Neuroendocrine Neoplasms of the Pancreas: Diagnostic Challenges and Practical Approach.

Most pancreatic neuroendocrine neoplasms are slow-growing, and the patients may survive for many years, even after distant metastasis. The tumors usually display characteristic organoid growth patterns with typical neuroendocrine morphology. A smaller portion of the tumors follows a more precipitous clinical course. The classification has evolved from morphologic patterns to the current World Health Organization classification, with better-defined grading and prognostic criteria. Recent advances in molecular pathology have further improved our understanding of the pathogenesis of these tumors. Various issues and challenges remain, including the correct recognition of a neuroendocrine neoplasm, accurate classification and grading of the tumor, and differentiation from mimickers. This review focuses on the practical aspects during the workup of pancreatic neuroendocrine neoplasms and attempts to provide a general framework to help achieve an accurate diagnosis, classification, and grading.

NOD2 Genetic Variants Predispose One of Two Familial Adenomatous Polyposis Siblings to Pouchitis Through Microbiome Dysbiosis.

BACKGROUND AND AIMS: Individuals with familial adenomatous polyposis (FAP) may undergo a total proctocolectomy with ileal pouch-anal anastomosis (IPAA) to surgically treat their disease. Inflammation of the ileal pouch, termed pouchitis, is uncommon in FAP patients but prevalent in patients who received IPAA for ulcerative colitis, a type of inflammatory bowel disease (IBD). METHODS AND RESULTS: We report on two FAP siblings, living in the same household, who underwent IPAA surgery within one week of each other. Their mother also had an IPAA for FAP. One sibling developed pouchitis while his brother and mother have remained pouchitis-free. We investigated the genetic and microbial factors that might explain the development of pouchitis in the one sibling. We surveyed DNA isolated from the two brothers and their parents for NOD2 IBD risk variants by Sanger sequencing. The composition of mucosa-associated bacteria was analyzed by 16S rRNA gene sequencing on terminal ileum and rectal tissue collected at the time of surgical resection from the two brothers. The sibling with pouchitis inherited the IBD-associated risk alleles for NOD2 (rs17221417 and rs2076756) from his healthy father. Both the mother and unaffected brother lacked these variants. Microbiome sequencing of the terminal ileum and rectum found reduced levels of potentially 'beneficial' bacteria (Faecalibacterium prausnitzii, Bacteroides, and Ruminococcaceae) in the sibling with pouchitis relative to his brother. CONCLUSION: These findings suggest that the NOD2 signaling pathway may contribute to intrinsic bacterial dysbiosis which is pre-existing and which may then predispose individuals to pouchitis after IPAA surgery.

Altered Expression of the Transcription Factor Forkhead Box A1 (FOXA1) Is Associated With Poor Prognosis in Urothelial Carcinoma of the Upper Urinary Tract.

OBJECTIVE: To determine the prognostic significance of Forkhead Box A1 (FOXA1) expression in patients with upper tract urothelial carcinoma (UTUC) undergoing radical nephroureterectomy (RNU). MATERIALS AND METHODS: A retrospective analysis of 566 patients undergoing RNU at seven academic medical centers was performed. Tissue microarrays were subjected to immunohistochemistry using a commercially available polyclonal FOXA1 antibody. Logistic regression determined the association of FOXA1 expression with pathologic features and survival outcomes. RESULTS: Three hundred twenty-two men and 244 women were included. The pathologic distribution of specimens included 53% muscle-invasive or greater (≥pT2), 74% high-grade, 16% with flat architecture, 13% with necrosis, 21% with lymphovascular invasion, 18% with concomitant carcinoma in situ, and 8% with positive lymph nodes. The median FOXA1 score was 5.0 (range: 0-8). Lower FOXA1 expression was significantly correlated with advanced pathologic stage (≥pT3) (P = .02), concomitant carcinoma in situ (P = .006), and renal pelvis (vs ureter) location (P < .0001). At a median follow-up of 27.0 months (range: 3-196), 139 patients (25%) experienced disease recurrence and 121 (21%) died from the disease. In a multivariate model, lower FOXA1 expression was independently associated with disease recurrence (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 1.05-1.62, P = .04), cancer-specific mortality (HR: 1.17, 95% CI: 1.03-1.92, P = .04), and all-cause mortality (HR: 1.08, 95% CI: 1.02-1.18, P = .05). CONCLUSION: Lower FOXA1 expression is associated with adverse pathologic features and inferior survival outcomes for UTUC patients undergoing RNU. These data indicate lower FOXA1 expression may be a marker of aggressive disease in UTUC.

The utility of villin and mammaglobin in the differential diagnosis between intrahepatic cholangiocarcinoma and breast cancer.

Liver metastasis is common for breast cancer. In breast cancer patients, differentiation between metastasis and intrahepatic cholangiocarcinoma (ICC) is crucial but not always possible, especially when estrogen receptor (ER) is negative. Villin and mammaglobin are gastrointestinal and breast markers, respectively, but were considered not useful in cholangiocarcinoma. The aim of this study was to reevaluate these 2 markers in the differential diagnosis between breast ductal carcinoma and ICC. Fifty-two cases of breast ductal carcinoma (including ER positive and negative, in situ, and invasive carcinomas), 27 cases of ICC, and 19 cases of extrahepatic bile duct adenocarcinoma were retrieved. Immunohistochemical staining for villin and mammaglobin was performed. The results showed that villin was negative in all breast cancers with a specificity of 100%, and positive in all ICCs with a sensitivity of 100%. Its sensitivity in extrahepatic bile duct adenocarcinoma was 63.2%. Mammaglobin was positive in a smaller percentage of breast cancers with no relationship to ER status. Discordant mammaglobin expression among matched invasive, in situ, and metastatic carcinomas of the same patient was common. Mammaglobin was negative in all ICCs with a specificity of 100%, when care was taken not to misinterpret patchy staining in adjacent normal hepatocytes as positive. In conclusion, the data showed that villin expression was highly accurate in the differential diagnosis between ICC and breast ductal carcinoma, which was particularly useful in ER-negative cases. Mammaglobin may be useful when it is positive.

Mitotic count by phosphohistone H3 immunohistochemical staining predicts survival and improves interobserver reproducibility in well-differentiated neuroendocrine tumors of the pancreas.

Well-differentiated neuroendocrine tumors (WDNETs) of the pancreas are graded on the basis of mitotic count or Ki67 index. Mitotic count has a narrow cutoff; its assessment is time consuming and carries poor interobserver reproducibility. Phosphohistone H3 (PHH3) is a mitosis-specific marker whose value has been validated in several tumor types. We sought to assess the utility of PHH3 in histologic grading of pancreatic WDNETs. Sixty-three cases of surgically resected primary pancreatic WDNETs were retrieved, and immunohistochemical analysis for PHH3 and Ki67 was performed. Mitotic rate was independently assessed by 4 pathologists on hematoxylin and eosin (HE; in 50 high-power fields [HPFs], expressed as mitoses/10 HPF) and PHH3 stains (in 50 HPFs, one 10×, and one 20× hotspot). PHH3 and Ki67 labeling indices were determined on a single 20× hotspot and expressed as the percentage of positive cells to total cells. We found that mitotic counts by various methods significantly correlated with each other and also with PHH3 and Ki67 indices, with the best correlation seen within the 3 different PHH3 counts (in 50 HPFs, one 10× and one 20× hotspot). Moreover, mitotic count on PHH3 was less time consuming than that on HE (1.68 vs. 3.67 min for 50 HPFs, P<0.0001). Histologic grade determined by PHH3 significantly correlated with disease-specific and disease-free survivals, with the best cutoffs of ≥4 mitoses/10 HPF (2 mm), ≥7 mitoses/10× hotspot, ≥5 mitoses/20× hotspot (log rank test, P<0.0001), and ≥0.16% for PHH3 labeling index (log rank test, P<0.0006). Tumor grades based on PHH3 stain also showed significant correlation with patient survivals in multivariate Cox proportional hazards models (P<0.05). Histologic grades by mitotic counts on PHH3 demonstrated high concordance and κ agreement with grades determined by mitotic count on HE. PHH3 stain also showed improved interobserver agreement in both original mitotic count (intraclass correlation 0.98 vs. 0.79) and final grade assignment (Fleiss κ 0.69 vs. 0.46) as compared with HE. Thus, our data confirmed that histologic grading by PHH3 stain has practical and prognostic values and offers reduced time and improved interobserver reproducibility in mitotic rate assessment and grade assignment. Although larger series are needed for validation, mitotic rate can potentially be determined by counting 1 hotspot, which will greatly facilitate the assessment of histologic grade in pancreatic WDNETs.