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Pancreatic cystic lesions (PCLs) are very common, and their detection is increasing with the advances in imaging techniques. Because of the major implications for management, distinguishing between neoplastic and nonneoplastic PCLs is critical. Neoplastic cysts with potential to progress into cancer include mucinous PCLs (intraductal papillary mucinous neoplasms and mucinous cystic neoplasms) and nonmucinous cysts (solid pseudopapillary tumors, serous cystic neoplasms, and neuroendocrine tumors with cystic degeneration). Nonneoplastic cysts with no risk of malignant transformation include pseudocysts, retention cysts, lymphoepithelial cysts, cystic pancreatic lymphangioma, and duplication cyst/ciliated foregut cysts. The role of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) cytology with cyst fluid analysis in the diagnosis of PCLs has evolved during the last decade; however, a definitive diagnosis on cytologic specimens is hampered by the sparse cellularity and can be challenging. EUS-FNA can play an important role to differentiate low-risk from high-risk pancreatic cysts and to distinguish between patients with cysts who need clinical follow-up versus those who require surgery. To provide an integrative approach to diagnose pancreatic cystic lesions using EUS-FNA cytology and cyst fluid analysis, along with clinical, radiologic, histologic, genetic, and molecular characteristics. The review and analysis of the latest literature describing pancreatic cystic lesions. Accurate diagnosis of PCLs requires a multidisciplinary and multimodal team approach, including the integration of clinical findings, imaging, cytology, cyst fluid analysis, and molecular testing.

Context.—Appendiceal mucinous neoplasms are considered enigmatic tumors of unpredictable biologic potential. Their importance lies in their potential to spread to the peritoneum and viscera in the form of gelatinous mucin deposits. Extra-appendiceal spread of these tumors is the most common etiology of pseudomyxoma peritonei, which is a descriptive term encompassing a number of neoplastic and nonneoplastic peritoneal disorders. Many studies aimed at evaluating the biologic importance of appendiceal mucinous neoplasms and pseudomyxoma peritonei have employed inconsistent histologic criteria for their diagnosis and descriptive terminology for their classification. As a result, appendiceal mucinous neoplasms and associated peritoneal disease represents one of the most confusing and controversial areas in gastrointestinal pathology. Objectives.—To summarize the literature regarding the biologic potential of appendiceal mucinous neoplasms and pseudomyxoma peritonei and to discuss the similarities and differences between proposed systems for their classification. Data Sources.—Literature review and case-derived material. Conclusions.—Many studies have contributed to an increased understanding of the natural progression of mucinous neoplasms of the appendix and peritoneum, and the adoption of a uniform reporting system, as advocated by the American Joint Committee on Cancer and the World Health Organization, will facilitate clear communication among pathologists and clinical colleagues.

Bcl-xL suppresses mitochondria-mediated apoptosis and is frequently overexpressed in cancer to promote cancer cell survival. Bcl-xL also promotes metastasis. However, it is unclear whether this metastatic function is dependent on its anti-apoptotic activity in the mitochondria. Here we demonstrate that Bcl-xL promotes metastasis independent of its anti-apoptotic activity. We show that apoptosis-defective Bcl-xL mutants and an engineered Bcl-xL targeted to the nucleus promote epithelial–mesenchymal transition, migration, invasion and stemness in pancreatic neuroendocrine tumour (panNET) and breast cancer cell lines. However, Bcl-xL proteins targeted to the mitochondria or outside of the nucleus do not have these functions. We confirm our findings in spontaneous and xenograft mouse models. Furthermore, Bcl-xL exerts metastatic function through epigenetic modification of the TGFβ promoter to increase TGFβ signalling. Consistent with these findings, we detect nuclear Bcl-xL in human metastatic panNETs. Taken together, the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence in the mitochondria. Bcl-xL is an anti-apoptotic protein that has also been implicated in metastasis. In this study, the authors show that nuclear Bcl-xL promotes metastasis by regulating TGFβ signaling, which is independent of the anti-apoptotic activity of Bcl-xL.

Intracholecystic papillary neoplasms (ICPNs) and biliary intraepithelial neoplasia (BilIN) are presumed precursors to gallbladder adenocarcinomas, but their relationship is incompletely understood. To perform morphologic and molecular characterization of concurrent ICPNs, nonpolypoid mucosa, and adenocarcinomas to determine whether these lesions are related at the DNA level. Background mucosa and 36 ICPNs were graded by a pathologist blinded to the original diagnoses. Separate areas of ICPNs, BilIN (n = 5), nondysplastic adjacent mucosa (n = 8), and invasive adenocarcinoma (n = 3) were amplified and sequenced on a next-generation sequencer. Data were manually curated to identify pathogenic somatic variants. High-grade ICPNs were associated with low-grade (n = 1) or high-grade (n = 3) BilIN or no dysplasia (n = 5). Fifteen were associated with invasive adenocarcinoma. Low-grade ICPNs were associated with low-grade BilIN (n = 3) or no dysplasia (n = 9). Pathogenic variants included CTNNB1 (catenin beta 1) exon 3 (7); TP53 (tumor protein p53) (6); APC (APC regulator of WNT signaling pathway) (2); RB1 (RB transcriptional corepressor 1) (1); KRAS (KRAS proto-oncogene, GTPase) (1); and PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) (1). Pathogenic variants in ICPNs were not detected in BilIN or nondysplastic mucosa. Mutations in invasive cancers included TP53, PIK3CA, and RB1, concordant with the ICPN, but not with BilIN, in all 3 cases. BilIN in the background of ICPNs was of the same or lower grade than ICPNs. Synchronous ICPNs and BilIN lacked concordant somatic mutations. Mutations in adenocarcinomas aligned with the ICPNs. This suggests that ICPN and BilIN are independent at the DNA level and that the presence of ICPNs may not imply risk for subsequent flat dysplasia elsewhere in the biliary tree.

Immune compromise may result from genetic abnormalities, HIV/AIDS, or consequences of therapy for neoplastic and autoimmune diseases. Many immunocompromised patients develop severe gastrointestinal symptoms, particularly diarrhea, accompanied by non-specific or mild endoscopic abnormalities; mucosal biopsy with pathologic interpretation has a major role in the diagnosis and management of these patients. Immunocompromised individuals are at risk for all the diseases that affect those with a healthy immune system, but they are also prone to other illnesses that rarely affect immunocompetent patients. This review discusses the gastrointestinal manifestations of primary and acquired immunodeficiency, chemotherapy-related injury, and infections that show a predilection for immunocompromised patients. Key histologic features and relevant differential diagnoses are emphasized.

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

Helicobacter pylori-associated and autoimmune gastritis may coexist in a subset of patients who require treatment for both disorders. To delineate findings that identify autoimmune gastritis in the background of H pylori infection. We examined cases of (1) patients with H pylori-associated gastritis who had successful eradication therapy and subsequent biopsies diagnostic of autoimmune gastritis and (2) H pylori-associated gastritis wherein pathologists noted features of autoimmune gastritis during original interpretation. Control patients underwent H pylori eradication but lacked evidence of autoimmune gastritis or H pylori infection after 10 years of follow-up. Eight subjects had H pylori-associated gastritis followed by H pylori-negative sampling that showed autoimmune gastritis. Review of original samples showed full-thickness inflammation of oxyntic mucosa in 8 of 8 and oxyntic gland loss in 7 of 8 cases. Enterochromaffin-like (ECL) cell hyperplasia, pyloric metaplasia, and intestinal metaplasia were present in 4 of 8 (80% of 5 tested cases), 4 of 8, and 3 of 8 cases, respectively. Features of autoimmune gastritis were noted at the time of their original H pylori diagnosis in 11 study subjects. Ten of 11 samples displayed full-thickness inflammation of oxyntic mucosa and/or partial loss of oxyntic glands, 8 of 11 had ECL cell hyperplasia (all tested cases), 6 of 11 showed pyloric metaplasia, and 4 of 11 harbored intestinal metaplasia. Except for full-thickness oxyntic mucosa inflammation, these features were absent in control cases. Full-thickness inflammation combined with oxyntic gland loss and ECL cell hyperplasia may help to identify autoimmune gastritis in patients with concomitant H pylori infection.

Recent data support that low-risk submucosally invasive (pT1) colonic adenocarcinomas (ie, completely resected tumors that lack high-grade morphology, tumor budding, and lymphovascular invasion) are considered cured via endoscopic resection, provided that the submucosal invasion is less than 1000 μm. Hence, the pathologists' assessment of depth of submucosal invasion may guide further management (ie, surveillance versus colectomy). To assess interobserver concordance among gastrointestinal pathologists in measuring submucosal depth of invasion in colonic endoscopic resections. Six gastrointestinal pathologists from 5 academic centers independently measured the greatest depth of submucosal invasion in micrometers on 52 hematoxylin-eosin-stained slides from colonic endoscopic specimens with pT1 adenocarcinomas, per published guidelines (round 1 scoring). Two separate measurements (round 2 scoring) were subsequently performed by each pathologist following a consensus meeting, (1) from the surface of the lesion and (2) from the muscularis mucosae, and pathologists were asked to choose their (3) \"real-life (best)\" assessment between the first 2 measurements. Interobserver agreement was assessed by the intraclass correlation coefficient (ICC) and Cohen κ statistics. Round 1 had poor ICC (0.43; 95% CI, 0.31-0.56). Round 2 agreement was good when measuring from the surface (ICC = 0.83; 95% CI, 0.76-0.88) but moderate (ICC = 0.59; 95% CI, 0.47-0.70) when measuring from the muscularis mucosae and became poor (ICC = 0.49; 95% CI, 0.36-0.61) for the best-assessment measurement. Our findings indicate that clearer and reproducible guidelines are needed if clinical colleagues are to base important management decisions on pathologists' estimate of the depth of submucosal invasion in colonic endoscopic resections.