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Nevins W Todd,1,2 Rachel G Scheraga,1,3 Jeffrey R Galvin,1,4 Aldo T Iacono,1 E James Britt,1 Irina G Luzina,1,2 Allen P Burke,5,* Sergei P Atamas1,2,* 1Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA; 2Baltimore VA Medical Center, Baltimore, MD, USA; 3Critical Care Medicine Department, National Institutes of Health, Bethesda, MD, USA; 4Department of Diagnostic Radiology, University of Maryland School of Medicine, Baltimore, MD, USA; 5Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, USA *These authors contributed equally to this work Background: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no known effective therapy. It is often assumed, but has not been objectively evaluated, that pulmonary inflammation subsides as IPF progresses. The goal of this work was to assess changes in the degree of inflammatory cell infiltration, particularly lymphocytic infiltration, over the duration of illness in IPF. Methods: Sixteen patients with confirmed IPF were identified in patients whom surgical lung biopsy (SLB) was performed in early disease, and in patients whom lung transplantation was subsequently performed in end stage disease. A numerical scoring system was used to histologically quantify the amount of fibrosis, honeycomb change, fibroblastic foci, and lymphocyte aggregates in each SLB and lung explant tissue sample. Analyses of quantitative scores were performed by comparing paired, matched samples of SLB to lung explant tissue. Results: Median time [1st, 3rd quartiles] from SLB to lung transplantation was 24 [15, 29] months. Histologic fibrosis and honeycomb change were more pronounced in the explant samples compared with SLB (P < 0.001 and P < 0.01, respectively), and most notably, higher numbers of lymphocyte aggregates were observed in the explant samples compared to SLB (P = 0.013). Immunohistochemical analyses revealed abundant CD3+ (T lymphocyte) and CD20+ (B lymphocyte) cells, but not CD68+ (macrophage) cells, within the aggregates. Conclusion: Contrary to the frequent assumption, lymphocyte aggregates were present in greater numbers in advanced disease (explant tissue) compared to early disease (surgical lung biopsy). This finding suggests that active cellular inflammation continues in IPF even in severe end stage disease. Keywords: idiopathic pulmonary fibrosis, inflammation, lymphocyte aggregates

Objective: To evaluate the prevalence of plaque erosion as a substrate for coronary thrombosis.Design: Pathological study in patients with acute myocardial infarction not treated with thrombolysis or coronary interventional procedures.Patients: 298 consecutive patients (189 men, mean (SD) age 66 (11) years; 109 women, 74 (8) years) dying in hospital between 1984 and 1996 from acute myocardial infarction, diagnosed by ECG changes and rise in cardiac enzymes.Main Outcome Measures: Histopathological determination of plaque erosion as substrate for acute thrombosis; location and histological type of coronary thrombosis; acute and healed myocardial infarcts; ventricular rupture.Results: Acute coronary thrombi were found in 291 hearts (98%); in 74 cases (25%; 40/107 women (37.4%) and 34/184 men (18.5%); p = 0.0004), the plaque substrate for thrombosis was erosion. Healed infarcts were found in 37.5% of men v 22% of women (p = 0.01). Heart rupture was more common in women than in men (22% v 10.5%, p = 0.01). The distribution of infarcts, thrombus location, heart rupture, and healed infarcts was similar in cases of plaque rupture and plaque erosion.Conclusions: Plaque erosion is an important substrate for coronary thrombosis in patients dying of acute myocardial infarction. Its prevalence is significantly higher in women than in men. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To perform a molecular autopsy involving the RyR2-encoded cardiac ryanodine receptor/calcium release channel to determine whether mutations responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT) represent a novel pathogenic basis for unexplained drownings. METHODS: A cardiac channel molecular autopsy was performed on 2 individuals who died of unexplained drowning and whose cases were referred to the Sudden Death Genomics Laboratory at the Mayo Clinic in Rochester, Minn. Comprehensive mutational analysis of all 60 protein-encoded exons of the 5 long QT syndrome-causing cardiac channel genes and a targeted analysis of 18 RyR2 exons known to host RyR2-mediated CPVT-causing mutations (CPVT1) was performed using polymerase chain reaction, denaturing high-performance liquid chromatography, and DNA sequencing. RESULTS: Both individuals harbored novel mutations in RyR2. Postmortem mutational analysis revealed a familial missense mutation in exon 14, R414C, in a 16-year-old girl. A 9-year-old boy possessed a sporadic missense mutation in exon 49, V2475F. Both amino acid positions involve highly conserved residues that localize to critical functional domains in the calcium release channel. Neither substitution was present in 1000 reference alleles. CONCLUSIONS: This molecular autopsy study provides proof of principle that RyR2 mutations can underlie some unexplained drownings. A population-based genetic epidemiology study that involves molecular autopsies of individuals who die of unexplained drowning is needed to determine the prevalence and spectrum of KCNQ1 and now RyR2 mutations as potential pathogenic mechanisms for drowning. [ABSTRACT FROM AUTHOR]

Sickle cell disease (SCD) is associated with substantial morbidity and early mortality in afflicted adults. Cardiopulmonary complications that occur at increased frequency in SCD such as pulmonary embolism, pulmonary arterial hypertension, and acute chest syndrome can acutely worsen right ventricular function and lead to cardiogenic shock. Mechanical circulatory support including venoarterial extracorporeal membrane oxygenation (VA ECMO) is being increasingly utilized to treat hemodynamic collapse in various patient populations. However, a paucity of literature exists to guide the use of mechanical circulatory support in adults with SCD where disease-related sequela and unique hematologic aspects of this disorder may complicate extracorporeal therapy and must be understood. Here, we review the literature and describe three cases of adult patients with SCD who developed cardiogenic shock from acute decompensated right heart failure and were treated clinically with VA ECMO. Using an in vitro ECMO system, we investigate a potential increased risk of systemic fat emboli in patients with SCD who may be experiencing vaso-occlusive events with bone marrow involvement given the high-volume shunting of blood from venous to arterial systems with VA ECMO. The purpose of this study is to describe available extracorporeal life support experiences, review potential complications, and discuss the special considerations needed to further our understanding of the utility of VA ECMO in those with SCD., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objectives: Present-day pathologists may be unfamiliar with the histopathologic features of measles, which is a reemerging disease. Awareness of these features may enable early diagnosis of measles in unsuspected cases, including those with an atypical presentation. Using archived tissue samples from historic patients, a unique source of histopathologic information about measles and other reemerging infectious diseases, we performed a comprehensive analysis of the histopathologic features of measles seen in commonly infected tissues during prodrome, active, and late phases of the disease., Methods: Subspecialty pathologists analyzed H&E-stained slides of specimens from 89 patients accessioned from 1919 to 1998 and correlated the histopathologic findings with clinical data., Results: Measles caused acute and chronic histopathologic changes, especially in the respiratory, lymphoid (including appendix and tonsils), and central nervous systems. Bacterial infections in lung and other organs contributed significantly to adverse outcomes, especially in immunocompromised patients., Conclusions: Certain histopathologic features, especially Warthin-Finkeldey cells and multinucleated giant cells without inclusions, allow pathologists to diagnose or suggest the diagnosis of measles in unsuspected cases., (© American Society for Clinical Pathology, 2022.)

We describe a 28-year-old man who sustained an open IIIB left ankle fracture dislocation with heel pad avulsion. The patient underwent formal angiography of the left lower extremity, followed by free tissue transfer of a rectus abdominis flap several days later. Intraoperatively, a thrombus was identified in the deep inferior epigastric artery above the femoral artery access site requiring thrombectomy. Histologic analysis estimated the thrombus age at 12 to 72 hours, raising concern that the thrombus was induced during angiogram instrumentation. Donor and recipient site-specific risks of arterial instrumentation (including invasive diagnostics) should be considered when planning free tissue transfer., (© 2022 The Author(s).)

Sarcomatoid mesotheliomas can be challenging to diagnose on small biopsy specimens, where limited material may preclude definitive assessment of invasion and lesional cells can have relatively bland cytology with no mesothelial marker expression. We report a case of a patient who presented with a pleural effusion and had subsequent pleural biopsy that showed a bland, uniform spindle cell proliferation in a mildly myxoid background. There was little if any collagen; no chest wall, soft tissue, or fat; and mesothelial markers were negative. The cells were positive for pancytokeratin and GATA3 by immunohistochemistry, and in situ hybridization showed a "negative" result for homozygous loss of CDKN2A; however, there was partial (heterozygous) loss of one allele. A diagnosis of atypical spindle cell proliferation was made based on these findings. Several months later, the patient had a repeat pleural biopsy that showed spindled cells with more pleomorphism, areas of invasion into the chest wall, and the same partial loss of CDKN2A, consistent with a sarcomatoid mesothelioma. This case underscores the challenges present on small biopsy specimens, the fact that sarcomatoid mesotheliomas can be relatively bland appearing with focal pleomorphism, and that heterozygous loss of CDKN2A should be considered a positive result indicative of a neoplastic process.

TP53 is one of the most frequently altered genes in prostate cancer. The precise assessment of its focal alterations in primary tumors by immunohistochemistry (IHC) has significantly enhanced its prognosis. p53 protein expression and lymphovascular invasion (LVI) were evaluated for predicting metastatic progression by IHC staining of representative whole-mounted prostate sections from a cohort of 189 radical prostatectomy patients with up to 20 years of clinical follow-up. Kaplan-Meier survival curves were used to examine time to distant metastasis (DM) as a function of p53 expression and LVI status. TP53 targeted sequencing was performed in ten tumors with the highest expression of p53 staining. Nearly half (49.8%) of prostate tumors examined showed focal p53 expression while 26.6% showed evidence of LVI. p53(+) tumors had higher pathologic T stage, Grade Group, Nuclear Grade, and more frequent LVI. p53 expression of > 5% and LVI, individually and jointly, are associated with poorer DM-free survival. TP53 mutations were detected in seven of ten tumors sequenced. Four tumors with the highest p53 expression harbored likely pathogenic or pathogenic mutations. High levels of p53 expression suggest the likelihood of pathogenic TP53 alterations and, together with LVI status, could enhance early prognostication of prostate cancer progression., (© 2022. The Author(s).)

Ischemic heart disease is a leading cause of death worldwide and comprises a large proportion of annual health care expenditure. Management of ischemic heart disease is now best guided by the physiologic significance of coronary artery stenosis. Invasive coronary angiography is the standard for diagnosing coronary artery stenosis. However, it is expensive and has risks including vascular access site complications and contrast material-induced nephropathy. Invasive coronary angiography requires fractional flow reserve (FFR) measurement to determine the physiologic significance of a coronary artery stenosis. Multiple noninvasive cardiac imaging modalities can also anatomically delineate or functionally assess for significant coronary artery stenosis, as well as detect the presence of myocardial infarction (MI). While coronary CT angiography can help assess the degree of anatomic stenosis, its inability to assess the physiologic significance of lesions limits its specificity. Physiologic significance of coronary artery stenosis can be determined by cardiac MR vasodilator or dobutamine stress imaging, CT stress perfusion imaging, FFR CT, PET myocardial perfusion imaging (MPI), SPECT MPI, and stress echocardiography. Clinically unrecognized MI, another clear indicator of physiologically significant coronary artery disease, is relatively common and is best evaluated with cardiac MRI. The authors illustrate the spectrum of imaging findings of ischemic heart disease (coronary artery disease, myocardial ischemia, and MI); highlight the advantages and disadvantages of the various noninvasive imaging methods used to assess ischemic heart disease, as illustrated by recent clinical trials; and summarize current indications and contraindications for noninvasive imaging techniques for detection of ischemic heart disease. Online supplemental material is available for this article. Published under a CC BY 4.0 license.

Background: Multidisciplinary discussion (MDD) is widely recommended for patients with interstitial lung disease (ILD), but published primary data from MDD has been scarce, and factors influencing MDD other than chest computed tomography (CT) and lung histopathology interpretations have not been well-described., Methods: Single institution MDD of 179 patients with ILD., Results: MDD consensus clinical diagnoses included autoimmune-related ILD, chronic hypersensitivity pneumonitis, smoking-related ILD, idiopathic pulmonary fibrosis, medication-induced ILD, occupation-related ILD, unclassifiable ILD, and a few less common pulmonary disorders. In 168 of 179 patients, one or more environmental exposures or pertinent features of the medical history were identified, including recreational/avocational, residential, and occupational exposures, systemic autoimmune disease, malignancy, medication use, and family history. The MDD process demonstrated the importance of comprehensively assessing these exposures and features, beyond merely noting their presence, for rendering consensus clinical diagnoses. Precise, well-defined chest CT and lung histopathology interpretations were rendered at MDD, including usual interstitial pneumonia, nonspecific interstitial pneumonia, and organizing pneumonia, but these interpretations were associated with a variety of MDD consensus clinical diagnoses, demonstrating their nonspecific nature in many instances. In 77 patients in which MDD consensus diagnosis differed from referring diagnosis, assessment of environmental exposures and medical history was found retrospectively to be the most impactful factor., Conclusions: A comprehensive assessment of environmental exposures and pertinent features of the medical history guided MDD. In addition to rendering consensus clinical diagnoses, MDD presented clinicians with opportunities to initiate environmental remediation, behavior modification, or medication alteration likely to benefit individual patients with ILD., (Published by Elsevier Ltd.)

Intimal sarcomas of the pulmonary artery and aorta are rare entities with a poor prognosis. In many instances, pulmonary artery sarcomas are misinterpreted as acute or chronic pulmonary thromboembolism, whereas aortic intimal sarcomas are often misdiagnosed as protuberant atherosclerotic disease or intimal thrombus. Discernment of intimal sarcomas from these and other common benign entities is essential for the timely initiation of aggressive therapy. The most useful imaging modalities for assessment of a suspected intimal sarcoma include CT angiography, fluorine 18-fluorodeoxyglucose PET, and MRI. The authors discuss the clinical features, current treatment options, characteristic imaging findings, and underlying pathologic features of intimal sarcomas. The authors emphasize imaging discernment of intimal sarcomas and how their differential diagnosis is informed by knowledge of radiologic-pathologic correlation. The most reliable distinguishing imaging features are also emphasized to improve accurate and timely diagnosis. Online supplemental material is available for this article. © RSNA, 2021.

Cardiac neoplasms are a rare finding of which a cardiac myxoma is the most commonly encountered. Therefore, a density identified in the left atrium commonly leads to the presumptive diagnosis of an atrial myxoma. However, other pathologies, such as atrial thrombi, can mimic in clinical presentation and appearance to a myxoma. Clinically, these pathologies may lead to obstructive symptoms such as syncope, palpitations, or sudden cardiac death. At present, echocardiography, magnetic resonance imaging, or computed tomography can be used to identify such masses, but fall short of identifying the primary cause. The management of atrial thrombi is not yet fully understood and definite recommendations have not been established. We present a case of an 87-year-old man complaining of syncopal episodes found to be secondary to an incidental intracardiac density resulting from age-related amyloidosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Nanda et al.)

Objectives . The criteria for "active surveillance" depend in part on quantification of tumor extent and grade on prostate biopsies. It is known that false-negative biopsies may occur from incomplete sectioning of cores within the paraffin blocks. Methods . We retrospectively analyzed a prostate biopsy series, which were subjected to a second round of sections, in order to determine the rate of missed cancers. Results . Of 1324 sets of prostate biopsies, 4.5% (60) showed additional involved cores or higher grade tumor on recut sections. In 27 patients (2.0%), the changed diagnosis resulted in a potential mild increase in National Comprehensive Cancer Network (NCCN) risk, from negative to very low (12), very low to low (12), and low to favorable intermediate (3). In 3 patients (0.2%), the changed diagnosis resulted in a significant increase in NCCN risk. Comparison of the initial sets of slides to the recuts demonstrated areas of absent tissue in many of the cases in which tumor segments were missed. In 2/3 cases with the significant grade increase, gaps were present in one that should have alerted the pathologist to incomplete sections, and the tumor was fragmented at the edge of the core appearing incompletely sampled. Conclusions . A significant increase in risk was seen in this study in 0.2% of patients when blocks were recut for further sampling, with minor increases in 2%. While embedding issues only rarely resulted in clinically significant sampling error, the 3 significantly underdiagnosed cases underscore the need for pathologists to be alert to incomplete sections of prostate cores.

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1. Presenting symptoms included abdominal pain=3, bleeding=1, nausea and vomiting=1, and nonresponsiveness=1. Imaging studies were often abnormal: thickened bowel wall=3 (1 with a mass), small bowel obstruction=2, and edematous and dilated bowel wall=2. Most specimens were surgical resections (n=7, autopsy=1): extended right colectomy=2, small bowel only=5 (terminal ileum=3, jejunum=2). Two specimens were grossly described as mahogany, and 1 case contained a perforation. Histologic sections of all cases showed finely granular, brown cytoplasmic pigment in smooth muscle cells on hematoxylin and eosin. This pigment was most conspicuous in the muscularis propria (small bowel>colon), and it was not identified in the mucosa. The pigment was reactive with Fontana-Masson, carbol lipofuscin, Periodic acid-Schiff, and Periodic acid-Schiff with diastase, and electron microscopy was compatible with lipofuscin. The mean clinical follow-up was 208 weeks: 1 patient died of complications of encephalitis, the others were alive and well. BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel.

A combination of genetic manipulations of donor organs and target-specific immunosuppression is instrumental in achieving long-term cardiac xenograft survival. Recently, results from our preclinical pig-to-baboon heterotopic cardiac xenotransplantation model suggest that a three-pronged approach is successful in extending xenograft survival: (a) α-1,3-galactosyl transferase (Gal) gene knockout in donor pigs (GTKO) to prevent Gal-specific antibody-mediated rejection; (b) transgenic expression of human complement regulatory proteins (hCRP; hCD46) and human thromboregulatory protein thrombomodulin (hTBM) to avoid complement activation and coagulation dysregulation; and (c) effective induction and maintenance of immunomodulation, particularly through co-stimulation blockade of CD40-CD40L pathways with anti-CD40 (2C10R4) monoclonal antibody (mAb). Using this combination of manipulations, we reported significant improvement in cardiac xenograft survival. In this study, we are reporting the survival of cardiac xenotransplantation recipients (n = 3) receiving xenografts from pigs without the expression of hTBM (GTKO.CD46). We observed that all grafts underwent rejection at an early time point (median 70 days) despite utilization of our previously reported successful immunosuppression regimen and effective control of non-Gal antibody response. These results support our hypothesis that transgenic expression of human thrombomodulin in donor pigs confers an independent protective effect for xenograft survival in the setting of a co-stimulation blockade-based immunomodulatory regimen., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Using recently proposed pathological criteria, we determined the incidence of neuroendocrine cell proliferation in a series of explants with lung disease. Cases were defined as NECH (≥3 bronchioles with ≥5 endocrine cells), borderline diffuse neuroendocrine cell hyperplasia (DPNECH) (1-3 tumourlets with or without NECH), and DPNECH (≥3 tumourlets with NECH). Endocrine cells were identified by immunohistochemical staining for synaptophysin. There were 65 explants with interstitial lung disease (57 with non-sarcoid fibrotic lung disease, 8 with sarcoidosis), and 21 with centrilobular emphysema. Over one-third of all explant cases demonstrated histological criteria for NECH. There were three cases of DPNECH in the non-sarcoid fibrotic lung disease group (5%) and 20 cases of NECH (35%). The emphysema group had one case of DPNECH (5%), two cases of borderline DPNECH (10%), and seven cases with NECH (33%). The sarcoidosis group had two cases of DPNECH (25%) and three cases of NECH (38%). NECH is common in interstitial lung disease and emphysema. These results suggest that fibrotic lung disease is a predisposing factor for neuroendocrine cell proliferation, in addition to the known risk of epithelial neoplasms., (Copyright © 2018 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Interstitial lung disease (ILD) and pulmonary fibrosis comprise a wide array of inflammatory and fibrotic lung diseases which are often confusing to general medicine and pulmonary physicians alike. In addition to the myriad of clinical and radiologic nomenclature used in ILD, histopathologic descriptors may be particularly confusing, and are often extrapolated to radiologic imaging patterns which may further add to the confusion. We propose that rather than focusing on precise histologic findings, focus should be on identifying an accurate etiology of ILD through a comprehensive and detailed medical history. Histopathologic patterns from lung biopsy should not be dismissed, but are often nonspecific, and overall treatment strategy and prognosis are likely to be determined more by the specific etiology of ILD rather than any particular histologic pattern. In this review, we outline a practical approach to common ILDs, highlight important aspects in obtaining an exposure history, clarify terminology and nomenclature, and discuss six common subgroups of ILD likely to be encountered by general medicine physicians in the inpatient or outpatient setting: Smoking-related, hypersensitivity pneumonitis, connective tissue disease-related, occupation-related, medication-induced, and idiopathic pulmonary fibrosis. Accurate diagnosis of these forms of ILD does require supplementing the medical history with results of the physical examination, autoimmune serologic testing, and chest radiographic imaging, but the importance of a comprehensive environmental, avocational, occupational, and medication-use history cannot be overstated and is likely the single most important factor responsible for achieving the best possible outcomes for patients.

Neonicotinoids have become the most widely used class of insecticides world-wide. Although numerous studies have documented neonicotinoid toxicity in bees and other insects, the effects of exposure during early development in mammals remain largely unexplored. We assessed the effects of the neonicotinoid imidacloprid (IMI) in adult male and female mice after in utero and early postnatal exposure. Pregnant mice were infused with IMI (0.5 mg/kg/day) from gestational day 4 to the end of nursing at postnatal day 21. The young adult offspring were studied in a series of biochemical and behavioral tests. To assess reproducibility, the behavioral analyses were conducted in three separate studies using multiple exposed litters. Exposure to IMI reduced fecundity, and in adult offspring, decreased body weight in male but not female pups. Offspring from IMI-treated mothers displayed lower triglycerides, elevated motor activity, enhanced social dominance, reduced depressive-like behavior, and a diminution in social aggression compared to vehicle treated controls. Low levels of IMI were detected in the brains and livers of the treated mothers, while trace levels were detected in some offspring. Our results demonstrate that transient exposure to a neonicotinoid over the early developmental period induces long-lasting changes in behavior and brain function in mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease manifested by overtly scarred peripheral and basilar regions and more normal-appearing central lung areas. Lung tissues from macroscopically normal-appearing (IPFn) and scarred (IPFs) areas of explanted IPF lungs were analyzed by RNASeq and compared with healthy control (HC) lung tissues. There were profound transcriptomic changes in IPFn compared with HC tissues, which included elevated expression of numerous immune-, inflammation-, and extracellular matrix-related mRNAs, and these changes were similar to those observed with IPFs compared to HC. Comparing IPFn directly to IPFs, elevated expression of epithelial mucociliary mRNAs was observed in the IPFs tissues. Thus, despite the known geographic tissue heterogeneity in IPF, the entire lung is actively involved in the disease process, and demonstrates pronounced elevated expression of numerous immune-related genes. Differences between normal-appearing and scarred tissues may thus be driven by deranged epithelial homeostasis or possibly non-transcriptomic factors., (Published by Elsevier Inc.)

Advances in medical diagnosis reveal that coronary artery aneurysms (CAAs) may develop in several clinical scenarios and manifest variable symptoms, imaging appearances, and outcomes. Aneurysms are pathologically classified into three groups: atherosclerotic, inflammatory, and noninflammatory. The last category is associated with congenital, inherited, and connective tissue disorders. Overlap exists among the groups, because secondary atherosclerotic change may be present in an aneurysm of any cause. Atherosclerosis is the most common cause of CAAs in adults, and inflammation is considered the underlying mechanism. In children, Kawasaki disease is the most likely cause of CAAs. In both conditions, the aneurysms are usually multiple and affect more than one coronary artery. Mycotic (infectious), iatrogenic, and cocaine-induced CAAs are also well documented. Most CAAs are discovered incidentally, but potential cardiovascular complications include thrombosis, occlusion, fistula formation, rupture, myocardial infarction, and cardiac tamponade. Imaging modalities to evaluate a suspected CAA include transthoracic echocardiography, angiographic cardiac catheterization, electrocardiographically gated computed tomographic angiography, cardiac magnetic resonance (MR) imaging, and MR angiography. Management is usually individualized, and options include surveillance, anticoagulant therapy, percutaneous stent or coil placement, surgical resection, and coronary artery bypass grafting.

Newly-appearing lung nodules on surveillance imaging in patients with pre-existing lung cancer can present a diagnostic dilemma when attempting to differentiate between metastatic disease, infection, and other inflammatory conditions. Here we report a case of an EGFR- / ALK- / BRAF+ metastatic adenocarcinoma patient who underwent lung biopsy for evaluation of upper-lobe predominant lung nodules revealed to represent pulmonary Langerhans cell histiocytosis (PLCH). The patient was a heavy smoker and admitted to increase her smoking habit after initially learning about her diagnosis with lung cancer. Interestingly, despite the association of both lung adenocarcinoma and PLCH with the BRAF V600E mutation in smokers, pyrosequencing of the patient's PLCH lesions was negative for this mutation. Co-occurrence of PLCH with lung cancer is extremely rare. While most reported cases of PLCH tend to precede the occurrence of lung cancer, a minority of cases appear after a diagnosis of lung cancer has already been established and are thought to represent a local immunologic reaction to the tumor. It is therefore postulated that the appearance of PLCH lesions in this patient's lungs is a result of her increase in cigarette smoking, possibly augmented by co-existence of adenocarcinoma., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Aims: Intraplaque haemorrhage is considered a major contributor to lesion progression. We assessed coronary lesions with intraplaque haemorrhage using intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS)., Methods and Results: We evaluated coronary arteries from autopsy hearts using 40MHz IVUS and NIRS and compared the imaging findings to histopathology. A total of 2324 2-mm long histological segments from 101 coronary arteries from 56 autopsy hearts were included. Intraplaque haemorrhage was found pathologically in 0.8% (18/2324) of segments. Segments with intraplaque haemorrhage had more fibroatheromas (FAs) with a greater IVUS plaque burden, a greater prevalence of IVUS echolucent zones, and a higher NIRS-lipid core burden index (LCBI) compared to segments without intraplaque haemorrhage (FAs: 72.2% vs. 18.3%, P < 0.0001; plaque burden: 59.7% [95% confidence interval: 55.5, 64.0] vs. 48.6% [45.8, 51.3], P < 0.0001; echolucent zones: 88.9% vs. 2.8%, P < 0.0001; NIRS-LCBI: 176 [88, 264] vs. 72 [53, 91], P = 0.02). The 16 IVUS superficial echolucent zones with intraplaque haemorrhage had more late FAs but shorter echolucent zone lengths (0.9 mm [0.7, 1.1] vs. 1.7 mm [1.5, 1.9], P < 0.0001) compared to 65 IVUS superficial echolucent zones without intraplaque haemorrhage., Conclusions: Intracoronary imaging features consistent with intraplaque haemorrhage included a greater plaque burden, a higher NIRS-LCBI, and a greater prevalence of IVUS echolucent zones compared to lesions without intraplaque haemorrhage., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions, please email: journals.permissions@oup.com.)

Thin-cap fibroatheromas (TCFAs) are considered precursors for plaque rupture and subsequent acute coronary events. We investigated intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) characteristics of lesions that were histopathologic TCFAs. IVUS, NIRS, and histopathology were performed in 271 atherosclerotic lesions from 107 fresh coronary arteries from 54 patients at necropsy. The plaque burden and remodeling index calculated by IVUS and maximum lipid core burden index within any 4-mm segment (maxLCBI 4mm ) calculated by NIRS were compared among each plaque type based on histopathologic classifications but focusing on TCFA. Lesions classified as TCFAs had the largest plaque burden, the highest remodeling index, and the greatest maxLCBI 4mm . Plaque burden ≥69% (90% sensitivity, 75% specificity, and area under the curve 0.87); remodeling index ≥1.07 (80% sensitivity, 79% specificity, and area under the curve 0.84); and maxLCBI 4mm ≥323 (80% sensitivity, 85% specificity, and area under the curve 0.84) predicted a histopathologic TCFA. In conclusion, a large plaque burden and a high remodeling index assessed by IVUS and lipid-rich plaque determined by the NIRS maxLCBI 4mm are useful predictive markers of TCFA., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Lymphoma of the heart and pericardium may develop in up to 25% of patients with disseminated nodal disease, but primary cardiac lymphoma is rare. The majority are diffuse large B-cell lymphomas, which arise in immunocompetent older individuals, men twice as often as women. Subsets are found in immunocompromised patients, including those with HIV-AIDS or allograft recipients. Cardiac lymphomas tend to arise in the wall of the right heart, especially right atrium, with contiguous infiltration of epicardium and pericardium. Pericardial implants and effusions are common. The disease is often multifocal in the heart, but cardiac valves are usually spared., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Malignant peritoneal mesothelioma (MPM) is a rare neoplastic condition that arises, usually diffusely, from the serosal membranes of the abdominal cavity. MPM represents about 7% to 10% of all mesothelioma diagnoses and this translates into approximately 800 cases per year in the United States. The disease has variable tumor biology but progression, when it occurs, is almost always within the abdominal cavity. Although many patients can be successfully treated at initial presentation, the disease is almost always fatal in time. It afflicts men and women almost equally and the median age at presentation is 50 years. The diagnosis is made when a diffuse malignant process within the abdominal cavity is observed and a tissue sample reveals the characteristic histopathology and immunohistochemical profile of mesothelioma. Initial staging is usually via a cross sectional imaging study of the abdomen and pelvis making sure that the lower thorax is also assessed. If the disease burden and distribution is favorable then operative exploration, cytoreduction, and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered first line treatment in selected patients. Systemic pemetrexed and cisplatin (or gemcitabine) have modest response rates that are of limited duration. Research advances with novel systemic or intraperitoneal agents hold promise.

Given its inconspicuous appearance on radiography, computed tomography (CT), and magnetic resonance imaging (MRI) the pulmonary valve (PV) is often overlooked as an important cause of both cardiac and pulmonary disease. In this pictorial essay, we review the normal appearance of the PV as well as various congenital anomalies including pulmonary atresia, pulmonary stenosis, and valvular fusion anomalies. Infectious entities, degenerative conditions, and malignant lesions are also depicted. We discuss surgical techniques used to repair both congenital and acquired pulmonary valvular diseases and describe postoperative appearances of the PV on imaging.

Background: Overlapping forms of interstitial pneumonia have been recognized, but are likely underappreciated, and their clinical, radiologic, and histologic characteristics are not well-defined., Methods: We identified 38 patients with surgical lung biopsy demonstrating histologic organizing pneumonia (OP) or histologic organizing pneumonia/non-specific interstitial pneumonia overlap (OP/NSIP) who met established multi-disciplinary clinical-radiologic-histologic criteria for OP. For each patient, radiologic and co-histologic findings were assessed, and clinical outcome was characterized as disease resolution (complete or near-complete resolution of radiologic opacities and absence of chronic respiratory symptoms) or unfavorable disease progression (death due to respiratory failure or forced vital capacity < 70% predicted > six months from diagnosis)., Results: Seven of 38 patients had clinical-radiologic-histologic focal OP. Focal OP was associated with histologic OP (p = 0.019), and all seven patients demonstrated disease resolution. In the remaining 31 patients with cryptogenic or autoimmune-associated OP, 21 patients had histologic OP/NSIP, and 10 had histologic OP. Histologic OP/NSIP was associated with ground glass opacity (GGO, p = 0.012), reticulation (p = 0.029), traction bronchiectasis (p = 0.029), reactive pneumocytes (p = 0.013), and unfavorable disease progression (p < 0.0001). Histologic OP was associated with consolidation (p = 0.028) and disease resolution (p < 0.0001). Multivariate analysis demonstrated histologic OP/NSIP (p < 0.001) and radiologic GGO (p = 0.041) to be independently associated with unfavorable disease progression., Conclusions: OP/NSIP overlap, either idiopathic or autoimmune-associated and identified by histologic and radiologic findings, was associated with unfavorable disease progression, and should therefore be recognized as a characteristic clinical-radiologic-histologic entity., (Published by Elsevier Ltd.)

Mycobacterial spindle cell pseudotumor (MSP) represents a rare, non-malignant, mass-forming reaction to various mycobacterial infections, typically occurring in immunocompromised patients. It is characterized by the proliferation of spindle-shaped fibrohistiocytic cells without the formation of epithelioid granulomas. Without staining for acid-fast bacilli, histological distinction from other spindle cell lesions, including malignancy, can be difficult. Most of the MSP cases reported in the literature have involved lymph nodes, skin, spleen, or bone marrow, but rarely involve the lung. MSP predominately occurs in patients who are immunosuppressed. We present a patient with MSP of the transplanted lung caused by non-tuberculous mycobacteria, in whom both the natural course of the untreated pseudotumor as well as the response to antimycobacterial treatments were observed., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cardiac sarcoidosis is a rare but potentially fatal disorder with a nonspecific spectrum of clinical manifestations, including conduction disorders, congestive heart failure, ventricular arrhythmias, and sudden cardiac death. Although early treatment to improve morbidity and mortality is desirable, sensitive and accurate detection of cardiac sarcoidosis remains a challenge. Except for the histopathologic finding of noncaseating granulomas in an endomyocardial biopsy specimen, most diagnostic tests are limited and nonspecific at best. Therefore, the decision to initiate treatment is based largely on the patient's clinical symptoms and the course of the disease, rather than histologic confirmation. Successful recognition of cardiac sarcoidosis ultimately requires rigorous collaboration among a clinician, radiologist, and pathologist. Advanced imaging modalities, such as cardiac magnetic resonance imaging and positron emission tomography with fluorodeoxyglucose, have become increasingly useful in facilitating diagnosis and therapeutic monitoring, although limited prospective studies exist. This article describes the clinical parameters and pathologic findings of cardiac sarcoidosis and the advanced imaging features and differential diagnostic challenges that must be considered for a successful diagnostic approach. In addition, to improve the understanding of abnormalities detected with different imaging modalities, we suggest a unified terminology in describing radiologic findings related to cardiac sarcoidosis., ((©)RSNA, 2015.)

Objectives: This study assessed grayscale intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) detection of a histological fibroatheroma (FA)., Background: NIRS-detected, lipid-rich plaques (LRPs) and IVUS-detected attenuated plaques are considered to be vulnerable., Methods: IVUS-attenuated plaque and NIRS-LRP (yellow or tan block chemogram) were compared with histopathology in 1,943 sections of 103 coronary arteries from 56 autopsied hearts., Results: IVUS-superficial attenuation and NIRS-LRP showed a similar high specificity of approximately 95%, whereas IVUS-superficial attenuation alone had a poor sensitivity (vs. NIRS-LRP) in detecting FAs (36% vs. 47%; p = 0.001). Compared with FA sections with superficial attenuation, FA sections without superficial attenuation had a smaller plaque burden (57.1% vs. 67.7%), a larger arc of calcium (79.7° vs. 16.8°), and a lower prevalence of a ≥20% histological necrotic core (28% vs. 50%) or late FA (14% vs. 37%; all p < 0.05). Compared with FA sections with NIRS-LRP, FA sections without NIRS-LRP showed a smaller plaque burden (58.0% vs. 63.3%) and a lower prevalence of a ≥20% necrotic core (27% vs. 46%). Conversely, non-FAs with NIRS-LRP (vs. non-FAs without LRP) showed a larger plaque burden (55.1% vs. 46.3%), a greater prevalence of a ≥20% histological lipid pool (34% vs. 5%), and mostly pathological intimal thickening (50%) or fibrocalcific plaque (33%). When sections showed either IVUS attenuation or NIRS-LRP, the sensitivity for predicting a FA was significantly higher compared with IVUS attenuation alone (63% vs. 36%; p < 0.001) or NIRS-LRP alone (63% vs. 47%; p < 0.001). When sections showed both IVUS attenuation and NIRS-LRP, the positive predictive value improved compared with IVUS attenuation alone (84% vs. 66%; p < 0.001) or NIRS-LRP alone (84% vs. 65%; p < 0.001)., Conclusions: NIRS-LRP was more accurate than IVUS for predicting plaque containing a necrotic core or a large lipid pool, and the combination was more accurate than either alone., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There are few studies on the histologic findings in native infective endocarditis, especially regarding mimics of autoimmune valvulitis., Methods: We prospectively studied 106 surgical specimens from 95 patients with a clinical diagnosis of infective endocarditis on native valves, and compared gross and histologic findings with culture results, underlying valve disease, risk factors and time interval from symptom onset to surgical intervention., Results: There were 41 (39%) aortic, 33 (31%) mitral, 9 (9%) tricuspid, 1(.9%) pulmonic and 11 (10%) multiple valve replacements. Underlying valve disease was present in 26 (27%) patients (non-calcified bicuspid aortic valve, 10 (38%) cases; mitral valve prolapse, 5 (19%) cases; calcified trileaflet aortic valve, 5 (19%) cases; calcified bicuspid aortic valve, 2 (8%) cases; post-rheumatic mitral valve disease, 2 (8%) cases; hypertrophic cardiomyopathy-related mitral valve disease, 1 (4%) case, trileaflet aortic insufficiency 1 (4%) case) and associated with streptococcal infection (p = .001). Absence of underlying valve disease was associated with intravenous drug abuse (p = .01) and dialysis dependent renal disease (p = .006). Intravenous drug abuse was associated with staphylococcal infection (p = .03). Vegetations were present in 80 (75%) of cases, and on the nonflow surface of the valve in 65 (81%) of these. Gram-stain positivity and neutrophilic microabscesses were associated with staphylococcal infection (p = .03). Epithelioid macrophages with palisading features mimicking necrobiotic granulomas were seen in 42 (40%) valves and more frequently associated with streptococcal infection (p=.03). As expected, the presence of valve necrosis and acute inflammation decreased with an increase in time with respect to symptomatic onset., Conclusion: Histologic findings that mimic autoimmune inflammation are frequent in infective endocarditis and associated with streptococcal infection. Risk factors for infective endocarditis include calcific valve disease., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

There are few studies addressing survival of diffuse peritoneal mesotheliomas (DPM).In this study, survival data were obtained retrospectively from 73 patients treated with intended cytoreductive surgery for DPM, with a mean follow-up of 42 months. Mesotheliomas were classified as well differentiated papillary (WDPM, n = 2), multicystic (MCM, n = 4), and epithelioid mesotheliomas were subclassified as tubulopapillary (TPM, n = 27), solid/deciduoid (S/DM, n = 34), and or biphasic mesothelioma (BPM, n = 6). Invasion was characterised as absent (grade 0), into stroma (grade 1), into fat (grade 2), and into adjacent structures (grade 3). Peritoneal cancer index (PCI) and completeness of cytoreduction (CCR) were assessed surgically.There were no deaths in the WDPM, MCM, and epithelioid DPM with ≤ grade 1 invasion. There was a stepwise decrease in overall survival from invasive TPM, S/DM, and BPM (p < 0.0001). By univariate analysis, advanced age (p = 0.01), incomplete CCR (p < 0.001), PCI (p = 0.004), mitotic count (p < 0.001), nuclear grade (p < 0.0001), stromal inflammation (p = 0.013), depth of invasion (p < 0.0001), necrosis (p = 0.002), and sarcomatoid growth (p < 0.0001) were associated with decreased overall survival. By multivariate analysis, only sarcomatoid growth (p = 0.0006), depth of invasion (p = 0.02), elevated CCR (CCR 2-3) (p = 0.02), and presence of inflammatory stroma (p = 0.04) were significant variables associated with decreased overall survival.DPM form a spectrum of indolent to highly aggressive tumours. Solid epithelioid/deciduoid tumours have a prognosis intermediate between biphasic mesotheliomas and invasive TPM. The presence and degree of invasion, sarcomatoid features, and inflammatory stroma are poor prognostic indicators.