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Aims/hypothesisWe sought to establish if stem cells contained in cord blood cell allografts have the capacity to differentiate into insulin-expressing beta cells in humans.MethodsWe studied pancreases obtained at autopsy from individuals (n = 11) who had prior opposite-sex cord blood transplants to reconstitute haematopoiesis. Pancreatic tissue sections were stained first by XY-fluorescence in situ hybridisation and then insulin immunohistochemistry. Pancreases obtained at autopsy from participants without cord blood cell infusions served as controls (n = 11).ResultsIn the men with prior transplant of female cord blood, there were 3.4 ± 0.3% XX-positive insulin-expressing islet cells compared with 0.32 ± 0.05% (p

The best treatment for intramuscular hemangiomas is unclear in part because the outcome is variable, with recurrence rates ranging from 18% to 61%. This variance is due to deficiencies in previous reports such as an inadequate population size, lack of life table analyses, lack of uniform pathologic criteria, and loose or absent definition of surgical margins. Our goal was to address these deficiencies and support or refute previous results. We identified 110 patients between 1981 and 2005. There were 48 males and 62 females with an average age of 22 years at the time of consult. Kaplan-Meier analysis showed 76% of patients managed initially without excision were surgery-free at 2 years and 66% at 5 years. For patients treated with surgery, 86% and 73% were recurrence free at 2 and 5 years, respectively. There were substantial differences in local recurrence when stratified by margin: 93% of patients were recurrence free at 5 years when the excision was marginal and wide, 65% when intralesional without any gross remaining tumor, and 33% when intralesional with gross remaining tumor. Surgical margins and tumor size were the only identified risk factors for recurrence. [ABSTRACT FROM AUTHOR]

Cocaine and amphetamine regulated transcript (CART) is a somatostatin-like polypeptide. CART has been localized in the CNS, hypothalamo-pituitary-adrenocortical (HPA) axis, pancreatic islets and enteric nervous system. We investigated the cellular localization of CART in normal human prostate, benign prostatic hyperplasia, prostatic intraepithelial neoplasia and acinar adenocarcinoma. CART was assessed using immunohistochemistry (IHC) and in situ hybridization (ISH), and its gene expression was identified by RTqPCR. We found cellular expression of CART in both normal prostatic luminal secretory epithelial cells neuroendocrine cells (NEC) of both ducts and acini. The cellular appearance indicated a cycle of neuropeptide synthesis and secretion as validated by ISH/IHC concordance. RTqPCR analysis also validated the immunohistochemical data and gene expression, which both indicated low to moderate expression in prostatic tissues. CART expression also was increased in both neuroendocrine and glandular epithelial cell populations from samples of benign prostatic hyperplasia as validated by IHC, ISH and RTqPCR. CART expression was markedly diminished and, in some cases, entirely absent in tissues of prostatic intraepithelial neoplasia and adenocarcinoma. Owing to loss of CART expression in adenocarcinoma and its increase in benign prostatic hyperplasia, CART may prove to be an important prostate marker.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Hepatocyte nuclear factor 4α (HNF4α) is a master regulator of liver function and a tumor suppressor in hepatocellular carcinoma (HCC). In this study, we explore the reciprocal negative regulation of HNF4α and cyclin D1, a key cell cycle protein in the liver. Transcriptomic analysis of cultured hepatocyte and HCC cells found that cyclin D1 knockdown induced the expression of a large network of HNF4α-regulated genes. Chromatin immunoprecipitation-sequencing (ChIP-seq) demonstrated that cyclin D1 inhibits the binding of HNF4α to thousands of targets in the liver, thereby diminishing the expression of associated genes that regulate diverse metabolic activities. Conversely, acute HNF4α deletion in the liver induces cyclin D1 and hepatocyte cell cycle progression; concurrent cyclin D1 ablation blocked this proliferation, suggesting that HNF4α maintains proliferative quiescence in the liver, at least, in part, via repression of cyclin D1. Acute cyclin D1 deletion in the regenerating liver markedly inhibited hepatocyte proliferation after partial hepatectomy, confirming its pivotal role in cell cycle progression in this in vivo model, and enhanced the expression of HNF4α target proteins. Hepatocyte cyclin D1 gene ablation caused markedly increased postprandial liver glycogen levels (in a HNF4α-dependent fashion), indicating that the cyclin D1-HNF4α axis regulates glucose metabolism in response to feeding. In AML12 hepatocytes, cyclin D1 depletion led to increased glucose uptake, which was negated if HNF4α was depleted simultaneously, and markedly elevated glycogen synthesis. To summarize, mutual repression by cyclin D1 and HNF4α coordinately controls the cell cycle machinery and metabolism in the liver., Competing Interests: Competing interest statement: P.S. has been a consultant at Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, and Exo Therapeutics; his laboratory receives research funding from Novartis.

Aims . The proximal colon derives from the midgut endoderm, the distal one third derives from the hindgut endoderm, and the distal anal canal is of ectodermal origin. At least 5 molecular subtypes of colorectal carcinomas (CRC) have been identified, and some have a marked preferential right-sided location. Histologically, some CRC are much more common in the appendix. We hypothesized that these findings suggest the existence of diverse molecular genetic colonic subregions and compared the expression of classic and recently discovered colorectal markers in tumors at various locations to determine if a site-specific immunophenotypic signature could be identified. Methods and Results . Immunostains for CK7, CK20, MUC2, MUC5AC, MUC6, SATB2, DCR3/TNF6B, CDX2, Ki-67, and MMR proteins were performed on 17 appendiceal low-grade mucinous neoplasms and 6 crypt cell adenocarcinomas of the appendix, 15 right-sided and 15 left-sided mucinous adenocarcinomas, 17 right-sided and 15 left-sided conventional adenocarcinomas, and 5 signet ring cell adenocarcinomas (SRCCA). Statistically significant differences in the expression of MUC2, MUC5AC, MUC6, CK7, and SATB2 by site and/or histologic type were documented. MMR deficiency showed a significant correlation with MUC5AC and MUC6 expression. DCR3, CDX2, and CK20 expression was consistent throughout the colon. A CK7+/CK20+ phenotype was most common in appendiceal tumors and SRCCA. Conclusions . Statistically significant differences in the expression of some markers by histologic type and site were documented, supporting the existence of regional molecular genetic heterogeneity in the colon that result in site-specific epigenetic susceptibilities, tumor phenotypes, and immunophenotypes.

During normal proliferation, hepatocytes accumulate triglycerides (TGs) in lipid droplets (LDs), but the underlying mechanisms and functional significance of this steatosis are unknown. In the current study, we examined the coordinated regulation of cell cycle progression and LD accumulation. As previously shown, hepatocytes develop increased LD content after mitogen stimulation. Cyclin D1, in addition to regulating proliferation, was both necessary and sufficient to promote LD accumulation in response to mitogens. Interestingly, cyclin D1 promotes LD accumulation by inhibiting the breakdown of TGs by lipolysis through a mechanism involving decreased lipophagy, the autophagic degradation of LDs. To examine whether inhibition of lipolysis is important for cell cycle progression, we overexpressed adipose TG lipase (ATGL), a key enzyme involved in TG breakdown. As expected, ATGL reduced LD content but also markedly inhibited hepatocyte proliferation, suggesting that lipolysis regulates a previously uncharacterized cell cycle checkpoint. Consistent with this, in mitogen-stimulated cells with small interfering RNA-mediated depletion of cyclin D1 (which inhibits proliferation and stimulates lipolysis), concurrent ATGL knockdown restored progression into S phase. Following partial hepatectomy, a model of robust hepatocyte proliferation in vivo , ATGL overexpression led to decreased LD content, cell cycle inhibition, and marked liver injury, further indicating that down-regulation of lipolysis is important for normal hepatocyte proliferation. Conclusion : We suggest a new relationship between steatosis and proliferation in hepatocytes: cyclin D1 inhibits lipolysis, resulting in LD accumulation, and suppression of lipolysis is necessary for cell cycle progression.

Adenomatous hyperplasia of the rete testis (AHRT) is an uncommon abnormality first described by Nistal and Paniagua in 1988. Congenital and acquired forms of AHRT are recognized. We present a case of AHRT in a patient who underwent bilateral orchiectomy for penile carcinoma; he had received chemotherapy for Hodgkin lymphoma 18 years prior. Proposed causes for this disorder include developmental, hormonal, and paracrine induction by adjacent testicular tumors and exposure to chemicals, based on clinical contexts but without experimental support. We performed immunohistochemical studies using markers of cell cycle (cyclin D1, p16), proliferation (Ki-67), apoptosis (bcl2), senescence (γ-H2AX), and androgen receptors to try to provide scientific support for or refute existing hypotheses. Our results indicate that, in this case of acquired AHRT after chemotherapy, the process is neither adenomatous nor hyperplastic but rather represents abnormal accumulation of rete testis cells with acquired senescence., (Published by Elsevier Inc.)

Caloric restriction (CR) and endurance exercise elicit wide-ranging health benefits including reduced risk of select cancers. In addition, diet composition influences oncogenesis, although its interactions with exercise and CR are not well understood. Therefore, to investigate the potential interactions between diet and lifestyle interventions on liver tumorigenesis, the carcinogen diethylnitrosamine was administered to 72 male C57Bl/6 mice that were subsequently fed diets enriched with lard (CTL) or olive oil and were further stratified to voluntary wheel running (Ex) or 30% CR for 49 weeks. Although Ex and diet composition did not influence liver oncogenesis, CR prevented hepatic tumor formation. In addition, CR reduced steatosis, hepatocyte ballooning, inflammation, and immune cell infiltration, all of which are hallmarks in the progression of nonalcoholic fatty liver disease to liver tumorigenesis. RNA sequencing of nontransformed liver tissues from CR mice revealed changes in metabolic pathways and reduced inflammation, cytokine production, stellate cell activation and migration, and genes associated with liver injury and oncogenesis. These data demonstrate that CR protects against steatosis, liver inflammation, and liver injury and is a robust deterrent of carcinogen-induced hepatic oncogenesis. Cancer Prev Res; 10(11); 660-70. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Testicular Sertoli cell tumors (SCTs) are rare, and most fall into the category of SCT-not otherwise specified (SCT-NOS). Only a few additional types of SCT are recognized. Sclerosing SCT (S-SCT), originally described in 1991, comprises a small fraction of SCTs and was considered a specific entity until the 2016 revision of the World Health Organization classification of non-germ cell tumors, where it was classified as a morphologic variant of SCT-NOS. In a recent study, differences in expression of PAX2/PAX8, inhibin, androgen receptor, and S100 protein between SCT-NOS and S-SCT were noted in a small number of cases. In this interinstitutional study, we compared the expression of these markers and β-catenin in 11 cases each of SCT-NOS and S-SCT to determine if differences exist that could justify keeping a separate classification of these neoplasms. PAX2/PAX8 cocktail was the only marker that was significantly overexpressed in S-SCT. Expression of androgen receptors was strong in S-SCT and variable in SCT-NOS but did not reach statistical significance. Expression of β-catenin was common in both, whereas inhibin was infrequent. The available material was insufficient for a conclusive evaluation of S100 protein expression. Overall, our results support the inclusion of S-SCT as a morphologic variant of SCT-NOS. Expression of PAX2/PAX8 in S-SCT may reflect an overactive epithelial-to-mesenchymal transition as has been shown in experimental models of acute and chronic seminiferous tubular injury and might be related to the process generating the stroma in these tumors., (Published by Elsevier Inc.)

Sertoli cell (SC) and sertoliform tumors of the testis are very uncommon; for this reason their differential diagnosis and classification can be challenging. We applied an extensive immunophenotypic panel that included androgenic hormones, enzymes and receptors, neuroendocrine, lineage and genitourinary markers to a series of these lesions to determine if and which immunostains can aid in their diagnostic workup. Study cases included: 2 androgen insensitivity syndrome-associated SC adenomas, 3 SC tumors (SCT) not otherwise specified (SCT-NOS), 3 sclerosing SCT, 2 large cell calcifying SCT, 1 SCT with heterologous sarcomatous elements, 1 malignant SCT, and 1 sertoliform rete testis adenoma (sertoliform RTA). We found that SCT-NOS and variants with sclerosis showed a phenotype akin to atrophic seminiferous tubules characterized by gain of expression of pankeratin, calretinin, CD56, which are negative in normal SC. Distinctive phenotypes were identified in: sclerosing SCT: androgen receptors (AR) + (strong)/PAX2/PAX8+ (subset)/S100+/inhibin-; large cell calcifying SCT: calretinin+ (strong)/S100+/AR-; sertoliform RTA: PAX2/PAX8+/pankeratin+/inhibin-. Androgenic hormones and enzymes did not show diagnostic utility. A panel of calretinin, inhibin, pankeratin, S100, PAX2/PAX8, and AR consistently allowed distinction between variants of Sertoli and sertoliform tumors., (Published by Elsevier Inc.)

Dr. Louis Dehner has contributed significantly to our understanding of testicular germ cell tumors in children. This review article considers the molecular biology, clinical attributes, pathologic findings, and prognosis of those lesions., (Published by Elsevier Inc.)

Background: Bladder cancer (BC) accounts for ∼14,680 deaths annually in the U.S. The prognosis of advanced disease remains dismal with current therapies. A phase III intergroup trial for metastatic BC adding bevacizumab to first-line cisplatin-gemcitabine chemotherapy (GCB regimen) is currently ongoing. We report the clinical-pathologic findings of a patient who developed fatal acute cardiac microvascular toxicity while receiving this regimen., Case Report: A 66 year old man consulted for epigastric pain, nausea, intermittent diarrhea and lightheadedness two weeks after receiving the first cycle of GCB chemotherapy for metastatic BC. Physical evaluation, laboratory studies and electrocardiogram (EKG) were within normal limits except for marked thrombocytopenia that was attributed to his recent chemotherapy. The patient was admitted for observation, rehydrated and started on a proton pump inhibitor. The following day, however, he experienced sudden severe chest and right upper quadrant pain. EKG showed tachycardia, ST elevations in leads V2 and V3, laboratory analyses revealed marked elevation of cardiac troponin I, and an echocardiogram showed a markedly reduced ejection fraction of 10-20%, consistent with rapidly progressive cardiogenic shock. Emergent cardiac catheterization showed no significant coronary artery disease. Sepsis work-up was negative. He became progressively hypotensive, developed multi-organ failure, and died 48 h after admission. Postmortem examination showed diffuse microvasculopathy and changes due to global hypoperfusion of 12-48 h evolution., Conclusions: We present the first case of acute, fatal cardiac failure due to microvasculopathy most consistent with bevacizumab-associated toxicity. The findings are discussed in light of the existing literature., (Published by Elsevier Ltd.)

Aims: An increased amount of submucosal (SM) fat in the colon on imaging is considered to be characteristic of inflammatory bowel disease (IBD); however, a recent study in patients without IBD reported a correlation between colonic SM fat deposition and body weight (BW). The aim of this study was to perform a morphometric investigation of SM thickness in areas of fat deposition in the terminal ileum (TI), ileocaecal valve (ICV), and colonic sections, to determine whether there are variations by site, and whether it shows a correlation with BW, body mass index (BMI), or age., Methods and Results: Representative samples of TI, ICV and colonic sections were collected prospectively from 115 autopsy cases without IBD. All of the study subjects were male (Veterans Hospital). SM thickness was measured in areas of fat deposition. Correlation analysis was performed between SM thickness and BW, BMI, and age. Fat deposition was common; however, with the exception of the ICV, it was neither consistent nor prominent, and it did not show a statistical correlation with BW, BMI, or age., Conclusions: SM fat deposition is common but not uniform or conspicuous in the TI or colon. In contrast to extravisceral intra-abdominal fat, it does not show a correlation with BW or BMI, and is not associated with ageing. As all study subjects were male, gender-dependent variability cannot be excluded., (© 2015 John Wiley & Sons Ltd.)

Netherton syndrome (NS) is a rare autosomal recessive skin disease with severe skin inflammation and scaling, a specific hair shaft defect (trichorrhexis invaginata or bamboo hair), and severe atopic manifestations including atopic dermatitis and hay fever with high serum immunoglobulin E levels and hypereosinophilia. NS is caused by loss-of-function mutations in serine protease inhibitor of Kazal-type 5 (SPINK5) encoding lympho-epithelial Kazal-type-related inhibitor (LEKTI) expressed in the stratified epithelia. We report the first case of penile squamous cell carcinoma in a patient with NS., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Reinke crystals (RC) are pathognomonic of Leydig cells (LCs); they are thought to be rare in normal testes and to occur only in approximately one third of LC tumors. We noticed that crystals present in touch imprint and frozen sections of an LC tumor disappeared after tissue fixation. This phenomenon led us to hypothesize that their reported low frequency in normal and neoplastic LCs may be secondary to degradation/dissolution of the crystals after formalin fixation. Our review of the literature also led us to hypothesize that RC are better preserved after air-drying and alcohol fixation. We collected testicular samples from 21 autopsies including air-dried cytologic preparations and tissue samples that were fixed in alcohol or formalin. We found that RC are common in normal LC but dissolve rapidly in formalin and slowly and only partially in alcohol. The composition of RC is unknown; however, they have been reported to stain specifically for nestin, an intermediate filament expressed mainly in neural and muscle tissue. Because the crystals have only been described in androgen-producing cells, we hypothesized that the crystals may represent a crystallized form of androgenic hormones, hormone complexes, or enzymes involved in their synthesis. We performed immunostains for androgens and enzymes involved in androgenesis. We also performed nestin immunostain to confirm the previous study. The crystals stain specifically with antibodies anti-3β-hydroxysteroid dehydrogenase and are negative for the remaining androgenic enzymes, androgenic hormones, and nestin., (Published by Elsevier Inc.)

Translation initiation factor eIF4E mediates normal cell proliferation, yet induces tumorigenesis when overexpressed. The mechanisms by which eIF4E directs such distinct biologic outputs remain unknown. We found that mouse mammary morphogenesis during pregnancy and lactation is accompanied by increased cap-binding capability of eIF4E and activation of the eIF4E-dependent translational apparatus, but only subtle oscillations in eIF4E abundance. Using a transgenic mouse model engineered so that lactogenic hormones stimulate a sustained increase in eIF4E abundance in stem/progenitor cells of lactogenic mammary epithelium during successive pregnancy/lactation cycles, eIF4E overexpression increased self-renewal, triggered DNA replication stress, and induced formation of premalignant and malignant lesions. Using complementary in vivo and ex vivo approaches, we found that increasing eIF4E levels rescued cells harboring oncogenic c-Myc or H-RasV12 from DNA replication stress and oncogene-induced replication catastrophe. Our findings indicate that distinct threshold levels of eIF4E govern its biologic output in lactating mammary glands and that eIF4E overexpression in the context of stem/progenitor cell population expansion can initiate malignant transformation by enabling cells to evade DNA damage checkpoints activated by oncogenic stimuli. Maintaining eIF4E levels below its proneoplastic threshold is an important anticancer defense in normal cells, with important implications for understanding pregnancy-associated breast cancer., (©2014 American Association for Cancer Research.)

Background: Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor affecting the minor salivary glands; nasopharyngeal involvement is uncommon., Methods and Results: A 38-year-old male patient presented with a 3.2 × 4.5 × 4.4 cm expansile mass obliterating the lumen of the nasopharynx and extending into the left nasal cavity. Histopathologically, the tumor was characterized by clear round to polygonal epithelial cells arranged in anastomosing trabeculae and solid nests. The stroma consisted of fibromyxoid connective tissue with areas of intense hyalinization and desmoplasia. Immunohistochemically, strong and diffuse reactivity for AE1/AE3, CK5/6, and p63 was observed. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization. The diagnosis of nasopharyngeal HCCC was rendered. Surgical excision was performed along with adjuvant radiotherapy and chemotherapy., Conclusions: HCCC generally demonstrates good prognosis with low metastatic potential. Identification of EWSR1 gene disruption is usefulin discerning HCCC from other neoplasms with overlapping microscopic features.

An adult man underwent arm amputation for a sarcoma. Pain and three masses observed radiologically prompted surgical exploration five years later. Microscopically, the masses represented amputation neuromas. One of them was located in the lumen of an artery, in a remote organized thrombus. Intravascular growth of an amputation neuroma has not been described previously., (© The Author(s) 2014.)

Ewing sarcoma (EWS) is a primary bone tumor that most often occurs in the long bones of young patients. EWS is typically an aggressive tumor that is highly sensitive to radiation therapy; recurrences often occur, usually within a year of treatment. We present a case of EWS that first presented in a patient at the age of 40 with extraosseous disease. The patient was treated initially with radiation and surgery. Over the following 36-year period, the tumor recurred once and metastasized twice. The morphologic, immunohistochemical, and cytogenetic features of this tumor were typical of EWS, and the tumor was highly responsive to radiation therapy. The unusually prolonged course in this patient demonstrates significant heterogeneity in the biological behavior of EWS, and the importance of randomized trials in cancer therapy.

Introduction: The mucopolysaccharidosis syndromes are a group of lethal inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Advances in treatment such as enzyme replacement and hematopoietic stem cell transplantation have significantly improved the outcome of these disorders. An in-depth understanding of the pathophysiology of heart disease in these disorders is essential since death from cardiac causes continues to be common. Epicardial coronary artery luminal narrowing from myointimal proliferation and glycosaminoglycan deposition is well described in severe mucopolysaccharidosis type I [Hurler syndrome, mucopolysaccharide IH] but poorly understood in other "non-Hurler" phenotypes of these disorders. Given the rarity of these conditions, autopsy specimens are uncommon., Methods: Tissue from epicardial coronary arteries from autopsies of four patients with non-Hurler mucopolysaccharidosis (attenuated type I, type IIIA, type IIIC, and type VI) who had died after hematopoietic cell transplantation (within 1 month in three cases; after 5 years in the fourth) was examined by light microscopy., Results: Unexpectedly, near-normal coronary arteries were observed in the patient with attenuated mucopolysaccharidosis type I, while the coronaries from patients with type IIIA, IIIC, and VI demonstrated classic histologic features of glycosaminoglycan deposition. The most severe findings were found in the MPS IIIC patient who had 5 years of full donor engraftment after transplantation., Conclusions: Our current understanding of the cardiac manifestations of the mucopolysaccharidoses fails to explain why near-normal coronary arteries may be observed when abnormalities would be most likely to be expected and, conversely, why significant histopathology is present when it would be least expected. Identification of downstream effects of glycosaminoglycan deposition may identify other metabolites or metabolic pathways that are important in the clinicopathologic manifestations of these diseases., Summary: The mucopolysaccharidosis diseases are a group of inherited disorders affecting multiple organ systems by the progressive deposition of glycosaminoglycan. Severe coronary artery disease is well recognized in severe type I mucopolysaccharidosis (Hurler syndrome), but unexpected coronary artery disease occurs in other, "non-Hurler" mucopolysaccharidoses. Factors responsible for the development of coronary pathology in the mucopolysaccharidoses remain elusive., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Endomyocardial fibrosis is a neglected tropical disease of unknown etiology and poor prognosis. It is endemic of tropical climates where it is the most common cause of restrictive cardiomyopathy in the second and fourth decades of life. A forme fruste of the disease is thought to be present in temperate climates where the diagnosis remains exceedingly rare., Case Presentation: We describe a case of isolated right ventricular endomyocardial fibrosis in a 27-year-old Caucasian man from a temperate climate who presented initially with frank hemoptysis and pulmonary thromboembolic disease. We further describe the approach utilized in the diagnosis, the surgical treatment and the outcome of the disease., Conclusions: We conclude that endomyocardial fibrosis should be included in the differential diagnosis of apical cardiomyopathies in patients from temperate climates.

Background: Soft tissue sarcomas are a heterogeneous group of malignant tumors. Standard treatment for soft tissue sarcoma of the extremity is surgical excision and adjuvant therapy; however, the role of neoadjuvant chemotherapy is controversial., Questions/purposes: We sought to (1) define the histologic characteristics of the pseudocapsule in soft tissue sarcomas; (2) compare the appearance of this structure in chemotherapy-treated versus untreated soft tissue sarcomas; and (3) evaluate the effect of chemotherapy on the presence and viability of tumor cells at the host-sarcoma interface., Methods: Twenty-eight patients with biopsy-proven, deep, high-grade extremity soft tissue sarcomas greater than 5 cm (AJCC stage III) treated with chemotherapy and surgical excision were compared histologically with 47 matched control subjects treated with surgery alone., Results: A pseudocapsule was identifiable in the majority of tumors and consisted of two identifiable layers, each with specific histological characteristics suggesting the biologic processes occurring in these layers are different. The pseudocapsule was more frequently observed in the group treated with chemotherapy and it was more frequently continuous, thicker, and better developed in this group. Chemotherapy decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule., Conclusions: Neoadjuvant chemotherapy contributed to the development of a pseudocapsule and decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule., Clinical Relevance: These findings may provide a histological explanation for the clinical effect of chemotherapy in soft tissue sarcoma., Level of Evidence: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Context: The use of p16 in cervical biopsies improves the accuracy of cervical intraepithelial neoplasia (CIN) diagnosis and grading and decreases its interpathologist variability., Objective: To determine the impact of the frequency of use of p16 immunostains in cervical biopsies on pathologists' diagnoses of CIN grade 1 and grade 2 or above (CIN1 and CIN2+) and on cytohistologic correlations., Design: We identified all cervical biopsy specimens with cytologic correlations subjected or not to p16 staining from January 1, 2005, to September 30, 2010; calculated each pathologist's percentage of p16 use; and correlated it with their major cytohistologic discrepancy rates, CIN2+ diagnoses, and CIN1/CIN2+ ratios., Results: During the study period, each of the 23 pathologists interpreted 59 to 1811 (mean, 518) of 11 850 cervical biopsy specimens, used p16 for 0% to 21.31% (mean, 10.14%) of these, had CIN2+ detection rates of 9.5% to 24.1% (mean, 18.9%), and CIN1/CIN2+ ratios of 0.7 to 4.5 (mean, 1.5). Compared to the 12 "low users" of p16, who used p16 fewer times than the institution's mean for p16 use, the 11 "high users" of p16 diagnosed more biopsies (8391 versus 3459), had a lower rate of major cytohistologic discrepancies (12.62% versus 14.92%, P < .001), a higher rate of CIN2+ diagnoses (19.9% versus 16.4%, P < .001), a lower range of CIN2+ rates (15.0%-23.1% versus 9.5%-24.1%), and lower CIN1/CIN2+ ratios (1.2 versus 2.3)., Conclusions: We found a high intrainstitutional variability of p16 use in cervical biopsies, CIN2+ rates, and CIN1/CIN2+ ratios. Use of p16 for greater than 10% of cervical biopsies was associated with improved cytohistologic correlation rates and with lower variability in the frequencies of histologic diagnoses.

Papillary fibroelastomas are benign cardiac tumors with high embolic potential typically found on the valvular surfaces of the heart. Nonvalvular papillary fibroelastomas are exceedingly rare. We report the case of a 66-year-old Caucasian male with acute bilateral basal ganglia infarctions found to have a mass adherent to the left ventricular septum by transesophageal echocardiography. The mass was identified as a rare nonvalvular cardiac papillary fibroelastoma based on echogenicity, pedunculated nature, and typical motion. Tissue characterization by cardiac magnetic resonance imaging demonstrated homogeneously hypo-intense signal on T2 weighted imaging and signal hyperintensity after administration of gadolinium contrast, confirming the fibroelastic nature of the mass. Surgical excision was performed via ventriculotomy and histopathologic examination was pathognomonic of a papillary fibroelastoma. We conclude that transesophageal echocardiography provides high diagnostic certainty in patients with cardiac papillary fibroelastomas and can reliably identify atypical locations of these tumors on nonvalvular surfaces. A multimodality imaging approach is not necessarily indicated in all patients with this condition., Learning Objective: Papillary fibroelastomas are benign cardiac tumors with high embolic potential typically found on the valvular surfaces of the heart. Nonvalvular papillary fibroelastomas are exceedingly rare. Transesophageal echocardiography readily identifies nonvalvular papillary fibroelastomas based on echogenicity, pedunculated nature, and characteristic motion, and reliably differentiates them from other cardiac masses. A multimodality imaging approach is not indicated in all patients with this condition.

Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) allows a reliable and accurate diagnosis of neoplasms of the gallbladder and bile ducts. We report the cytopathologic findings of a case of large cell neuroendocrine carcinoma (LCNEC) of the gallbladder and extrahepatic bile ducts in a 67-year-old woman who presented with progressive abdominal pain and jaundice. EUS-FNA of the mass involving the common bile duct and of a porta hepatis lymph node showed abundant cellularity with tumor cells arranged singly and occasionally in tight and loose clusters and rosette-like structures in a background showing extensive necrotic debris. The tumor cells were predominantly plasmacytoid, showed a moderate amount of focally vacuolated cytoplasm and large round to oval hyperchromatic nuclei with prominent nucleoli, numerous mitoses, and apoptotic bodies. The differential diagnosis included poorly differentiated adenocarcinoma, lymphoma, melanoma, and poorly differentiated neuroendocrine carcinoma (NEC), large cell type. The tumor cells were strongly and diffusely positive for cytokeratin AE1/AE3, CD56, synaptophysin, and chromogranin and showed a very high proliferative fraction on Ki67 staining, supporting the diagnosis of a high-grade NEC. Due to the large size of the neoplastic cells, moderate amounts of cytoplasm and prominent nucleoli, a diagnosis of LCNEC was made on the EUS-FNA sample. Despite the prompt institution of chemotherapy, the patient died shortly thereafter and the diagnosis was confirmed at autopsy. This is to our knowledge the first case of LCNEC of the gallbladder and bile ducts diagnosed by EUS-FNA., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration (EBUS-TBNA) is a reliable and accurate method for the diagnosis of mediastinal metastases in patients with pulmonary and extrathoracic neoplasms. We report the cytopathologic findings of a case of metastatic signet-ring cell carcinoma with abundant extracellular mucin production in the mediastinal lymph nodes of a 41-year-old woman, who presented with nausea, abdominal pain, and weight loss. Imaging studies showed a renal mass, numerous lung nodules, and mediastinal and retroperitoneal lymphadenopathy. EBUS-TBNA of level 4R and 7 lymph nodes showed abundant, thick, "clean" mucus with entrapped ciliated bronchial cells, rare histiocytes, and fragments of cartilage. No neoplastic cells could be identified in Diff-Quik®-stained smears during the rapid on-site evaluation, but rare signet-ring cells were identified in the Papanicolaou-stained smears and cellblock sections. A distinctive feature of the aspirates was the presence of large branching (arborizing), "spidery" stromal fiber meshwork fragments. These stained metachromatically (magenta) with Romanowsky-type stains and cyanophilic to orangeophilic with Papanicolaou stains and showed occasional attached bland spindle cells, but had no capillary lumina or CD31-staining endothelial cells. The tumor cells were strongly and diffusely positive for CEA, CDX2, CK7, CK20, and MUC2, supporting the diagnosis of a metastatic signet-ring cell adenocarcinoma, most likely of gastrointestinal origin. We believe that the presence of the large spidery stromal fiber fragments is a useful clue to the presence of a mucinous neoplasm in EBUS-TBNA and allows the differentiation of the neoplastic mucus from contaminating endobronchial mucus., (Copyright © 2011 Wiley Periodicals, Inc., a Wiley company.)

Although rare, synovial sarcoma (SS) is one of the most common soft tissue sarcomas affecting young adults. To investigate potential tumor markers related to synovial sarcoma prognosis, we carried out a single-institution retrospective analysis of 103 patients diagnosed with SS between 1980 and 2009. Clinical outcome data were obtained from medical records, and archived tissue samples were used to evaluate the relationship between progression-free survival (PFS) and several prognostic factors, including tumor expression of FGFR3 and FGFR4. No associations were found between PFS and gender, body mass index, tumor site, SS18-SSX translocation, or FGFR4 expression. As seen in previous studies, age at diagnosis (<35, 63% versus ≥35 years, 31% 10-year PFS; P = .033), histologic subtype (biphasic, 75% versus monophasic 34% 10-year PFS; P = .034), and tumor size (≤5 cm, 70% versus >5 cm, 22% 10-year PFS; P < .0001) were associated with PFS in SS patients. In addition, in a subset of patients with available archived tumor samples taken prior to chemotherapy or radiation (n = 34), higher FGFR3 expression was associated with improved PFS (P = .030). To the best of our knowledge, this is the largest study of SS to date to suggest a potential clinical role for FGFR3. While small numbers make this investigation somewhat exploratory, the findings merit future investigation on a larger scale., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Mixed germ cell tumors of the ovary have rarely been reported in veterinary species. A 3-year-old intact female Labrador Retriever dog was presented for lethargy, abdominal distention, and a midabdominal mass. An exploratory laparotomy revealed a large (23 cm in diameter) left ovarian tumor and multiple small (2-3 cm in diameter) pale tan masses on the peritoneum and abdominal surface of the diaphragm. Histological examination of the left ovary revealed a mixed germ cell tumor with a yolk sac component with rare Schiller-Duval bodies and a teratomatous component comprised primarily of neural differentiation. The abdominal metastases were solely comprised of the yolk sac component. The yolk sac component was diffusely immunopositive for cytokeratin with scattered cells reactive for α-fetoprotein and placental alkaline phosphatase. Within the teratomatous component, the neuropil was diffusely immunopositive for S100, neuron-specific enolase, and neurofilaments with a few glial fibrillary acidic protein immunopositive cells. Ovarian germ cell tumors may be pure and consist of only 1 germ cell element or may be mixed and include more than 1 germ cell element, such as teratoma and yolk sac tumor.