Cannabidiol Reduces Systemic Immune Activation in Experimental Acute Lung Injury.

Background: The underlying pathomechanism of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is the immune response to inflammation or infection within the pulmonary microcirculation. Systemic spread of pathogens, activated immune cells, and inflammatory mediators contributes significantly to mortality in patients with ARDS. Objective: The endogenous cannabinoid system is a major modulator of the immune response during inflammation and infection. Phytocannabinoids, such as cannabidiol (CBD), have shown promising anti-inflammatory effects in several pathologies. The overall objective of this study was to evaluate the effects of CBD on local and systemic inflammation in endotoxin-induced ALI in mice. Materials and Methods: ALI was induced by pulmonary endotoxin challenge. Four groups of male C57BL/6 mice were randomized in this study: control, ALI, ALI with CBD treatment, and control with CBD treatment. Analyses of local and systemic cytokine levels, lung histology, and leukocyte activation as visualized by intravital microscopy of the intestinal and pulmonary microcirculation were performed 6 h following intranasal endotoxin administration. Results: Pulmonary endotoxin challenge induced significant inflammation evidenced by local and systemic cytokine and chemokine release, lung histopathology, and leukocyte adhesion. Intraperitoneal CBD treatment resulted in a significant decrease in systemic inflammation as shown by reduced leukocyte adhesion in the intestinal microcirculation and reduced plasma cytokine and chemokine levels. Pulmonary chemokine levels were decreased, while pulmonary cytokine levels were unchanged. Surprisingly, the ALI score was slightly increased by CBD treatment in a manner driven by enhanced neutrophil infiltration of the alveoli. Conclusion: In this model of experimental ALI, CBD administration was associated with reduced systemic inflammation and heterogeneous effects on pulmonary inflammation. Future studies should explore the mechanisms involved as they relate to neutrophil infiltration and proinflammatory mediator production within the lungs.

Consensus statement on the processing, interpretation and reporting of temporal artery biopsy for arteritis.

Giant cell arteritis (GCA) is the most common systemic vasculitis in adults in Europe and North America, typically involving the extra-cranial branches of the carotid arteries and the thoracic aorta. Despite advances in noninvasive imaging, temporal artery biopsy (TAB) remains the gold standard for establishing a GCA diagnosis. The processing of TAB depends largely on individual institutional protocol, and the interpretation and reporting practices vary among pathologists. To address this lack of uniformity, the Society for Cardiovascular Pathology formed a committee tasked with establishing consensus guidelines for the processing, interpretation, and reporting of TAB specimens, based on the existing literature. This consensus statement includes a discussion of the differential diagnoses including other forms of arteritis and noninflammatory changes of the temporal artery.

Dataset for the reporting of neoplasms of the heart, pericardium, and great vessels: recommendations from the International Collaboration on Cancer Reporting (ICCR).

The International Collaboration on Cancer Reporting (ICCR) was founded by major pathology organizations from around the world to produce internationally standardized and evidence-based datasets for pathologists' reporting of cancer. Its goal is to improve cancer patient outcomes worldwide and to advance international benchmarking in cancer management. The ICCR cancer dataset development schedule is aligned with revisions of the WHO Classification of Tumours ("Blue Book") series, and in 2015 ICCR developed an initial series of thoracic datasets including a dataset for neoplasms of the heart, pericardium, and great vessels. This edition has now been updated to align with the 2021 WHO Blue Book series. An expert panel was convened to review and revise the dataset. While the majority of ICCR datasets are focused on malignant tumors, the scope of this dataset includes a number of benign tumors and tumor-like entities because of the rarity of cardiac malignancies and the serious implications of even histologically benign lesions. Due to the rarity of cardiac tumors, evidence in support of reporting elements is limited.

Resection of a Large Growing Mediastinal Germ Cell Tumor Using a Multidisciplinary Approach.

Mediastinal germ cell tumors (GCTs) are rare. Post-chemotherapy residual masses in patients with a nonseminomatous GCT require resection. A patient with a large mediastinal GCT involving the left subclavian artery, superior vena cava (SVC) and hilum of the right lung is presented. Despite a biochemical response to chemotherapy, the tumor enlarged on serial imaging. With guidance from medical oncology, a multidisciplinary surgical team, including cardiac anesthesia, cardiac surgery and thoracic surgery resected the tumor with a staged reconstruction of the SVC. The procedure was well tolerated and yielded clear margins. The final pathology showed a significant associated component of rhabdomyosarcoma.

Selective CB2 Receptor Agonist, HU-308, Reduces Systemic Inflammation in Endotoxin Model of Pneumonia-Induced Acute Lung Injury.

Acute respiratory distress syndrome (ARDS) and sepsis are risk factors contributing to mortality in patients with pneumonia. In ARDS, also termed acute lung injury (ALI), pulmonary immune responses lead to excessive pro-inflammatory cytokine release and aberrant alveolar neutrophil infiltration. Systemic spread of cytokines is associated with systemic complications including sepsis, multi-organ failure, and death. Thus, dampening pro-inflammatory cytokine release is a viable strategy to improve outcome. Activation of cannabinoid type II receptor (CB2) has been shown to reduce cytokine release in various in vivo and in vitro studies. Herein, we investigated the effect of HU-308, a specific CB2 agonist, on systemic and pulmonary inflammation in a model of pneumonia-induced ALI. C57Bl/6 mice received intranasal endotoxin or saline, followed by intravenous HU-308, dexamethasone, or vehicle. ALI was scored by histology and plasma levels of select inflammatory mediators were assessed by Luminex assay. Intravital microscopy (IVM) was performed to assess leukocyte adhesion and capillary perfusion in intestinal and pulmonary microcirculation. HU-308 and dexamethasone attenuated LPS-induced cytokine release and intestinal microcirculatory impairment. HU-308 modestly reduced ALI score, while dexamethasone abolished it. These results suggest administration of HU-308 can reduce systemic inflammation without suppressing pulmonary immune response in pneumonia-induced ALI and systemic inflammation.

Pleural solitary fibrous tumour with brain metastasis: an aggressive tumour and pathologic conundrum.

Solitary fibrous tumours of the pleura are a rare finding; those with brain metastases are rarer still. Here, we present the evolution of a pleural solitary fibrous tumour in a 70-year-old male treated surgically, and subsequent brain metastasis requiring emergent craniotomy and excision. The patient received adjuvant radiotherapy to the brain and had no recurrence of brain metastases; however, 1 year surveillance imaging demonstrated metastases to the lungs, liver and spleen for which he received chemotherapy but eventually succumbed to the disease process. Solitary fibrous tumours are most often slow-growing, relatively benign neoplasms. However, up to 10% are malignant. This case highlights the importance of surgical resection of these benign tumours with malignant potential.

HER2 testing in metastatic breast cancer - Is reflex ISH testing necessary on HER2 IHC-equivocal (2+) cases?

Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes.

Profiling non-small cell lung cancer reveals that PD-L1 is associated with wild type EGFR and vascular invasion, and immunohistochemistry quantification of PD-L1 correlates weakly with RT-qPCR.

Most lung cancer patients are diagnosed at an advanced stage, limiting their treatment options with very low response rate. Lung cancer is the most common cause of cancer death worldwide. Therapies that target driver gene mutations (e.g. EGFR, ALK, ROS1) and checkpoint inhibitors such anti-PD-1 and PD-L1 immunotherapies are being used to treat lung cancer patients. Identification of correlations between driver mutations and PD-L1 expression will allow for the best management of patient treatment. 851 cases of non-small cell lung cancer cases were profiled for the presence of biomarkers EGFR, KRAS, BRAF, and PIK3CA mutations by SNaPshot/sizing genotyping. Immunohistochemistry was used to identify the protein expression of ALK and PD-L1. Total PD-L1 mRNA expression (from unsorted tumor samples) was quantified by RT-qPCR in a sub-group of the cohort to assess its correlation with PD-L1 protein level in tumor cells. Statistical analysis revealed correlations between the presence of the mutations, PD-L1 expression, and the pathological data. Specifically, increased PD-L1 expression was associated with wildtype EGFR and vascular invasion, and total PD-L1 mRNA levels correlated weakly with protein expression on tumor cells. These data provide insights into driver gene mutations and immune checkpoint status in relation to lung cancer subtypes and suggest that RT-qPCR is useful for assessing PD-L1 levels.

Age-related histologic features of the sinoatrial node from normal human hearts during the first 10 decades of life: a study of 200 cases.

Knowledge of the histologic constituency of the sinoatrial (SA) node is based on small studies with unevenly distributed ages and subjective assessments of nodal composition, leading to difficulties in interpreting what constitutes true pathology of the SA node. SA nodes from two-hundred normal hearts (10 male and 10 female from each of the first 10 decades of life) were digitally analyzed to assess their histologic composition. Both nodal area and nodal fat content (≥5%) showed a quadratic relationship with age, peaking in the fifth to eighth decades of life. Increased fat content was also more prevalent with increased BMI (≥25 kg/m2). No differences between sexes were observed. Mean nodal collagen ranged from 7.1% to 50.3%, without a statistically significant differences by age or body mass index (BMI). The data suggests that the designation of pathologic fibrosis should be reserved for SA nodes with >50% collagen content. These findings expand and refine our understanding of the anatomy of the SA node.

Increased mast cell density is associated with decreased fibrosis in human atrial tissue.

Fibrotic remodelling of the atria is poorly understood and can be regulated by myocardial immune cell populations after injury. Mast cells are resident immune sentinel cells present in the heart that respond to tissue damage and have been linked to fibrosis in other settings. The role of cardiac mast cells in fibrotic remodelling in response to human myocardial injury is controversial. In this study, we sought to determine the association between mast cells, atrial fibrosis, and outcomes in a heterogeneous population of cardiac surgical patients, including a substantial proportion of coronary artery bypass grafting patients. Atrial appendage from patients was assessed for collagen and mast cell density by histology and by droplet digital polymerase chain reaction (ddPCR) for mast cell associated transcripts. Clinical variables and outcomes were also followed. Mast cells were detected in human atrial tissue at varying densities. Histological and ddPCR assessment of mast cells in atrial tissue were closely correlated. Patients with high mast cell density had less fibrosis and lower severity of heart failure classification or incidence mortality than patients with low mast cell content. Analysis of a homogeneous population of coronary artery bypass graft patients yielded similar observations. Therefore, evidence from this study suggests that increased atrial mast cell populations are associated with decreased clinical cardiac fibrotic remodelling and improved outcomes, in cardiac surgery patients.

Molecular profiling of non-small cell lung cancer.

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.

Fibrosis independent atrial fibrillation in older patients is driven by substrate leukocyte infiltration: diagnostic and prognostic implications to patients undergoing cardiac surgery.

BACKGROUND: The objectives of the study were to characterize and quantify cellular inflammation and structural remodeling of human atria and correlate findings with molecular markers of inflammation and patient surrogate outcome. METHODS: Voluntary participants undergoing heart surgery were enrolled in the study and blood samples were collected prior to surgery, and right atrium samples were harvested intraoperatively. Blood samples were analyzed by flow cytometry and complete blood counts. Atrial samples were divided for fixed fibrosis analysis, homogenized for cytokine analysis and digested for single cell suspension flow cytometry. RESULTS: A total of 18 patients were enrolled and samples assessed. Isolated cells from the atria revealed a CD45+ population of ~ 20%, confirming a large number of leukocytes. Further characterization revealed this population as 57% lymphocytes and 26% monocyte/macrophages (MoΦ), with the majority of the latter cells being classical (CD14++/CD16-). Interstitial fibrosis was present in 87% of samples and correlated significantly with patient age. Older patients (> 65) had significantly more atrial fibrosis and cellular inflammation. AFib patients had no distinguishing feature of atrial fibrosis and had significantly greater CD45+ MoΦ, increased expression of MMP9 and presented with a significant correlation in length of stay to CCL-2/MCP-1 and NLR (neutrophil-to-lymphocyte ratio). CONCLUSION: Atrial fibrosis is correlated with age and not determinate to AFib. However, severity of atrial leukocyte infiltration and markers of matrix degradation are determinant to AFib. This also correlated with CCL2 (or MCP-1) and NLR-indicative of marked inflammation. These data show the potential importance of diagnostic and prognostic assessments that could inform clinical decision making in regard to the intensity of AFib patient management.

Global PD-L1 Signals and Tumor-Infiltrating Lymphocytes: Markers of Immunogenicity in Different Subsets of Merkel Cell Carcinoma and Potential Therapeutic Implications.

We previously studied the genetic and immunohistochemical profiles of subsets of Merkel cell carcinoma (MCC) stratified by morphology and Merkel cell polyomavirus (MCPyV) status. Recent advances in the immunotherapy of this disease prompted us to examine markers of immunogenicity [PD-L1 expression and tumor-infiltrating lymphocytes (TILS) in these subsets]. The observed clinical responses to checkpoint inhibition of the PD-1/PD-L1 pathway have not correlated with PD-L1 expression by MCC cells, and recent evidence suggests that functions of this pathway within the immune tumor microenvironment may be relevant. We conducted a semiquantitative (high, moderate, and minimal) immunohistochemical evaluation of the global PD-L1 signal in 52 cases of MCC, segregated in 3 subsets [pure MCPyV-positive (n = 28), pure MCPyV-negative (n = 9), and combined MCPyV-negative (n = 15)]. TILS were categorized as brisk, nonbrisk, or absent. Intersubset comparisons revealed that high global PD-L1 signals were exclusively associated with pure MCPyV-positive MCCs contrasted with virus-negative cases (P = 0.0003). Moderate signals were seen across all 3 groups. Brisk TILS were significantly associated with MCPyV-positive MCCs compared with MCPyV-negative cases (P = 0.029). Neither parameter (PD-L1 or TILS) was significantly different between the MCPyV-negative groups. Of potential clinical relevance, MCPyV seems to convey greater immunogenicity to MCCs than the high mutational burden/greater neoantigen load of MCPyV-negative cases. Interesting too is the fact that subset-related profiles of these markers mirrored those noted at genetic and immunohistochemical levels, separating pure MCPyV-positive MCCs from the virus-negative subsets.

Treatment outcomes and incidence of brain metastases in pulmonary large cell neuroendocrine carcinoma.

INTRODUCTION: Large cell neuroendocrine carcinoma (LCNEC) is a rare type of high-grade pulmonary neuroendocrine tumor. The study objective is to investigate its survival outcomes, incidence of brain metastases, and patterns of recurrence. METHODS: This is a single center study of patients with pathologic diagnosis of pulmonary LCNEC. Patient data were collected retrospectively and analyzed, including survival, incidence of brain metastases, and patterns of recurrence. RESULTS: Of 87 patients (stages I: 24, II: 14, III: 23, IV: 26), 52 were managed curatively and 35 palliatively. The median follow-up time was 17.3 months (range 0.6-89.5) for those treated with curative intent and 7.0 months (range 0.1-28.6) for those treated palliatively. The 2- and 5-year overall survival (OS) rates are 48.4% and 25.5% for the curative group, with a median OS of 13.5 months. In the palliative group, the OS are 30.8% at 1 year and 6.8% at 2 years, with a median OS of 7.0 months. Thirty-eight of 52 (73%) patients treated with curative intent had disease relapse, with the common sites being regional lymph nodes (20), brain (18), bones (11), and liver (9). The incidence of brain recurrence among those managed curatively are 21.4% and 41.3%, respectively at 1 and 2 years. Of 18 patients experiencing brain metastases, 14 developed them as part of a first relapse. CONCLUSIONS: LCNEC's survival outcomes are poor. The incidence of brain metastases is higher than what is observed for other types of nonsmall cell lung cancers. Prophylactic cranial irradiation should be investigated as a means of improving outcomes.

Goblet cell carcinoid of the appendix - An interobserver variability study using two proposed classification systems.

Goblet cell carcinoid (GCC) is an uncommon tumor of the vermiform appendix. Due to a broad spectrum of morphological differentiation, subclassification and grading of GCCs remains an area of controversy. Two separate systems have proposed classifying GCC tumors into three (classical GCC; adenocarcinoma ex-GCC, signet ring cell type; adenocarcinoma ex-GCC, poorly differentiated carcinoma type) OR two subgroups (low and high grade GCC) based on morphological criteria. We independently compared the inter-observer variability associated with each classification system. Overall, both systems had moderate interobserver agreement, with the two-tiered system (κ=0.54) performing slightly better than the three-tiered system (κ=0.42). GI-specialist pathologists had substantial agreement for both two and three-tiered systems (κ=0.65 vs. 0.65). Non-GI trained pathologists had lower overall agreement than GI trained pathologists, but their agreement was better using the two-tiered system (κ=0.44) than the three-tiered system (κ=0.22). A sub-analysis of 6 cases with a high rate of discordant classification revealed several challenges that exist in applying current criteria, including differentiating "goblet" vs. "signet ring" cell morphology, applying a 1 mm2 criteria to multifocal non-contiguous glandular and single infiltrating cell architecture, differentiating fibro-inflammatory stroma from desmoplastic stroma, and solid architecture in cases with abundant extracellular mucin, and distinguishing "reactive" nuclear atypia from true "cytologic atypia". Despite these challenges, the study identified better agreement among GI pathologists than non-GI trained pathologists. While GI pathologist review may be helpful, further research on objective classification criteria remains an area of interest.

Positron Emission Tomography/Computerized Tomography in Newly Diagnosed Patients with Giant Cell Arteritis Who Are Taking Glucocorticoids.

OBJECTIVE: Large vessel uptake on positron emission tomography/computerized tomography (PET/CT) supports the diagnosis of giant cell arteritis (GCA). Its value, however, in patients without arteritis on temporal artery biopsy and in those receiving glucocorticoids remains unknown. We compared PET/CT results in GCA patients with positive (TAB+) and negative temporal artery biopsies (TAB-), and controls. METHODS: Patients with new clinically diagnosed GCA starting treatment with glucocorticoids underwent temporal artery biopsy and PET/CT. Using a visual semiquantitative approach, 18F-fluorodeoxyglucose (FDG) uptake was scored in 8 vascular territories and summed overall to give a total score in patients and matched controls. RESULTS: Twenty-eight patients with GCA and 28 controls were enrolled. Eighteen patients with GCA were TAB+. Mean PET/CT scores after an average of 11.9 days of prednisone were higher in patients with GCA compared to controls, for both total uptake (10.34 ± 2.72 vs 7.73 ± 2.56; p = 0.001), and in 6 of 8 specific vascular territories. PET/CT scores were similar between TAB+ and TAB- patients with GCA. The optimal cutoff for distinguishing GCA cases from controls was a total PET/CT score of ≥ 9, with an area under the receiver-operating characteristic curve of 0.75, sensitivity 71.4%, and specificity 64.3%. Among patients with GCA, these measures correlated with greater total PET/CT scores: systemic symptoms (p = 0.015), lower hemoglobin (p = 0.009), and higher platelet count (p = 0.008). CONCLUSION: Vascular FDG uptake scores were increased in most patients with GCA despite exposure to prednisone; however, the sensitivity and specificity of PET/CT in this setting were lower than those previously reported.

Aortic intimal separation resulting from manual cardiopulmonary resuscitation-completing the spectrum of blunt thoracic aortic injury complicating CPR.

Blunt thoracic aortic injury (BTAI) resulting from cardiopulmonary resuscitation (CPR) is rarely reported and most reports are of aortic rupture. Clinical reports have also documented aortic dissection and intramural hematomas with sequential imaging showing the development of these aortic injuries after the administration of CPR, suggesting that non-transmural aortic injury may also result from CPR. We report partial separation of an aortic intimal atheromatous plaque as a component injury in a case with multiple complications of manual CPR. A 74-year-old male presented to the emergency room (ER) with a 2-day history of chest pain. While in the ER, he suffered witnessed cardiac arrest and resuscitative attempts were pursued for 60 min prior to declaring death. At autopsy, there were numerous injuries attributable to CPR, including bilateral rib fractures, sternal fracture, retrosternal and mediastinal hemorrhage, epicardial ecchymoses, and ruptured pericardium. There was a perforated inferior wall myocardial infarct with a large left hemothorax. There was partial separation/laceration of an intimal atheromatous plaque on the anterior wall of the ascending aorta proximal to the origin of the brachiocephalic artery, forming a triangular flap, without associated intramedial dissection or hematoma. There was no thrombus formation, effectively excluding existence of the laceration prior to circulatory arrest. This aortic injury provides pathologic confirmation of non-transmural BTAI definitively sustained during manual CPR. Pathologists and clinicians alike should be cognizant of the possibility of BTAI resulting from CPR, which may manifest the full range of severity from intimal tear through aortic rupture.

Granulomas and giant cells in hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP) is an immunologically mediated form of diffuse lung disease, with histopathologic features that include cellular bronchiolitis, interstitial pneumonia, poorly formed granulomas, isolated multinucleated giant cells (MNGCs), organizing pneumonia, and interstitial fibrosis. This study describes the clinical and histopathologic findings in a retrospective series of 40 consecutive patients diagnosed with HP at the Mayo Clinic in Rochester, MN, between 1997 and 2011. Because the literature indicates that granulomas and MNGCs are located in the interstitium, particular attention was given to their distribution. Of the 40 patients, 33 underwent surgical lung biopsy and 7 underwent lung transplantation. Thirty-eight (95%) patients had interstitial pneumonia; 37 (93%), cellular bronchiolitis; 32 (80%), nonnecrotizing granulomas; 31 (78%), isolated MNGCs; 34 (85%) organizing pneumonia, and 31 (78%); interstitial fibrosis. In 27 cases, the granulomas were within airspaces; and in 26, they were interstitial. In 25 cases, MNGCs were within airspaces; and in 24, they were interstitial. In 3 (8%) cases, both granulomas and MNGCs were seen only within airspaces. Interstitial fibrosis was centrilobular in 22 cases, resembled usual interstitial pneumonia in 18 cases, and resembled nonspecific interstitial pneumonia in 11 cases. The "classic triad" of bronchiolitis, interstitial pneumonia, and granulomas was seen in 29 (73%) cases and was most frequent in biopsy than explant specimens (P = .004). This study confirms that granulomas and MNGCs are not confined to the pulmonary interstitium in HP.

PRKAR1A in the development of cardiac myxoma: a study of 110 cases including isolated and syndromic tumors.

Cardiac myxoma usually occurs as a solitary mass, but occasionally develops as part of a familial syndrome, the Carney complex (CNC). Two thirds of CNC-associated cardiac myxomas exhibit mutations in PRKAR1A. PRKAR1A mutations occur in both familial and sporadic forms of CNC but have not been described in isolated (nonsyndromic) cardiac myxomas. A total of 127 consecutive cardiac myxomas surgically resected at Mayo Clinic (1993 to 2011) from 110 individuals were studied. Clinical, radiologic, and pathologic findings were reviewed. Of these, 103 patients had isolated cardiac myxomas, and 7 patients had the tumor as a component of CNC. Age and sex distributions were different for CNC (mean 26 y, range 14 to 44 y, 71% female) and non-CNC (mean 62 y, range 18 to 92 y, 63% female) patients. PRKAR1A immunohistochemical analysis (IHC) was performed, and myxoma cell reactivity was graded semiquantitatively. Bidirectional Sanger sequencing was performed in 3 CNC patients and 29 non-CNC patients, to test for the presence of mutations in all coding regions and intron/exon boundaries of the PRKAR1A gene. IHC staining showed that all 7 CNC cases lacked PRKAR1A antigenicity and that 33 (32%) isolated cardiac myxomas were similarly nonreactive. Of tumors subjected to sequencing analysis, 2 (67%) CNC myxomas and 9 (31%) non-CNC myxomas had pathogenic PRKAR1A mutations. No germline mutations were found in 4 non-CNC cases tested. PRKAR1A appears to play a role in the development of both syndromic and nonsyndromic cardiac myxomas. Routine IHC evaluation of cardiac myxomas for PRKAR1A expression may be useful in excluding a diagnosis of CNC.