Recently described types of dysplasia associated with IBD: tips and clues for the practising pathologist.

Longstanding inflammatory bowel disease (especially in patients with severely active disease or primary sclerosing cholangitis) is associated with an increased risk of developing dysplasia and adenocarcinoma. This review covers critical clinical aspects, such as risk factors and screening endoscopy basics, emphasising the SCENIC (Surveillance for Colorectal Endoscopic Neoplasia Detection in Inflammatory Bowel Disease International Consensus) guidelines. The histopathological and molecular features of both conventional (adenomatous) dysplasia and the non-conventional subtypes (hypermucinous dysplasia, goblet cell-deficient dysplasia, crypt cell dysplasia, serrated dysplasias) are discussed with an emphasis on challenging diagnostic areas and helpful tips to allow correct categorisation by the practising pathologist.

Characterization of Amyloidosis in the Gastrointestinal Tract With an Emphasis on Histologically Distinct Interstitial Patterns of Deposition and Misinterpretations.

Amyloidosis can involve the gastrointestinal (GI) tract, and deposition can present with varied histologic patterns that make recognition challenging. This retrospective observational study aimed to characterize the deposition patterns in the GI tract and evaluate key quality metrics, including discrepant cases, to improve recognition and provide insight for accurate diagnosis. Sixty-two patients (195 biopsies) with amyloid involvement of the luminal tract were reviewed. Amyloid subtyping by mass spectrophotometry was available for 59 patients. Immunoglobulin light chain (AL) was the most commonly identified subtype (60%), followed by serum amyloid A (AA; 19%) and transthyretin (ATTR; 16%). 150/195 biopsies (77%) were positive for amyloid deposition, with an average of 2.4 positive biopsies per every 3.1 taken per patient. The sites with the highest yield were duodenum (37/37, 100%) and colon (63/74, 85%). Gastric biopsies were most likely to involve the lamina propria (41/45, 91%, P < 0.001), with the background mucosa showing reactive epithelial changes in almost half of the biopsies (20/45, 44%). Several distinct histologic patterns of interstitial deposition were identified, including muscularis mucosae deposition (n = 40, 27% of positive biopsies), peri-Brunner gland (n = 6, 17% of duodenal biopsies), mass-forming (n = 4, 2.7% of positive biopsies, including 3 suspected cases with localized involvement), collagenous colitis-like (n = 3, 4.8% of positive colonic biopsies), and globular (n = 19, 12.7% of positive biopsies). Congo Red was ordered in 81% of cases in which it was requested clinically, with a positivity rate of 30%. Of the 34 cases in which an amyloid workup was requested (but Congo Red was not performed), 14 were positive on reevaluation. Several missed cases had deposition in multiple biopsies, and almost half were missed by subspecialist GI pathologists. Nine misinterpretations were from the stomach, with seven initially diagnosed as chemical or reactive gastropathy. Additional discrepant cases were identified from the duodenum (n = 2) and colon (n = 3), with the vascular-only deposition pattern (n = 3), muscularis mucosae-only deposition (n = 3), and globular pattern (n = 1) identified. Given the challenges of identifying amyloid on hematoxylin and eosin staining, Congo Red ordering percentage should be 100% in clinically suspicious cases unless deposition is definitively seen on hematoxylin and eosin staining.

Histologic Inflammation can Predict Future Clinical Relapse in Ulcerative Colitis Patients in Endoscopic Remission.

Background: In ulcerative colitis (UC), endoscopic improvement, defined as a Mayo Endoscopic Score (MES) of 0 or 1, is a target of treatment. The aim of our study was to evaluate the risk of clinical relapse between patients with an MES of 0 or 1 and determine if histologic activity using the Robarts Histopathologic Index (RHI) was predictive of clinical relapse. Methods: UC patients with an MES score of 0 or 1, no prior colectomy, and at least 1 year of outpatient follow-up after colonoscopy were included. Demographic, clinical characteristics, and clinical relapse were retrospectively collected. Biopsy specimens were read by a gastrointestinal pathologist. Primary outcome was defined as a composite of relapse requiring change in medical therapy, new steroid use, UC-related hospitalization, and/or colectomy. Results: Four hundred and forty-five UC patients were identified. Ninety-five percent of patients with MES 0 were in histologic remission by the RHI whereas only 35% of patients with MES 1 were in histologic remission. Twenty-six percent of patients experienced a clinical relapse; patients with MES 1 or RHI > 3 were significantly more likely to relapse (P < .01) compared to patients with MES 0 or RHI ≤ 3. When patients were stratified into 4 groups (MES 0, RHI ≤ 3; MES 0, RHI > 3; MES 1, RHI ≤ 3; MES 1, RHI > 3) and adjusted for age and sex, RHI > 3 was predictive of relapse (P = .008). Conclusions: UC patients with endoscopic improvement have a high rate of clinical relapse over time. Histologic activity is a predictor of clinical relapse.

Surgical Management of Germline Gastrointestinal Stromal Tumor.

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and usually results from a sporadic mutation in KIT or, less frequently, platelet-derived growth factor alpha (PDGFRA). Rarely, a germline mutation in the KIT, PDGFRA, succinate dehydrogenase (SDH), or neurofibromatosis 1 (NF1) gene is responsible for GIST. These tumors are found in the stomach (PDGFRA and SDH), small bowel (NF1), or a combination of both (KIT). There is a need to improve care for these patients regarding genetic testing, screening, and surveillance. Since most GISTs due to a germline mutation do not respond to tyrosine kinase inhibitors, the role of surgery is critical, especially when considering germline gastric GIST. However, in contrast to the established recommendation for prophylactic total gastrectomy in cadherin 1 (CDH1) mutation carriers once they reach adulthood, there are no formal guidelines as to the timing or extent of surgical resection for patients who are either carriers of a germline GIST mutation causing gastric GIST or have already developed gastric GIST(s). Surgeons must balance treating what is often multicentric, yet initially indolent disease with the chance of cure and the complications associated with total gastrectomy. Here, we consider the major issues in performing surgery in patients with germline GIST and illustrate the principles with a previously unreported patient harboring a germline KIT 579 deletion.

Ghost Cell Odontogenic Carcinoma Arising in a Previous Calcifying Odontogenic Cyst: A Case Report and Review of Literature.

Ghost cell odontogenic carcinoma (GCOC) is a rare malignant tumor of odontogenic origin, with only about 50 cases reported in the English literature so far. Histologically, it is characterized by ghost cells, dentinoid deposits, high grade malignant cellular features, and areas of necrosis and invasion. Having common histological features with other odontogenic ghost cell lesions (OGCL) like calcifying odontogenic cyst (COC) and dentinogenic ghost cell tumors, it is crucial to recognize GCOC malignant features, as it can be destructive and invasive, sometimes showing distant metastases and high recurrence rate. For this reason, it may entail more aggressive surgical approach and multimodal therapeutic regimen. Here we present a case report of GCOC arising in a previous COC, treated with surgical excision that showed persistence and recurrence after two years. The clinical and histological features of this rare occurrence are presented, in addition to the surgical approach, and a summary of literature review of OGCL.

Gastrointestinal Tract Injury by Yttrium-90 Appears Largely Restricted to Resin Microspheres But Can Occur Years After Embolization.

Radioembolization therapy utilizes yttrium-90 (Y90) impregnated resin (SIR-Spheres) or glass (TheraSpheres) microspheres to selectively target hepatic lesions via transarterial radioembolization. Occasional cases of gastrointestinal tract injury, secondary to nontargeted delivery of microspheres, have been reported, but large descriptive pathology series are lacking. We identified 20 cases of histologically confirmed mucosal injury associated with Y90 from 17 patients and assessed the corresponding clinical and pathologic sequelae. The mucosal biopsies were obtained from 1 to 88 months following Y90 therapy (median: 5 mo). Most cases were gastric (17, 85%), while the remaining were duodenal. Endoscopic ulceration was seen in the majority of cases (16, 80%), and mucosal erythema in the remaining 4. Histologically, a majority (19, 95%) of cases showed rounded, dark blue to purple microspheres measuring 4 to 30 µm, consistent with resin microspheres. A single case with glass microspheres demonstrated 26 µm translucent beads. Histologic evidence of ulceration was appreciated in 14 (70%) cases, and the microspheres were clearly intravascular in 6 (30%). A foreign body giant cell reaction to the microspheres was uncommon (3 cases, 15%). We additionally performed a retrospective review of all gastrointestinal tissue obtained postprocedure from 784 sequential patients treated with Y90 microspheres. Three patients (0.4%) demonstrated the presence of resin microspheres upon histologic examination. No cases involving glass-based Y90 were identified ( P =0.0078), despite the majority of patients having received glass radioembolization (630, 80%). This increased risk of secondary sphere dissemination is likely related to the increased number of particles required per activity for resin versus glass microspheres. We conclude that Y90 microspheres may be encountered in the gastrointestinal tract years after initial liver-targeted therapy and, when present, are often associated with mucosal ulceration. This finding is less likely to be encountered in patients who received Y90 radioembolization utilizing glass microspheres.

Characterization of Mycophenolate Mofetil Gastrointestinal Toxicity and Risk Factors for Severe Disease and Poor Prognosis.

Authors performed a chart review to identify cases of mycophenolate mofetil gastrointestinal toxicity at our institution. In this cohort, friability was associated with severe disease; and nausea and erythema were associated with poor prognosis.

Educational Case: Dermatitis Herpetiformis.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040.1.

Gastric AA amyloidosis secondary to chronic infection presenting with hematemesis: a case report.

AA amyloidosis, previously known as secondary amyloidosis, has been associated with multiple chronic inflammatory conditions, including various autoimmune diseases and rarely chronic infection. Hereby, we present a case of AA amyloidosis secondary to chronic infection which initially presented with nausea and hematemesis. Endoscopic biopsies revealed diffuse AA amyloid deposition in the stomach, but not the esophagus. AA Amyloidosis presumably compromised gastric motility, promoted reflux related esophageal ulcers and erosions, and caused his cardiac and renal insufficiency. Therefore, endoscopic biopsies could be practical investigation to identify AA amyloidosis in the setting of chronic inflammatory diseases, especially with multi-organ involvement.

Predictors of Recurrence and Survival in Patients With Surgically Resected Pancreatic Neuroendocrine Tumors.

OBJECTIVE: Given the lack of consensus on surveillance guidelines after pancreatic neuroendocrine tumor (PanNET) resection, we assessed outcomes in a large cohort of patients with nonmetastatic, surgically resected PanNETs. METHODS: Data of patients with PanNETs resected between 1990 and 2017 were retrospectively collected using databases at 3 academic institutions. The National Death Index was queried to determine vital status. Kaplan-Meier analysis was used to estimate recurrence-free survival (RFS) and disease-specific survival (DSS) rates. Variables associated with recurrence and disease-related death were identified through Cox multivariate analyses. RESULTS: Of 307 patients with PanNET who underwent resection, recurrence occurred in 79 (26%) of patients. For stage I and II disease, 5-year RFS rates were 90% and 43%, whereas 5-year DSS rates were 98% and 86% (P < 0.0001 and P = 0.0038, respectively). For grades 1, 2, and 3 disease, 5-year RFS rates were 87%, 49%, and 18%, and 5-year DSS rates were 98%, 89%, and 51% (P < 0.0001 for both). Stage II, grade 2, and grade 3 disease were each associated with increased recurrence and disease-specific death. CONCLUSIONS: Stage and grade are important prognostic factors that should be utilized to tailor postsurgical surveillance after curative resection of PanNET.

Brown Bowel Syndrome: A Multi-institutional Case Series.

Brown bowel syndrome (BBS) is a rare condition associated with vitamin E deficiency and defined by prominent lipofuscin deposition in the muscularis propria. Eight unique cases of BBS were identified: 5 men and 3 women (mean age=58.6 y). Pertinent comorbidities included bariatric surgery=2, malnourishment=2, Crohn=2, cystic fibrosis=1, alcohol and cocaine abuse=1, and prior small bowel resections=1. Presenting symptoms included abdominal pain=3, bleeding=1, nausea and vomiting=1, and nonresponsiveness=1. Imaging studies were often abnormal: thickened bowel wall=3 (1 with a mass), small bowel obstruction=2, and edematous and dilated bowel wall=2. Most specimens were surgical resections (n=7, autopsy=1): extended right colectomy=2, small bowel only=5 (terminal ileum=3, jejunum=2). Two specimens were grossly described as mahogany, and 1 case contained a perforation. Histologic sections of all cases showed finely granular, brown cytoplasmic pigment in smooth muscle cells on hematoxylin and eosin. This pigment was most conspicuous in the muscularis propria (small bowel>colon), and it was not identified in the mucosa. The pigment was reactive with Fontana-Masson, carbol lipofuscin, Periodic acid-Schiff, and Periodic acid-Schiff with diastase, and electron microscopy was compatible with lipofuscin. The mean clinical follow-up was 208 weeks: 1 patient died of complications of encephalitis, the others were alive and well. BBS is important to recognize because it is linked with malnutrition, specifically vitamin E deficiency, and it can (rarely) clinically simulate malignancy. The diagnosis is based on the identification of the lipofuscin pigment in the cytoplasm of smooth muscle cells, which is most easily seen in the muscularis propria of the small bowel.

Grade is a Dominant Risk Factor for Metastasis in Patients with Rectal Neuroendocrine Tumors.

BACKGROUND: Small (< 2 cm) and diminutive (< 1 cm) rectal neuroendocrine tumors (RNETs) are often described as indolent lesions. A large single-center experience was reviewed to determine the incidence of metastasis and the risk factors for its occurrence. METHODS: Cases of RNET between 2010 and 2017 at a single institution were retrospectively reviewed. The rate of metastasis was determined, and outcomes were stratified by tumor size and grade. Uni- and multivariable predictors of metastasis were identified, and a classification and regression tree analysis was used to stratify the risk for distant metastasis. RESULTS: The study identified 98 patients with RNET. The median follow-up period was 28 months. Of the 98 patients, 79 had primary tumors smaller than 1 cm, 8 had tumors 1 to 2 cm in size, and 11 had tumors 2 cm in size or larger. In terms of grade, 86 patients had grade 1 (G1) tumors, 8 patients had grade 2 (G2) tumors, and 4 patients had grade 3 (G3) tumors. Twelve patients developed metastatic disease. Both size and grade were associated with distant metastasis in the uni- and multivariable analyses, but when stratified by grade, size was predictive of metastasis only for G1 tumors (p < 0.001). Among the 12 patients with metastatic disease, 3 (25%) had diminutive primary tumors, and 9 (75%) had primary tumors 2 cm in size or larger. Diminutive tumors that metastasized were all G2. CONCLUSIONS: Patients with diminutive and small RNETs are at risk for metastatic disease. Tumor grade is a dominant predictor of dissemination. More rigorous staging, closer surveillance, or more aggressive initial management may be warranted for patients with G2 tumors, irrespective of size.

The incidence of neoplasia in patients with autoimmune metaplastic atrophic gastritis: a renewed call for surveillance.

BACKGROUND: Autoimmune metaplastic atrophic gastritis (AMAG) is an immune-mediated process that may lead to pernicious anemia (PA) and an increased risk of gastric cancer. Although some literature supports 3- or 5-year endoscopic surveillance for gastric cancer in patients with PA, no formal guidance exists for the general AMAG population. We sought to identify the prevalence and incidence rates of dysplasia or adenocarcinoma in patients with AMAG in order to clarify endoscopic best practices. METHODS: A retrospective study of 150 patients diagnosed with AMAG on endoscopic gastric biopsy between 1/2010 and 11/2015 was performed at a tertiary medical center. Clinical and pathologic data were obtained in order to calculate the prevalence and the incidence rate of dysplasia or adenocarcinoma. RESULTS: The cohort was predominantly female (82%) and white (61%), with median age 64 years. PA was present in 47% of patients. On index endoscopy, the prevalence of adenocarcinoma was 5.3%. A total of 59 patients with AMAG, but without neoplasia on initial biopsy, underwent subsequent endoscopic surveillance. Two patients, both of whom had confirmed PA, developed adenocarcinoma. The incidence rate of adenocarcinoma among this group was 14.2 cases per 1000 person-years, which far exceeds that of the general population (0.073 per 1000 person-years) based on Surveillance, Epidemiology, and End Results data. CONCLUSIONS: AMAG is associated with a high prevalence and incidence of gastric cancer, and endoscopic surveillance should be considered. Prospective cohort studies and cost effectiveness analyses are needed to better estimate cancer risk and recommended endoscopic surveillance intervals in these patients.

Endoscopic Resection of Duodenal Carcinoid Tumors: A Single-Center Comparison Between Simple Polypectomy and Endoscopic Mucosal Resection.

OBJECTIVES: Endoscopic resection is preferred for duodenal carcinoids less than 20 mm; however, the efficacy of simple polypectomy has not been compared with advanced endoscopic resection techniques. METHODS: We performed a retrospective review of 33 patients who underwent endoscopic duodenal carcinoid resection (10 simple, 23 endoscopic mucosal resection) at the Hospital of the University of Pennsylvania between January 1, 2006, and June 15, 2017. The primary outcomes were resection margin positivity and local tumor recurrence. RESULTS: There were no significant differences in demographics or tumor functionality. Lesions managed with simple polypectomy had smaller median gross specimen size (6.0 mm vs 8.0 mm, P = 0.043). There was no significant difference in pathology resection margins between simple polypectomy and endoscopic mucosal resection (86% vs 68% positive, P = 0.64). Local recurrence on surveillance endoscopy was also similar (14.3% vs 17.7%, respectively; P = 1.000), with median time to recurrence 2.3 months (interquartile range, 1.2-5.4 months). The median follow-up time in patients without local recurrence was 21.4 months (interquartile range, 7.1-39.6 months). CONCLUSIONS: Simple polypectomy may be adequate treatment of small duodenal carcinoids, although further studies are needed for validation and to define the upper limits of tumor size that can be managed with this technique.

Clusterin in Neuroendocrine Epithelial Neoplasms: Absence of Expression in a Well-differentiated Tumor Suggests a Jejunoileal Origin.

Clusterin, a widely expressed, tissue-specific glycoprotein, is a diagnostic marker of several tumor types, including anaplastic large cell lymphoma, follicular dendritic cell sarcoma, and tenosynovial giant cell tumor. A recent study has suggested it is highly expressed by well-differentiated neuroendocrine tumors (NET) arising at most anatomic sites, with the exception of jejunoileal tumors, and that it is similarly not expressed by poorly differentiated neuroendocrine carcinomas (NEC). We sought to validate this result in a large cohort of NETs and NECs. Clusterin immunohistochemistry was performed on tissue microarrays of 255 NETs [45 lung, 4 stomach, 8 duodenum, 75 pancreas (62 primary, 13 metastatic), 107 jejunoileum (69 primary, 38 metastatic), 16 appendix] and 88 NECs (43 visceral, 45 Merkel cell). Extent (%) and intensity (0, 1+, 2+, 3+) of staining were assessed and an H-score (extent x intensity) calculated. An average H-score >5 was considered positive. Clusterin expression was noted in 82.4% of 148 nonjejunoileal NETs (average H-score 183) and only 8.4% of 107 jejunoileal NETs (average H-score, 31), as well as 19.3% of NECs (average H-score, 36). Clusterin is frequently, strongly expressed by NETs of diverse anatomic sites, with the exception of jejunoileal tumors, in which it is only rarely, weakly expressed. It is occasionally, weakly expressed by NECs. Most metastatic NETs of occult origin arise in the pancreas or the jejunoileum. For cases in which an initial site of origin immunopanel (eg, islet 1, PAX6, CDX2) is ambiguous, addition of clusterin may be diagnostically useful, with absence of expression suggesting a jejunoileal origin.