Neuroendocrine Carcinoma and Intracystic Papillary Neoplasm: A Rare Association in the Gallbladder

Neuroendocrine carcinoma of the gallbladder is a very rare neoplasia comprising only 0.2% of all the gastrointestinal neuroendocrine tumors. We present the case of an 85-year-old male with nonspecific gastrointestinal symptoms, progressive weight loss, and deterioration in the preceding 15 days. Imaging study showed a 5-cm polypoid mass localized at the gallbladder fundus, leading to a radical cholecystectomy. Pathology revealed the known lobulated polypoid lesion, on cut section, constituted by friable tissue without evident infiltration of the gallbladder wall and a contiguous friable, brown, flat lesion. Histological evaluation displayed a small cell neuroendocrine carcinoma, consisting of intermediate and small cells, rounded or spindle, with extensive areas of necrosis, with positivity for neuroendocrine immunomarkers, associated with intracystic papillary neoplasm with high and low dysplasia. This is an uncommon association with few cases presented in the literature

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

TERT promoter mutations in pancreatic endocrine tumours are rare and mainly found in tumours from patients with hereditary syndromes

One of the hallmarks of cancer is its unlimited replicative potential that needs a compensatory mechanism for the consequential telomere erosion. Telomerase promoter (TERTp) mutations were recently reported as a novel mechanism for telomerase re-activation/expression in order to maintain telomere length. Pancreatic endocrine tumors (PETs) were so far recognized to rely mainly on the alternative lengthening of telomeres (ALT) mechanism. It was our objective to study if TERTp mutations were present in pancreatic endocrine tumors (PET) and could represent an alternative mechanism to ALT. TERTp mutations were detected in 7% of the cases studied and were mainly associated to patients harbouring hereditary syndromes. In vitro, using PET-derived cell lines and by luciferase reporter assay, these mutations confer a 2 to 4-fold increase in telomerase transcription activity. These novel alterations are able to recruit ETS transcription factor members, in particular GABP-α and ETV1, to the newly generated binding sites. We report for the first time TERTp mutations in PETs and PET-derived cell lines. Additionally, our data indicate that these mutations serve as an alternative mechanism and in an exclusive manner to ALT, in particular in patients with hereditary syndromes.Fundação para a Ciência e a Tecnologia; Norte 2020 – Programa Operacional Regional do Norte project: (“Advancing cancer research: from basic knowledgment to application” - grant: NORTE-01-0145-FEDER-000029); Associate Laboratory of the Portuguese Ministry of Science, Technology and Higher Education: (I3S)

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

The clinical extremes of autoimmune cholangitis

Autoimmune cholangitis (AIC) was first described in 1987 as immunocholangitis in three women who presented with signs and symptoms of primary biliary cholangitis (PBC), but who were antimitochondrial (AMA) negative and antinuclear antibodies (ANA) positive, and responded to immunosuppressive therapy with azathioprine and prednisolone (1). AIC is a rare chronic cholestatic inflammatory disease characterized by the presence of high ANA or smooth muscle antibodies (SMA) but AMA seronegativity. Histologically, AIC exhibits bile duct injury (2). In terms of therapeutics, in addition to response to ursodeoxycholic acid, a prompt response to corticosteroids has also been reported in earlier stages, distinguishing it from PBC. Herein the authors describe two cases with mixed signs of PBC and autoimmune hepatitis (AIH). The diagnostic differentiation between these diseases (AIC, PBC and AIH) is essential because of the different therapeutic strategies. Our cases highlight the importance of clinician awareness of the autoimmune spectrum of liver diseases