Muc expression and their prognostic value in cholangiocarcinoma

Cholangiocarcinoma (CC) is a malignant tumour composed of cells resembling those of the bile ducts and the second most common primary hepatic tumor after hepatocellular carcinoma, comprising 5-10% of primary liver neoplasms. Worldwide, cholangiocarcinoma accounts for 3% of all gastrointestinal cancers. Several studies have shown that the incidence and mortality rates of intrahepatic CC (IHCC) are rising, and those of extrahepatic cholangiocarcinoma (EHCC) are declining worldwide. To date, radical surgery is the only therapy offering a potential cure for CC patients, whose prognosis is generally poor with survival limited to few months. At present, the lack of a sensitive and specific early diagnostic marker is one of the reasons why CC has a fairly late presentation. Our aim was to find out a sensitive and specific marker which could be detected in patient serum and be correlated with tumor type and tumor burden since the potential survival benefit from early detection is shown by 70-80% survival for patients with early cholangiocarcinoma that was discovered incidentally on transplantation for primary sclerosing cholangitis. Mucins are heavily glycosylated glycoproteins and play a protective role in cells, in part serving as a barrier to the epithelial surface and to tumor cells. Boonla C. et al. recently showed that MUC5AC mucin is present in significant concentrations in serum from patients with CC. In a recent report, MUC5AC significantly correlated with neural invasion and advanced CC stage. Only a few studies have been carried out about mucins expression, in particular the gastric type and their relationship with CC morphology and prognosis. We stained all tissue for MUC1, MUC2, MUC6 and MUC5AC. The only interesting results were with MUC5AC. Recently the Liver Cancer Study Group of Japan divided IHCC into three morphological types: mass-forming (MF), periductal infiltrating (PI) and intraductal growth (IG). MF type is characterized by the presence of a spherical mass with a distinct border in the liver parenchyma, PI type presents tumor infiltration along the bile duct, occasionally involving the surrounding blood vessels and/or hepatic parenchyma, IG is characterized by papillary and/or granular growth into the bile duct lumen. PI type of CC present a significantly higher frequency of perineural invasion, lymph node metastasis and extrahepatic recurrence than MF type. The 5-year survival rates of patients with IG tumors or MF tumors is significantly better than those of patients with MF plus PI tumors or PI type alone. There is increasing evidence that intrahepatic cholangiocarcinoma should be divided in peripheral CC and perihilar CC based on etiopathogenesis, biological behaviour and clinical features. Perihilar CC may evolve from the lining epithelia of the major branches of the right and left hepatic bile duct and also from peribiliary glands around them and histologically is an adenocarcinoma resembling many of the features of hilar or extrahepatic CC. Peripheral CC presumably develop from small bile duct, ductules or canals of Hering. Hepatic progenitor cell may be involved in the tumorigenesis of peripheral CC. Distinguishing perihilar from hilar CC is often difficult, especially in advanced cases. In this study together with the surgeons we propose a different classification: peripheral CC for tumors that growth inside the liver parenchima, perihilar for tumors located in the liver but involving the hilum and for Klatskin tumors and extrahepatic for tumors of the distal biliary tract. This classification correlates well with morphology. Most (30/35) peripheral CC are of the MF type with only 5 cases MF+PI. Perihilar CC and EHCC are mostly PI or MF+PI reflecting a different growth pattern between the two. Beside a different growth pattern there is a statistical difference between the tumor types when comparing MUC5AC expression. 30 out of 35 (85,7%) peripheral CC were MUC5AC negative. 26 out of 39 (66,6%) perihilar CC were MUC5AC positive with different intensities but positive. 13 cases were negative. Of these 13 cases in 8 cases there were same positive cells but not enough to reach 5% of the total (our cut-off value), we don’t know if this positivity is of any significance, but it is something different compared to the true negativity that we see in MF. In our study MUC5AC seems to be a good immunohistochemical marker that can distinguish peripheral from perihilar CC, that correlates well with morphology and has a prognostic significance as well. This marker can be measured in the serum and can be used in the panel of tumor markers to search for in CC and could be useful in the follow-up.