A Case of Whipple Disease With Cutaneous Manifestations.

ABSTRACT: Whipple disease (WD) is a rare bacterial infectious disease that is classically characterized by years of arthralgia, followed by malabsorption, diarrhea, and weight loss. However, WD may manifest in virtually any organ system, and patients with WD rarely develop subcutaneous erythema nodosum-like lesions. We report a case of a 51-year-old man diagnosed with WD who subsequently developed widely distributed erythematous subcutaneous nodules after 5 months of antibiotic therapy.

Ciliated columnar epithelium in the esophagus and gastroesophageal junction: A different perspective from study of a North American population.

An index case of ciliated columnar epithelium in a gastroesophageal (GE) junction biopsy identified in routine surgical pathology practice struck us as highly unusual. However, pathology literature, mainly from Asian populations, reports ciliated columnar epithelium in up to 40% of tissue samples from the upper GI tract. This was inconsistent with our pathology practice experience, so we initiated a local review of cases at our Canadian centre. 1048 consecutive tissue samples from the esophagus and GE junction were reviewed retrospectively and no ciliated epithelium was identified. This review included 1000× oil immersion microscopy of 22 cases with "multilayered epithelium". In 971 cases verified in prospective surgical pathology practice following identification of the index case, 3 additional cases of ciliated columnar epithelium were identified. The index case had ciliated pseudostratified columnar epithelium, resembling respiratory epithelium, and had strong, diffuse expression of TTF-1 by immunohistochemistry. In the other 3 cases, the cilia were located on the surface of a pseudostratified columnar epithelium, a multilayered epithelium, or a low columnar epithelium, all TTF-1 negative. Over a year later, the index case proved to have arisen from a bronchial-esophageal fistula. The other cases were not associated with a fistula. Our conclusion is that ciliated columnar epithelium is rare in Canadian adults (<0.5% of patients). Ciliated epithelium due to a bronchial-esophageal fistula is exceptional, but something to consider if there is a suspicious clinical picture and TTF-1 expression. Other cases might represent a rare metaplastic phenomenon or remnant from fetal development.

Fat-Containing Liver Lesions on Imaging: Detection and Differential Diagnosis.

OBJECTIVE: The purpose of this article is to review how fat is detected on imaging and to discuss the differential diagnosis of fat-containing liver lesions. CONCLUSION: Fat is a highly useful feature in characterizing liver lesions on imaging. Although a variety of liver lesions can show fat on cross-sectional imaging, the presence of fat usually indicates that the lesion is of hepatocellular origin. Less commonly, nonhepatocellular fatty lesions may be distinguished by ancillary clinical and imaging features.

Primary large cell neuroendocrine carcinoma of the skin: An under-recognized entity and a mimic of metastatic disease.

Primary large cell neuroendocrine carcinomas of the skin are exceptionally rare and can be diagnosed only when a metastasis from another organ has been excluded. We report the case of a 62-year-old woman with a cutaneous papule on the mid-chest which generated a differential diagnosis of vascular lesion and basal cell carcinoma. Following excision, microscopic evaluation revealed a dermal large cell undifferentiated carcinoma, with a brisk mitotic rate and focal geographic necrosis. Mucin production was absent. On immunohistochemistry, the lesion expressed CK7, AE1AE3, CK8/18, chromogranin, synaptophysin, CD56, calcitonin (patchy) and TTF-1 (minimal focal). Stains for neurofilament, CK20, CK5/6, p40, p63, SOX10, MART-1, EMA, CEA, ER/PR, GATA3, GCDFP, mammoglobin, PAX-8, CDX2, napsin, ERG and MCPyV proved negative. The histopathological diagnosis was of a large cell neuroendocrine carcinoma, probably metastatic. The patient underwent comprehensive clinical, laboratory and radiographic investigations and no underlying primary carcinoma was detected. During a 20-month follow-up period with an oncologist, the patient remains well and free of any apparent carcinoma. This suggests a primary large cell neuroendocrine carcinoma of skin. To date, 3 such cases have been reported in Japanese patients. This is the first in a Caucasian resident of North America.

Goblet cell carcinoid of the appendix - An interobserver variability study using two proposed classification systems.

Goblet cell carcinoid (GCC) is an uncommon tumor of the vermiform appendix. Due to a broad spectrum of morphological differentiation, subclassification and grading of GCCs remains an area of controversy. Two separate systems have proposed classifying GCC tumors into three (classical GCC; adenocarcinoma ex-GCC, signet ring cell type; adenocarcinoma ex-GCC, poorly differentiated carcinoma type) OR two subgroups (low and high grade GCC) based on morphological criteria. We independently compared the inter-observer variability associated with each classification system. Overall, both systems had moderate interobserver agreement, with the two-tiered system (κ=0.54) performing slightly better than the three-tiered system (κ=0.42). GI-specialist pathologists had substantial agreement for both two and three-tiered systems (κ=0.65 vs. 0.65). Non-GI trained pathologists had lower overall agreement than GI trained pathologists, but their agreement was better using the two-tiered system (κ=0.44) than the three-tiered system (κ=0.22). A sub-analysis of 6 cases with a high rate of discordant classification revealed several challenges that exist in applying current criteria, including differentiating "goblet" vs. "signet ring" cell morphology, applying a 1 mm2 criteria to multifocal non-contiguous glandular and single infiltrating cell architecture, differentiating fibro-inflammatory stroma from desmoplastic stroma, and solid architecture in cases with abundant extracellular mucin, and distinguishing "reactive" nuclear atypia from true "cytologic atypia". Despite these challenges, the study identified better agreement among GI pathologists than non-GI trained pathologists. While GI pathologist review may be helpful, further research on objective classification criteria remains an area of interest.

Prevalence of oesophageal epidermoid metaplasia in 1048 consecutive patients and 58 patients with squamous neoplasms.

AIMS: Oesophageal epidermoid metaplasia is defined by a dense granular layer with overlying hyperorthokeratosis, resembling the epidermis of skin. A possible association between epidermoid metaplasia, squamous dysplasia and squamous cell carcinoma has been proposed. The aim of this study was to compare the prevalence of epidermoid metaplasia in patients with oesophageal squamous neoplasms with that in a control cohort. METHODS AND RESULTS: Medical records and slides from 1048 consecutive oesophageal biopsies and resections for any indication and 58 patients with oesophageal squamous neoplasms were reviewed. Two cases (0.19%) of epidermoid metaplasia were identified in the 1048-patient control group. The prevalence of epidermoid metaplasia was significantly higher (P < 0.05) in the 58 patients with oesophageal squamous neoplasms, two of whom (3.5%) had concurrent epidermoid metaplasia (odds ratio 18.1, 95% confidence interval 2.5-131). One case was associated with a verrucous carcinoma and the other with a well-differentiated, superficial (pT1), exophytic squamous cell carcinoma. No patients had epidermoid metaplasia in a biopsy prior to the diagnosis of squamous neoplasia. CONCLUSIONS: The increased prevalence of epidermoid metaplasia observed in patients with squamous neoplasms provides some additional support for the proposed association. The hypothesis that epidermoid metaplasia is a precursor to squamous neoplasms remains unproven.

Management of Hepatocellular Adenoma: Recent Advances.

Hepatocellular adenoma (HCA) is a rare benign liver cell neoplasm that occurs more frequently in young women with a history of prolonged use of oral contraceptives. Surgical resection is considered because of the risk of hemorrhage in 25% and of malignant transformation in 5% of patients with HCA. HCA is a heterogeneous disease comprising 3 subtypes with distinct molecular and complication profiles. The inflammatory or telangiectatic subtype is at increased risk for hemorrhage, the ß-catenin-activated subtype is at increased risk for malignant transformation, and the hepatocyte nuclear factor-1α-inactivated or steatotic subtype is at the least risk for complications. One-third of the patients with HCA have multiple tumors on imaging with no increased risk of complications. Magnetic resonance imaging is the modality of choice for the diagnosis and subtype characterization of HCA. Systematic resection of HCA is recommended in male patients owing to the higher incidence of malignant transformation, and surgical excision in women should be reserved for tumors 5 cm or larger associated with an increased risk of complications. Cessation of hormonal therapy and radiologic surveillance in women with HCA tumors smaller than 5 cm shows that the vast majority of HCA remain stable or undergo spontaneous regression. Percutaneous core needle biopsy is of limited value because the therapeutic strategy is based primarily on patient sex and tumor size. Transarterial embolization is the initial treatment for HCA complicated by hemorrhage. Pregnancy should not be discouraged in the presence of HCA, however, frequent sonographic surveillance is recommended.

Collagenous gastritis: a morphologic and immunohistochemical study of 40 patients.

Collagenous gastritis is a rare condition defined histologically by a superficial subepithelial collagen layer. This study further characterizes the morphologic spectrum of collagenous gastritis by evaluating a multi-institutional series of 40 patients (26 female and 14 male). The median age at onset was 16 years (range 3-89 years), including 24 patients (60%) under age 18. Twelve patients (30%) had associated celiac disease, collagenous sprue, or collagenous colitis. Hematoxylin and eosin slides were reviewed in biopsies from all patients and tenascin, gastrin, eotaxin, and IgG4/IgG immunohistochemical stains were applied to a subset. The distribution of subepithelial collagen favored the body/fundus in pediatric patients and the antrum in adults. There were increased surface intraepithelial lymphocytes (>25 lymphocytes/100 epithelial cells) in five patients. Three of these patients had associated celiac and/or collagenous sprue/colitis, while the remaining two had increased duodenal lymphocytosis without specific etiology. An eosinophil-rich pattern (>30 eosinophils/high power field) was seen in 21/40 (52%) patients. Seven patients' biopsies demonstrated atrophy of the gastric corpus mucosa. Tenascin immunohistochemistry highlighted the subepithelial collagen in all 21 specimens evaluated and was a more sensitive method of collagen detection in biopsies from two patients with subtle subepithelial collagen. No increased eotaxin expression was identified in 16 specimens evaluated. One of the twenty-three biopsies tested had increased IgG4-positive cells (100/high power field) with an IgG4/IgG ratio of 55%. In summary, collagenous gastritis presents three distinct histologic patterns including a lymphocytic gastritis-like pattern, an eosinophil-rich pattern, and an atrophic pattern. Eotaxin and IgG4 were not elevated enough to implicate these pathways in the pathogenesis. Tenascin immunohistochemistry can be used as a sensitive method of collagen detection.

Ileitis associated with Meckel's diverticulum.

AIMS: Histological features of chronic active ileitis in the small intestine neighbouring a Meckel's diverticulum raise the possibility of concurrent Crohn's disease. Several studies have reported a significant association between Meckel's diverticulum and Crohn's disease, whereas some case reports have proposed that the ileitis is attributable to acid-secreting gastric heterotopia. The aim of this study was to evaluate the incidence, histomorphology and clinical follow-up of Meckel's diverticulum-associated ileitis. METHODS AND RESULTS: Medical records and slides from 48 consecutive surgical resections performed for Meckel's diverticulum were reviewed. Nine of 48 adults had significant inflammatory changes in the small intestine neighbouring the diverticulum. Two were transmural ulcers attributable to ingestion of a sharp object. Two patients had established Crohn's disease, both with long segments (>95 mm) of transmural inflammation located >100 mm from the diverticulum. The remaining five patients had inflammatory changes (ulceration, pseudopyloric metaplasia, submucosal fibrosis, and muscularis mucosa hyperplasia) confined to a short segment (<20 mm) of mucosa/submucosa within 50-60 mm of the diverticulum. Two had gastric heterotopia in the diverticulum. None of these five patients used non-steroidal anti-inflammatory drugs (NSAIDs). On follow-up, none had symptoms, imaging or pathology suggestive of Crohn's disease. CONCLUSIONS: Ileitis affecting a short segment of mucosa and submucosa in the small intestine near a Meckel's diverticulum is relatively common, and is not necessarily related to Crohn's disease.

Morphology and natural history of familial adenomatous polyposis-associated dysplastic fundic gland polyps.

AIMS: Most patients with familial adenomatous polyposis (FAP) develop gastric fundic gland polyps, with many displaying low-grade dysplasia. This study evaluates the natural history and morphological phenotype of dysplasia in FAP-associated fundic gland polyps. METHODS AND RESULTS: Patients with FAP and dysplastic fundic gland polyps (n = 24) were identified. Twenty-two of 24 FAP-associated dysplastic fundic gland polyps showed a gastric phenotype and two had mixed phenotype. During a mean 6.1-year follow-up (range 0.8-12.6 years) and 5.7 endoscopies (range 2-22), one patient (4%) was diagnosed with a fundic gland polyp with high-grade dysplasia, while 23 patients (96%) in this cohort had either no dysplasia or persistent low-grade dysplasia. Contemporary patients with sporadic fundic gland polyps with low-grade dyplasia had similar morphology and outcomes to the FAP-associated fundic gland polyp cohort. Dysplasia in fundic gland polyps (FAP-associated and sporadic) was associated less frequently with intestinal phenotype, high-grade dysplasia and the finding of concurrent or subsequent carcinoma compared to contemporary patients with sporadic gastric dysplasia not occurring in fundic gland polyps. CONCLUSIONS: This cohort of patients with FAP-associated dysplastic fundic gland polyps rarely developed high-grade dysplasia and gastric adenocarcinoma was absent.

Esophageal-guided biopsy with volumetric laser endomicroscopy and laser cautery marking: a pilot clinical study.

BACKGROUND: Biopsy surveillance protocols for the assessment of Barrett's esophagus can be subject to sampling errors, resulting in diagnostic uncertainty. Optical coherence tomography is a cross-sectional imaging technique that can be used to conduct volumetric laser endomicroscopy (VLE) of the entire distal esophagus. We have developed a biopsy guidance platform that places endoscopically visible marks at VLE-determined biopsy sites. OBJECTIVE: The objective of this study was to demonstrate in human participants the safety and feasibility of VLE-guided biopsy in vivo. DESIGN: A pilot feasibility study. SETTING: Massachusetts General Hospital. PATIENTS: A total of 22 participants were enrolled from January 2011 to June 2012 with a prior diagnosis of Barrett's esophagus. Twelve participants were used to optimize the laser marking parameters and the system platform. A total of 30 target sites were selected and marked in real-time by using the VLE-guided biopsy platform in the remaining 10 participants. INTERVENTION: Volumetric laser endomicroscopy. MAIN OUTCOME MEASUREMENTS: Endoscopic and VLE visibility, and accuracy of VLE diagnosis of the tissue between the laser cautery marks. RESULTS: There were no adverse events of VLE and laser marking. The optimal laser marking parameters were determined to be 2 seconds at 410 mW, with a mark separation of 6 mm. All marks made with these parameters were visible on endoscopy and VLE. The accuracies for diagnosing tissue in between the laser cautery marks by independent blinded readers for endoscopy were 67% (95% confidence interval [CI], 47%-83%), for VLE intent-to-biopsy images 93% (95% CI, 78%-99%), and for corrected VLE post-marking images 100% when compared with histopathology interpretations. LIMITATIONS: This is a single-center feasibility study with a limited number of patients. CONCLUSION: Our results demonstrate that VLE-guided biopsy of the esophagus is safe and can be used to guide biopsy site selection based on the acquired volumetric optical coherence tomography imaging data. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT01439633.).

Inflammatory hepatocellular adenomas can mimic focal nodular hyperplasia on gadoxetic acid-enhanced MRI.

OBJECTIVE: Inflammatory hepatocellular adenoma (HCA) is a recently categorized entity of hepatocellular neoplasms. We investigated whether gadoxetic acid-enhanced MRI can distinguish inflammatory HCA from focal nodular hyperplasia (FNH). MATERIALS AND METHODS: From January 1, 2009, through January 1, 2013, gadoxetic acid-enhanced MRI examinations from two institutions were reviewed for HCA, with specific histologic features of inflammatory HCA. Biopsy and resection slides were reviewed, and immunohistochemistry for glutamine synthetase was performed in a subset to confirm the initial diagnosis. RESULTS: A total of 10 possible cases of inflammatory HCA were identified in the pathology database. On the basis of glutamine synthetase staining performed for this study, three cases were rediagnosed as FNH and thus were excluded from the study. Therefore, a total of seven patients with inflammatory HCA were identified. On gadoxetic acid-enhanced MRI, four of these patients had classic features of FNH (group A, FNH mimics), and three had imaging features suggestive of HCA (group B, typical inflammatory HCA). Imaging features that were considered diagnostic of FNH included isointense or minimal T2 hyperintensity, arterial enhancement, and diffuse hyperintensity on hepatobiliary phase. Three of the four patients with FNH mimics had slides available for pathologic rereview, and the diagnosis of inflammatory HCA was supported by glutamine synthetase immunohistochemistry findings. The pathology reports of the remaining four cases were rereviewed and were also found to have features consistent with inflammatory HCA. CONCLUSION: Inflammatory HCA can mimic FNH on MRI, including hepatobiliary phase hyperintensity. Moreover, conventional pathology using histopathology alone may lead to misclassification of inflammatory HCA.

Very well-differentiated gastric carcinoma of intestinal type: analysis of diagnostic criteria.

Very well-differentiated gastric adenocarcinoma of intestinal type is a rare variant of gastric cancer characterized by low-grade nuclear atypia, and for which the diagnostic criteria and clinical behavior are not fully established. This study presents a detailed histologic, immunohistochemical, and clinical analysis of 21 cases. Nuclear atypia was mild in all cases. Characteristic architectural features of this gastric adenocarcinoma variant were pit and glandular anastomosis, spiky glands, distended glands, discohesive cells, abortive glands, and glandular outgrowth. At least three of these features were present in all the cases. Retrospective review of preoperative biopsies in 18 patients revealed that half of the biopsies were originally reported as negative or indeterminate for malignancy. On the basis of immunohistochemical stains for intestinal (MUC2, CD10, and CDX-2) and gastric (MUC5AC and MUC6) markers, 11 (52%) cases had an intestinal immunophenotype and 10 (48%) cases had a mixed immunophenotype. Foci of discohesive neoplastic cells, indicating dedifferentiation toward a poorly cohesive carcinoma, were observed exclusively in neoplasms of mixed immunophenotype (n=5). All patients with follow-up but one were alive without disease at a mean of 19 months (range 1-60 months). One individual with a pT4 tumor with associated poorly cohesive carcinoma died of disease. In summary, very well-differentiated gastric adenocarcinomas are diagnostically challenging. Architectural features are critical to making the diagnosis. Cases with pure intestinal immunophenotype have not been associated with transformation into poorly cohesive carcinoma, and appear to behave as biologically low grade. Those with mixed immunophenotype appear more likely to dedifferentiate and behave more aggressively.

Peritumoral hyperplasia of the liver: a response to portal vein invasion by hypervascular neoplasms.

AIMS: Several cases of focal nodular hyperplasia (FNH) or similar hyperplastic lesions have been reported adjacent to hepatic neoplasms, including hepatocellular carcinoma, epithelioid haemangioendothelioma and hepatoblastoma. We refer to this hyperplastic response as peritumoral hyperplasia (PTH). Here, we report eight cases of PTH adjacent to primary hepatocellular carcinomas (two) and metastatic neuroendocrine tumours (three), gastrointestinal stromal tumour (one) and colon carcinomas (two). METHODS AND RESULTS: Sections were stained with H&E and trichrome, and for glutamine synthetase, CD34 and cytokeratin 7. PTH was composed of a peritumoral rim of hyperplastic hepatocytes up to 7.0 mm wide, delimited by adjacent hepatocellular atrophy. PTH had altered plate architecture, strong glutamine synthetase expression and variable sinusoidal endothelial cell CD34 expression. The central tumour deposit typically invaded portal veins and was markedly hypervascular with CD34-positive capillaries. CONCLUSIONS: We suggest that PTH is a hyperplastic response to increased blood flow in the peritumoral parenchyma. The increased flow occurs when portal vein invasion by a hypervascular tumour causes arterio-portal shunting. While PTH shares some morphological features with FNH, it lacks the defining nodular architecture, central scar and bile ductules. PTH may be related pathophysiologically to FNH, but should be classified as a separate entity because of its distinct morphology and peritumoral location.

Improved overall survival in patients with high-grade serous ovarian cancer is associated with CD16a+ immunologic neighborhoods containing NK cells, T cells and macrophages.

Background: For patients with high grade serous carcinoma of the ovary (HGSC), survival rates have remained static for the last half century. Despite the presence of tumor mutations and infiltration of immune cells, existing immunotherapies have achieved little success against HGSC. These observations highlight a gap in the understanding of how the immune system functions and interacts within HGSC tumors. Methods: We analyzed duplicate core samples from 939 patients with HGSC to understand patterns of immune cell infiltration, localization, and associations with clinical features. We used high-parameter immunohistochemical/Opal multiplex, digital pathology, computational biology, and multivariate analysis to identify immune cell subsets and their associations with HGSC tumors. Results: We defined six patterns of cellular infiltration by spatially restricted unsupervised clustering of cell subsets. Each pattern was represented to some extent in most patient samples, but their specific distributions differed. Overall (OS) and progression-free survival (PFS) corresponded with higher infiltration of CD16a+ cells, and their co-localization with macrophages, T cells, NK cells, in one of six cellular neighborhoods that we defined with our spatial assessment. Conclusions: Immune cell neighborhoods containing CD16a+ cells are associated with improved OS and PFS for patients with HGSC. Patterns of immunologic neighborhoods differentiate patient outcomes, and could inform future, more precise approaches to treatment.

PAXgene Fixation for Pancreatic Cancer: Implications for Molecular and Surgical Pathology.

Genomic profiling of pancreatic cancer using small core biopsies has taken an increasingly prominent role in precision medicine. However, if not appropriately preserved, nucleic acids (NA) from pancreatic tissues are known to be susceptible to degradation due to high intrinsic levels of nucleases. PAXgene fixation (PreAnalytix, Switzerland) represents a novel formalin-free tissue preservation method. We sought to compare the NA and histomorphological preservation of pancreatic cancer tissues preserved with PAXgene-fixed paraffin-embedding (PFPE) and formalin-fixed paraffin-embedding (FFPE). Tissues from 19 patients were obtained prospectively from pancreaticoduodenectomy specimens and evaluated by four gastrointestinal pathologists. The extracted NA were quantified by Nanodrop and Qubit and assessed for quality by qPCR, targeted next-generation sequencing (NGS) assay, and RNA-sequencing. Our results demonstrated that, when assessed blindly for morphological quality, the four pathologists deemed the PFPE slides adequate for diagnostic purposes. PFPE tissues enable greater yields of less fragmented and more amplifiable DNA. PFPE tissues demonstrated significantly improved quality control (QC) metrics in a targeted NGS assay including Median Absolute Pair-wise Difference (MAPD) scores. Our results support the use of PAXgene fixative for the processing of specimens from pancreatic cancers with the potential benefits of improved yields for more amplifiable DNA in low-yield biopsy specimens and its ideal use for amplicon-based NGS assays.

Immunohistochemical expression and prognostic value of ER, PR and HER2/neu in pancreatic and small intestinal neuroendocrine tumors.

BACKGROUND AND AIMS: There has been limited study of estrogen and progesterone receptor (ER/PR) expression in gastrointestinal neuroendocrine tumors (GINETs) despite emerging evidence of hormone receptor regulation of pancreatic islet cells. Beta cells express PR and progesterone has been implicated in the pathogenesis of gestational diabetes. There is conflicting information regarding HER2/neu protein overexpression in GINETs. Investigation of ER, PR and HER2/neu expression in GINETs is therefore warranted. METHODS: A pathology database search identified 77 patients with primary pancreatic (40) or small intestinal (37) NETs diagnosed from 1991 to 2009. Ki67, ER, PR and HER2/neu were assessed via immunohistochemistry. ER and PR were interpreted as negative (0), 1+ (Allred score 3-7/8) or 2+ (Allred score 8/8), and HER2/neu was assessed according to ASCO/CAP guidelines for breast carcinoma. Clinical correlation and survival outcomes were ascertained by a retrospective clinical chart review. RESULTS: 2+ PR staining was observed more often in pancreatic compared to small intestinal cases (55 vs. 8%; p < 0.001). All small intestinal NETs with 2+ PR were duodenal primaries. Cases with 2+ PR presented significantly less often with nodal or distant metastases compared to cases with 0/1+ PR (13 vs. 61.5%; p < 0.001) and had significantly improved disease-free survival (median 155 vs. 38 months; p = 0.037). Only one case demonstrated 2+ ER staining and all were negative for HER2/neu. CONCLUSION: GINETs with strong (2+) PR expression are associated with pancreatic/duodenal origin, lower stage disease, and more favorable clinical prognosis. Further study is needed to determine the clinical utility of PR expression in GINETs.

Deep learning for computer-assisted diagnosis of hereditary diffuse gastric cancer.

BACKGROUND: Patients with hereditary diffuse gastric cancer often undergo prophylactic gastrectomy to minimize cancer risk. Because intramucosal poorly cohesive carcinomas in this setting are typically not grossly visible, many pathologists assess the entire gastrectomy specimen microscopically. With 150 or more slides per case, this is a major time burden for pathologists. This study utilizes deep learning methods to analyze digitized slides and detect regions of carcinoma. METHODS: Prophylactic gastrectomy specimens from seven patients with germline CDH1 mutations were analyzed (five for training/validation and two for testing, with a total of 133 tumor foci). All hematoxylin and eosin slides containing cancer foci were digitally scanned, and patches of size 256×256 pixels were randomly extracted from regions of cancer as well as from regions of normal background tissue, resulting in 15,851 images for training/validation and 970 images for testing. A model with DenseNet-169 architecture was trained for 150 epochs, then evaluated on images from the test set. External validation was conducted on 814 images scanned at an outside institution. RESULTS: On individual patches, the trained model achieved a receiver operating characteristic (ROC) area under the curve (AUC) of 0.9986. This enabled it to maintain a sensitivity of 90% with a false-positive rate of less than 0.1%. On the external validation dataset, the model achieved a similar ROC AUC of 0.9984. On whole slide images, the network detected 100% of tumor foci and correctly eliminated an average of 99.9% of the non-cancer slide area from consideration. CONCLUSIONS: Overall, our model shows encouraging progress towards computer-assisted diagnosis of hereditary diffuse gastric cancer.

Urachal Mucinous Cystic Tumor of Low Malignant Potential with Concurrent Sigmoid Colon Adenocarcinoma.

Urachal mucinous tumors are rare neoplasms with behaviour that can range from relatively benign to malignancy that can spread distantly or throughout the peritoneum as pseudomyxoma peritonei or peritoneal carcinomatosis. Here we describe a unique case of urachal mucinous cystic tumor of low malignant potential confined to an intact cyst at the dome of the urinary bladder, without rupture or peritoneal spread. The urachal mucinous tumor was an incidental finding on a staging CT scan performed for sigmoid colon adenocarcinoma. We believe that this case illustrates a potential diagnostic pitfall which could have prognostic and therapeutic implications. Due to the intestinal phenotype of these neoplasms, a urachal tumor of low malignant potential could be mistaken for metastatic spread from a colonic adenocarcinoma in the rare situation such as this case, where the two neoplasms occur concurrently.

ACTH-Secreting Neuroendocrine Carcinoma of the Cecum: Case Report and Review of the Literature.

BACKGROUND: Approximately 30% of neuroendocrine tumors (NETs) present with secretory syndromes or develop one during the course of the disease. Cushing syndrome caused by a gastrointestinal tract NET is rare, with limited published information. We describe a patient with florid Cushing syndrome due to ectopic adrenocorticotropic hormone (ACTH) from a NET of colonic origin. A literature review was conducted to describe the spectrum of this clinical and pathologic entity as reported in the scientific literature. PATIENT AND METHODS: Next-generation sequencing and microsatellite instability testing was carried out on the tumor from our case. A preliminary PubMed search was conducted using the following terms under the publication type "Case Reports": "Cushing" AND "colon," "neuroendocrine" AND "colon" and "neuroendocrine AND Cushing AND "colon." A manual search was performed to review all references for inclusion and relevant clinical, biochemical and pathologic data was abstracted. RESULTS: Mutations in BRAF V600E and TP53 were detected in our case. We retrieved 18 previously reported cases of Cushing syndrome associated with a NET of colonic origin, none of which had next-generation sequencing performed. Median age at diagnosis was 54.5 years (range, 24-74 years), with equal gender distribution. ACTH was detected by immunohistochemistry in the primary tumor and/or metastatic lesion in 61.5%. Review of the reports suggested that ectopic ACTH secretion from a colonic tumor might be more common in mixed glandular and NETs, including mixed adenocarcinoma-neuroendocrine carcinoma. Among studies reporting outcomes, the unadjusted mortality rate was 77.7%, with median overall survival from presentation of 63 days (range, 17-380 days). CONCLUSION: Cushing syndrome associated with ectopic ACTH from tumors of colonic origin is a rare phenomenon with poor outcomes and can be associated with pure NETs, adenocarcinomas, and mixed-phenotype tumors, including mixed adenocarcinoma-neuroendocrine carcinoma.