepts in our understanding of these abnormalities and explains how the recognition of smoking-related interstitial fibrosis has advanced the field.

Assessment of Pathology Domain-Specific Knowledge of ChatGPT and Comparison to Human Performance.

CONTEXT.­: Artificial intelligence algorithms hold the potential to fundamentally change many aspects of society. Application of these tools, including the publicly available ChatGPT, has demonstrated impressive domain-specific knowledge in many areas, including medicine. OBJECTIVES.­: To understand the level of pathology domain-specific knowledge for ChatGPT using different underlying large language models, GPT-3.5 and the updated GPT-4. DESIGN.­: An international group of pathologists (n = 15) was recruited to generate pathology-specific questions at a similar level to those that could be seen on licensing (board) examinations. The questions (n = 15) were answered by GPT-3.5, GPT-4, and a staff pathologist that recently passed their Canadian pathology licensing exams. Participants were instructed to score answers on a 5-point scale and to predict which answer was written by ChatGPT. RESULTS.­: GPT-3.5 performed at a similar level to the staff pathologist, while GPT-4 outperformed both. The overall score for both GPT-3.5 and GPT-4 was within the range of meeting expectations for a trainee writing licensing examinations. In all but one question, the reviewers were able to correctly identify the answers generated by GPT-3.5. CONCLUSIONS.­: By demonstrating the ability of ChatGPT to answer pathology-specific questions at a level similar to (GPT-3.5) or exceeding (GPT-4) a trained pathologist, this study highlights the potential of large language models to be transformative in this space. In the future, more advanced iterations of these algorithms with increased domain-specific knowledge may have the potential to assist pathologists and enhance pathology resident training.