De Rosa A, Gomez D, Zaitoun AM, Cameron IC
Neurofibroma of the bile duct: a rare cause of obstructive jaundice.
Ann R Coll Surg Engl. 2013; 95(2):e38-40 [PubMed]

Neurofibromas of the common bile duct are extremely rare. The lack of specific clinical or radiological features makes preoperative diagnosis in the absence of histology difficult. We report the case of a female patient who presented with obstructive jaundice and evidence of a common bile duct stricture on imaging. She underwent an exploratory laparotomy, and intraoperative frozen section confirmed clear margins and a benign lesion. Excision of the extrahepatic bile duct and A Rouxen-Y hepaticojejunostomy was performed. We discuss the clinical features and management of neurofibromas of the bile duct in light of the literature.

Gurusamy KS, Kumar S, Davidson BR
Prophylactic gastrojejunostomy for unresectable periampullary carcinoma.
Cochrane Database Syst Rev. 2013; 2:CD008533 [PubMed]

BACKGROUND: The role of prophylactic gastrojejunostomy in patients with unresectable periampullary cancer is controversial.
OBJECTIVES: To determine whether prophylactic gastrojejunostomy should be performed routinely in patients with unresectable periampullary cancer.
SEARCH METHODS: For the initial version of this review, we searched the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, issue 3), MEDLINE, EMBASE and Science Citation Index Expanded until April 2010. Literature searches were re-run in August 2012.
SELECTION CRITERIA: We included randomised controlled trials comparing prophylactic gastrojejunostomy versus no gastrojejunostomy in patients with unresectable periampullary cancer (irrespective of language or publication status).
DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and independently extracted data. We analysed data with both the fixed-effect and the random-effects models using Review Manager (RevMan). We calculated the hazard ratio (HR), risk ratio (RR), and mean difference (MD) with 95% confidence intervals (CI) based on an intention-to-treat or available case analysis.
MAIN RESULTS: We identified two trials (of high risk of bias) involving 152 patients randomised to gastrojejunostomy (80 patients) and no gastrojejunostomy (72 patients). In both trials, patients were found to be unresectable during exploratory laparotomy. Most of the patients also underwent biliary-enteric drainage. There was no evidence of difference in the overall survival (HR 1.02; 95% CI 0.84 to 1.25), peri-operative mortality or morbidity, quality of life, or hospital stay (MD 0.97 days; 95%CI -0.18 to 2.12) between the two groups. The proportion of patients who developed long-term gastric outlet obstruction was significantly lower in the prophylactic gastrojejunostomy group (2/80; 2.5%) compared with no gastrojejunostomy group (20/72; 27.8%) (RR 0.10; 95%CI 0.03 to 0.37). The operating time was significantly longer in the gastrojejunostomy group compared with no gastrojejunostomy group (MD 45.00 minutes; 95%CI 21.39 to 68.61).
AUTHORS' CONCLUSIONS: Routine prophylactic gastrojejunostomy is indicated in patients with unresectable periampullary cancer undergoing exploratory laparotomy (with or without hepaticojejunostomy).

Aoba T, Ebata T, Yokoyama Y, et al.
Assessment of nodal status for perihilar cholangiocarcinoma: location, number, or ratio of involved nodes.
Ann Surg. 2013; 257(4):718-25 [PubMed]

OBJECTIVE: To analyze lymph node status in resected perihilar cholangiocarcinoma, to clarify which index (ie, location, number, or ratio of involved nodes) is better for staging, and to determine the minimum requirements for node examination.
BACKGROUND: In the TNM classification for perihilar cholangiocarcinoma, the number or ratio of involved nodes is not considered for nodal staging. The minimum requirement for histologic examination of lymph nodes is arbitrary.
METHODS: This study involved 320 patients with perihilar cholangiocarcinoma who underwent resection from January 2000 to December 2009 at Nagoya University Hospital. The relationship between lymph node status and patient survival was retrospectively analyzed.
RESULTS: Total lymph node counts (TLNCs), ie, the number of lymph nodes examined histologically, averaged 12.9 ± 8.3 (range: 1-59). Lymph node metastasis was found in 146 (45.6%) patients and was an independent, powerful prognostic factor. The survival rates were not significantly different between patients with regional node metastasis alone and those with distant node metastasis (19.2% vs 11.5% at 5 years, P = 0.058). The survival for patients with multiple node metastases was significantly worse than that for patients with single metastasis (12.1% vs 27.6% at 5 years, P = 0.002), regardless of the presence or absence of distant lymph node metastasis. The survival for patients with lymph node ratios (LNRs) of 0.2 or less was significantly better than that for patients with LNRs greater than 0.2 (21.4% vs 13.5% at 5 years, P = 0.032). Upon multivariate analysis of the 146 patients with lymph node metastasis, the number of involved nodes (single vs multiple) was identified as an independent prognostic factor (RR of 1.61, P = 0.045), whereas the locations (regional alone vs distant) and ratios (LNR ≤ 0.2 vs LNR > 0.2) of involved nodes were not. When the 148 pN0-R0 patients were divided into 3 groups (ie, those with TLNC ≥ 8, with TLNC = 5, 6, or 7, and with TLNC ≤ 4), survivals were identical between the first and second groups, whereas they were largely different between the former two and the third.
CONCLUSIONS: Lymph node metastasis is a powerful, independent prognostic factor in perihilar cholangiocarcinoma and is better classified based not on location but on the number of involved nodes. To adequately assess nodal status, histologic examination of 5 or more nodes is recommended.

Akiba J, Nakashima O, Hattori S, et al.
Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification.
Am J Surg Pathol. 2013; 37(4):496-505 [PubMed]

Combined hepatocellular-cholangiocarcinoma comprises <1% of all liver carcinomas. The histogenesis of combined hepatocellular-cholangiocarcinoma has remained unclear for many years. However, recent advances in hepatic progenitor cell (HPC) investigations have provided new insights. The concept that combined hepatocellular-cholangiocarcinoma originates from HPCs is adopted in the chapter "combined hepatocellular-cholangiocarcinoma" of the latest World Health Organization (WHO) classification. In this study, we conducted clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification. Fifty-four cases were included in this study. Pathologic diagnosis was made according to the WHO classification. When a tumor contained plural histologic patterns, predominant histologic pattern (≥50%) was defined. Minor histologic patterns were also appended. Immunohistochemical staining with biliary markers (CK7, CK19, and EMA), hepatocyte paraffin (HepPar)-1, HPC markers (CD56, c-kit, CD133, and EpCAM), and vimentin was performed. Forty-five and 50 patients were analyzed for progression-free survival and overall survival, respectively. Ten, 1, 32, and 11 cases were diagnosed as: combined hepatocellular-cholangiocarcinoma, classical type; combined hepatocellular-cholangiocarcinoma, stem cell features, typical subtype; combined hepatocellular-cholangiocarcinoma, stem cell features, intermediate cell subtype; and combined hepatocellular-cholangiocarcinoma, stem cell features, cholangiolocellular type, respectively. Combined hepatocellular-cholangiocarcinomas usually have high expression of biliary markers. CD56, c-kit, and EpCAM were expressed to various degrees in all combined hepatocellular-cholangiocarcinomas apart from the hepatocellular carcinoma component of combined hepatocellular-cholangiocarcinoma, classical type. The expression of CD133 and vimentin was observed only in combined hepatocellular-cholangiocarcinoma, stem cell features of intermediate cell subtype and cholangiolocellular subtype. The expression of CD133, EpCAM, and vimentin was significantly high in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, especially cholangiolocellular subtype. Minor histologic patterns were significantly frequent in combined hepatocellular-cholangiocarcinoma, subtypes with stem cell features, compared with combined hepatocellular-cholangiocarcinoma, classical type. There was no significant difference in clinical outcome between each subtype. Combined hepatocellular-cholangiocarcinoma has wide histologic diversity and shows immunophenotypic expression of not only biliary markers but also HPC markers to various degrees, suggesting that the histogenesis of combined hepatocellular-cholangiocarcinoma could be strongly associated with HPCs. Our results pathologically validate the latest WHO classification of combined hepatocellular-cholangiocarcinoma. However, the complex mixture of histologic subtypes has presented a challenge to the classification of combined hepatocellular-cholangiocarcinoma. Further study should be conducted using a large cohort to support this classification.

Wang Y, Li J, Xia Y, et al.
Prognostic nomogram for intrahepatic cholangiocarcinoma after partial hepatectomy.
J Clin Oncol. 2013; 31(9):1188-95 [PubMed]

PURPOSE: This study aimed to establish an effective prognostic nomogram for intrahepatic cholangiocarcinoma (ICC) after partial hepatectomy.
PATIENTS AND METHODS: The nomogram was based on a retrospectively study on 367 patients who underwent partial hepatectomy for ICC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2007. The predictive accuracy and discriminative ability of the nomogram were determined by concordance index (C-index) and calibration curve and compared with five currently used staging systems on ICC. The results were validated using bootstrap resampling and a prospective study on 82 patients operated on from 2007 to 2008 at the same institution.
RESULTS: On multivariate analysis of the primary cohort, independent factors for survival were serum carcinoembryonic antigen, CA 19-9, tumor diameter and number, vascular invasion, lymph node metastasis, direct invasion, and local extrahepatic metastasis, which were all selected into the nomogram. The calibration curve for probability of survival showed good agreement between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.74 (95% CI, 0.71 to 0.77), which was statistically higher than the C-index values of the following systems: American Joint Committee on Cancer (AJCC) seventh edition (0.65), AJCC sixth edition (0.65), Nathan (0.64), Liver Cancer Study Group of Japan (0.64), and Okabayashi (0.67; P < .001 for all). It was also higher (0.74) in predicting survival for the mass-forming type of ICC (P < .001). In the validation cohort, the nomogram discrimination was superior to the five other staging systems (C-index: 0.75 v 0.60 to 0.63; P < .001 for all).
CONCLUSION: The proposed nomogram resulted in more-accurate prognostic prediction for patients with ICC after partial hepatectomy.

Kaiser GM, Paul A, Sgourakis G, et al.
Novel prognostic scoring system after surgery for Klatskin tumor.
Am Surg. 2013; 79(1):90-5 [PubMed]

Klatskin tumor is a rare hepatobiliary malignancy whose outcome and prognostic factors are not clearly documented. Between April 1998 and January 2007, 96 patients with hilar cholangiocarcinoma underwent resection. Data were collected prospectively. Thirty-one variables were evaluated for prognostic significance. There were 40 trisectionectomies, 40 hemihepatectomies, five central hepatectomies, and 11 biliary hilar resections. Thirty-seven (n = 37) patients required vascular reconstruction. There were 68 R0, 26 R1, and two R2 resections. Age (P = 0.048), pT status (P = 0.046), R class (P = 0.034), and adjuvant chemoradiation (P = 0.045) showed predictive significance by multivariate Cox proportional hazard regression analysis. A point scoring system was determined as follows: age younger than 62 years:age 62 years or older = 1:2 points; pT1:pT2 to 4 = 1:2 points; R0:R1/2 = 1:2 points; and chemoradiation yes:no = 1:2 points. The only model that reached statistical significance (P = 0.0332) described the following three groups: score 6 or less; score = 7; and score = 8. Median survival for score 6 or less, score = 7, and score = 8 was 26.5, 12, and 2.2 months, respectively (P = 0.032). The corresponding 1- and 3-year survival rates were 73 to 56 per cent, 52 to 38 per cent, and 17 to 0 per cent, respectively. We propose a scoring system predictive of long-term surgical outcome that could potentially improve patient selection for further postoperative oncologic treatment for Klatskin tumors.

Gardini A, Saragoni L, La Barba G, et al.
Challenge in differential diagnosis of a liver mass histologically defined as a metastatic lesion from an occult primary intestinal tumour. The importance of clinical findings and the limitations of histology and molecular profiles. A case report.
Pathologica. 2012; 104(4):177-81 [PubMed]

Differential diagnosis of liver lesion in the absence of proven primary tumor is still a challenge. We experienced a case of an asymptomatic 14 cm lesion of right hemiliver in a 67 year-old man submitted to right hepatectomy in December 2010. One year before the patient underwent to endoscopic removal of a tubular adenoma of the right colon. Preoperative diagnosis was supported by ultrasound, CT scan, PET and liver biopsy. The patient received 6 cycles of preoperative chemotherapy (FOLFOX) with down-staging of the lesion diameter. Immunohistochemistry on the surgical specimen showed positivity for cytokeratins 19 and 20, CEA, MUC-2, negativity for cytokeratin 7 and a-fetoprotein. Moreover, the neoplastic cells showed a focal positivity with lower intensity for MUC-1 and MUC-5AC. The immunohistochemical profile suggested the possibility of a metastatic tumour from the large bowel, without excluding a primitive mucinous cholangiocarcinoma with intestinal phenotype. At 6 months after intervention, the patient was submitted to chemotherapy (FOLFOX). At present he is in good condition, without radiological signs of recurrence. Oncologists must evaluate the possible benefits of further adjuvant treatments based on the differential diagnosis between a primitive or metastatic liver tumour. In conclusion, correct diagnosis of liver masses is mandatory and remains a challenge that can differentiate either follow-up or surgical and adjuvant treatment. Histology and immunohistochemistry must be related to clinical findings as they may not always be sufficient to reach a correct final diagnosis, and can even be confusing. At present, molecular biology cannot be considered a helpful for diagnosis in these cases.

Loehrer AP, House MG, Nakeeb A, et al.
Cholangiocarcinoma: are North American surgical outcomes optimal?
J Am Coll Surg. 2013; 216(2):192-200 [PubMed]

BACKGROUND: Cholangiocarcinomas are deadly and require complex decisions as well as major surgery. A few referral centers have reported good results, but no robust, risk-adjusted outcomes data are available. The aims of this study were to analyze the surgical outcomes of a very large cohort of patients undergoing operations for cholangiocarcinoma in North America.
STUDY DESIGN: The American College of Surgeons National Surgical Quality Improvement Program Participant Use File was queried for patients with bile duct cancers. Patients (n = 839) were classified as having intrahepatic (36.5%), perihilar (34.4%), or distal (29.1%) cholangiocarcinomas by the type of procedure performed. Observed and expected (O/E) morbidity and mortality rates, O/E indices, and regression-adjusted risk factors were determined.
RESULTS: Mortality was highest for perihilar tumors that were managed with hepatectomy and biliary-enteric anastomosis (11.9%) and lowest for distal cholangiocarcinomas (1.2%). After risk adjustment, mortality was considerable greater than expected for patients undergoing hepatectomy with biliary-enteric anastomosis (O/E = 3.0) or hepatectomy alone (O/E = 2.4).
CONCLUSIONS: This analysis suggests that postoperative outcomes are best for distal and worst for perihilar cholangiocarcinomas, and hepatectomy for bile duct cancers is associated with a 2- to 3-fold mortality risk. We conclude that North American surgical outcomes can be improved for patients with proximal cholangiocarcinomas.

Wakai T, Shirai Y, Sakata J, et al.
Clinicopathological features of benign biliary strictures masquerading as biliary malignancy.
Am Surg. 2012; 78(12):1388-91 [PubMed]

Discrimination between benign and malignant biliary strictures is difficult, with 5.2 to 24.5 per cent of biliary strictures proving to be benign after histological examination of the resected specimen. This study aimed to evaluate the clinicopathological features of benign biliary strictures in patients undergoing resection for presumed biliary malignancy. From January 1990 to August 2010, 5 of 153 (3.3%) patients who had undergone resection after a preoperative diagnosis of biliary malignancy had a final histological diagnosis of benign biliary stricture. The infiltration of immunoglobulin G4-positive plasma cells was evaluated by immunohistochemistry. None of the five patients had a history of trauma or earlier hepatobiliary surgery and all five underwent hemihepatectomy (combined with extrahepatic bile duct resection in three patients). Postoperative morbidity was recorded in two patients (transient cholangitis and biliary fistula), but there was no postoperative mortality. Histological re-examination identified immunoglobulin G4-related sclerosing cholangitis (n = 2) and nonspecific fibrosis/inflammation (n = 3). No preoperative clinical or radiographic features were identified that could reliably distinguish patients with benign biliary strictures from those with biliary malignancies. Although benign biliary strictures are rare, differentiating benign strictures from malignancy remains problematic. Thus, the treatment approach for biliary strictures should remain surgical resection for presumed biliary malignancy.

Sugiyama H, Tsuyuguchi T, Sakai Y, et al.
Potential role of peroral cholangioscopy for preoperative diagnosis of cholangiocarcinoma.
Surg Laparosc Endosc Percutan Tech. 2012; 22(6):532-6 [PubMed]

BACKGROUND/PURPOSE: We evaluated the utility of peroral cholangioscopy (POCS) for preoperative diagnosis of cholangiocarcinoma.
METHODS: POCS was performed to assess the horizontal extension of the carcinoma. We compared the results of assessment with those of histologic analysis of 44 surgically resected specimens.
RESULTS: Cholangiocarcinoma types were described as filling defects and strictures in 16 and 28 patients, respectively, using cholangiography. Endoscopic retrograde cholangiography (ERC) identified tumor extension in 5 and 15 patients with filling defects (31.25%) and strictures (53.57%), respectively. ERC+POCS identified tumor extension in 15 and 16 patients with filling defects (93.75%) and strictures (60.71%), respectively. ERC+POCS was significantly useful for patients with filling defects compared with ERC alone (P=0.002). ERC+POCS was not significantly useful for patients with strictures compared with ERC alone.
CONCLUSIONS: POCS is a useful preoperative examination modality for assessing tumor extension in cholangiocarcinoma patients, especially in those with filling defects.

Jang KM, Kim SH, Lee SJ, et al.
Added value of diffusion-weighted MR imaging in the diagnosis of ampullary carcinoma.
Radiology. 2013; 266(2):491-501 [PubMed]

PURPOSE: To evaluate the added value of diffusion-weighted magnetic resonance (MR) imaging in diagnostic performance of conventional MR imaging for diagnosis of ampullary carcinoma.
MATERIALS AND METHODS: This retrospective study was institutional review board approved, and informed consent was waived. Twenty-three patients with malignant ampullary obstruction and 39 patients with benign ampullary obstruction were included. Qualitative (signal intensity and enhancement pattern) and quantitative (apparent diffusion coefficient [ADC]) analyses were conducted for visible or expected locations of duodenal papillae. Two observers independently reviewed conventional MR images and subsequently reviewed combined conventional and diffusion-weighted MR images. A five-point scale for likelihood of ampullary carcinoma was used. Fisher exact test and Mann-Whitney U test were used for comparing groups, and diagnostic performance (receiver operating characteristic [ROC] curve analysis), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were evaluated.
RESULTS: Visible or expected duodenal papillae in benign group showed isointensity (27-38 of 39, 69%-97%) and similar enhancement pattern (27 of 39, 69%) to that of normal duodenal wall more frequently than in malignant group (seven to 18 of 23 [30%-78%] and three of 23 [13%], respectively) on conventional MR images (P < .05). On diffusion-weighted images, 21 of 23 (91%) ampullary carcinomas showed hyperintensity, whereas all benign cases showed isointensity compared with normal duodenal wall (P < .001). Mean ADC of ampullary carcinomas (1.23 × 10(-3) mm(2)/sec) was significantly lower than that of benign group (1.69 × 10(-3) mm(2)/sec) (P < .001). Diagnostic performance (area under ROC curve [Az]) of both observers improved significantly after additional review of diffusion-weighted images; Az improved from 0.923 to 0.992 (P = .029) for observer 1 and from 0.910 to 0.992 (P = .025) for observer 2. In addition, diagnostic accuracy, sensitivity, specificity, PPV, and NPV of combined conventional and diffusion-weighted MR images were higher than those of conventional MR images alone.
CONCLUSION: Addition of diffusion-weighted imaging to conventional MR imaging improves detection of ampullary carcinoma when compared with conventional MR imaging alone.

Nakajima Y, Takagi H, Kakizaki S, et al.
Gefitinib and gemcitabine coordinately inhibited the proliferation of cholangiocarcinoma cells.
Anticancer Res. 2012; 32(12):5251-62 [PubMed]

BACKGROUND: Cholangiocarcinoma (CCC) is the second most common type of primary liver cancer, and is associated with a high rate of mortality due to the difficulty of early detection and resistance to chemotherapeutic agents. To evaluate the possibility for new therapeutic strategies, we examined the combined effect of gefitinib and gemcitabine on CCC.
MATERIALS AND METHODS: The effect of gefitinib, an inhibitor of epidermal growth factor receptor (EGFR) signaling, gemcitabine, which is a pyrimidine analog, and the combined effect of gefitinib and gemcitabine on CCC cells were evaluated both in vitro and in vivo.
RESULTS: EGFR mRNA expression and phosphorylation of EGFR were elevated in both human CCC cell lines studied, HuCCT1 and RBE, suggesting EGFR signaling is up-regulated in CCC cell lines. Gefitinib treatment at high concentration inhibited the proliferation of the CCC cell lines. Furthermore, gefitinib reduced the transforming growth factor alpha (TGFα)-induced proliferation of these cells. Gemcitabine also suppressed the growth of the CCC cell lines in a concentration-dependent manner. The combination of gefitinib and gemcitabine synergistically suppressed the growth of the CCC cell lines and induced greater apoptosis compared to the use of either agent alone. As a mechanism for this effect, we found less phosphorylation of the extracellular signal-regulated kinase (ERK) protein, which means the suppression of EGFR signaling, when these compounds were administered together. Cell transplantation assay dramatically demonstrated the synergistic effect of this combination on HuCCT1 xenografts in vivo.
CONCLUSION: The combination of gefitinib and gemcitabine inhibited the proliferation of CCC cells via induction of apoptosis. The combination of EGFR inhibitor and additional chemicals could be a new therapeutic approach for CCC.

Mertens JC, Fingas CD, Christensen JD, et al.
Therapeutic effects of deleting cancer-associated fibroblasts in cholangiocarcinoma.
Cancer Res. 2013; 73(2):897-907 [PubMed] Article available free on PMC after 15/01/2014

Cancer-associated fibroblasts (CAF) are abundant in the stroma of desmoplastic cancers where they promote tumor progression. CAFs are "activated" and as such may be uniquely susceptible to apoptosis. Using cholangiocarcinoma as a desmoplastic tumor model, we investigated the sensitivity of liver CAFs to the cytotoxic drug navitoclax, a BH3 mimetic. Navitoclax induced apoptosis in CAF and in myofibroblastic human hepatic stellate cells but lacked similar effects in quiescent fibroblasts or cholangiocarcinoma cells. Unlike cholangiocarcinoma cells, neither CAF nor quiescent fibroblasts expressed Mcl-1, a known resistance factor for navitoclax cytotoxicity. Explaining this paradox, we found that mitochondria isolated from CAFs or cells treated with navitoclax both released the apoptogenic factors Smac and cytochrome c, suggesting that they are primed for cell death. Such death priming in CAFs appeared to be due, in part, to upregulation of the proapoptotic protein Bax. Short hairpin RNA-mediated attenuation of Bax repressed navitoclax-mediated mitochondrial dysfunction, release of apoptogenic factors, and apoptotic cell death. In a syngeneic rat model of cholangiocarcinoma, navitoclax treatment triggered CAF apoptosis, diminishing expression of the desmoplastic extracellular matrix protein tenascin C, suppressing tumor outgrowth, and improving host survival. Together, our findings argue that navitoclax may be useful for destroying CAFs in the tumor microenvironment as a general strategy to attack solid tumors.

Artifon EL, Ferreira F, Benevides G, et al.
Extrahepatic anterograde covered self-expandable metallic stent placement across malignant biliary obstruction passed by endoscopic ultrasound guidance access: a challenging technique.
Acta Gastroenterol Latinoam. 2012; 42(3):224-9 [PubMed]

The authors report the case of a female patient submitted to endoscopic cholangiography intending to drain the biliary tree due to jaundice. The patient had gastrointestinal deviation due to an advanced gastric cancer that evolved with a distal extrahepatic mass. Abdominal CT scan demonstrated a distal mass, extrahepatic biliary dilation and a normal intra-hepatic tree. In this condition and after a multidisciplinary discussion, an endoscopic ultrasound guided extrahepatic access with the deployment of a partially covered self-expandable metallic stent was performed. The patient normalized her bilirubin levels after a successful procedure.

Jamnongkan W, Techasen A, Thanan R, et al.
Oxidized alpha-1 antitrypsin as a predictive risk marker of opisthorchiasis-associated cholangiocarcinoma.
Tumour Biol. 2013; 34(2):695-704 [PubMed]

The oxidized alpha-1 antitrypsin (ox-A1AT) is one modified form of A1AT, generated via oxidation at its active site by free radicals released from inflammatory cells which subsequently are unable to inhibit protease enzymes. The presence of ox-A1AT in human serum has been used as oxidative stress indicator in many diseases. As oxidative/nitrative damage is one major contributor in opisthorchiasis-driven cholangiocarcinogenesis, we determined A1AT and ox-A1AT expression in human cholangiocarcinoma (CCA) tissue using immunohistochemical staining and measured serum ox-A1AT levels by ELISA. A1AT and ox-A1AT were found to be expressed in the tumor of CCA patients. The group with high expression has a significant poor prognosis. Serum levels of ox-A1AT were also significantly higher in groups of patients with heavy Opisthorchis viverrini infection, advanced periductal fibrosis (APF) and CCA when compared with healthy controls (P < 0.001). Odds ratio (OR) analysis implicated high ox-A1AT levels as a risk predictor for APF and CCA (P < 0.001; OR = 140.5 and 22.0, respectively). In conclusion, as APF may lead to hepatobiliary diseases and an increased risk of CCA development, our results identified ox-A1AT as a potential risk indicator for opisthorchiasis-associated CCA. This marker could now be explored for screening of subjects living in endemic areas where the prevalence of opisthorchiasis still remains high.

Sulpice L, Rayar M, Boucher E, et al.
Intrahepatic cholangiocarcinoma: impact of genetic hemochromatosis on outcome and overall survival after surgical resection.
J Surg Res. 2013; 180(1):56-61 [PubMed]

BACKGROUND: The influence of genetic hemochromatosis (GH) on outcomes following surgical resections for intrahepatic cholangiocarcinoma (ICC) has not been evaluated.
METHODS: All patients with ICC who underwent a surgical resection between January 1997 and August 2011 were analyzed retrospectively. Risk factors were assessed by univariate and multivariate analyses.
RESULTS: Eighty-seven patients were analyzed; 16 of these patients (18.4%) had GH. Among the 71 non-GH patients, 52 (73.2%) and 19 (26.8%) had normal or cirrhotic parenchyma, respectively. There was no significant difference in survival between the GH and non-GH patients. A univariate analysis showed that major hepatectomy (P = 0.012), intraoperative blood transfusion (P = 0.007), tumor size >5 cm (P = 0.006), several nodules (P < 0.001), and microvascular invasion (P = 0.04) were significantly associated with poor survival. A multivariate analysis showed that intraoperative blood infusion (HR 0.37; CI 95% [0.19; 0.71]) and more than one nodule (HR 2.5; CI 95% [1.06; 5.8]) were associated with a lower survival rate.
CONCLUSION: Although the incidence of GH was high in our series, the presence of GH did not affect the outcomes after a liver hepatectomy for ICC. GH does not appear to increase recurrences or worsen the overall and disease-free survival.

El Khatib M, Kalnytska A, Palagani V, et al.
Inhibition of hedgehog signaling attenuates carcinogenesis in vitro and increases necrosis of cholangiocellular carcinoma.
Hepatology. 2013; 57(3):1035-45 [PubMed]

UNLABELLED: The Hedgehog signaling pathway plays a pivotal role during embryonic development, stem cell maintenance, and wound healing. Hedgehog signaling also is deregulated in many cancers. However, the role of this signaling pathway in the carcinogenesis of cholangiocarcinoma (CCC) is still unknown. In this study, we investigated the effects of Hedgehog inhibition by cyclopamine and 5E1 in cultured human CCC cell lines and in vivo using a xenograft mouse model. We also investigated the involvement of Hedgehog in epithelial to mesenchymal transition (EMT), migration, and CCC tumor growth. Sonic hedgehog (Shh) ligand was highly expressed in 89% of human CCC tissues and in CCC cell lines. Cyclopamine and 5E1 treatments effectively inhibited cell proliferation, migration, and invasion by down-regulating the Hedgehog target genes glioblastoma 1 and glioblastoma 2. In vitro and in vivo, we detected an increase in epithelial marker, E-cadherin, after Hedgehog inhibition. In addition, we saw an increase in necrotic areas and a decrease in mitotic figures in cyclopamine and 5E1-treated CCC xenograft tumors.
CONCLUSION: This study supports the presence of autocrine Hedgehog signaling in human CCC, where CCC cells produce and respond to Shh ligand. Blocking the Hedgehog pathway inhibited EMT and decreased the viability of CCC cells. In addition, cyclopamine and 5E1 inhibited the growth of CCC xenograft tumors.

Yalav O, Yağmur Ö, Ülkü A, et al.
A rare cause of obstructive jaundice: Fasciola hepatica mimicking cholangiocarcinoma.
Turk J Gastroenterol. 2012; 23(5):604-7 [PubMed]

Fasciola hepatica is an endemic zoonotic disease in Turkey and neighboring countries. The usual definitive host is the sheep; humans are accidental hosts in the life cycle of the Fasciola. There are two disease stages: the hepatic (acute) and biliary (chronic) stages. When the flukes enter the bile ducts, the symptoms of cholestasis and cholangitis may present, which can easily be misdiagnosed as obstructive jaundice of other causes. We present a case of fascioliasis, which was difficult to differentiate from cholangiocarcinoma. A 47-year-old woman from Eastern Turkey presented with fever, right upper quadrant abdominal pain, and jaundice. Total bilirubin was 4.2 mg/dl, aspartate aminotransferase 55 IU/L, alanine aminotransferase 65 IU/L, alkaline phosphatase 325 IU/L, and gamma-glutamyl transpeptidase 172 IU/L. All tumor markers including carcinoembryonic antigen and Ca19-9 were in normal values. After extended evaluation, an explorative laparotomy with cholecystectomy, choledochostomy and T-tube drainage was performed. Multiple flukes were removed from the choledochus. One of the parasites was sent to the parasitological clinic for identification. The result of an indirect hemagglutination test for F. hepatica was 1/320 (+). In conclusion, the chronic phase of this zoonotic infection can be easily misdiagnosed as any other cause of obstructive jaundice. Thus, F. hepatica should be considered in the differential diagnosis of common bile duct obstruction, especially in endemic areas.

Nanashima A, Abo T, Nonaka T, et al.
Photodynamic therapy using talaporfin sodium (Laserphyrin®) for bile duct carcinoma: a preliminary clinical trial.
Anticancer Res. 2012; 32(11):4931-8 [PubMed]

The efficacy of adjuvant photodynamic therapy (PDT) using the new photosensitizer, talaporfin sodium (TPS), was assessed in 7 patients with bile duct carcinoma (BDC). The 664-nm semiconductor laser (100 J/cm(2)) was applied through endoscopy to the tumor lesion within 6 h after injection of TPS. Cases included three non-resectable and 4 resected BDC with remnant cancer cells at the bile duct stump. Radiated lesions exhibited mild inflammatory responses. Locally advanced tumor occluding bile duct was relieved by PDT and patency was maintained for 16 months. Two patients developed mild photodermatitis but no severe morbidity. One patient died of other disease, and two patients died of liver metastasis within 6 months, but local recurrence was not observed. Three patients maintained cancer-free survival for 6-13 months. One patient survived with good status for 24 months. Adjuvant TPS-PDT is a safe and useful treatment for local control of BDC. Compared to the conventional PDT, the patient's quality of life is remarkably improved.

Kamphues C, Seehofer D, Collettini F, et al.
Preliminary experience with CT-guided high-dose rate brachytherapy as an alternative treatment for hepatic recurrence of cholangiocarcinoma.
HPB (Oxford). 2012; 14(12):791-7 [PubMed] Article available free on PMC after 01/12/2013

BACKGROUND: Intrahepatic recurrence after resection of intrahepatic or hilar cholangiocarcinoma represents a main reason for the poor prognosis of bile duct cancer. As no standard treatment has been established so far, the aim of this study was to analyse the safety and efficacy of computed tomography-guided high-dose rate brachytherapy (CT-HDRBT) as an alternative treatment in those patients.
METHODS: The outcomes of 10 patients, who had been treated at least once for recurrent cholangiocarcinoma by CT-HDRBT, were retrospectively analysed.
RESULTS: The median survival of all patients after primary liver resection was 85 months [95% confidence interval (CI) 68.129-101.871] with overall 1- and 5-year survival rates of 100% and 78.7%, respectively. After the occurrence of intrahepatic tumour recurrence, a total of 15 CT-HDRBT procedures were performed, alone or combined with other recurrence treatments, without any major complications according to the Society of Interventional Radiology classification. The 1-year and 5-year survival rates after recurrence treatment were 77.1% and 51.4%, respectively.
CONCLUSIONS: CT-HDRBT represents a safe treatment option for patients with recurrent bile duct cancer. As a part of a multimodal concept, CT-HDRBT might lead to a prolongation of survival in selected patients but further studies are urgently needed to prove this concept.

Shi RY, Yang XR, Shen QJ, et al.
High expression of Dickkopf-related protein 1 is related to lymphatic metastasis and indicates poor prognosis in intrahepatic cholangiocarcinoma patients after surgery.
Cancer. 2013; 119(5):993-1003 [PubMed]

BACKGROUND: Dickkopf-related protein 1 (DKK1) has been reported involved in metastasis and invasion in several tumors. This study sought to investigate the prognostic value of DKK1 in intrahepatic cholangiocarcinoma (ICC) and its role in promoting ICC metastasis.
METHODS: Tissue microarrays of 138 ICC patient samples were employed to detect DKK1, vascular endothelial growth factor C (VEGF-C), and matrix metalloproteinase 9 (MMP9) expression using immunohistochemistry. The prognostic significances were assessed by Kaplan-Meier survival estimates. DKK1 expression was measured in an ICC cell line (HCCC-9810) and ICC tissues by immunofluorescence assay, quantitative real-time polymerase chain reaction, and western blot. Serum levels of DKK1 from 37 ICC patients were tested by enzyme-linked immunosorbent assay. The role of DKK1 in proliferation, migration, invasion, and gene expression regulation was assessed by DKK1 depletion using small interfering RNA.
RESULTS: Multivariate analyses revealed that DKK1 was an unfavorable predictor for overall survival and time to recurrence. The prognostic significance was retained in ICC patients with low recurrence risk (P < .05). DKK1 expression was elevated in an ICC cell line, tumor samples, and patient sera. High levels of DKK1 in ICC tissues correlated with elevated MMP9, VEGF-C, and metastasis of hepatic hilar lymph nodes. DKK1 depletion caused a decrease in cell migration and invasiveness, and down-regulation of MMP9 and VEGF-C expression.
CONCLUSIONS: DKK1 is a novel prognostic biomarker for ICC, and it enhances tumor cell invasion and promotes lymph node metastasis of ICC through the induction of MMP9 and VEGF-C. DKK1 may be a potential therapeutic target for ICC.

Sulpice L, Rayar M, Boucher E, et al.
Treatment of recurrent intrahepatic cholangiocarcinoma.
Br J Surg. 2012; 99(12):1711-7 [PubMed]

BACKGROUND: The aims of this study were to evaluate risk factors for recurrence following hepatectomy with curative intent for intrahepatic cholangiocarcinoma (ICC), and predictors of survival after intrahepatic recurrence.
METHODS: All patients with ICC who underwent liver resection between January 1997 and August 2011 in a single centre were analysed retrospectively. Clinicopathological factors likely to influence recurrence and postrecurrence survival were assessed by univariable and multivariable analysis.
RESULTS: A total of 87 patients were analysed. R0 resection was achieved in 65 patients (75 per cent). Eighty-three patients survived more than 1 month after resection. Median survival was 33 months, with 1-, 3- and 5-year actuarial survival rates of 79, 47 and 31 per cent respectively. Recurrence occurred in 45 (54 per cent) of the 83 patients, most frequently in the liver (25 patients). Satellite nodules (odds ratio (OR) 8·17, 95 per cent confidence interval 1·38 to 48·53; P = 0·021), hilar lymph node metastases (OR 5·24, 1·07 to 25·75; P = 0·041) and perineural invasion (OR 9·68, 1·07 to 87·54; P = 0·043) were identified as independent risk factors for recurrence. Repeat hepatectomy (P = 0·003) and intra-arterial yttrium-90 radiotherapy (P = 0·048) were associated with longer survival after intrahepatic recurrence.
CONCLUSION: Satellite nodules, hilar lymph node metastases and perineural invasion are risk factors for recurrence following resection with curative intent for ICC. Repeat hepatectomy and labelled yttrium-90 radiotherapy may improve survival after intrahepatic recurrence.

Farges O, Regimbeau JM, Fuks D, et al.
Multicentre European study of preoperative biliary drainage for hilar cholangiocarcinoma.
Br J Surg. 2013; 100(2):274-83 [PubMed]

BACKGROUND: Indications for preoperative biliary drainage (PBD) in the context of hepatectomy for hilar malignancies are still debated. The aim of this study was to investigate current European practice regarding biliary drainage before hepatectomy for Klatskin tumours.
METHODS: This was a retrospective analysis of all patients who underwent formal or extended right or left hepatectomy for hilar cholangiocarcinoma between 1997 and 2008 at 11 European teaching hospitals, and for whom details of serum bilirubin levels at admission and at the time of surgery were available. PBD was performed at the physicians' discretion. The primary outcome was 90-day mortality. Secondary outcomes were morbidity and cause of death. The association of PBD and of preoperative serum bilirubin levels with postoperative mortality was assessed by logistic regression, in the entire population as well as separately in the right- and left-sided hepatectomy groups, and was adjusted for confounding factors.
RESULTS: A total of 366 patients were enrolled; PBD was performed in 180 patients. The overall mortality rate was 10·7 per cent and was higher after right- than left-sided hepatectomy (14·7 versus 6·6 per cent; adjusted odds ratio (OR) 3·16, 95 per cent confidence interval 1·50 to 6·65; P = 0·001). PBD did not affect overall postoperative mortality, but was associated with a decreased mortality rate after right hepatectomy (adjusted OR 0·29, 0·11 to 0·77; P = 0·013) and an increased mortality rate after left hepatectomy (adjusted OR 4·06, 1·01 to 16·30; P = 0·035). A preoperative serum bilirubin level greater than 50 µmol/l was also associated with increased mortality, but only after right hepatectomy (adjusted OR 7·02, 1·73 to 28·52; P = 0·002).
CONCLUSION: PBD does not affect overall mortality in jaundiced patients with hilar cholangiocarcinoma, but there may be a difference between patients undergoing right-sided versus left-sided hepatectomy.

Ahn SJ, Bae JI, Han TS, et al.
Percutaneous biliary drainage using open cell stents for malignant biliary hilar obstruction.
Korean J Radiol. 2012; 13(6):795-802 [PubMed] Article available free on PMC after 01/12/2013

OBJECTIVE: To evaluate the feasibility, safety and the effectiveness of the complex assembly of open cell nitinol stents for biliary hilar malignancy.
MATERIALS AND METHODS: During the 10 month period between January and October 2007, 26 consecutive patients with malignant biliary hilar obstruction underwent percutaneous insertion of open cell design nitinol stents. Four types of stent placement methods were used according to the patients' ductal anatomy of the hilum. We evaluated the technical feasibility of stent placement, complications, patient survival, and the duration of stent patency.
RESULTS: Bilobar biliary stent placement was conducted in 26 patients with malignant biliary obstruction-T (n = 9), Y (n = 7), crisscross (n = 6) and multiple intersecting types (n = 4). Primary technical success was obtained in 24 of 26 (93%) patients. The crushing of the 1st stent during insertion of the 2nd stent occurred in two cases. Major complications occurred in 2 of 26 patients (7.7%). One case of active bleeding from hepatic segmental artery and one case of sepsis after procedure occurred. Clinical success was achieved in 21 of 24 (87.5%) patients, who were followed for a mean of 141.5 days (range 25-354 days). The mean primary stent patency period was 191.8 days and the mean patient survival period was 299 days.
CONCLUSION: Applying an open cell stent in the biliary system is feasible, and can be effective, especially in multiple intersecting stent insertions in the hepatic hilum.

Radwan NA, Ahmed NS
The diagnostic value of arginase-1 immunostaining in differentiating hepatocellular carcinoma from metastatic carcinoma and cholangiocarcinoma as compared to HepPar-1.
Diagn Pathol. 2012; 7:149 [PubMed] Article available free on PMC after 01/12/2013

BACKGROUND: The ability to distinguish hepatocellular carcinoma (HCC) from metastatic carcinoma (MC) involving the liver and cholangiocarcinoma (CC) by immunohistochemistry has been limited by the lack of a reliable positive marker for hepatocellular differentiation. Arginase-1 is a marker for HCC recently described in some literature.
AIM: To examine the immunohistochemical staining of arginase-1 in cases of HCC, MC involving the liver and CC as compared to hepatocyte paraffin antigen -1 (HepPar-1) in an attempt to further define the diagnostic utility of arginase-1 in differentiating these tumors.
MATERIALS AND METHODS: A comparative immunohistochemical study of arginase-1 and HepPar-1expression was performed in 50 HCC cases, 38 cases of MC to the liver from varying sites, 12 cases of CC and 10 specimens of normal liver tissues. The predictive capacity of arginase-1 and HepPar-1 staining was determined using sensitivity, specificity, positive predictive value, and negative predictive value calculations.
RESULTS: All normal liver tissues (no=10), non- neoplastic cirrhotic liver tissues adjacent to HCC (no=42) as well as those adjacent to MC (no= 9) showed diffuse and strong immunostaining for both arginase-1 and HepPar-1. Arginase-1 demonstrated positive immunoreactivity in 42 of 50 (84%) cases of HCC compared with 35 of 50 (70%) for HepPar-1. Only one of 38 (2.6%) cases of MC and one of 12 (8.3%) cases of CC showed positive immunoreactivity for arginase-1. In contrast, HepPar-1 immunoreactivity was detected in 6 of 38 (15.8%) cases of MC and in 2 of 12 (16.7%) cases of CC. Arginase -1 showed a significantly higher sensitivity for HCC diagnosis (84%) compared to HepPar -1(70%) (p=0.016). The specificity of arginase-1 for HCC diagnosis was higher (96%) than that of HepPar -1 (84%); nevertheless, this was not statistically significant (p=0.109). Howerver, the combination of both immunomarkers for the diagnosis of HCC, raised the specificity to 100%.
CONCLUSION: Arginase-1 immunostaining has a higher sensitivity and specificity than HepPar-1 for HCC diagnosis. Furthermore, the combined use of arginase-1 and HepPar-1 can provide a potentially promising tool to improve the accuracy in distinguishing HCC from metastatic carcinoma and cholangiocarcinoma. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/9991436558072434.

Tolek A, Wongkham C, Proungvitaya S, et al.
Serum α1β-glycoprotein and afamin ratio as potential diagnostic and prognostic markers in cholangiocarcinoma.
Exp Biol Med (Maywood). 2012; 237(10):1142-9 [PubMed]

Cholangiocarcinoma (CCA) affects the intra- and extrahepatic bile ducts and is commonly burdened by a late presentation and resulting high mortality rate. Accordingly, finding non-invasive biomarkers with adequate diagnostic/prognostic values is a priority in high-risk populations. In this study, we analyzed proteomes of serum samples from six CCA cases and ten healthy subjects using two-dimensional polyacrylamide gel electrophoresis to identify CCA-associated spots. Thirty-six CCA-associated proteins found in sera were identified by mass spectrometry. α1β-Glycoprotein (A1BG) and afamin (AFM) were detected consistently at different degrees in CCA sera compared with controls and were validated for their diagnostic and prognostic potential in a larger cohort of 64 patients with CCA, 4 with benign biliary diseases and 20 healthy subjects and compared between pre- and postsurgery serum samples from 26 CCA patients to ascertain a prognostic correlation. A single blot test developed to assess the serum A1BG/AFM ratio could detect CCA cases with 87.5% specificity, 84.4% sensitivity and the levels were significantly higher in CCA compared with controls. A high level of postoperative serum A1BG/AFM ratio was associated with worse outcomes and the infiltration of resection margins. The A1BG/AFM ratio may constitute a novel non-invasive candidate marker to diagnose CCA and its outcomes with high specificity and sensitivity. Prospective studies are awaited to demonstrate the clinical value of this observation.

Machado MA, Makdissi FF, Surjan RC, Mochizuki M
Laparoscopic resection of hilar cholangiocarcinoma.
J Laparoendosc Adv Surg Tech A. 2012; 22(10):954-6 [PubMed]

BACKGROUND: Surgical resection is the only curative treatment for hilar cholangiocarcinoma. Laparoscopic hepatectomy has been used to treat several types of liver neoplasms. However, technical issues have limited the adoption of laparoscopy for the treatment of hilar cholangiocarcinoma. To date there is only one report of minimally invasive procedure for hilar cholangiocarcinoma in the literature. The present video-assisted procedure shows a laparoscopic resection of hilar cholangiocarcinoma.
PATIENT AND METHODS: A 43-year-old woman with progressive jaundice due to left-sided hilar cholangiocarcinoma was referred for treatment. The decision was to perform a laparoscopic left hepatectomy with lymphadenectomy and resection of extrahepatic bile ducts. Biliary reconstruction was performed using the hybrid method.
RESULTS: Operative time was 300 minutes with minimum blood loss and no need for blood transfusion. Recovery was uneventful, and the patient was discharged on postoperative Day 7. Pathology revealed a well-differentiated cholangiocarcinoma with negative lymph nodes and clear surgical margins. The patient is well with no signs of the disease 18 months after the procedure.
CONCLUSIONS: Laparoscopic left hepatectomy with lymphadenectomy is safe and feasible in selected patients and when performed by surgeons with expertise in liver surgery and minimally invasive techniques. The use of a hybrid method may be needed for biliary reconstruction, especially in cases where position and size of remnant bile ducts may jeopardize the anastomosis. Further studies are still needed to confirm the benefit of this approach over conventional surgery for hilar cholangiocarcinoma.

Khaenam P, Niibori A, Okada S, et al.
Contribution of RIZ1 to regulation of proliferation and migration of a liver fluke-related cholangiocarcinoma cell.
Asian Pac J Cancer Prev. 2012; 13(8):4007-11 [PubMed]

PURPOSE: Retinoblastoma-interacting zinc finger gene (RIZ1) is a tumor suppressor gene which is highly inactivated by promoter hypermethylation in patients with liver fluke-related cholangiocarcinoma (CCA). Epigenetic aberration of this gene might withdraw the ability to restrain tumor cell proliferation and migration. We aimed to define the role of RIZ1 on cell proliferation and migration in CCA cell line.
MATERIALS AND METHODS: Small interference RNA (siRNA) was used to knock down the expression of RIZ1 in a CCA-derived cell line in which cell proliferation and cell migration were performed.
RESULTS: A predominant nuclear localization of RIZ1 was observed. Reduction of RIZ1 by siRNA augmented cell proliferation and migration.
CONCLUSION: The result suggested that RIZ1 might play a role in regulating cell proliferation and migration in CCA. Reduction of RIZ1 expression may aggravate the progression of CCA.

Bilgin M, Toprak H, Bilgin SS, et al.
CT and MRI findings of sarcomatoid cholangiocarcinoma.
Cancer Imaging. 2012; 12:447-51 [PubMed]

Computed tomography (CT) and magnetic resonance imaging (MRI) findings for a case of intrahepatic sarcomatoid cholangiocarcinoma is presented. A 48-year-old man with upper abdominal pain underwent contrast-enhanced CT and MRI. A 13 × 10 × 7 cm mass was seen in the left liver lobe, which had hypodense internal architecture on CT and mixed signal intensities on both T1- and T2-weighted images with an overwhelmingly hypointense signal on T1-weighted images and a hyperintense signal on T2-weighted images. The lesion had heterogeneous enhancement on both CT and MRI. A satellite nodule with the same imaging features was distinctive for the lesion.

Kahaleh M
Photodynamic therapy in cholangiocarcinoma.
J Natl Compr Canc Netw. 2012; 10 Suppl 2:S44-7 [PubMed]

Most patients with hilar cholangiocarcinoma have unresectable disease and require palliation with biliary stenting to alleviate symptoms. Although chemotherapy and radiotherapy have been ineffective, many studies have suggested that the use of photodynamic therapy (PDT) may improve quality of life and perhaps survival in these patients. The ability of PDT to transmit through bile makes it a unique platform for intervention in the biliary tree. This article addresses the clinical implications of endoscopic biliary drainage, explores past and present study findings with PDT for cholangiocarcinoma, and offers an introduction to the novel techniques for direct visualization.