Search

Background and Aims: Although a common pathogen in much of Asia, liver flukes are believed to be a rare cause of disease in the United States. In this series, we describe 3 patients diagnosed with Clonorchis sinensis during ERCP within 1 year at our institution., Methods: Three patients referred to a large community hospital underwent ERCP with direct visualization of a worm in the biliary tree and subsequent histopathologic confirmation., Results: The patients had variable clinical presentations, and 2 had repeat negative stool studies for ova and parasites. Each patient had imaging studies showing abnormalities within the biliary tree, after which ERCP was performed with direct visualization and extraction of a wormlike structure. It was confirmed that all 3 patients had emigrated from China within the last decade. The epidemiologic data and the histopathologic characteristics of the fluke eggs in utero were consistent with a diagnosis of C sinensis., Conclusions: The diagnosis of clonorchiasis should remain on the differential diagnosis for patients with nonspecific biliary symptoms who have known risk factors for this uncommonly common pathogen., (Copyright © 2022 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objectives: Misplaced epithelium in adenomas can occasionally be difficult to distinguish from invasive adenocarcinoma. We evaluated interobserver variability in the assessment of left-sided colon polypectomies for pseudoinvasion versus invasive adenocarcinoma and further investigated relevant histological findings., Methods: 28 consecutive left-sided colon polyps with the keywords "pseudoinvasion", "epithelial misplacement", "herniation", "prolapse" or "invasive adenocarcinoma" were collected from 28 patients and reviewed by eight gastrointestinal pathologists. Participants assessed stromal hemosiderin, lamina propria/eosinophils surrounding glands, desmoplasia, high grade dysplasia/intramucosal adenocarcinoma and margin status and rendered a diagnosis of pseudoinvasion, invasive adenocarcinoma, or both., Results: Agreement among pathologists was substantial for desmoplasia (κ=0.70), high grade dysplasia/intramucosal adenocarcinoma (κ=0.66), invasive adenocarcinoma (κ=0.63) and adenocarcinoma at the margin (κ=0.65). There was moderate agreement for hemosiderin in stroma (κ=0.53) and prolapse/pseudoinvasion (κ=0.50). Agreement was low for lamina propria/eosinophils around glands (κ=0.12). For invasive adenocarcinoma, seven or more pathologists agreed in 24 of 28 cases (86%), and there was perfect agreement in 19/28 cases (68%). For pseudoinvasion, seven or more pathologists agreed in 19 of 28 cases (68%), and there was perfect agreement in 16/28 cases (57%)., Conclusion: Moderate to substantial, though imperfect, agreement was achieved in the distinction of pseudoinvasion from invasive carcinoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: To determine if gadolinium is necessary for the diagnosis of a pancreatic cystic lesion (PCL) as benign or malignant by assessing inter- and intra-observer agreement and diagnostic accuracy for the presence of worrisome features/high-risk stigmata on non-contrast MRI compared to MRI with and without contrast, with cytopathology as a reference standard., Methods: The institutional database was searched to identify consecutive patients that underwent EUS/FNA or surgical resection of an asymptomatic PCL performed from 01/01/2015 to 01/01/2019. Two abdominal radiologists independently evaluated PCLs on MRI with all sequences except for contrast-enhanced sequences followed by a second reading with data from the entire MRI including pre- and post-contrast sequences. Cyst size, growth, and the presence of worrisome features/high-risk stigmata were assessed for each cyst on both datasets., Results: There were 87 patients with 87 pancreatic cysts; 76(87.4%) were benign and 11 (12.7%) were malignant. The presence of any worrisome features/high-risk stigmata for reader 1 was concordant on both MRIs in 95.4% (83/87; k = 0.874) of cases and for reader 2 was concordant in 96.6% (84/87; k = 0.920) of cases. The diagnostic accuracy of the two datasets when the presence of any worrisome feature/high-risk stigmata was predictive of malignancy was identical for reader 1 (AUC = 0.622 for both; p = 1.0) and similar for reader 2 (AUC 0.569 and 0.589; p = 0.08) for both MRI datasets., Conclusion: The addition of gadolinium had no significant impact in the diagnosis of a benign versus malignant PCL, with similar intra-observer agreement and diagnostic accuracy for both readers when using contrast-enhanced and unenhanced MRI datasets., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

This review summarizes our current understanding of lymphocytic esophagitis (LE), a novel form of chronic esophagitis that incorporates distinctive histologic, clinical, and endoscopic features. First described as a histologic entity, a diagnosis of LE requires intraepithelial lymphocytosis without significant granulocytic inflammation and some evidence of epithelial damage; the rationale for and studies supportive of these histologic criteria are discussed within. Clinically, the majority of patients who present with histologically confirmed LE are older women or patients with underlying immunologic abnormalities, such as Crohn disease, rheumatologic disorders, or common variable immunodeficiency. The most common presenting symptom of LE is dysphagia, and the endoscopic findings can vary from normal mucosa to mucosal changes that resemble eosinophilic esophagitis: edema, rings, furrows, and plaques. The incidence of luminal strictures and the persistent dysphagia and/or lymphocytosis present in some patients provide evidence that LE is a chronic inflammatory disorder, at least within a subset of individuals. Several histologic mimics of LE are examined, as are disagreements surrounding the LE diagnosis., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The diagnosis of inflammatory bowel disease (IBD)-associated dysplasia is challenging, and past studies have demonstrated considerable interobserver variability in such diagnoses. This study aimed to assess interobserver agreement in IBD dysplasia diagnoses among subspecialty GI pathologists and to explore the impact of mentorship on diagnostic variability. Twelve GI pathologist mentees and 7 GI pathologist mentors reviewed 163 digitized slides. Participants rendered a diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, or high-grade dysplasia and provided a confidence level for each case. Interobserver agreement and reliability were assessed using Cohen's and Fleiss' kappa (κ) statistics and intraclass correlation coefficient (ICC) analysis. The overall κ coefficient was 0.42 (95% CI: 0.38-0.46). The overall ICC was 0.67 (95% CI: 0.62-0.72). Κ coefficients ranged from 0.31 to 0.49 for mentor/mentee pairs and from 0.34 to 0.55 for pairs of mentees of the same mentor. The combined κ coefficient was 0.44 (95% CI: 0.39-0.48) for all mentees and 0.39 (95% CI: 0.34-0.43) for all mentors. Common features in low agreement cases included mucosal atrophy, areas of stark contrast, serrations, decreased goblet cells, absent surface epithelium, and poor orientation. Participants were confident in most diagnoses, and increased confidence levels generally correlated with higher interobserver agreement. Interobserver agreement among subspecialist GI pathologists in this curated cohort of IBD dysplasia cases was fair to moderate. Mentorship during GI pathology fellowship does not appear to be a significant factor contributing to interobserver variability, but increased experience also does not seem to improve interobserver agreement.

Lymphoepithelioma-like intrahepatic cholangiocarcinoma is a rare variant of cholangiocarcinoma that is associated with the Epstein-Barr virus. The intimate relationship between the malignant epithelial cells and the numerous lymphoid cells can make the diagnosis challenging on limited tissue samples. We present 2 cases in which the presence of a dense hematolymphoid infiltrate served to mask the diagnosis of carcinoma on initial frozen section and biopsy review, respectively. We bring awareness to this potential diagnostic pitfall and offer morphologic and immunohistochemical clues that may aid in recognition of this unusual and sometimes perplexing carcinoma.

Purpose: We examined cabazitaxel, a novel next-generation taxoid, in patients with metastatic gastric cancer in a multicenter phase II study., Patients and Methods: Patients who have progressed on one or more prior therapies for locally advanced, unresectable, or metastatic disease were eligible, and prior taxane therapy was allowed. Taxane-naïve and pretreated cohorts were analyzed independently for efficacy. The primary endpoint for both cohorts was progression-free survival (PFS) using RECIST 1.1, using a Simon's two-stage design (10% significance and 80% power) for both cohorts. Comprehensive molecular annotation included whole exome and bulk RNA sequencing., Results: Fifty-three patients enrolled in the taxane-naïve cohort (Arm A) and 23 patients in the prior-taxane cohort (Arm B), from January 8, 2013, to April 8, 2015: median age 61.7 years (range, 35.5-91.8 years), 66% male, 66% Caucasian. The most common adverse events included neutropenia (17% Arm A and 39% Arm B), fatigue/muscle weakness (13%), and hematuria (12%). In Arm A, the 3-month PFS rate was 28% [95% confidence interval (CI), 17%-42%] and did not meet the prespecified efficacy target. The 3-month PFS rate in Arm B was 35% (95% CI, 16%-57%) and surpassed its efficacy target. HER2 amplification or overexpression was associated with improved disease control ( P = 0.003), PFS ( P = 0.04), and overall survival ( P = 0.002). An M2 macrophage signature was also associated with improved survival ( P = 0.031)., Conclusions: Cabazitaxel has modest activity in advanced gastric cancer, including in patients previously treated with taxanes. Her2 amplification/overexpression and M2 high macrophage signature are potential biomarkers for taxane efficacy that warrant further evaluation., (©2020 American Association for Cancer Research.)

Lymphocytic esophagitis is a well-known manifestation of Crohn disease among children but is not considered to be an immune-mediated mucositis in adults. We hypothesize that adult-onset lymphocyte-predominant esophagitis is also an immune-mediated inflammatory pattern, the nature of which has been masked by other conditions that feature esophageal lymphocytosis and occur in older patients. We performed this study to consolidate diagnostic criteria for lymphocyte-predominant esophagitis and determine its clinical significance. We identified 61 patients with lymphocyte-rich inflammation in the mid or proximal esophagus, none of whom had another explanation for esophageal lymphocytosis. Affected patients were usually older adults and 72% were women. Most (56%) presented with dysphagia and 34% had eosinophilic esophagitis-like changes with rings, exudates, and/or edematous mucosa and linear furrows. Intraepithelial lymphocytosis was accompanied by mucosal injury featuring edema, basal zone hyperplasia, and scattered dyskeratotic cells. Some cases displayed occasional neutrophils or even superficial microabscesses; eosinophils were consistently infrequent. Most (67%) patients had at least 1 systemic immune-mediated disorder, particularly Crohn disease (30%) and connective tissue diseases (23%); only 1 had mucocutaneous lichen planus. We conclude that mild mucosal lymphocytosis (ie, ≥20 lymphocytes/HPF) alone is a frequent and nonspecific finding; criteria for lymphocyte-predominant esophagitis should include evidence of mucosal injury and allow for more than the occasional neutrophil. When this diagnosis is limited to cases that feature lymphocytosis unattributed to acid reflux, motility disorders, or infection, lymphocyte-predominant esophagitis may represent an immune-mediated disorder with characteristic clinical manifestations and a predilection for middle-aged women.

Colorectal carcinoma screening programs have shown success in lowering both the incidence and mortality rate of colorectal carcinoma at a population level, in part because this carcinoma is relatively slow growing and has an identifiable premalignant lesion. Still, many patients do not undergo the recommended screening for colorectal carcinoma, and of those who do, a subset may be over- or under-diagnosed by the currently available testing methods. The primary purpose of this article is to review the data regarding currently available colorectal cancer screening modalities, which include fecal occult blood testing, direct colonic visualization, and noninvasive imaging techniques. In addition, readers will be introduced to a variety of biomarkers that may serve as stand-alone or adjunct tests in the future. Finally, there is a brief discussion of the current epidemiologic considerations that public health officials must address as they create population screening guidelines. The data we provide as laboratory physicians and scientists are critical to the construction of appropriate recommendations that ultimately decrease the burden of disease from colorectal carcinoma.

A new evaluation of previously published data suggested to us that the accumulation of mutations might slow, rather than increase, as individuals age. To explain this unexpected finding, we hypothesized that normal stem cell division rates might decrease as we age. To test this hypothesis, we evaluated cell division rates in the epithelium of human colonic, duodenal, esophageal, and posterior ethmoid sinonasal tissues. In all 4 tissues, there was a significant decrease in cell division rates with age. In contrast, cell division rates did not decrease in the colon of aged mice, and only small decreases were observed in their small intestine or esophagus. These results have important implications for understanding the relationship between normal stem cells, aging, and cancer. Moreover, they provide a plausible explanation for the enigmatic age-dependent deceleration in cancer incidence in very old humans but not in mice., Competing Interests: The authors declare no conflict of interest.

Epstein-Barr virus (EBV) is implicated in the tumorigenesis of a variety of malignancies, including Burkitt's lymphoma, Hodgkin's disease and nasopharyngeal carcinoma (NPC). EBV+ lymphoepithelioma-like cholangiocarcinoma (LELCC) is a rare type of intrahepatic cholangiocarcinoma with a distinct pathology and poorly understood treatment options. Morphologically, this neoplasm resembles undifferentiated NPC, a commonly EBV+ tumour with a prominent lymphoid infiltrate. Almost all of the current literature regarding LELCC describes early stage tumours that are treated surgically and achieve good outcomes. In contrast, this report documents a late stage LELCC treated unsuccessfully with systemic chemotherapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Selective internal radiation therapy with Y-TheraSphere or Y-SIRSphere is used in the treatment of unresectable hepatic malignancies. To the best of our knowledge, this is the first Y-TheraSpheres series. BTG International Canada Inc. provided nonradiated microspheres from the Nordion manufacturer. The histologic processed microspheres were colorless, refractile, polarizable, 20 to 30 μm in diameter, and an occasional internal bulls'-eye seen with the condenser out and an internal cross seen with polarized light. Identical microspheres were identified in 15 hepatectomy specimens from four centers between February 2016 and March 2018. The patients were usually male (male=10, female=5) with a mean age of 59 years. All patients had a prior diagnosis of hepatocellular carcinoma (HCC) and documented Y-TheraSphere (mean duration from last deployment=32 wk). All surgical pathology specimens in these 15 patients were reviewed, but the microspheres were only identified in the hepatectomy specimens. During manuscript preparation, one case of Y-TheraSpheres gastritis was prospectively identified from a separate patient with a history of HCC and Y-TheraSpheres. In conclusion, recognition of Y-TheraSpheres is important so that one may consider the possibility of a nearby malignancy and or establish the cause of the background inflammatory or radiation-related injury. These structures can be easy to miss because the subtle morphology is distinct from previously reported Y-SIRSphere. Clues to the diagnosis include a history of HCC and background radiation change. We report the characteristic morphology as microspheres that overlap in size with Y-SIRSphere, but can be differentiated based on Y-TheraSpheres' colorless appearance with occasional internal bulls'-eyes with the condenser out and an internal cross with polarized light.

Objectives: Portal cavernoma cholangiopathy (formerly portal biliopathy) is a type of biliary injury that occurs in association with a portal vein thrombus or cavernoma. Although the radiographic features of portal cavernoma cholangiopathy have been enumerated in the literature, its histologic features have not been described in detail., Methods: We describe the histologic findings in liver specimens from three patients with radiologically confirmed portal cavernoma cholangiopathy., Results: Of the three patients, one underwent surgical resection due to a clinical suspicion for cholangiocarcinoma, one had a liver biopsy sample obtained for evaluation of possible cirrhosis, and one had a clinically suspicious "hilar mass" at the time of orthotopic liver transplant. Histologic features common among the three liver specimens included portal venous abnormalities, where the portal veins were obliterated or small relative to the portal tract size, and obstructive biliary changes, such as ductular reaction and reactive epithelial atypia accompanied by a mixed inflammatory cell infiltrate with neutrophils., Conclusions: This case series provides clinicopathologic characteristics of portal cavernoma cholangiopathy. Histologic changes are reminiscent of hepatoportal sclerosis and/or bile duct obstruction. Attention to portal veins can provide helpful diagnostic clues, especially when biopsy samples are obtained from patients with a known portal vein thrombus or cavernoma.

The histologic differential diagnosis of perianal Paget disease includes malignant melanoma, pagetoid spread of squamous cell carcinoma, and secondary involvement by colorectal carcinoma. While consideration of these entities is useful when establishing a diagnosis, it does not apply when patients with Paget disease undergo surveillance for recurrent disease. Treatment of perianal Paget disease consists of a combination of surgical excision with skin grafts and topical chemotherapeutic agents that induce cytologic alterations in benign cells and simulate recurrent malignancy. To evaluate the therapy-related changes and possible diagnostic pitfalls in patients with Paget disease, we reviewed 412 posttreatment tissue samples from 3 women with primary perianal Paget disease who underwent wide excision, skin grafting, and topical 5-fluorouracil therapy. Biopsy samples from engrafted skin often displayed single and clustered cells with hyperchromatic nuclei dispersed in the deep epidermis. Similar cells were scattered throughout all levels of the epidermis in biopsy samples following topical chemotherapy. The abnormal cells were negative for cytokeratin 7 (CK7) and mucicarmine in both situations. Disease ultimately recurred in all patients; some Paget cells showed classic features with eosinophilic or mucinous cytoplasm and eccentric nuclei, whereas others were smaller with less conspicuous atypia. All Paget cells showed strong, membranous CK7 staining. In short, treatment of perianal Paget disease can elicit cytologic abnormalities in benign epithelial cells that simulate the cytologic features of recurrent disease, and can diminish the atypia of Paget cells. Immunohistochemical stains for CK7 can be helpful when evaluating surveillance samples from these patients.

Intraoperative consultation requires skills in gross examination and histologic diagnosis, as well as an ability to perform rapid interpretations under time constraints. The aim of this review is to provide surgical pathologists with a framework for dealing with hepatic specimens in the frozen section area by covering common clinical scenarios and histologic findings. Differential diagnoses are considered in relation to primary hepatic neoplasia and metastatic diseases. Benign mimics of malignancy and other pitfalls in frozen section diagnosis of lesional tissue are covered. Finally, assessment of donor liver biopsy for organ transplant evaluation is discussed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The Adverse Outcome Pathway (AOP) framework describes the progression of a toxicity pathway from molecular perturbation to population-level outcome in a series of measurable, mechanistic responses. The controlled, computer-readable vocabulary that defines an AOP has the ability to, automatically and on a large scale, integrate AOP knowledge with publically available sources of biological high-throughput data and its derived associations. To support the discovery and development of putative (existing) and potential AOPs, we introduce the AOP-DB, an exploratory database resource that aggregates association relationships between genes and their related chemicals, diseases, pathways, species orthology information, ontologies, and gene interactions. These associations are mined from publically available annotation databases and are integrated with the AOP information centralized in the AOP-Wiki, allowing for the automatic characterization of both putative and potential AOPs in the context of multiple areas of biological information, referred to here as "biological entities". The AOP-DB acts as a hypothesis-generation tool for the expansion of putative AOPs, as well as the characterization of potential AOPs, through the creation of association networks across these biological entities. Finally, the AOP-DB provides a useful interface between the AOP framework and existing chemical screening and prioritization efforts by the US Environmental Protection Agency., (Published by Elsevier Inc.)

Renal transplant recipients who present with gastrointestinal complaints may have symptoms related to their underlying renal disease or secondary to their immunosuppressive regimen. Immunosuppression increases patients' risk for infection and medication-induced injury, and a subset of transplant patients develop a form of inflammatory bowel disease (IBD) despite being immunosuppressed. In this study, we present the spectrum of changes in colonic biopsy histology that occur in the postrenal transplant population, with emphasis on the clinical and histologic features that may allow distinction between several common disorders. Over a 15-year period, 51 postrenal transplant patients underwent colonoscopy with biopsy. Eleven (22%) patients had infectious colitis, and 10 of these had biopsy proven acute colitis. Another 17 (33%) patients were determined to have a medication-related injury based on resolution of symptoms following drug cessation. The majority (53%) of these colonic biopsies demonstrated crypt epithelial cell apoptosis and/or architectural distortion, although 41% were histologically normal. Four (8%) patients were ultimately diagnosed with a form of IBD after exclusion of other etiologies; biopsies from these patients demonstrated chronic active colitis or enteritis with plasma cell-rich expansion of the lamina propria and basal lymphoplasmacytosis. The increased prevalence of IBD in this patient cohort (4/700) compared with that reported in the overall North American population (1 to 2/700) is in line with prior studies and is likely related to the therapeutic regimen and associated immune dysregulation that occurs in solid-organ transplant recipients. We demonstrate that a combination of clinical, endoscopic, and histologic features are useful to distinguish among causes of gastrointestinal symptoms in this high risk population.

Context: - Invasive pancreatic ductal adenocarcinoma has a greater than 90% mortality rate at 5 years. Understanding noninvasive, curable precursor lesions gives us the best hope for reducing mortality from pancreatic ductal adenocarcinoma. The 3 pancreatic precursor lesions that have been well studied include intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia., Objective: - To give an update on the latest clinical, molecular, and pathologic advances in intraductal papillary mucinous neoplasm, mucinous cystic neoplasm, and pancreatic intraepithelial neoplasia for the general surgical pathologist., Data Sources: - The current literature was analyzed and the authors' experiences with institutional and consult material were incorporated., Conclusions: - Our understanding of the molecular alterations that lead from pancreatic precursor lesion to invasive carcinoma continues to evolve. These advances aid clinicians in their treatment decisions and researchers in their search for actionable, druggable targets.

High-grade pancreatic intraepithelial neoplasia (HG-PanIN) is the major precursor of pancreatic ductal adenocarcinoma (PDAC) and is an ideal target for early detection. To characterize pure HG-PanIN, we analysed 23 isolated HG-PanIN lesions occurring in the absence of PDAC. Whole-exome sequencing of five of these HG-PanIN lesions revealed a median of 33 somatic mutations per lesion, with a total of 318 mutated genes. Targeted next-generation sequencing of 17 HG-PanIN lesions identified KRAS mutations in 94% of the lesions. CDKN2A alterations occurred in six HG-PanIN lesions, and RNF43 alterations in five. Mutations in TP53, GNAS, ARID1A, PIK3CA, and TGFBR2 were limited to one or two HG-PanINs. No non-synonymous mutations in SMAD4 were detected. Immunohistochemistry for p53 and SMAD4 proteins in 18 HG-PanINs confirmed the paucity of alterations in these genes, with aberrant p53 labelling noted only in three lesions, two of which were found to be wild type in sequencing analyses. Sixteen adjacent LG-PanIN lesions from ten patients were also sequenced using targeted sequencing. LG-PanIN harboured KRAS mutations in 94% of the lesions; mutations in CDKN2A, TP53, and SMAD4 were not identified. These results suggest that inactivation of TP53 and SMAD4 are late genetic alterations, predominantly occurring in invasive PDAC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Despite the recommendation of expert gastrointestinal pathologists, private and academic centers (including our own) have continued to use ancillary stains for identification of Helicobacter pylori. For a 1-month period, gastric biopsies were prospectively evaluated for H pylori using routine hematoxylin and eosin (H&E) and a reflex Diff-Quik stain. During this time, 379 gastric biopsies were collected on 326 patients. H pylori organisms were prospectively identified in 23 (7%) patients, all of whom had superficial dense lymphoplasmacytic inflammation expanding the lamina propria. An additional 2 patients with neutrophilic inflammation were found to have H pylori by immunohistochemical staining. One patient diagnosed as having normal gastric mucosa was retrospectively found to have inflammation with rare H pylori organisms originally overlooked on both H&E and Diff-Quik but later identified on immunostain (0.5%). No patients with chemical gastritis (16%) or chronic inflammation (27%) were found to have H pylori. During the study month, 9 immunostains for H pylori were performed in addition to the 379 Diff-Quik. After discontinuation of reflex Diff-Quik, approximately 20 immunostains are performed for H pylori each month, which decreases technical time spent for processing gastric biopsies and reduces cost to the health care system. In our population with a low prevalence of H pylori, reflex staining for organisms is not cost-effective. The organisms can be seen on routine H&E; when suspicious superficial or active inflammation is present without visible organisms, immunohistochemical stains will confirm presence or absence within a day. Discontinuation of up-front ancillary studies is cost-effective without compromising patient care., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Although the pancreas is affected by only a small fraction of known inherited disorders, several of these syndromes predispose patients to pancreatic adenocarcinoma, a cancer that has a consistently dismal prognosis. Still other syndromes are associated with neuroendocrine tumors, benign cysts, or recurrent pancreatitis. Because of the variability of pancreatic manifestations and outcomes, it is important for clinicians to be familiar with several well-described genetic disorders to ensure that patients are followed appropriately. The purpose of this review was to briefly describe the hereditary syndromes that are associated with pancreatic disorders and neoplasia., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: No standardized treatment strategies exist for patients with gynecologic malignancies complicated by brain metastases. Identification of poor outcome characteristics, long-term survival indicators, and molecular markers could help individualize and optimize treatment., Methods: This retrospective cohort study included 100 gynecologic cancer patients with brain metastases treated at our institution between January 1990 and June 2009. Primary outcome was overall survival (OS) from time of diagnosis of brain metastases. We used univariate and multivariate analyses to evaluate associations between OS and clinical factors. We used immunohistochemistry to examine expression of five molecular markers in primary tumors and brain metastases in a subset of patients and matched controls. Statistical tests included the Student's paired t-test (for marker expression) and Kaplan-Meier test (for correlations)., Results: On univariate analysis, primary ovarian disease, CA-125<81units/mL at brain metastases diagnosis, and isolated versus multi-focal metastases were all associated with longer survival. Isolated brain metastasis remained the only significant predictor on multivariate analysis (HR 2.66; CI 1.19-5.93; p=0.017). Expression of vascular endothelial growth factor A (VEGF-A) was higher in metastatic brain samples than in primary tumors of controls (p<0.0001). None of the molecular markers were significantly associated with survival., Conclusions: Multi-modality therapy may lead to improved clinical outcomes, and VEGF therapy should be investigated in treatment of brain metastases., Competing Interests: Dr. Hagemann reports that research reported in this publication was supported by the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH. All other authors have nothing to disclose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background & Aims: A long duration of inflammatory bowel disease (IBD) increases the risk for colorectal cancer. Mutation analysis of limited numbers of genes has indicated that colorectal tumors that develop in patients with IBD differ from those of patients without IBD. We performed whole-exome sequencing analyses to characterize the genetic landscape of these tumors., Methods: We collected colorectal tumor and non-neoplastic tissues from 31 patients with IBD and colorectal cancer (15 with ulcerative colitis, 14 with Crohn's disease, and 2 with indeterminate colitis) and performed whole-exome sequencing analyses of the microdissected tumor and matched nontumor tissues. We identified somatic alterations by comparing matched specimens. The prevalence of mutations in sporadic colorectal tumors was obtained from previously published exome-sequencing studies., Results: Two specimens had somatic mutations in the DNA proofreading or mismatch repair genes POLE, MLH1, and MSH6 and the tumor cells had a hypermutable phenotype. The remaining tumors had, on average, 71 alterations per sample. TP53 was the most commonly mutated gene, with prevalence similar to that of sporadic colorectal tumors (63% of cases). However, tumors from the patients with IBD had a different mutation spectrum. APC and KRAS were mutated at significantly lower rates in tumors from patients with IBD than in sporadic colorectal tumors (13% and 20% of cases, respectively). Several genes were mutated more frequently or uniquely in tumors from patients with IBD, including SOX9 and EP300 (which encode proteins in the WNT pathway), NRG1 (which encodes an ERBB ligand), and IL16 (which encodes a cytokine). Our study also revealed recurrent mutations in components of the Rho and Rac GTPase network, indicating a role for noncanonical WNT signaling in development of colorectal tumors in patients with IBD., Conclusions: Colorectal tumors that develop in patients with IBD have distinct genetic features from sporadic colorectal tumors. These findings could be used to develop disease-specific markers for diagnosis and treatment of patients with IBD and colorectal cancer., Competing Interests: The authors disclose no personal or financial conflicts, (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Autoimmune metaplastic atrophic gastritis (AMAG) is a significant risk factor for pernicious anemia and gastric neoplasia. Still, the histologic features of AMAG are frequently overlooked, especially in the early stages of the disease. The purpose of our study, therefore, was to catalogue the progression of histologic changes that precede the development of AMAG in affected individuals. Over a 2-year period (2012 to 2014), the diagnosis of AMAG was rendered on material from 113 patients seen at Johns Hopkins Hospital (∼1.8% of "in house" gastric biopsies). Prior gastric body biopsies had been performed on 54 (48%) patients in the cohort, and the majority of these specimens had also shown AMAG. Eighteen of the previous biopsies, however, carried a diagnosis other than AMAG: 13 inactive chronic gastritis, 2 acute Helicobacter pylori gastritis, and 1 each of eosinophilic gastritis, iron pill gastritis, and proton-pump inhibitor-like effect. Upon review of these 18 biopsies, the most common histologic findings were heavy full-thickness or deep lamina propria chronic inflammation (12), inflammatory destruction of oxyntic glands (12), metaplasia (intestinal, pyloric, or pancreatic acinar) (10), prominent lamina propria eosinophils (8), and parietal cell pseudohypertrophy (4). At least 2 of these features were present in the majority (13, 72%) of the biopsies. In addition, 7 (58%) of these patients were also found to have another autoimmune or inflammatory disorder before the diagnosis of AMAG. Although subtle, histologic features of developing AMAG are identifiable in routine gastric body biopsies. When metaplasia, full-thickness chronic inflammation, and/or oxyntic destruction are seen, a note suggesting laboratory testing and/or close clinical follow-up in this subset of patients may be warranted.

Tactile corpuscle-like bodies (TCLB) are microscopic Schwannian structures that simulate the superficial mechanoreceptors of the peripheral nervous system (Wagner-Meissner corpuscles). They have been described nearly exclusively in peripheral nerve sheath tumors, namely diffuse neurofibromas, and schwannomas but also in cellular nevi. There are rare reports of these structures in the gastrointestinal tract (predominantly the lower tract), with the presumption that they are incidental reactive neural proliferations. We compiled 9 cases showing this rare phenomenon in gastrointestinal-type mucosa in nonsyndromic patients to further characterize its features. There were 6 men and 3 women (age range, 39 to 79 y, mean 56 y) with lesions involving esophagus/gastro-esophageal junction (n=7), sigmoid colon (n=1), and gastric heterotopia of the cricopharynx (n=1). Endoscopic examination was abnormal in 6 of the 7 cases (including changes consistent with Barrett esophagus and polypoid/nodular mucosa) and normal in 1 of 7 cases for which this information was available. The histologic features were similar in all cases, with unencapsulated clusters of lamellated and concentrically arranged spindle cells in the lamina propria. The foci of TCLB ranged in size from <0.1 to 1.5 mm in the greatest dimension. Abnormal histopathologic findings were identified in the background mucosa in 6 of 9 cases (including Barrett esophagus, active and inactive chronic gastritis, enterochromaffin-like cell hyperplasia, and gastric intestinal metaplasia). None of the patients showed signs of neurofibromatosis type 1, multiple endocrine neoplasia type 2B, Cowden syndrome, or other inherited syndrome. No morbidity related to TCLB was reported for the patients with available follow-up.

Most cancers in humans are large, measuring centimetres in diameter, and composed of many billions of cells. An equivalent mass of normal cells would be highly heterogeneous as a result of the mutations that occur during each cell division. What is remarkable about cancers is that virtually every neoplastic cell within a large tumour often contains the same core set of genetic alterations, with heterogeneity confined to mutations that emerge late during tumour growth. How such alterations expand within the spatially constrained three-dimensional architecture of a tumour, and come to dominate a large, pre-existing lesion, has been unclear. Here we describe a model for tumour evolution that shows how short-range dispersal and cell turnover can account for rapid cell mixing inside the tumour. We show that even a small selective advantage of a single cell within a large tumour allows the descendants of that cell to replace the precursor mass in a clinically relevant time frame. We also demonstrate that the same mechanisms can be responsible for the rapid onset of resistance to chemotherapy. Our model not only provides insights into spatial and temporal aspects of tumour growth, but also suggests that targeting short-range cellular migratory activity could have marked effects on tumour growth rates.

Hepatocellular carcinoma can be diagnosed on a needle biopsy of the liver; however, uncertainty may arise because of the inherent complexity of liver histology. This article aims to provide practicing pathologists with tools for the approach to mass-directed liver biopsies clinically concerning for hepatocellular carcinoma. The examination of routine hematoxylin-eosin stains and the use of ancillary histochemical and immunohistochemical stains are discussed. Sections reviewing liver carcinoma with biphenotypic differentiation and the challenge of dysplastic nodules are included., (Copyright © 2015 Elsevier Inc. All rights reserved.)

It is well established that nonkeratinizing squamous cell carcinoma (SCC) of the oropharynx is causally related to transcriptionally active human papillomavirus (HPV) and has better survival as compared with carcinomas with a keratinizing phenotype (KSCC). Although the great majority of KSCCs are unrelated to HPV, transcriptionally active HPV is detected in a minority of oropharyngeal cases. To date, it has not been established whether the HPV status in KSCC also confers a survival advantage as it does in HPV-related nonkeratinizing SCC. This study compares clinical outcomes between patients with HPV-positive versus HPV-negative oropharyngeal KSCC. Among a total of 54 cases, 7 (13%) were diffusely and strongly positive for p16. HPV E6/E7 RNA was positive in 5 of the 6 (83%) p16-positive cases that were tested and in only 1 of the 47 (2%) p16-negative cases. Only 1 of the 7 (14%) p16-positive patients developed disease recurrence and died in the follow-up period. Kaplan-Meier survival analysis showed significantly better overall and disease-specific survival in the p16-positive than in the p16-negative patients (P=0.01 and 0.046, respectively). These data, although with relatively small patient numbers, suggest that HPV-related SCC in the oropharynx is associated with highly favorable outcomes, regardless of the keratinizing or nonkeratinizing phenotype.

In North America, the widespread use of vaccines targeting Haemophilus influenzae type b and Streptococcus pneumoniae have dramatically altered the epidemiology of bacterial meningitis, while the methodology for culturing cerebrospinal fluid (CSF) specimens has remained largely unchanged. The aims of this study were 2-fold: to document the current epidemiology of bacterial meningitis at a tertiary care medical center and to assess the clinical utility of routinely querying for anaerobes in CSF cultures. To that end, we assessed CSF cultures submitted over a 2-year period. A brucella blood agar (BBA) plate, incubated anaerobically for 5 days, was included in the culture procedure for all CSF specimens during the second year of evaluation. In the pre- and postimplementation years, 2,353 and 2,302 CSF specimens were cultured, with 49 and 99 patients having positive culture results, respectively. The clinical and laboratory data for patients with positive cultures were reviewed. Anaerobic bacteria were isolated in the CSF samples from 33 patients post-BBA compared to two patients pre-BBA (P = 0.01). The anaerobic isolates included Bacteroides thetaiotaomicron (n = 1), Propionibacterium species (n = 15), and Propionibacterium acnes (n = 19) isolates; all of these isolates were recovered on the BBA. Eight of the 35 patients from whom anaerobic organisms were isolated received antimicrobial therapy. Although six of these patients had central nervous system hardware, two patients did not have a history of a neurosurgical procedure and had community-acquired anaerobic bacterial meningitis. This study demonstrates that the simple addition of an anaerobically incubated BBA to the culture of CSF specimens enhances the recovery of clinically significant anaerobic pathogens., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

The chemokine receptor CXCR3 has been proposed to play a critical role in host antitumor responses. In this study, we defined CXCR3-expressing immune cell infiltration in human skin squamous cell carcinomas and then used CXCR3-deficient mice to assess the contribution of CXCR3 to skin tumorigenesis. Our studies employed two established protocols for chemical skin carcinogenesis [methylcholanthrene (MCA) or 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA) models]. CXCR3 deletion did not affect tumor development in the MCA model; however, CXCR3 was important in the DMBA/TPA model where gene deletion reduced the incidence of skin tumors. This decreased incidence of skin tumors did not reflect differences in epidermal development but rather was associated with reduced epidermal thickness and proliferation in CXCR3(-/-) mice, implicating the CXCR3 pathway in DMBA/TPA-induced epidermal inflammation and proliferation. Notably, CXCR3 expressed in CD4(+) and CD8(+) T cells was found to be important for enhanced epidermal proliferation. Specifically, CXCR3-deficient mice reconstituted with T cells isolated from wild-type mice treated with DMBA/TPA restored wild-type levels of epidermal proliferation in the mutant mice. Taken together, our findings establish that CXCR3 promotes epidermal tumorigenesis likely through a T-cell-dependent induction of keratinocyte proliferation., (©2011 AACR.)

Background: We examined prescription adherence rates by contraceptive method among women who used oral contraceptive pills (OCP), transdermal patch or vaginal ring., Study Design: Women in the St. Louis area were provided their choice of OCP, patch or ring at no cost and followed for 18 months. Time between monthly refills was obtained from pharmacy data and analyzed as a marker of adherence. Risk factors for initial nonadherence were estimated using Cox proportional hazards; predictors for repeated nonadherence were analyzed using Poisson regression with robust error variance., Results: Overall, 619 participants filled 6435 contraceptive prescriptions with a median of 10 refills per participant. Only 30% of women (n = 187) obtained all refills on time. In the time-to-failure analysis, use of vaginal ring and increased parity were predictors of early nonadherence (p < .05). In the multivariable analysis, use of the vaginal ring and history of abortion were risk factors for repeated nonadherence (p < .01)., Conclusions: Even with financial barriers removed, pharmacy data show that many women inconsistently refill their contraception and may be at risk for unintended pregnancy., (Copyright © 2011 Elsevier Inc. All rights reserved.)