Liver flukes diagnosed by ERCP in a local immigrant community.

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.

Cell division rates decrease with age, providing a potential explanation for the age-dependent deceleration in cancer incidence.

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.

A spatial model predicts that dispersal and cell turnover limit intratumour heterogeneity.

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.

Colorectal carcinoma screening: Established methods and emerging technology.

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.

Genetic analyses of isolated high-grade pancreatic intraepithelial neoplasia (HG-PanIN) reveal paucity of alterations in TP53 and SMAD4.

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.

Whole-Exome Sequencing Analyses of Inflammatory Bowel Disease-Associated Colorectal Cancers.

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.

Clinicopathologic characteristics and survival of patients with gynecologic malignancies metastatic to the brain.

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.

Routine testing for anaerobic bacteria in cerebrospinal fluid cultures improves recovery of clinically significant pathogens.

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.

Malignant Pericardial Effusion due to Colorectal Cancer in a Young Man.

A 28-year-old man presented with sudden-onset right lower quadrant abdominal pain and shortness of breath at rest. On examination, he had tachycardia with distant heart sounds and right lower quadrant tenderness. A computed tomography scan showed segmental thickening of the proximal ascending colon and ileum with proximal cecal distension. Echocardiogram confirmed large pericardial effusion with impending tamponade. Video-assisted thoracoscopic surgery was performed for pericardial fluid drainage from a pericardial window. The mediastinal lymph node biopsy revealed metastatic adenocarcinoma cells. A colonoscopy showed a large polypoidal mass in the ascending colon with biopsy confirming poorly differentiated adenocarcinoma, thereby suggesting a possible lymphatic or hematogenous spread without liver or lung involvement.

Lymphocytic Esophagitis: Current Understanding and Controversy.

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.

Utility of gadolinium for identifying the malignant potential of pancreatic cystic lesions.

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.

Invasive carcinoma versus pseudoinvasion: interobserver variability in the assessment of left-sided colorectal polypectomies.

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.

Interobserver agreement and the impact of mentorship on the diagnosis of inflammatory bowel disease-associated dysplasia among subspecialist gastrointestinal pathologists.

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.

Hidden Carcinoma: Pitfalls in the Diagnosis of Lymphoepithelioma-Like Cholangiocarcinoma.

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.

Lymphocyte-predominant Esophagitis: A Distinct and Likely Immune-mediated Disorder Encompassing Lymphocytic and Lichenoid Esophagitis.

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.

Multicenter Phase II Study of Cabazitaxel in Advanced Gastroesophageal Cancer: Association of HER2 Expression and M2-Like Tumor-Associated Macrophages with Patient Outcome.

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.

An EBV+ lymphoepithelioma-like cholangiocarcinoma in a young woman with chronic hepatitis B.

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.

90Y-TheraSpheres: The New Look of Yttrium-90.

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.