Congenital portosystemic shunt (CPSS)/Abernethy malformation: morpho-molecular aspects of a rare hepatic tumour risk disease

Liver tissue in congenital portosystemic shunt (CPSS) is analysed for morphologic and molecular genetic alterations with special regard to hepatocarcinogenesis. The material comprises 8 cases of CPSS between 1.5 and 65 years. Beyond lacking portal veins as the characteristic finding of CPSS, liver arteries were part of the malformative vascular disease. Lack of portovenous perfusion, hyperplasia, obliterating intimal fibrosis, absence of arterial branches, arteriovenous shunting and intralobular arterioles caused disarrangement of the liver parenchyma. Atypical expression of glutamine synthetase (GS) mirrored zonal dysfunctionality of the lobular parenchyma. Three cases contained four nodular lesions. Two hepatocellular carcinomas (HCC) were surrounded by peritumoral nodular hyperplasia with dysplastic changes. One HCC and surrounding precursor lesions strongly expressed GS and nuclear β-catenin, but displayed wild-type CTNNB1 sequences, indicating functional β-catenin activation. The other HCC tested positive for nuclear β-catenin staining in few tumour cells and carried two activating β-catenin mutations in exons 3 and 7. Another activating β-catenin mutation in exon 3 was detected in peritumoral nodules and background liver tissue > 1.0 cm away from the HCC in decreasing frequency. An HNF1A-inactivated hepatocellular adenoma coincident with a focal nodular hyperplasia harboured two different mutations in HNF1A. hTERT promotor mutation or events in other genes involved in HCC development, angiogenesis and angioproliferation were found in neither tumour tissue nor the background liver. Pathological vascularisation, followed by altered zonation, appears to be the basis for functional or mutational activation of β-catenin-driven tumour development in CPSS. Our findings underline CPSS as a tumour risk disease.