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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.

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.

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.

Background The relationship between race, prostate tumor location, and BCR‐free survival is inconclusive. This study examined the independent and joint roles of patient race and tumor location on biochemical recurrence‐free (BCR) survival. Methods A retrospective cohort study was conducted among men with newly diagnosed, biopsy‐confirmed, NCCN‐defined low risk CaP who underwent radical prostatectomy (RP) at the Walter Reed National Military Medical Center from 1996 to 2008. BCR‐free survival was modeled using Kaplan‐Meier estimation curves and multivariable Cox proportional hazards (PH) analyses. Results There were 539 eligible patients with low‐risk CaP (25% African American, AA; 75% Caucasian American, CA). Median age at CaP diagnosis and post‐RP follow‐up time was 59.2 and 8.1 years, respectively. Kaplan‐Meier analyses showed no significant association between race (P = .52) or predominant tumor location (P = .98) on BCR‐free survival. In Cox PH multivariable analysis, neither race (HR = 1.18; 95% CI = 0.68‐2.02; P = .56) nor predominant tumor location (HR = 1.13; 95% CI = 0.59‐2.15; P = .71) was an independent predictor of BCR‐free survival. Conclusions Neither race nor predominant tumor location was associated with adverse oncologic outcome., Neither race nor predominant tumor location was associated with decreased biochemical recurrence (BCR)‐free survival, either independently or jointly.

BACKGROUND AND PURPOSE: Clozapine is an atypical antipsychotic drug that is very efficacious in treating psychosis, but the risk of severe cardiotoxicity limits its clinical use. The present study investigated the harmful effects of clozapine on myocardium and assessed the involvement of cannabinoid receptors in its cardiotoxicity. EXPERIMENTAL APPROACH: Clozapine alone or in combination with selective cannabinoid receptor antagonists or agonists were used to treat mice and cardiomyocytes. KEY RESULTS: Clozapine induced myocardial inflammation and infiltration 7 days after i.p. injection. Mice survival rate and myocardial infiltration, and fibrotic lesions were dose‐dependently worsened by clozapine. Clozapine decreased major endocannabinoid levels in sera and cultured cardiomyocytes. Cannabinoid CB(1) receptors decreased in clozapine‐treated hearts and were translocated from cytomembranes to cytoplasm and nuclei, whereas CB(2) receptors increased in clozapine‐treated hearts and inversely translocated from nuclei to the cytomembrane. Selective antagonists of CB(1) receptors, rimonabant and AM281, but not its selective agonist arachidonyl‐2′‐chloroethylamide, ameliorated clozapine‐induced myocardial inflammatory infiltration and fibrotic lesions. In contrast, selective agonists of CB(2) receptors, AM1241 and JWH‐133, but not its selective antagonist AM630, blunted clozapine‐mediated cardiotoxicity in mice. In cultured cardiomyocytes, clozapine increased the pro‐inflammatory factor IL‐1β and the concentrations of myocardial injury markers (LDH and aspartate aminotransferase); these effects were reversed by either a CB(1) antagonist or CB(2) agonist and further prevented by combined pretreatments. CONCLUSIONS AND IMPLICATIONS: Our data provide evidence that cannabinoid CB(1) and CB(2) receptors have opposite effects and selective antagonists of CB(1) or agonists of CB(2) receptors might confer protective effects against clozapine in myocardium.

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.

Increasing evidence suggests a role of epigenetic mechanisms at chromosome 8q24, an important cancer genetic susceptibility region, in prostate cancer. We investigated whether MYC DNA methylation at 8q24 (six CpG sites from exon 3 to the 3&prime, UTR) in prostate tumor was associated with tumor aggressiveness (based on Gleason score, GS), and we incorporated RNA expression data to investigate the function. We accessed radical prostatectomy tissue for 50 Caucasian and 50 African American prostate cancer patients at the University of Maryland Medical Center, selecting an equal number of GS 6 and GS 7 cases per group. MYC DNA methylation was lower in tumor than paired normal prostate tissue for all six CpG sites (median difference: &minus, 14.74 to &minus, 0.20 percentage points), and we observed similar results for two nearby sites in The Cancer Genome Atlas (p &lt, 0.0001). We observed significantly lower methylation for more aggressive (GS 7) than less aggressive (GS 6) tumors for three exon 3 sites (for CpG 212 (chr8:128753145), GS 6 median = 89.7%, GS 7 median = 85.8%, p-value = 9.4 &times, 10&minus, 4). MYC DNA methylation was not associated with MYC expression, but was inversely associated with PRNCR1 expression after multiple comparison adjustment (q-value = 0.04). Findings suggest that prostate tumor MYC exon 3 hypomethylation is associated with increased aggressiveness.

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.

Summary 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.

Background Mucinous adenocarcinoma is often considered a relatively poor prognostic group among adenocarcinomas of the lung and has a high rate of pulmonary recurrence. Pathologic parameters predicting poor outcome have not been extensively studied, including the presence of spread through alveolar spaces (STAS). Methods We retrospectively studied time to lung recurrence and time to distant metastasis in 30 mucinous lung tumors, in relationship to histologic parameters, including spread through alveolar spaces, tumor size, invasive size, % invasive size, growth pattern (solid or cribriform, acinar, papillary, micropapillary, and lepidic), type of mucin-producing cell, and TTF-1 positivity. Results Median follow-up was 40 months. There were 7 patients (23%) with lung recurrence (mean 22 months) and 7 (23%) with distant metastases (mean 3.7 months). Columnar / goblet cell type was inversely correlated with TTF-1 expression (p = 0.01). The only pathologic parameters associated with outcome were STAS for lung recurrence (p = .005) and solid/cribriform growth (≥ 20% of tumor) for distant metastasis (p = 0.003). Conclusions Mucinous adenocarcinomas of the lung are similar to non-mucinous prognostically, in that STAS and solid growth are poor prognosticators, for local and distant recurrence, respectively. The growth patterns of mucinous adenocarcinomas should be reported similar to reporting of non-mucinous adenocarcinomas.

A 60-year-old woman, a nonsmoker, with medical history of hypertension and chronic back pain, presented with sudden-onset left-sided weakness and facial droop to an outside hospital with symptoms of approximately 1 hour duration. Her NIH Stroke Scale (NIHSS) score, a validated tool to quantitatively measure stroke severity,1 was 17, significant for a right gaze preference, left-sided hemiparesis, and left-sided neglect. Her initial head CT demonstrated an Alberta Stroke Programme Early CT Score (ASPECTS) of 9. ASPECTS is a 10-point quantitative CT scan topography score used to measure ischemic changes on head CT.2 The patient's head CT demonstrated subtle right basal ganglia ischemic involvement and an absence of hemorrhage. IV tissue plasminogen activator (tPA) was administered and CT angiography of the head and neck was performed, demonstrating a right middle cerebral artery (MCA) (M1) occlusion. Our institution was consulted as per protocol for ischemic strokes associated with large artery occlusion and she was transferred for potential intra-arterial (IA) thrombectomy. Upon arrival, the patient was mildly lethargic but attended to the examination; she was able to follow simple commands to open/close her eyes and make a fist. The patient was dysarthric, but with time, answered questions appropriately. She had left-sided facial weakness and right gaze preference but was able to cross midline. She demonstrated left-sided neglect to visual and tactile stimuli and was slow to move her left extremities to repeated command, with decreased left-sided extremity strength rated 4/5. NIHSS upon arrival to our institution was 9.

This study was designed to determine the clinical significance of preoperative thrombocytosis in patients with malignant peritoneal mesothelioma (MPM) undergoing operative cytoreduction (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). CRS and HIPEC have been associated with prolonged survival in patients with MPM and is the preferred treatment in select patients. However, patient selection criteria remain ill-defined for this operation that is also associated with significant morbidity and mortality. Preoperative thrombocytosis has been associated with poor outcomes in various malignancies but never studied in MPM. Between January 2006 and December 2015, 100 patients with high-grade epithelioid MPM were evaluated and selected for CRS and HIPEC at our center (M: 53, F: 47; mean age: 54 years [range 17–81 years]). We analyzed various patient and treatment related factors potentially associated with overall survival (OS). The median actuarial overall survival was 32.8 months; the actuarial 1-, 3-, 5-year survivals were 70, 49, and 36%, respectively. On multivariate analysis, suboptimal resection (CCR > 1), high tumor burden (PCI > 20), and elevated preoperative platelet count (>367,000/mm3) were independently associated with shortened OS (P

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.

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

coagulation and possibly improve patients’ outcomes. As we have shown that hemolysis does not falsely elevate aPTT values, both tests should be used to characterize anti-coagulation intensity in patients with suspected pump thrombosis. In conclusion, aPTT and anti-Xa levels may be discordant in many CF-LVADs patients. In our experience, hemolysis does not falsely raise aPTT values. More studies are needed to prove the superiority of one assay over the other. For now, the decision to titrate UFH based on aPTT or anti-Xa should be carefully weighed in appropriate clinical contexts.

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.

Overlapping forms of interstitial pneumonia have been recognized, but are likely underappreciated, and their clinical, radiologic, and histologic characteristics are not well-defined.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 capacity70% predictedsix months from diagnosis).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 (p0.0001). Histologic OP was associated with consolidation (p = 0.028) and disease resolution (p0.0001). Multivariate analysis demonstrated histologic OP/NSIP (p0.001) and radiologic GGO (p = 0.041) to be independently associated with unfavorable disease progression.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.

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.

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.

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.

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.

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 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.

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.

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 BRAFV600E 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.

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.

Restenosis after stenting occurs secondary to the neointima formation. Neovessels have been found in the neointima within stents. However, there are few studies correlating neointimal angiogenesis and in-stent restenosis in humans. We analyzed 65 post-mortem stented arteries from 33 patients with duration >3 months. Cause of death was determined incidental to the coronary findings in every case. Stented segments were embedded in paraffin and stained immunohistochemically for CD68 (macrophages), and endothelial marker PECAM-1 (CD31). Computerized morphometry was performed to quantitate neovessel density for CD31, macrophage infiltrates, as well as plaque and neointimal area. In-stent restenosis was defined as luminal narrowing ≥ 75% cross-section of the stented area. Underlying plaque morphology was classified as fibrous or atheromatous. Neovessels were present in the neointima of 57 stented segments (88%). Mean neovessel density was greater in restenotic vs. non-restenotic neointimas (p = 0.009) and macrophage density was also greater (p = 0.006). Neointimal area correlated positively with density of neointimal vessels (p = 0.002), as well as neointimal macrophage density (p = 0.006), but not type of stent, underlying plaque type, or underlying plaque macrophage score. We conclude that in-stent restenosis is associated with neointimal angiogenesis which is accompanied by macrophage inflammation. The relevance of these findings to treatment and prevention of in-stent restenosis needs to be further explored.

Aortic sarcomas are predominantly endoluminal tumours that are believed derived from the intima. Because of their rarity, relatively little is known about their pathological features. We report a series of 26 aortic and iliofemoral tumours with histopathological and clinical data.Of the 26 cases, there were 16 men (63.6 ± 13 years) and 10 women (58.6 ± 18 years). Tumours occurred in the abdominal aorta (13), descending thoracic aorta (8), iliac or femoral arteries (4) and ascending aorta (1). Presenting tumour manifestations included claudication or peripheral vascular disease (6), pain (5), pulsatile aneurysm (2) abdominal aortic aneurysm (AAA; 2), occluded graft (2), renal artery stenosis (1), pain from bone metastasis (1), aortic rupture (1), fever (1), weight loss (1), vasculitis (1) impotence (1), incidental finding (1) and bowel ischaemia (1). The diagnosis was not suspected clinically in any case. The tumours were sampled by endarterectomy (9), aortic resection (8), repair of aneurysm (5), and in four the diagnosis was made at autopsy. Histologically and immunohistochemically, 13 were categorised as poorly differentiated angiosarcomas, seven as undifferentiated sarcomas, three as osteosarcomas, two as myxofibrosarcomas, and one as myxoid sarcoma, not otherwise specified. The undifferentiated sarcomas and angiosarcomas were histologically similar to one another and were characterised by tumour cells within and overlying thrombus. The angiosarcomas were defined by diffuse CD31 expression with co-expression of pancytokeratin in 10 (77%). Undifferentiated sarcomas were composed of spindled and/or epithelioid cells and 71% expressed smooth muscle actin. Histological material from metastatic tumours was available in two osteosarcomas and two undifferentiated sarcomas, and showed undifferentiated pleomorphic sarcoma in all cases.In this series, half of aortic intimal sarcomas are histologically undifferentiated and express endothelial and epithelial markers (epithelioid angiosarcoma). The second largest group is undifferentiated sarcoma without immunohistochemical evidence of endothelial differentiation and frequent actin positivity. Rare types include myxofibrosarcoma and osteosarcoma.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a rare type of kidney tumor with relatively indolent behavior. Non-classic morphological variants have not been well studied and rarely been reported. We report a challenging case MTSCC with a peculiar morphology in a 42-year-old man, arising in a background of end-stage renal disease (ESRD). Predominant areas with extensive papillary architecture, psammoma bodies and stromal macrophageal aggregates, reminiscent of a papillary renal cell carcinoma (papillary RCC), were intermixed with foci that transitioned into a MTSCC-like morphology exhibiting elongated tubules and a low grade spindle cell component in a background of mucinous stroma. Immunohistochemistry demonstrated diffuse positivity for P504s/AMACR and vimentin in tumor cells. Focal positivity for RCC, CD10 and CK7 was also noted. Kidney-specific cadherin, cytokeratin 34betaE12 and TFE3 stains were negative in the tumor. The major differential diagnostic considerations were papillary RCC, clear cell papillary RCC, and Xp11.2 translocation carcinoma. Negative FISH studies for trisomy 7 and 17 in both papillary and spindled components supported the diagnosis of MTSCC. The ultrastructural profile was not entirely indicative of the cellular origin of the tumor. Cytogenetic analysis should be performed in atypical cases of MTSCC for precise diagnosis.

Objectives Three intravascular ultrasound (IVUS) signatures have been associated with coronary artery disease instability: echo attenuation, an intraplaque echolucent zone, and spotty calcification. The aim of this study was to investigate the substrates responsible for these IVUS signatures in a relatively large series of post-mortem human coronary samples. Background The exact mechanisms and pathological correlates underlying echo attenuation, an intraplaque echolucent zone, and spotty calcification remain poorly understood. Methods IVUS was compared with near-infrared spectroscopic detection of lipid core plaque and histopathology in 2,294 vessel segments from 151 coronary specimens from 62 patients at necropsy using the modified American Heart Association classification. Results IVUS detected echo-attenuated plaques in 18.3% of segments, echolucent plaques in 10.5% of segments, and spotty calcification in 14.4% of segments. Histopathologically, 91.4% of echo-attenuated plaques corresponded to either a fibroatheroma (FA) with a necrotic core (NC) or pathological intimal thickening with a lipid pool; almost all segments with superficial echo attenuation indicated the presence of an FA with an advanced NC. Echolucent plaques indicated the presence of a relatively smaller lipid or NC compared with echo-attenuated plaques (thickness: 0.51 mm [interquartile range (IQR): 0.35 to 0.64 mm] vs. 0.70 mm [IQR: 0.54 to 0.92 mm] [p Conclusions This study demonstrated that echo-attenuated plaque, especially superficial echo attenuation, was the most reliable IVUS signature for identifying a high-risk plaque (i.e., an FA containing a large NC).

Background Antibody-mediated rejection (AMR) is characterized histologically by intracapillary macrophages. Macrophage density may be an alternative method of determining inflammatory changes in AMR. Methods We identified 118 heart transplant patients with serologic testing for HLA alloantibodies. Macrophage density was graded as 1+ ( 90/mm2). Maximal macrophage density and complement staining over multiple biopsies were correlated with peak panel reactive antibodies (PRA), donor-specific antibodies (DSA), and the clinical diagnosis of AMR. Results The presence of PRA correlated with macrophage score (p = 0.001). Macrophage density correlated with any DSA (p

Purpose The goal of this study was to investigate the pathology of graft failure in a series of explants and autopsies with special emphasis on chronic lung allograft dysfunction (CLAD). Methods Histopathologic evaluation was performed on a series of pulmonary allografts, received either at the time of re-transplantation or at autopsy, from patients with primary lung allograft failure, over a 13-year period. The findings were categorized as acute and organizing alveolar injury, obliterative bronchiolitis (OB), restrictive CLAD (including acute fibrinoid organizing pneumonia [AFOP]/interstitial-pleuroparenchymal fibrosis), mixed obliterative and restrictive, and other. Results Twenty-two lungs were examined retrospectively. Of these, 19 (86%) were explants and 3 (14%) were from autopsies. Fourteen patients were male (64%) and 8 were female (36%). For men, the average age was 58 ± 4 years at transplant, while the average age for females was 48 ± 5 at transplant. The median duration of transplant was 468 days. Eight cases showed acute and organizing alveolar injury (36%, mean 300 days post-transplant), 4 showed pure OB (18%, mean 1400 days post-transplant), zero showed pure restrictive CLAD, 6 showed mixed obliterative and restrictive disease (27%, mean 1076 days post-transplant), and 4 were categorized as other (18%, mean 375 days post-transplant). The latter 4 allografts showed aspiration, HPE, bronchiectasis, and acute cellular rejection. Of the restrictive CLAD allografts, 5 showed AFOP with interstitial fibrosis, while 1 was primarily pleuroparenchymal fibroelastosis. One of 4 allografts with OB and 4 of 6 allografts with mixed CLAD + OB had focal acute and organizing alveolar injury. Vasculitis was present in 3 of 6 allografts with mixed CLAD + OB and 1 of 4 allografts with pure OB. Irregular scars with plasma cell infiltrates seen in 2 of 6 allografts with mixed CLAD + OB and in 1 of 4 allografts with pure OB. Conclusion CLAD and acute alveolar injury are the most common causes of graft failure. Alveolar injury is usually soon after transplant but may also occur late. Restrictive CLAD was not seen in the absence of OB in this study. The median graft survival was similar in the pure OB and mixed CLAD groups.

Summary Background Diffuse peritoneal mesothelioma (DPM) forms a spectrum of indolent surface tumours to malignant invasive cancers. There are few pathological series that span well and poorly differentiated lesions that show diffuse peritoneal spread. Methods Sixty-four DPM treated by initial cytoreductive therapy were retrospectively reviewed. Tumours were classified by surface and invasive growth pattern and correlated with riskfactors, peritoneal cancer index (PCI) and completeness of cytoreduction (CCR). Degree of invasion was quantitated as absent (0), into stroma (I), into fat (II), and into adjacent structures (III) and was correlated with cytological features. Selected immunohistochemical stains were performed. Results There were three well differentiated papillary mesotheliomas (WDPM; type A), four multicystic mesothelioma (type B), 22 tubulopapillary epithelioid mesotheliomas (type C), and 35 poorly differentiated epithelioid mesotheliomas with solid or sarcomatoid growth (Type D). Seven type D tumours had prominent sarcomatoid areas, 12 deciduoid areas, and four lymphohistiocytoid features. Risk factors were present in all groups except type A, and included prior abdominal surgery ( n = 24), asbestos exposure ( n = 5) and radiation ( n = 2). Extra-pleural mesothelioma was present in all groups except type B (total n — 7, 11%). Two type A and eight type C tumours lacked invasion; only type D showed level III invasion. The invasive portion of one type A tumour and two type B tumours showed adenomatoid features. PCI and CCR were greater in type D compared to the other groups ( p— 0.02), as well as mitotic rate, degree of necrosis, and nuclear pleomorphism ( p 0.001). Degree of invasion was strongly correlated with CCR (p — 0.007), necrosis ( p 0.0001), nuclear grade ( p 0.0001), and mitotic rate (p — 0.001), but not PCI (p — 0.1). Immuno- histochemical results were similar across groups, with frequent positivity for CA125 (94%), EGFR (94%) and calretinin (93%), followed by p16 (85%), cytokeratin 5,6 (76%), D2-40 (71%) and WT-1 (47%). PAX-8 was negative in all tumours, except one type A tumour that showed diffuse nuclear positivity. Conclusions Diffuse peritoneal mesotheliomas can be classified into four groups that reflect invasive potential, degree of adverse histological features, and amenability for CCR. Noninvasive tumours include both type A and type C tumours.

The International Association for the Study of Lung Cancer (IASLC) recently reclassified adenocarcinomas of the lung on the basis of histologic patterns. However, there is lack of consensus about a grading system for these tumors. We studied a series of invasive lung adenocarcinomas and correlated histologic features with lymph node and distant metastases. A series of invasive lung carcinomas resected over a 5-year period were retrospectively reviewed and classified by the IASLC system. The proportion of each histologic subtype was estimated at 5% increments, and cytologic features were blindly recorded and subsequently correlated with lymph node and distant metastases. The 125 tumors were classified on the basis of the predominant pattern as lepidic predominant (LPA) (n=9), acinar (n=71), solid (n=23), papillary (n=11), and mucinous (n=11). The acinar pattern was heterogeneous, in that a cribriform subgroup (n=34) was significantly more likely to demonstrate lymph node metastases compared with a tubular subgroup (n=37) and had a higher mitotic rate, rate of necrosis, vascular invasion, and prominent nucleoli. Mucinous tumors were LPA (n=3), tubular (n=4), and cribriform predominant (n=4). The rate of lymph node metastasis was greatest in the solid type (P=0.02). The rate of distant metastasis was greatest in the mucinous and solid groups (P0.02). Mitotic activity (≥ 1/HPF), desmoplasia20% of the tumor, prominent nucleoli, and vascular invasion, along with a solid growth pattern ≥ 20%, were independently associated with metastatic potential and considered poor prognostic histologic features. A 3-tiered grading system separated tumors into well differentiated (predominantly LPA, papillary, and tubular patterns), moderately differentiated (predominantly cribriform tumors), and poorly differentiated (≥ 20% solid growth pattern). Tumors in the well-differentiated group were elevated to moderately differentiated if there were poor prognostic histologic features. Using this system, there was a stepwise increase in the rate of lymph node metastasis (P0.0001) and distant metastasis (P=0.0004) from well-differentiated, moderately differentiated, to poorly differentiated tumors, the rate being 40, 46, and 39, respectively. Application of the IASLC classification in this series resulted in a predominance of acinar adenocarcinomas. To stratify tumors into clinically relevant grades, grading by pattern (tubular, cribriform, solid), mitotic activity, and nuclear features is useful.

Sarcoid lung disease may result in progressive lung failure, necessitating transplant. There is a debate on whether the scarring is similar to or distinct from that seen in other fibrotic lung disease such as usual interstitial pneumonia (UIP). We prospectively evaluated histologic sections from 9 lung explants with end-stage sarcoid lung disease diagnosed clinically and by chest computed tomographic scans. The study included 7 women and 2 men. Four lungs showed active granulomatous disease, with nonfibrotic nodular granulomas in the interstitium; the other 5 were predominantly fibrotic, of which 3 had areas of honeycombing (cysts lined by respiratory epithelium with surrounding scar). Chest computed tomographs of 8 cases were all read as either probable or definite sarcoid. Patients in the fibrotic phase were significantly older (P=0.016). All cases showed dense acellular collagen, which was more extensive in the fibrotic phase. Granulomas were present in a lymphatic distribution (along bronchi, the lobular septa, and the pleura) and were predominantly small clusters of macrophages or giant cells embedded in scar in the fibrotic phase. Granulomas were not identified in 2 lungs in the fibrotic phase. In contrast to the honeycombing of UIP, the honeycombing was predominantly central, with prominent bronchiectasis. These end-stage sarcoid lungs were characterized by a fibrotic and active granulomatous pattern, both of which are very distinct from that seen in UIP.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder related to mutations in desmosomal proteins. The current study tests the hypothesis that immunohistochemical staining for desmosomal proteins is of diagnostic utility by studying autopsy-confirmed cases of ARVC. Methods and Results: We studied 23 hearts from patients dying suddenly with ARVC. Control subject tissues were 21 hearts from people dying from non-cardiac causes (n=15), dilated cardiomyopathy (n=3) and coronary artery disease (n=3). Areas free of fibrofatty change or scarring were assessed on 50 sections from ARVC (24 left ventricle, 26 right ventricle) and 28 sections from controls. Immunohistochemical stains against plakoglobin, plakophilin, desmoplakin, connexin-43, and N-cadherin were applied and area expression analyzed by computerized morphometry. Desmin was stained as a control for fixation and similarly analyzed. The mean area of desmin expression was similar in controls and ARVC (86% vs. 85%, p=0.6). Plakoglobin expression was 4.9% ± 0.3% in controls, vs. 4.6% ± 0.3% in ARVC (p=0.3). Plakophilin staining was 4.8% ± 0.3% in controls vs. 4.4% ± 03% in ARVC (p=0.3). Desmoplakin staining was 3.4% in controls vs. 3.2 ± 0.2% in ARVC (p=0.6). There were no significant differences when staining was compared between right and left ventricles (all p > 0.1). For non-desmosomal proteins, the mean area of connexin-43 staining showed no significant difference by presence of disease. Conclusions: The small and insignificant decrease in junction protein expression in ARVC suggests that immunohistochemistry is not a useful tool for the diagnosis.