Revisiting the cytologic features of autoimmune pancreatitis: An institutional experience.

BACKGROUND: Autoimmune pancreatitis (AIP) is a known mimicker of pancreatic ductal adenocarcinoma both clinically and radiologically. In this study, the authors present their institutional experience in diagnosing AIP on cytology and correlate results with the histologic findings. METHODS: A 14-year computerized search for patients who had histologically confirmed AIP with concurrent or prior cytology was performed. Clinical data, cytology findings, and surgical pathology results were reviewed for analysis. RESULTS: Eighteen patients were identified. The patients showed a male predominance, with a mean age of 59 years. Jaundice, weight loss, and abdominal pain were the most common clinical presentation. Five of 12 patients who were tested for serum immunoglobulin G4 had elevated levels. Cytologic findings of 16 cases that were available for review showed markedly inflamed fibrous stroma (54%) and cytologic atypia (50%). The final cytologic diagnoses were suspicious for adenocarcinoma (n = 1), atypical (n = 8), and benign/negative (n = 9). The corresponding surgical pathology diagnoses were classified as type 1 (n = 10), type 2 (n = 6), and AIP, not otherwise specified (n = 2). All type 2 AIP cases had at least atypical cytologic diagnoses, with one called suspicious for adenocarcinoma and another called adenocarcinoma at the time of rapid on-site evaluation. In contrast, eight of 10 type 1 AIP cases were negative/benign, and two of 10 were atypical. In these two atypical cases, the possibility of AIP was raised because of the presence of inflamed stroma. CONCLUSION: AIP is a pitfall in cytology because moderate-to-marked atypia can be present, especially in type 2 AIP. Because atypia can be severe, the presence of cellular fibrous stroma with lymphocytic stromal infiltrates and the integration of serum immunoglobulin G4 levels could be helpful in avoiding diagnostic overcall in AIP.

Identifying factors associated with detection of sessile gastric polyps in patients with familial adenomatous polyposis.

Background and study aims Gastric cancer (GC) is increasingly reported and a leading cause of death in patients with familial adenomatous polyposis (FAP). Identifying features in patients with FAP who harbor sessile gastric polyps, likely precursors to GC, may lead to alterations in endoscopic surveillance in those patients and allow endoscopic intervention to decrease the risk of GC. The aim of this study was to identify demographic and clinical factors in patients with FAP who harbor sessile gastric polyps. Patients and methods We retrospectively compared demographic, clinical, and endoscopic features in consecutive adult patients with FAP who presented for a surveillance endoscopy at a tertiary-care center with a FAP registry who harbor sessile gastric polyps to those without them. Sessile gastric polyps included pyloric gland adenomas, gastric adenomas, hyperplastic polyps, and fundic gland polyps with high-grade dysplasia. We also display the location of germline APC pathogenic variants in patients with and without sessile gastric polyps. Results Eighty patients with FAP were included. Their average age was 48 years and 70 % were male . Nineteen (24 %) had sessile gastric polyps. They were older ( P  < 0.03), more likely to have a family history of GC ( P  < 0.05), white mucosal patches in the proximal stomach ( P  < 0.001), and antral polyps ( P  < 0.026) compared to patients without a gastric neoplasm. No difference in Spigelman stage, extra-intestinal manifestations, or surgical history was note. 89 % of patients with a gastric neoplasm had an APC pathogenic variant 5' to codon 1309. Conclusions Specific demographic, endoscopic, and genotypic features are associated with patients with FAP who harbor sessile gastric polyps. We recommend heightened awareness of these factors when performing endoscopic surveillance of the stomach with resection of gastric neoplasia when identified.

Endoscopic Findings in Patients With PTEN Hamartoma Tumor Syndrome Undergoing Surveillance.

GOALS AND BACKGROUND: Phosphatase and tensin homolog hamartoma tumor syndrome (PHTS) is an inherited disorder that increases the risk for cancer in multiple organ systems, including breast, endometrial, thyroid, and the gastrointestinal tract. Surveillance is recommended however there lacks data to describe the change in polyposis phenotype and cancer incidence over surveillance. Our aim is to describe the polyposis phenotype and cancer incidence in PHTS patients undergoing endoscopic surveillance. STUDY: PHTS patients, ages 17 through 89, who underwent at least 2 esophagogastroduodenoscopy (EGDs) or colonoscopies were identified. Number and sizes of polyps were noted, from which 5 categories were recreated. Incidence of colorectal and gastric cancer was evaluated. RESULTS: Seventy patients were included. Patients were clustered and classified into 1 of 5 categories: no polyps, few small polyps (<1 cm, < 10 polyps), few large polyps (≥1 cm, < 10 polyps), many small polyps (<1 cm, ≥10 polyps), many large polyps (≥1 cm, ≥10 polyps). There was no significant difference in polyp number or size on EGD (P=0.47 and 0.83, respectively) or colonoscopy (P=0.49 and 0.10, respectively) over the surveillance period (4.8±3.9 y for stomach and 5.6±4.4 y for colon). The average interval between endoscopies was 28±24 months for EGDs and 29±23 months for colonoscopies. A stage II transverse colon adenocarcinoma and stage IV gastric adenocarcinoma were identified. Standardized incidence rates for gastric and colon cancers were 5427 (P=0.0002) and 353 (P=0.002), respectively. CONCLUSIONS: PTHS individuals can be classified into polyposis phenotypes which do not change over an endoscopic surveillance period. Two cancers were associated with a large size polyp phenotype. Surveillance intervals should be determined by polyp size ≥1 cm and pathology.

Impact of margin status on outcomes after endoscopic resection of well-differentiated duodenal neuroendocrine tumors.

BACKGROUND AND AIMS: Duodenal neuroendocrine tumors (DNETs) are known to have low metastatic potential and follow an indolent course. Although DNETs <1 cm in size are amenable to endoscopic resection, little is known about the long-term outcomes and recurrence rates of this approach. METHODS: Sixty-three patients with DNETs from 3 centers were retrospectively studied from 2003 to 2018. We analyzed their resection modality (EMR, snare polypectomy, or forceps polypectomy), margin status, risk factors for recurrence, recurrence rate, and endoscopic surveillance patterns. RESULTS: Of the 63 patients who underwent endoscopic resection, 13 (20.6%) had recurrence. The presence of R1 margins was found to be a statistically significant risk factor for recurrence (P = .048). Mean surveillance time for all DNETs was 2.8 ± 2.6 years. Ninety-two percent of recurrences were detected within 3 years of resection. CONCLUSIONS: Our data suggest that the main predictor of recurrence in low-grade DNETs <1.0 cm is the presence of positive tumor margins at the initial endoscopic resection. More frequent, earlier surveillance after resection than that currently recommended by European Neuroendocrine Tumor Society guidelines may be warranted to promptly capture DNET recurrences. Additionally, no recurrences occurred in our cohort after 4 years of surveillance.

The Prevalence and Significance of Jejunal and Duodenal Bulb Polyposis After Duodenectomy in Familial Adenomatous Polyposis: Retrospective Cohort Study.

OBJECTIVE: To evaluate the prevalence, natural history, and severity of polyposis of the duodenal bulb and jejunum after duodenectomy in patients with FAP. SUMMARY OF BACKGROUND DATA: Advanced duodenal polyposis stage in FAP requires consideration of duodenal resection to prevent cancer; pylorus-preserving approach of pancreas-sparing duodenectomy (PSD) is preferred. Post-duodenectomy data indicate polyps occur in the duodenal bulb and the post-anastomotic jejunum, but limited data exists regarding their significance. METHODS: We identified consecutive FAP patients After duodenal resection, including pancreaticoduodenectomy, PSD, or segmental duodenectomy, at Cleveland Clinic. Medical records were used to determine time to diagnosis of duodenal bulb or jejunal polyps, length of follow up, and severity of polyposis including maximal Spigelman stage (SS) of jejunal polyposis (neo-SS). RESULTS: 64 patients with FAP underwent duodenectomy and endoscopic follow up. 28% underwent pancreaticoduodenectomy, 61% PSD, and 11% segmental duodenectomy. Postoperatively, 38/64 (59%) were diagnosed with jejunal polyposis, with median time to diagnosis of 55 months and follow up time of 127 months. Jejunal polyposis was advanced in 21% (neo- SS III or IV). Fifty percent were treated endoscopically, 1 patient required surgery. Jejunal polyp-free survival after duodenectomy differed by surgery type (P = 0.008). A total of 55/64 patients underwent a pylorus-preserving procedure, and 6/55 (11%) developed duodenal bulb polyps. All bulb polyps were large (>20 mm) and found after PSD. Endoscopic resection was unsuccessful in 5 patients, but no surgical intervention was required. CONCLUSIONS: Polyposis occurs in the remaining duodenal and jejunal mucosa in the majority of patients after surgical duodenectomy. Jejunal polyposis is advanced in 1 in 5 patients, but rarely requires surgery. Endoscopic management of jejunal polyposis seems feasible but has proven difficult for duodenal bulb polyps.

Loss of ß-Cytoplasmic Actin in the Intestinal Epithelium Increases Gut Barrier Permeability in vivo and Exaggerates the Severity of Experimental Colitis.

Intestinal epithelial barrier is critical for the maintenance of normal gut homeostasis and disruption of this barrier may trigger or exaggerate mucosal inflammation. The actin cytoskeleton is a key regulator of barrier structure and function, controlling the assembly and permeability of epithelial adherens and tight junctions. Epithelial cells express two actin isoforms: a ß-cytoplasmic actin and γ-cytoplasmic actin. Our previous in vitro studies demonstrated that these actin isoforms play distinctive roles in establishing the intestinal epithelial barrier, by controlling the organization of different junctional complexes. It remains unknown, whether ß-actin and γ-actin have unique or redundant functions in regulating the gut barrier in vivo. To address this question, we selectively knocked out ß-actin expression in mouse intestinal epithelium. Mice with intestinal epithelial knockout of ß-actin do not display gastrointestinal abnormalities or gross alterations of colonic mucosal architecture. This could be due to compensatory upregulation of γ-actin expression. Despite such compensation, ß-actin knockout mice demonstrate increased intestinal permeability. Furthermore, these animals show more severe clinical symptoms during dextran sodium sulfate induced colitis, compared to control littermates. Such exaggerated colitis is associated with the higher expression of inflammatory cytokines, increased macrophage infiltration in the gut, and accelerated mucosal cell death. Consistently, intestinal organoids generated from ß-actin knockout mice are more sensitive to tumor necrosis factor induced cell death, ex vivo. Overall, our data suggests that ß-actin functions as an essential regulator of gut barrier integrity in vivo, and plays a tissue protective role during mucosal injury and inflammation.

Surveillance for pathology associated with cancer on endoscopy (SPACE): criteria to identify high-risk gastric polyps in familial adenomatous polyposis.

BACKGROUND AND AIMS: Gastric cancer is an extracolonic manifestation of familial adenomatous polyposis (FAP) and is associated with high-risk gastric polyps. There are no known endoscopic criteria to identify these high-risk polyps. Our aim was to develop endoscopic criteria to identify high-risk polyps on endoscopy in FAP. METHODS: We prospectively collected 150 gastric polyps in consecutive patients undergoing surveillance EGD at the Cleveland Clinic. Pictures were taken of each polyp under narrow-band imaging and high-definition white light. In an exploratory phase, 5 endoscopists developed consensus criteria using the images to distinguish high-risk (pyloric gland adenoma, tubular adenoma, hyperplastic) from low-risk (fundic gland with low-grade or no dysplasia) polyps. In the assessment phase, endoscopists were blinded to polyp pathology and used the criteria to predict the individual polyp risk category. To measure diagnostic accuracy, we reported the mean sensitivity, specificity, and interrater agreement (κ). RESULTS: Consensus criteria were developed based on 16 low-risk and 9 high-risk polyps. The final 149 polyps consisted of 128 low-risk and 22 high-risk polyps (1 polyp was excluded from analysis). Using the criteria, the 5 endoscopists distinguished high- from low-risk polyps with a mean sensitivity and specificity of 79% (16.3%) and 78.8% (10.8%), respectively. The κ coefficient was .45, indicating moderate agreement. CONCLUSIONS: We developed endoscopic criteria to distinguish between high- and low-risk polyps associated with gastric cancer in FAP. The criteria provide guidance to endoscopists in targeting high-risk polyps while surveying the stomach of patients with proximal gastric polyposis.

Molecular testing in metastatic colorectal adenocarcinoma cytology cell pellets.

BACKGROUND: Mutational status for KRAS, NRAS, and BRAF genes should be performed on all colorectal carcinoma (CRC) specimens in order to guide targeted therapy selection for metastatic disease. Mutations are typically assessed via polymerase chain reaction and/or next generation sequencing (NGS) on formalin-fixed paraffin-embedded tissues. With minimally invasive diagnostic methodologies, the cytology cell pellet obtained by fine-needle aspiration (FNA) can serve as an alternative source of tumor deoxyribonucleic acid. METHODS: An electronic record review of the cytopathology files (CoPathPlus, Cerner Corp., North Kansas City, Missouri) from September 1, 2015 through December 31, 2018 was conducted. All cytology specimens obtained via FNA and diagnosed as metastatic CRC on which NGS was performed were included. NGS for KRAS, NRAS, and BRAF mutations using the AmpliSeq Cancer Hotspot Panel v2.0 kit (Thermo Fisher Scientific, Waltham, Massachusetts) was performed on cytology cell pellets. RESULTS: Forty-eight cases were identified. Forty-six of 48 specimens (96%) were adequate for molecular testing. Of those adequate specimens, proportion of malignant cells in the sample ranged from 5% to 95% (mean 46%). Twenty-seven of 48 cases (56%) were positive for clinically relevant mutations. Twenty-four of 27 cases (89%) were positive for KRAS mutations, with exon 2 most frequently involved (22/24 cases, 92%). Two of 27 cases (7%) were positive for NRAS mutations and one case (1/27, 4%) was positive for a BRAF mutation involving codon 594. CONCLUSION: Mutational analysis performed on cytology cell pellets serves as a useful means of gathering clinically actionable information on tumor mutation status in metastatic CRC.

Disseminated Metacestode Versteria Species Infection in Woman, Pennsylvania, USA1.

A patient in Pennsylvania, USA, with common variable immunodeficiency sought care for fever, cough, and abdominal pain. Imaging revealed lesions involving multiple organs. Liver resection demonstrated necrotizing granulomas, recognizable tegument, and calcareous corpuscles indicative of an invasive cestode infection. Sequencing revealed 98% identity to a Versteria species of cestode found in mink.

Paraduodenal inflammatory pseudotumor masquerading as malignancy.

A 30-year-old woman presented with severe abdominal pain and abdominal distension. CT demonstrated two intra-abdominal masses, one involving the left lateral segment of the liver and the other adjacent to the duodenum. Initial biopsies were consistent with focal nodular hyperplasia of the liver and non-specific lymphocytic infiltrate in the paraduodenal mass. Due to persistent symptoms, the patient underwent laparoscopic resection of the paraduodenal mass. Final pathology was consistent with an inflammatory pseudotumour and the patient's symptoms subsequently resolved.

Endoscopic and histologic features associated with gastric cancer in familial adenomatous polyposis.

BACKGROUND AND AIMS: Gastric cancer (GC) is a newly described cancer risk in Western patients with familial adenomatous polyposis (FAP). Little is known about clinical, endoscopic, and pathologic features associated with FAP-related GC. We compared these features in FAP patients with and without GC. METHODS: FAP patients were identified through the David G. Jagelman Inherited Colorectal Cancer Registries Cologene database. FAP patients with GC and randomly selected FAP patients without GC who had undergone at least 2 EGDs were analyzed. Demographic, clinical, endoscopic, and pathologic features were compared. RESULTS: Ten FAP patients with GC were identified, and 40 age-matched FAP control subjects were selected. No demographic differences were noted between patients and control subjects. All GC cases arose in the proximal stomach among gastric polyposis, with only 2 endoscopically visible. The prevalence of gastric polyposis was similar (100% vs 93%). Endoscopic features associated with GC included a carpeting of gastric polyps (100% vs 22.5%), solitary polyps >20 mm (100% vs 0%), and a polypoid mound of polyps (80% vs 0%; all P < .001). GC patients had a higher prevalence of gastric adenomas (30% vs 5%, P = .048) and polyps with high-grade dysplasia, including fundic gland polyps (50% vs 10%, P = .01) and pyloric gland adenomas (20% vs 0%, P = .037). CONCLUSIONS: We identified endoscopic features and advanced pathology present in the stomachs of Western patients with FAP who developed GC. Upper GI surveillance in FAP should include the stomach and awareness of features associated with GC. Optimal approaches to treatment of gastric polyposis and methods of identification of early GC precursors in FAP are needed.

Loss of tolerance to glycoprotein 2 isoforms 1 and 4 is associated with Crohn's disease of the pouch.

BACKGROUND: Zymogen granule glycoprotein 2 (GP2) is a major autoantigen of Crohn's disease-specific pancreatic autoantibodies. AIM: To test a link between loss of tolerance to isoforms of GP2 and pouch disorders in a cross-sectional study in ulcerative colitis patients with ileal pouch-anal anastomosis (IPAA). METHODS: Serum samples of 117 consecutive ulcerative colitis patients after IPAA were tested for presence of Anti-GP2 isoforms 1 (GP21 ) & 4 (GP24 ) IgG and IgA as well as anti-Saccaromyces cervisiae (ASCA) IgG and IgA antibodies in a blinded fashion via enzyme-linked immunosorbent assay. Pouch disorders were diagnosed based on clinical, endoscopic, histological and radiographic criteria. Crohn's disease of the pouch was defined as involvement of the small bowel mucosa proximal to the ileal pouch with Crohn's disease, development of perianal complications or pouch fistula more than 3 months after ileostomy closure. RESULTS: Positivity and level of Anti-GP21 IgG (AUC 0.77; P < 0.001 & P = 0.02, respectively), Anti-GP24 IgG (AUC 0.74; P < 0.001 & P = 0.025, respectively) and Anti-GP24 IgA (AUC 0.77; P < 0.001 to P = 0.018, respectively) were specifically associated with Crohn's disease of the pouch. Anti-GP2 was not associated with endoscopic or histological pouch disease activity index. Neither positivity nor levels of ASCA IgG (AUC 0.63; P = 0.12 & P = 0.35, respectively) or ASCA IgA (AUC 0.67; P = 0.38 & P = 0.53) were associated with pouch phenotypes. CONCLUSIONS: The novel anti-GP21 and GP24 antibodies are associated with Crohn's disease of the pouch in ulcerative colitis patients after IPAA. Serological anti-GP2 antibodies could aid in diagnosis of Crohn's disease of the pouch.

Cancer-predicting transcriptomic and epigenetic signatures revealed for ulcerative colitis in patient-derived epithelial organoids.

Ulcerative colitis (UC) is a prevalent form of inflammatory bowel disease (IBD) whose pathogenic mechanisms remain unclear. Elucidating these mechanisms is important to reduce UC symptoms and to prevent UC progression into colitis-associated colon cancer (CAC). Our goal was to develop and validate faithful, human-derived, UC models and analyze them at histologic, transcriptomic and epigenetic levels to allow mechanistic studies of UC and CAC pathogenesis. We generated patient-derived primary-organoid cultures from UC and non-IBD colonic epithelium. We phenotyped them histologically and used next-generation-sequencing approaches to profile whole transcriptomes and epigenomes of organoids and primary tissues. Tissue organization and expression of mucin 2 (MUC2) and lysozyme (LYZ) demonstrated histologic faithfulness of organoids to healthy and diseased colonic epithelium. Transcriptomic analyses showed increased expression of inflammatory pathways in UC patient-derived organoids and tissues. Profiling for active enhancers using the H3K27ac histone modification revealed UC-derived organoid enrichment for pathways indicative of gastrointestinal cancer, including S100 calcium-binding protein P (S100P), and revealed novel markers for GI cancer, including both LYZ and neuropeptide S receptor 1 (NPSR1). Immunolocalization showed increased levels of LYZ, S100P, and NPSR1 proteins in UC and CAC. In conclusion, primary colonic organoid cultures from UC and non-IBD patients can be established that faithfully represent diseased or normal colonic states. These models reveal precancerous molecular pathways that are already activated in UC. The findings demonstrate the suitability of primary organoids for dissecting UC and CAC pathogenic mechanisms and suggest new targets for therapeutic intervention.

Endoscopic ultrasound FNA: An illustrated review of spindle cell neoplasms of the upper gastrointestinal tract including a novel case of gastric plexiform fibromyxoma.

Plexiform fibromyxoma (PF) is a recently-described and rare mesenchymal neoplasm of the gastric wall. A few small case series reports of this spindle cell entity exist in the surgical pathology literature, but to our knowledge no prior endoscopic ultrasound guided fine needle aspiration cytology examples have been reported. In clinical practice, mural gastrointestinal (GI) lesions are often initially evaluated by endoscopic ultrasound guided (EUS) fine needle aspiration (FNA). In addition, newer EUS fine needle biopsy techniques also allow for reliable retrieval of core tissue samples with intact cellular architecture, making EUS histopathologic analyses possible. We report a combined EUS FNA and core biopsy case of PF and correlate the findings with imaging results. The cytomorphology of PF is described and illustrated, and important entities in the differential diagnosis of upper GI spindle cell lesions (including GI stromal tumor, leiomyoma, schwannoma, carcinoid tumor, desmoid-type fibromatosis, and inflammatory fibroid polyp) are reviewed. Illustrated examples of relevant cytomorphologic, cell block histomorphologic and immunohistochemical characteristics are emphasized.