Chanjuan Shi

OBJECTIVES: The pathogenesis for non-type 1/2 gastric neuroendocrine tumors (G-NETs) remains unclear. The aim of this study was to examine the clinicopathologic features of G-NETs and associated mucosal changes. METHODS: The electronic health records of patients with non-type 1/2 G-NETs were reviewed. H&E slides were reviewed for pathologic features and mucosal changes. The t test and Fisher exact test were used for statistical analysis. RESULTS: In total, 33 patients were assigned to either group 1 (n = 23) or group 2 (n = 10). Group 1 included patients with a history of proton pump inhibitor (PPI) use, increased gastrin levels, or significant PPI effect (PPI/gastrin-associated). All other patients were assigned to group 2. There was no significant difference in age and sex between the 2 groups. Group 2 tumors were more likely to be larger, invade deeper, and develop metastases (P < .05). Tumors in patients with cirrhosis tended to be larger. Peritumoral mucosal changes included loss of oxyntic glands, foveolar hyperplasia, and intestinal metaplasia. Background mucosa in group 1 patients showed PPI effect and neuroendocrine hyperplasia or dysplasia. CONCLUSIONS: Although PPI/gastrin-associated non-type 1/2 G-NETs were smaller and more indolent than typical type 3 G-NETs, tumors in patients with cirrhosis tended to be larger. Additionally, peritumoral mucosal changes could mimic chronic atrophic gastritis.

The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor κB (TNF-NFκB) and cell cycle (cycling S and cycling G2-M) programs occurred with relative prominence in PB and INT subtypes, respectively. Together, this study delineates markers of high-risk IPMN and insights into malignant progression.

AIMS: Criteria for the interpretation of digestive system neuroendocrine neoplasms (NENs) continue to evolve. Although there are some literature recommendations regarding workup and diagnosis of these lesions, different practice patterns exist among pathologists when signing out these specimens. The aim of this study was to assess practice trends among pathologists worldwide when reporting these neoplasms. METHODS AND RESULTS: We created an online survey with multiple questions pertaining to digestive NENs. The results were analysed based on type of practice setting, years of sign-out experience, and practice location. Respondents included 384 practicing pathologists: 70% academic, 30% private practice; 63% gastrointestinal (GI) pathology-subspecialised, 37% not; 39% North American, 42% European, 19% others; 45% with ≤10 years in practice; 55% with >10 years. Some question responses were chosen by the majority (e.g. 85% use both mitotic count and Ki67 index for grading NENs, 82% complete a synoptic, and Ki67 stain even for small incidental appendiceal neuroendocrine tumours [NETs], and 96% utilize the diagnosis of grade 3 NET). However, some questions showed varying responses, including counting mitotic figures, Ki67 stain interpretation, and pancreatic grade 3 NEN workup. Pathologists also had some variability in interpreting regional metastatic foci of small bowel NETs and in choosing blocks for Ki67 staining in multifocal lesions. CONCLUSION: There existed scenarios wherein practice patterns varied despite recommendations in the literature, and there were also scenarios lacking clear guidelines wherein pathologists used varying judgement. This survey highlights current key grey areas in digestive system NEN evaluation, leading to variation in practice patterns.

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs), although curable when localized, frequently metastasize and require management with systemic therapies, including somatostatin analogues, peptide receptor radiotherapy, small-molecule targeted therapies, and chemotherapy. Although effective for disease control, these therapies eventually fail as a result of primary or secondary resistance. For small-molecule targeted therapies, the feedback activation of the targeted signaling pathways and activation of alternative pathways are prominent mechanisms, whereas the acquisition of additional genetic alterations only rarely occurs. For somatostatin receptor (SSTR)-targeted therapy, the heterogeneity of tumor SSTR expression and dedifferentiation with a downregulated expression of SSTR likely predominate. Hypoxia in the tumor microenvironment and stromal constituents contribute to resistance to all modalities. Current studies on mechanisms underlying therapeutic resistance and options for management in human GEP-NETs are scant; however, preclinical and early-phase human studies have suggested that combination therapy targeting multiple pathways or novel tyrosine kinase inhibitors with broader kinase inhibition may be promising.

Pancreatic cancer is the fourth leading cause of cancer death in the United States, with an estimated 38,000 American deaths in 2013. Worldwide it causes approximately 227,000 deaths each year and is the eighth most common cause of cancer-related death. The major type, pancreatic ductal adenocarcinoma, is a nearly uniformly metastatic and fatal disease, and the mortality rate for pancreatic ductal adenocarcinoma closely follows that of the incidence. Pancreatic cancer presents clinically with pain, with symptoms related to obstruction of the biliary or pancreatic ducts, or with protean symptoms such as weight loss and cachexia. Pancreatic neuroendocrine tumor is a separate major category of pancreatic neoplasms, often has endocrine clinical sequelae, and is less frequently metastatic and fatal.Although most carcinomas of the pancreas appear to be sporadic, studies suggest that 3-10% of all cases of pancreatic ductal adenocarcinoma are hereditary. Some of the genes responsible for the familial aggregation of pancreatic cancer are known, and they most convincingly include germline mutations in the BRCA2, PALB2, CDKN2A, PRSS1, ATM, STK11/LKB1, and DNA mismatch-repair genes.The profile of somatic genetic mutations in pancreatic cancer is distinct from other neoplasms. The KRAS oncogene is commonly activated by somatic mutations in pancreatic cancer, whereas three tumor-suppressor genes are commonly inactivated. Ninety percent or more of pancreatic cancers harbor activating point mutations in codon 12 of KRAS. The CDKN2A tumor-suppressor gene is inactivated in 90-100% of pancreatic cancers, TP53 in 75%, and SMAD4 in 50%. In addition, recurrent somatic mutations of the MKK4, STK11/LKB1, TGFβ receptors, Smad and Fanconi anemia pathways, ATM, and ARID1A genes have also been reported. Various loci of gene amplifications each affect a minority of carcinomas.Inactivation of the SMAD4 gene may be rather specific for pancreatic ductal adenocarcinoma. SMAD4 is inactivated in as few as 15% of metastatic colorectal cancers and in less than 10% of other major cancer types. SMAD4 belongs to a class of proteins that mediate signals of the TGF-β superfamily.Microsatellite instability (RER+) is seen in a small minority (~ 4%) of pancreatic cancers. These RER+ cancers have a characteristic histologic appearance (medullary histology) and frequently have wild-type KRAS gene.The diagnosis of pancreatic cancer is suspected based on clinical findings, and often can be confirmed with radiologic and endoscopic techniques. Effective screening tests are not available yet. However, DNA-based testing appears promising.Recently, the exomes of the four most common cystic neoplasms of the pancreas have been sequenced, and each cyst type has its own unique mutational profile. Serous cystic neoplasms are characterized by VHL mutations, solid-pseudopapillary neoplasms harbor CTNNB1mutations, intraductal papillary mucinous neoplasms have GNAS, RNF43, KRAS, and, in advanced cases, TP53 and SMAD4 gene mutations, and mucinous cystic neoplasms have RNF43, KRAS, and, in advanced cases, TP53 and SMAD4 alterations.DAXX, ATRX, MEN-1 and mTOR pathway genes are mutated in pancreatic neuroendocrine tumors.