Abstract
Simple SummaryIntrahepatic cholangiocarcinoma is a rare disease with increasing incidence and mortality still characterized by an insufficient clinical outcome. Growing attention has recently surrounded this disease, and liver transplantation has emerged as a novel curative treatment for cholangiocarcinoma, along with a better understanding of genetic alterations potentially capable of driving tumorigenesis. The aim of this paper is to present a clinical description of our case series of patients affected by intrahepatic cholangiocarcinoma and by mixed forms of hepatocellular and cholangiocellular carcinoma, together with a genomic profiling of mutations occurring in a panel of genes relevant to solid tumor cancer investigations. Mutations were observed in genes activating signaling pathways known to be involved in intrahepatic cholangiocarcinoma tumorigenesis; a strong association was observed between mutation in genes involving the Notch signaling pathway and tumor size (point-biserial rhopb = 0.93). Intrahepatic cholangiocarcinoma (iCCA) is a rare and aggressive primary liver tumor, characterized by a range of different clinical manifestations and by increasing incidence and mortality rates even after curative treatment with radical resection. In recent years, growing attention has been devoted to this disease and some evidence supports liver transplantation (LT) as an appropriate treatment for intrahepatic cholangiocarcinoma; evolving work has also provided a framework for better understanding the genetic basis of this cancer. The aim of this study was to provide a clinical description of our series of patients complemented with Next-Generation Sequencing genomic profiling. From 1999 to 2021, 12 patients who underwent LT with either iCCA or a combined hepatocellular and cholangiocellular carcinoma (HCC-iCCA) were included in this study. Mutations were observed in gene activating signaling pathways known to be involved with iCCA tumorigenesis (KRAS/MAPK, P53, PI3K-Akt/mTOR, cAMP, WNT, epigenetic regulation and chromatin remodeling). Among several others, a strong association was observed between the Notch pathway and tumor size (point-biserial rhopb = 0.93). Our results are suggestive of the benefit potentially derived from molecular analysis to improve our diagnostic capabilities and to devise new treatment protocols, and eventually ameliorate long-term survival of patients affected by iCCA or HCC-iCCA.
Highlights
Intrahepatic cholangiocarcinoma is a relatively rare and highly aggressive form of primary liver tumor, characterized by increasing incidence and mortality rates worldwide, which have given rise to growing scientific interest aimed at better disease classification, molecular diagnostics, and pathology accuracy [1,2,3,4,5,6,7]
Patients selected for this study are of three different subtypes: (1) 5 patients whose diagnosis was incidentally established on pathologic examination as hepatocellular carcinoma (HCC)-Intrahepatic cholangiocarcinoma (iCCA); (2) 5 patients whose diagnosis was incidentally established on pathologic examination as iCCA; (3) 2 patients whose biopsy-proven diagnosis was established before transplant
Of the 2 patients who were properly diagnosed before liver transplantation (LT) as HCC-ICCA and iCCA, respectively, one was affected by a 8 cm diameter cholangiocarcinoma lesion infiltrating the three suprahepatic veins and imprinting the vena cava, the other was affected by a 8 cm centrally located cholangiocarcinoma lesion with infiltration of the hilar plate and the left portal branch
Summary
Intrahepatic cholangiocarcinoma (iCCA) is a relatively rare and highly aggressive form of primary liver tumor, characterized by increasing incidence and mortality rates worldwide, which have given rise to growing scientific interest aimed at better disease classification, molecular diagnostics, and pathology accuracy [1,2,3,4,5,6,7]. The majority of iCCA patients have no underlying liver disease and the clinical presentation is non-specific, most of the risk factors for hepatocellular carcinoma (HCC) have been discovered to be risk factors for iCCA as well, including cirrhosis, chronic viral hepatitis, excessive alcohol consumption, diabetes, and obesity, supporting the hypothesis of common pathobiological pathways to all primary liver parenchymal tumors. This would explain why mixed HCC and iCCA forms (HCC-iCCA) are increasingly evident in the anatomopathological examinations of native livers among transplant series [5,13]. Diagnosis is rarely made preoperatively because radiological features are hardly distinguishable from other primary liver tumors, due to the atypical enhancing patterns, the small size of each component, and because the tumors are composed of intermediate cells [15,16]
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