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Background: Several clinicopathological predictors of survival after curative surgery for perihilar cholangiocarcinoma (pCCA) have been identified; however, conflicting reports remain. The aim was to analyse clinical and oncological outcomes after curative resection of pCCA and to determine prognostic factors., Methods: Eighty-eight consecutive patients with pCCA underwent surgery with curative intent between 1998 and 2017. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Twenty-one prognostic factors were evaluated using multivariate Cox regression models., Results: Postoperative complications were observed in 73 (83%) patients of which 41 (47%) were severe complications (therapy-oriented severity grading system (TOSGS) grade > 2), including a 90-day mortality of 9% (n = 8). Overall survival (OS) and disease-free survival (DFS) rates at 5 and 10 years after surgery were 33% and 19%, and 37% and 30%, respectively. Independent predictors of OS were locoregional lymph node metastasis (LNM) (risk ratio (RR) 2.12, confidence interval (CI) 1.19-3.81, p = 0.011), patient American Society of Anesthesiologists (ASA) physical status classification system > 2 (RR 2.10, CI 1.03-4.26, p = 0.043), and depth of tumour penetration (pT) > 2 (RR 2.58, CI 1.03-6.30, p = 0.043). The presence of locoregional LNM (RR 2.95, CI 1.51-5.90, p = 0.002) and caudate lobe resection (RR 2.19, CI 1.01-5.14, p = 0.048) were found as independent predictors of DFS., Conclusions: Curative surgery for pCCA carries high risks with poor long-term survival. Locoregional LNM was the only predictor for both OS and DFS.

Unlabelled: Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin-producing cholangiocytes are located in large bile ducts and the cuboidal non-mucin-producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so-called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC-1, KMCH-1, and KMCH-2. Among 51 ICCs, 31 (60.8%) contained only mucin-producing CC features (muc-ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed-ICCs). Clinicopathologically, muc-ICCs and hilar CCs showed a predominantly (peri-)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed-ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc-ICCs and hilar CCs and in mixed-ICCs and CLCs. S100P and MUC1 were significantly up-regulated in hilar CCs and muc-ICCs compared with mixed-ICCs and CLCs, whereas NCAM1 and ALB tended to be up-regulated in mixed-ICCs and CLCs compared with other tumors. KMC-1 showed significantly higher invasiveness than KMCH-1 and KMCH-2., Conclusion: Muc-ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin-producing cholangiocytes), whereas mixed-ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Unlabelled: Cholangiolocellular carcinoma (CLC), a subtype of cholangiocellular carcinoma (CC), is thought to originate from the ductules/canals of Hering, where hepatic progenitor cells (HPCs) are located. We investigated the clinicopathological features of 30 CLCs and their relationship to HPCs. We evaluated the expression of hepatocytic markers (hepatocyte paraffin-1, canalicular polyclonal carcinoembryonic antigen, and CD10), biliary/HPC markers (keratin [K]7, K19, and neural cell adhesion molecule), the adenosine triphosphate binding cassette transporters: multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1, MRP3, and breast cancer resistance protein, using immunohistochemistry and electron microscopy. In addition, gene expression profiling of CLC was performed and compared with the profile of hepatocellular carcinoma (HCC) with or without HPC features (K19 expression). In surrounding nontumoral tissue, K7-positive and K19-positive HPCs/ductular reaction were observed. More than 90% of the tumor was composed of CLC areas that showed small monotonous and/or anastomosing glands, strongly positive for K7 and K19. Especially at the tumor boundary, all cases showed a HCC-like trabecular area characterized by canalicular CD10/polyclonal carcinoembryonic antigen expression, and submembranous K7 expression, similar to intermediate hepatocytes. K7-positive/K19-positive HPCs were also seen. Out of 30 cases, 19 showed papillary and/or clear glandular formation with mucin production, representing CC areas. These three different areas showed transitional zones with each other. We observed an increased expression of MRP1, MRP3, and breast cancer resistance protein in the tumor. Electron microscopy findings in HCC-like trabecular areas confirmed the presence of HPCs and intermediate hepatocytes. HPC markers, K7, K19, prominin-1, receptor for stem cell factor c-kit, octamer-4 transcription factor, and leukemia inhibitory factor were upregulated (P < 0.05), while albumin was downregulated in CLC (P = 0.007) toward K19-negative HCCs. Comparison of CLC with K19-positive HCCs indicated a high homology., Conclusion: All these findings highly suggest a progenitor cell origin of CLC.

Primary sclerosing cholangitis (PSC) can lead to the development of cholangiocarcinoma (CCA). The tumor may present as an intrahepatic focal cholangiocellular carcinoma but more often as a ductal infiltrating desmoplastic lesion. CCA is found synchronously with the diagnosis of PSC in 20-30% and within 1 year in 50%. During later follow-up, the yearly developmental rate of CCA is 0.5-1.5%. Most patients with PSC and CCA do not yet have cirrhosis but present with a severe stenosis at the hilum of the liver. This type of tumor is difficult to diagnose by imaging techniques.(18)F-FDG-PET scanning and CEA or CA 19-9 are not early diagnostic tools. Regular MRI, multislice CT, and repeated endoscopically obtained brush cytology of stenotic lesions are recommended. The recent use of more extensive surgical resection techniques in patients with CCA results in 5-year survival rates of > or =50%. If tumors are small or incidental findings, liver transplantation leads to a 3- to 5-year survival rate of 35%. Pretransplant radiotherapy with 5-FU chemosensitization followed by endoscopic brachytherapy with iridium-192 seems to greatly improve the outcome of transplantation. Treatment with ursodeoxycholic acid may prevent development of CCA.

Radiofrequency ablation (RFA) is a safe and effective treatment in patients with unresectable liver malignancies. Since there is little information on its optimal approach, the feasibility, clinical outcome, and efficacy of laparoscopic RFA need further investigation. Twenty-three consecutive patients with unresectable hepatic malignancies were treated with RFA. RFA was performed percutaneously in 5 patients (5 tumors; median maximum diameter of 25 mm [range, 20-73]), via laparotomy in 9 (28 tumors; median maximum diameter of 38 mm [5-90]), and via laparoscopy in 9 (16 tumors; median maximum diameter of 35 mm [8-58]). Mortality and intraoperative complication rates were 0. In the laparoscopy and laparotomy groups, mean blood loss was 13 mL versus 421 mL and mean hospital stay was 5.7 versus 11.2 days, respectively (P = 0.0008 and P = 0.04). Postoperative complications occurred in one patient after laparoscopic RFA and in three after RFA via laparotomy. After a median follow-up of 12.2 months, local recurrence occurred in 2 patients (laparoscopic RFA, 1; percutaneous RFA, 1), and new hepatic tumors developed in 7 (laparoscopic RFA, 2/9; RFA via laparotomy, 5/9). Laparoscopic RFA is a safe and feasible treatment modality to achieve tumor destruction in selected patients with unresectable hepatic malignancies.