Large Cell Neuroendocrine Carcinoma Presenting as Adult Intussusception.

Large cell neuroendocrine carcinoma (LCNEC) is an extremely rare malignant tumor of the colon, presenting with more severe clinical outcomes in comparison to colonic adenocarcinoma. There are very few reported cases in the literature. We hereby add our voice to the incidence of this disease by presenting the first report of a patient with ileocolic intussusception secondary to a large cell neuroendocrine cancer of the cecum. The patient was a 48-year-old woman who presented with acute onset of generalized abdominal pain and leukocytosis. CT scan revealed an ileocecal intussusception and multiple liver metastases suggestive of a malignant bowel lesion. She underwent emergency surgery, and an extended right hemicolectomy with ileo-transverse anastomosis was performed. Histology of the resected lesion revealed large cell neuroendocrine carcinoma of the cecum with invasion through the muscularis propria into peri colorectal tissues. The tumor retained mismatch repair (MMR) proteins with low potential for microsatellite instability (MSI). With a clinical diagnosis of stage IV LCNEC, the patient began platinum doublet chemotherapy with carboplatin and etoposide; however, her disease progressed, and the patient expired within a few months after her diagnosis. Clinical diagnosis of adult intussusception should prompt clinicians to rule out malignant etiology. This patient had a large cell neuroendocrine carcinoma of the colon, a rare and extremely aggressive malignancy. Patients with LCNEC will benefit from a multidisciplinary approach to treatment.

Gastrointestinal Amyloidosis as a Cause of Anemia: Rare and Rarely Considered.

Gastrointestinal involvement in amyloidosis is reported in 3% of cases, mostly associated with multiple myeloma. An elderly man with chronic kidney disease presented to the hospital after a large melenic bowel movement. The patient was tachycardic and anemic to 3.8 g/dL on admission and was transfused blood. Endoscopy and colonoscopy were unremarkable. Subsequently, the patient had 2 more admissions for severe anemia requiring blood transfusion. Repeat esophagoduodenoscopy with capsule endoscopy were unremarkable. The patient was diagnosed with monoclonal gammopathy of undetermined significance by hemoglobin electrophoresis, and endoscopy biopsy revealed intestinal amyloidosis in a duodenal specimen. The patient's recurrent anemia was attributed to bleeding from gastrointestinal amyloidosis, in the absence of other identifiable sources of anemia, and was managed with intravenous iron infusions.

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.

Painful Anal Ulcers in an HIV-Negative Young Woman: An Atypical Presentation of Syphilis.

Anorectal syphilis is relatively uncommon and diagnostically challenging given the wide differential diagnosis for anal lesions. Risk factors, such as men who have sex with men or HIV-positive status, are especially important to elicit from patients during the clinical history. In this report, we present a rare case of painful anal syphilis diagnosed in an HIV-negative woman by tissue biopsy.

Human hepatocyte PNPLA3-148M exacerbates rapid non-alcoholic fatty liver disease development in chimeric mice.

Advanced non-alcoholic fatty liver disease (NAFLD) is a rapidly emerging global health problem associated with pre-disposing genetic polymorphisms, most strikingly an isoleucine to methionine substitution in patatin-like phospholipase domain-containing protein 3 (PNPLA3-I148M). Here, we study how human hepatocytes with PNPLA3 148I and 148M variants engrafted in the livers of broadly immunodeficient chimeric mice respond to hypercaloric diets. As early as four weeks, mice developed dyslipidemia, impaired glucose tolerance, and steatosis with ballooning degeneration selectively in the human graft, followed by pericellular fibrosis after eight weeks of hypercaloric feeding. Hepatocytes with the PNPLA3-148M variant, either from a homozygous 148M donor or overexpressed in a 148I donor background, developed microvesicular and severe steatosis with frequent ballooning degeneration, resulting in more active steatohepatitis than 148I hepatocytes. We conclude that PNPLA3-148M in human hepatocytes exacerbates NAFLD. These models will facilitate mechanistic studies into human genetic variant contributions to advanced fatty liver diseases.

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.

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.

Histologically Remarkable Eosinophilic Esophagitis Responsive to Dupilumab in a Gastrostomy Tube-Dependent Pediatric Patient on Amino Acid Formula.

Eosinophilic esophagitis (EoE), an eosinophil predominant, TH2-mediated condition increasing in prevalence in pediatric and adult populations, is typically treated with dietary manipulations to avoid triggering antigens. However, identifying specific dietary causes remains a persistent challenge, and restrictive diets are burdensome. Total dietary modification using amino acid-based formula does not always produce symptomatic or histologic resolution, suggesting that exposure to ingested aeroallergens drives their disease. EoE patients demonstrate symptomatic exacerbation from July to September correlating with higher grass and ragweed pollen counts. We present a 7-year-old tracheostomy- and gastrostomy-dependent girl who was found on surveillance endoscopy to have profound eosinophilic infiltration throughout the esophagus with inflammatory changes including basal cell hyperplasia on histology. She responded partially to topical corticosteroid therapy with fluticasone and had complete resolution of esophageal eosinophilic infiltrate with subcutaneous dupilumab.

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.

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.

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.

Next-generation sequencing of residual cytologic fixative preserved DNA from pancreatic lesions: A pilot study.

BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is a sensitive and specific tool in the risk stratification of pancreatic lesions, including cysts. The sensitivity and specificity of EUS-FNA has been shown to improve when cytology is combined with next-generation sequencing (NGS). Ideally, fresh cyst fluid is used for NGS. In this pilot study, we explore the possibility of sequencing DNA derived from residual alcohol-fixed pancreatic aspirates. METHODS: Residual cytologic fixatives (n = 42) from 39 patients who underwent EUS-FNA for pancreatic lesions were collected along with demographics, imaging, and laboratory studies. Samples were designated as nonneoplastic/nonmucinous benign (NB), mucinous cyst (MC), pancreatic ductal adenocarcinoma (PDAC), or well-differentiated neuroendocrine tumor (NET) on the basis of cytopathologic evaluation and sequenced on the Oncomine platform (ThermoFisher Scientific, Waltham, Massachusetts). RESULTS: Ten of 14 (71.4%) MCs exhibited clinically significant variants, including KRAS, GNAS, and TP53. Ten of 15 (66.7%) PDACs had KRAS alterations, and 9 of 15 (60%) showed variants in TP53. No variants were detected in any NETs. Only 1 of 9 (11.1%) NB aspirates showed variants in KRAS and MAP2K. Sequencing of formalin-fixed, paraffin-embedded tissue revealed variants identical to those detected in fixative-derived DNA in 4 of 5 cases (80%). CONCLUSION: Residual DNA from alcohol-fixed aspirates are an underutilized source for NGS. Sequencing residual fixative-derived DNA has the potential to be integrated into the workup of pancreatic aspirates, possibly impacting management.

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.

Gastrointestinal Malakoplakia: Clinicopathologic Analysis of 26 Cases.

Malakoplakia is an inflammatory process related to defective macrophage response to bacterial infection. To further characterize the clinicopathologic manifestations of gastrointestinal malakoplakia, 26 cases were identified from 6 institutions. Hematoxylin and eosin-stained slides and available stains were reviewed, and pertinent clinicopathologic features analyzed. Sixteen patients were women (62%). Mean patient age was 64 (range: 24 to 83). Sites included the colorectum (n=23), appendix (n=1), and stomach (n=2). Clinical indications for tissue procurement included screening (n=14), tumor resection (n=5), diarrhea (n=1), adenoma surveillance (n=1), ulcerative colitis flare (n=1), abdominal pain (n=1), and appendicitis (1). All cases featured histiocytes with abundant, pale, eosinophilic cytoplasm focally containing Michaelis-Gutmann bodies. The process frequently involved the mucosa (n=19), with architectural distortion in 13 cases. Lymphoid aggregates were present in 18 cases, which were prominent or obscuring in 11 (all colon biopsies) and provoked concern for lymphoma in 2. Associated findings included adenocarcinoma (n=5), adenoma (n=2), gastric hyperplastic polyps (n=1), chemical gastritis (n=1), collagenous colitis (n=1), and active chronic colitis (n=2). In cases with available stains, Michaelis-Gutman bodies were highlighted by Periodic Acid-Schiff with diastase, Von Kossa, and iron stains. Although 2 cases were positive for Tropheryma whipplei antibody, no T. whipplei transcripts were detected on real-time polymerase chain reaction. All patients with available follow-up are alive and well with no additional instances of malakoplakia. Malakoplakia of the gastrointestinal tract is a benign, incidental finding. Although histologic features in the stomach and colon resections are similar to those at other sites, exuberant lymphocytic response in colon biopsies and immunoreactivity with T. whippleii antibody may provoke initial confusion and lead to unnecessary time and resource investment.

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.

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.

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.

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.