HIF-1alpha-pathway activation in cholangiocytes of patients with biliary atresia : an immunohistochemical/molecular exploratory study

Background: Biliary atresia is a neonatal disease characterized by choledochal obstruction and progressive cholangiopathy requiring liver transplantation in most patients. Hypoxia-ischemia affecting the biliary epithelium may lead to biliary obstruction. We hypothesized that ischemic cholangiopathy involving disruption of the peribiliary vascular plexus could act as a triggering event in biliary atresia pathogenesis. Methods: Liver and porta hepatis paraffin-embedded samples of patients with biliary atresia or intrahepatic neonatal cholestasis (controls) were immunohistochemically evaluated for HIF-1alpha-nuclear signals. Frozen histological samples were analyzed for gene expression in molecular profiles associated with hypoxia-ischemia. Prospective clinical-laboratory and histopathological data of biliary atresia patients and controls were reviewed. Results: Immunohistochemical HIF-1alpha signals localized to cholangiocytes were detected exclusively in liver specimens from biliary atresia patients. In 37.5% of liver specimens, HIF-1alpha signals were observed in biliary structures involving progenitor cell niches and peribiliary vascular plexus. HIF-1alpha signals were also detected in biliary remnants of 81.8% of porta hepatis specimens. Increased gene expression of molecules linked to REDOX status, biliary proliferation, and angiogenesis was identified in biliary atresia liver specimens. In addition, there was a trend towards decreased GSR expression levels in the HIF-1alpha-positive group compared to the HIF-1alpha-negative group. Conclusion: Activation of the HIF-1alpha pathway may be associated with the pathogenesis of biliary atresia, and additional studies are necessary to confirm the significance of this finding. Ischemic cholangiopathy and REDOX status disturbance are putative explanations for HIF-1alpha activation. These findings may give rise to novel lines of clinical and therapeutic investigation in the BA field

De novo colorectal cancer after liver and kidney transplantation–Microenvironment disturbance

Colorectal cancer (CRC) is a major health burden and may arise as a complication of solid organ transplantation. Our study aimed to assess the incidence of the CRC in kidney and liver transplanted patients at a tertiary and reference center and to describe their clinical and pathological features. Twelve patients, 10 men and two women, with a mean age of 60 years, composed our cohort, ten of them submitted to CRC resection. Transplanted organ was liver in five patients and kidney in seven. Regarding overall survival, patients submitted to renal transplantation were all deceased 5 years after CRC diagnosis, while those subjected to hepatic transplantation had a survival of 60% at the fifth year. Pathology examination showed seven patients with advanced disease (stage III/IV) and high amount of necrosis. Tumor microenvironment was disturbed, with low inflammatory infiltrate, absence of natural killer cells and no PD-L1 expression. CRC exhibited microsatellite instability in 40%, with expression of cancer stem cell markers (CD133, CD44 and ALDH1), as well as P53 (50%) and KRAS mutations (41.7%). CRC cancer after kidney and hepatic transplantation is a rare, but aggressive and deadly event. Regular follow-up should be instituted in these patients

Intraductal Papillary Mucinous Neoplasia of the Pancreas - Pathologic Features and Molecular Markers - A Review

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas are pre neoplastic lesions defined by the World Health Organization as a grossly visible intraductal epithelial neoplasm that arises in the pancreatic ductal system, composed of mucin producing cells. The predisposing factor for their development as well as genetics are still largely unknown. Pathologists have a pivotal role in IPMN management since features like IPMN subtype, degree of atypia, margins status and presence or absence of an invasive component imply different patient management. In this article, we perform a review of the pathological features and molecular markers of IPMNs