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Background: Intrahepatic cholangiocarcinoma (ICC) is subclassified into small and large duct types. The impact of these subclassifications for identifying appropriate surgical strategies remains unclear., Patients and Methods: This study included 118 patients with ICC who underwent liver resection. Based on the pathological examination results, the participants were divided into the small duct-type ICC group (n = 64) and large duct-type ICC group (n = 54). The clinicopathological features and postoperative outcomes were compared between the two groups to investigate the impact of subclassification for selecting appropriate surgical strategies., Results: Ten patients in the small duct-type ICC group had synchronous or metachronous hepatocellular carcinoma. The large duct-type ICC group had higher proportions of patients who underwent major hepatectomy, extrahepatic bile duct resection, portal vein resection, and lymph node sampling or dissection than the small duct-type ICC group. The large duct-type ICC group had significantly higher incidences of lymph node metastasis/recurrence and pathological major vessel invasion than the other. The small duct-type ICC group exhibited significantly higher recurrence-free and overall survival rates than the large duct-type ICC group. Further, the large duct-type ICC group had a significantly higher incidence of lymph node metastasis/recurrence than the small duct-type ICC at the perihilar region group., Conclusions: Suitable surgical strategies may differ between the small and large duct-type ICCs. In patients with large duct-type ICCs, hepatectomy with lymph node dissection and/or biliary reconstruction should be considered, whereas hepatectomy without these advanced procedures can be suggested for patients with small duct-type ICCs., (© 2024. Society of Surgical Oncology.)

This study aimed to investigate the clinicopathological findings of intraductal papillary neoplasm of the bile duct (IPNB) in patients with occupational cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane to elucidate the development of IPNB to cholangiocarcinoma. The clinicopathological findings of 17 IPNB lesions according to the size (1.5-20 mm in diameter) and their comparison between type 1 (n = 9) and type 2 IPNBs (n = 8) were investigated. An IPNB of <5 mm in size was classified as micro IPNB (n = 7), while those ≥5 mm in size were classified as ordinary IPNB (n = 10). Both types 1 and 2 IPNBs were observed in micro IPNB, and their proportions were not different between micro and ordinary IPNBs. The clinicopathological characteristics of types 1 and 2 IPNBs were fundamentally similar to those previously reported. IPNB with invasive carcinoma was only found in ordinary IPNB although the proportions of low-grade and high-grade epithelium were not different between micro IPNB and ordinary IPNB. All IPNB exhibited γH2AX and S100P, indicating the occurrence of DNA injury and malignant transformation in micro and ordinary IPNBs. These results indicate that the carcinogens may induce micro IPNB with types 1 or 2 at the initiation and then develop ordinary IPNB with types 1 or 2, subsequently, progressing to IPNB with invasive carcinoma in patients with occupational cholangiocarcinoma., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Cholangiocarcinoma (CC) has a poor prognosis and different driver genes depending on the site of onset. Intrahepatic CC is the second-most common liver cancer after hepatocellular carcinoma, and novel therapeutic targets are urgently needed. The present study was conducted to identify novel therapeutic targets by exploring differentially regulated genes in human CC. MicroRNA (miRNA) and mRNA microarrays were performed using tissue and serum samples obtained from 24 surgically resected hepatobiliary tumor cases, including 10 CC cases. We conducted principal component analysis to identify differentially expressed miRNA, leading to the identification of miRNA-3648 as a differentially expressed miRNA. We used an in silico screening approach to identify its target mRNA, the tumor suppressor Sloan Kettering Institute (SKI). SKI protein expression was decreased in human CC cells overexpressing miRNA-3648, endogenous SKI protein expression was decreased in human CC tumor tissues, and endogenous SKI mRNA expression was suppressed in human CC cells characterized by rapid growth. SKI-overexpressing OZ cells (human intrahepatic CC cells) showed upregulation of cyclin-dependent kinase inhibitor p21 mRNA and protein expression and suppressed cell proliferation. Nuclear expression of CDT1 (chromatin licensing and DNA replication factor 1), which is required for the G1/S transition, was suppressed in SKI-overexpressing OZ cells. SKI knockdown resulted in the opposite effects. Transgenic p21-luciferase was activated in SKI-overexpressing OZ cells. These data indicate SKI involvement in p21 transcription and that SKI-p21 signaling causes cell cycle arrest in G1, suppressing intrahepatic CC cell growth. Therefore, SKI may be a potential therapeutic target for intrahepatic CC., (© 2022 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Tanaka et al. previously reported a case in which nivolumab for recurrent occupational cholangiocarcinoma resulted in complete response persisting for 26 months after discontinuation. Afterward, in that clinical trial, nivolumab was administered to two patients for recurrence. Both patients achieved complete response, suggesting that nivolumab is effective for occupational cholangiocarcinoma., (© 2022 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Although it has recently been reported that immune checkpoint inhibitors (ICIs) constitute effective treatment for solid tumors, the success rate in patients with intrahepatic cholangiocarcinoma is limited. We administered pembrolizumab to a patient as treatment for liver and lymph node metastases of intrahepatic cholangiocarcinoma. The patient had abundant infiltration of programmed death ligand 1-positive macrophages, cytotoxic T cells (CD8-positive lymphocytes), and programmed death 1-positive lymphocytes as well as a high combined positive score of 33.1, high-frequency microsatellite instability, and mismatch repair deficiency. These characteristics are predictive biomarkers of the efficacy of ICIs. After pembrolizumab was administered four times (triweekly administration), the carbohydrate antigen 19-9 serum level fell within the normal range, and computed tomography revealed that the size of the metastatic liver tumors and enlarged hilar lymph node had markedly decreased. However, the patient developed pruritus and exanthema on the trunk and limbs after 14 administrations and was diagnosed with bullous pemphigoid. We discontinued pembrolizumab therapy and started treatment for bullous pemphigoid. Nine months after discontinuation of pembrolizumab therapy, the patient remains alive without tumor relapse. This patient had durable response even after discontinuation of pembrolizumab therapy for multiple metastases of intrahepatic cholangiocarcinoma.

Objective: Fibroblast growth factor receptor gene alterations have emerged as promising drug targets for intrahepatic cholangiocarcinoma, a rare cancer that has a poor prognosis. This study evaluated the frequency of fibroblast growth factor receptor 2 fusions in clinical specimens from Japanese patients with iCCA., Methods: This study enrolled 116 patients who had histologically or cytologically confirmed adenocarcinoma and been diagnosed as relapsing after resection or with unresectable intrahepatic cholangiocarcinoma. We evaluated the frequency of fibroblast growth factor receptor 2 fusions-positive cells in their specimens using break-apart fluorescent in situ hybridization 'for 114 patients who met the study protocol'., Results: Of a total of 114 cases, six (5.3%) were identified as fibroblast growth factor receptor 2 fusions-positive with a high frequency (87% or more) of fibroblast growth factor receptor 2 fusions-positive tumour cells whereas the remainder, with the exception of three cases with indeterminate results, were identified as fibroblast growth factor receptor 2 fusions-negative. The patients' baseline characteristics as well as their objective response rates, disease control rates, times to progression, and times to treatment failure with previous or ongoing first-line chemotherapy did not have any obvious relationship to the proportion of fibroblast growth factor receptor 2 fusions-positive case., Conclusions: Further detailed elucidation of fibroblast growth factor receptor 2 fusion status is expected to contribute to the development of promising therapeutic options for patients suffering from recurrent or unresectable intrahepatic cholangiocarcinoma., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Cholangiocarcinoma and secondary biliary cirrhosis can develop after liver resection for hepatolithiasis and are causes of hepatolithiasis-related death. We determined potential risk factors for hepatolithiasis-related death and subsequent cholangiocarcinoma, including precancerous lesions such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct, in patients undergoing liver resection for hepatolithiasis., Methods: The study cohort included 62 patients who underwent liver resection for hepatolithiasis without concomitant cholangiocarcinoma and had surgical specimens available for pathological examination. Univariate and multivariate analyses were conducted to examine risk factors associated with subsequent cholangiocarcinoma after hepatolithiasis and hepatolithiasis-related death. In 28 patients with BilIN lesions, the specimens were immunohistochemically stained for γ-H2AX and S100P., Results: In the study cohort, the causes of death were subsequent cholangiocarcinoma, biliary cirrhosis, and other diseases in 5, 3, and 7 patients, respectively. Liver atrophy, precancerous lesions, postoperative repeated cholangitis, and jaundice for ≥1 week during the follow-up period were risk factors for hepatolithiasis-related death. Multivariate analysis showed that liver atrophy and precancerous lesions were independent risk factors for hepatolithiasis-related death. Liver atrophy or precancerous lesions were also risk factors for subsequent cholangiocarcinoma by univariate analysis. The positive expression of γ-H2AX and S100P was observed in 18 and 14 of the 28 BilIN lesions, respectively., Conclusions: Liver atrophy and precancerous lesions with malignant transformation were risk factors not only for subsequent cholangiocarcinoma but also hepatolithiasis-related death after liver resection for hepatolithiasis, indicating that long-term follow-up is necessary even after liver resection in patients harboring these risk factors., .

A woman in her seventies visited our hospital because of abdominal pain. Multiple hepatic tumors were detected and a liver biopsy revealed mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN), which was composed of cholangiocellular carcinoma and neuroendocrine tumor (NET). Diagnostic imaging ruled out primary malignancies other than the liver and identified that the tumor originated from the liver. Because a predominant and aggressive part of the tumor was considered to be cholangiocellular carcinoma, gemcitabine and S-1 were used as first-line treatment. After the treatment, octreotide acetate was administered for the NET component, followed by transcatheter arterial embolization. Subsequently, her gallbladder (GB) rapidly swelled with biliary tract obstruction, and cholecystectomy revealed carcinosarcoma of the GB. She is still undergoing treatment at 44 months after diagnosis. Herein we report this case of primary hepatic MiNEN consisting of cholangiocarcinoma and NET, followed by GB carcinosarcoma. This is the first case illustrating that a multidisciplinary treatment approach for MiNEN accompanied with carcinosarcoma, involving assessment and treatment targeting the most aggressive component, can result in a long survival time.

Background: Occupational cholangiocarcinoma (CCA) was first described in patients who were working at a printing company in Osaka, Japan. Recently, the therapeutic efficacy and safety of a PD1 inhibitor nivolumab are being evaluated in patients with occupational CCA in an investigator-initiated clinical trial. The therapeutic effects of immune checkpoint inhibitors are closely associated with immune cells., Methods: Immunohistochemical analysis was performed to characterize immune cells in the tumor microenvironment of occupational CCA. The status of mismatch repair (MMR)/microsatellite instability (MSI) was also examined., Results: The tumor stroma of occupational CCA was characterized by abundant infiltration of immune cells expressing CD3, CD4, CD8, CD163, FOXP3, and granzyme B. Additionally, lymphocytes expressing immune checkpoint receptors, such as PD1, CTLA4, LAG3, TIM3, and TIGIT, were frequently infiltrated. The loss of immunohistochemical expression of the MMR proteins (MLH1, MSH2, PMS2, and MSH6) was not observed in cases of occupational CCA, and MSI was not detected., Conclusions: The tumor microenvironment of occupational CCA had features of immunosuppression, and the occurrence of T-cell dysfunction or exhaustion was suggested. The results provide supportive evidence for the efficacy of immune checkpoint inhibitor therapy for this disease., (© 2020 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: The present study aimed to investigate the impact of preoperative C-reactive protein to albumin (CRP/Alb) ratio on the long-term outcomes of patients with intrahepatic cholangiocarcinoma (ICC)., Methods: 82 patients who underwent hepatic resection for mass-forming type of ICC were evaluated. The relationship between preoperative CRP/Alb ratio and survival outcomes was investigated., Results: The optimal cutoff value of CRP/Alb ratio for assessing overall survival (OS) was determined as 0.089. Univariate analysis for recurrence-free survival (RFS) showed that CRP/Alb ratio >0.089, carbohydrate antigen 19-9 (CA 19-9) >37 U/mL, lymph node metastasis, vascular invasion, and multiple tumors were significantly associated with postoperative recurrence. On multivariate analysis, the independent prognostic factors identified were CRP/Alb ratio >0.089 (p < 0.001), lymph node metastasis (p = 0.006), and multiple tumors (p < 0.001). Univariate analysis for OS showed that CRP/Alb ratio >0.089, CA 19-9 >37 U/mL, lymph node metastasis, vascular invasion, multiple tumors, and positive surgical margin were significantly associated with overall death. On multivariate analysis, the independent prognostic factors identified were CRP/Alb ratio >0.089 (p < 0.001), lymph node metastasis (p = 0.01), and multiple tumors (p = 0.005)., Conclusion: Preoperative CRP/Alb ratio may predict poor long-term outcomes after hepatic resection in patients with ICC., .

Objective: To identify optimal surgical methods and the risk factors for long-term survival in patients with hepatocellular carcinoma accompanied by macroscopic bile duct tumor thrombus (BDTT)., Summary Background Data: Prognoses of patients with hepatocellular carcinoma accompanied by BDTT have been known to be poor. There have been significant controversies regarding optimal surgical approaches and risk factors because of the low incidence and small number of cases in previous reports., Methods: Records of 257 patients from 32 centers in Korea and Japan (1992-2014) were analyzed for overall survival and recurrence rate using the Cox proportional hazard model., Results: Curative surgery was performed in 244 (94.9%) patients with an operative mortality of 5.1%. Overall survival and recurrence rate at 5 years was 43.6% and 74.2%, respectively. TNM Stage (P < 0.001) and the presence of fibrosis/cirrhosis (P = 0.002) were independent predictors of long-term survival in the Cox proportional hazards regression model. Both performing liver resection equal to or greater than hemihepatectomy and combined bile duct resection significantly increased overall survival [hazard ratio, HR = 0.61 (0.38-0.99); P = 0.044 and HR = 0.51 (0.31-0.84); P = 0.008, respectively] and decreased recurrence rate [HR = 0.59 (0.38-0.91); P = 0.018 and HR = 0.61 (0.42-0.89); P = 0.009, respectively]., Conclusions: Clinical outcomes were mostly influenced by tumor stage and underlying liver function, and the impact of BDTT to survival seemed less prominent than vascular invasion. Therefore, an aggressive surgical approach, including major liver resection combined with bile duct resection, to increase the chance of R0 resection is strongly recommended.

Background: Data are inconsistent regarding the effects of a wide surgical margin for intrahepatic cholangiocarcinoma on recurrence-free survival and overall survival. This study was performed to investigate the effect of surgical margin width in patients undergoing R0 resection for intrahepatic cholangiocarcinoma, using a nationwide database in Japan., Methods: In total, 635 patients with intrahepatic cholangiocarcinoma who were treated by an R0 resection from 2000 to 2007 were identified from the database of a Japanese nationwide survey. Patients were divided into quartiles of the surgical margin width as follows: marginal (<1 mm), narrow (1-4 mm), intermediate (5-9 mm), and wide groups (≥10 mm). Multivariable Cox regression models for recurrence-free survival and overall survival were constructed with adjustment for preoperative and postoperative clinicopathologic factors., Results: Compared with the marginal group, the risk-adjusted hazard ratios (95% confidence intervals) in the narrow, intermediate, and wide groups for recurrence-free survival were 0.92 (0.62-1.37), 0.91 (0.61-1.37), and 0.81 (0.56-1.17), and those for overall survival were 0.79 (0.51-1.24), 0.93 (0.59-1.47), and 0.70 (0.46-1.08), respectively. In 398 patients without lymph node metastasis, the hazard ratios for overall survival were 0.62 (0.34-1.11), 0.63 (0.34-1.17), and 0.51 (0.29-0.90), and those of mass-forming type intrahepatic cholangiocarcinoma were 0.48 (0.21-1.08), 0.43 (0.19-0.96), and 0.40 (0.19-0.82), respectively., Conclusion: Surgical margin width appears to have a limited effect on the prognosis of intrahepatic cholangiocarcinoma except in patients without lymph node metastasis, where a wide surgical margin is associated with favorable outcomes. This survival benefit of a wide surgical margin is especially apparent for the mass-forming type intrahepatic cholangiocarcinoma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: We investigated the indications for laparoscopic liver resection (LLR) of mass-forming intrahepatic cholangiocarcinoma (MF-ICC), including the need for lymph node dissection for improved postoperative prognosis., Methods: This study involved 36 patients who underwent surgery for solitary peripheral MF-ICC. Fifteen patients underwent LLR, and 21 underwent open liver resection (OLR). Surgical outcomes and prognostic factors were investigated to determine the indications for LLR., Results: No significant differences were observed in perioperative outcomes between patients who underwent LLR and OLR. A significantly worse disease-free survival (DFS) rate was observed in patients who preoperatively had a tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum carbohydrate antigen (CA) 19-9 and carcinoembryonic antigen (CEA) levels. A significantly worse overall survival (OS) rate was observed in patients with a tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum CA19-9 levels. Therefore, a tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum CA19-9 and CEA levels were determined to be preoperative prognostic factors. DFS and OS rates were significantly better in patients without these factors. Moreover, in six patients without these factors who underwent LLR, neither lymph node metastasis nor postoperative recurrence was observed., Conclusion: A tumor diameter ≥3 cm, vascular invasion on diagnostic imaging, and elevated serum CA19-9 and CEA levels are preoperative prognostic factors for peripheral MF-ICC. LLR is indicated for patients without these factors., (© 2019 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and John Wiley & Sons Australia, Ltd.)

Highlight Tanaka and Kubo reported the first case of recurrent occupational cholangiocarcinoma treated with programmed death-1 inhibitor. A programmed death-1 inhibitor was administered every 2 weeks for para-aortic lymph node metastasis after curative hepatectomy. After seven cycles of administration, positron emission tomography demonstrated diminished lymph node size without 18 F-fluorodeoxy glucose uptake., (© 2019 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objective: The present study aimed to identify the clinical significance of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in patients with occupational cholangiocarcinoma. Methods: This study included 10 men with occupational cholangiocarcinoma who were former or current workers at a printing company in Osaka, Japan. Of the 10 patients, 2 had 2 main tumors and 1 had 3 main tumors. Twelve FDG-PET imaging findings in the 10 patients could be analyzed. We evaluated the relationships between FDG-PET imaging parameters and clinicopathological findings of occupational cholangiocarcinoma. Results: Abnormal FDG uptake was observed in 8 of the 14 main tumors, with maximum standardized uptake values ranging from 2.9 to 11.0, and the sensitivity was 57.1%. Four patients had lymph node metastases, and abnormal marrow uptake was detected in all these patients. Although precancerous lesions, such as biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB) without any invasion, were not detected, abnormal FDG uptake was demonstrated in 2 of 4 patients with IPNB having an associated invasive carcinoma.Conclusions: Although FDG-PET may be useful for assessing tumor progression factors, such as lymph node metastasis, it cannot accurately detect precancerous lesions, such as BilIN and IPNB without invasive carcinoma., (Creative Commons Attribution License)

Purpose: To retrospectively investigate magnetic resonance (MR) imaging findings of occupational cholangiocarcinoma (oCC) occurring among workers in printing companies in Japan, compared to those of non-occupational cholangiocarcinoma (nCC), primary sclerosing cholangitis (PSC), and age-matched normal controls (NORs)., Materials and Methods: Participants comprised 27 consecutive patients (oCC, n = 5; nCC, n = 8; PSC, n = 6; NOR, n = 8) who underwent MR imaging between May 2009 and October 2012. MR imaging was evaluated with respect to tumor characteristics, abnormal MR cholangiographic findings (PSC-like findings), bile duct stricture, and signal changes of the hepatic parenchyma., Results: Tumors were detected in all nCCs and four oCCs. Tumors displayed a mass-forming type in all nCCs and two oCCs, and an intraductal growth type in two oCCs. Abnormal cholangiographic findings were detected in all oCCs and PSCs, but not in any nCCs or NORs. All oCCs and seven nCCs showed biliary strictures longer than 1 cm; five PSCs showed biliary strictures shorter than 1 cm. Both intra- and extrahepatic biliary strictures were detected in three PSCs and two oCCs. Peripheral hepatic hyperintensity on T2-weighted imaging was detected in two nCCs, two PSCs, and two oCCs., Conclusion: These results indicated that MR imaging of oCC showed findings of both PSC and nCC.

Background and Objectives: We determined the rates of initial lymph node metastasis following curative resection of mass-forming type-intrahepatic cholangiocarcinoma (ICC) in patients with and without hepatitis virus infection., Methods: We enrolled 87 patients between January 2000 and December 2013 with ICC without preoperative lymph node metastasis and without lymph node dissection. Patients included 32 who were seropositive for hepatitis B or C virus (virus group) and 55 who had no evidence of hepatitis virus infection (nonvirus group). Postsurgical outcomes and initial recurrence of the groups were compared, and we identified the risk factors for lymph node metastasis as initial recurrence., Results: Platelet counts and prothrombin activities were significantly lower in the virus group compared with those of the nonvirus group. The number of patients with chronic hepatitis or liver cirrhosis was significantly higher in the virus group compared with the nonvirus group as well as their respective rates of recurrence-free survival. One patient (3%) in the virus group and 14 patients (25%) in the nonvirus group had lymph node metastasis as initial recurrence (p = 0.007). Multivariate analysis revealed that the absence of hepatitis virus infection as an independent risk factor (p = 0.047)., Conclusion: Hepatitis virus-associated mass-forming-type ICC confers a low risk of lymph node metastasis as initial postoperative recurrence.

An outbreak of cholangiocarcinoma in a printing company was reported in Japan, and these cases were regarded as an occupational disease (occupational cholangiocarcinoma). This study examined the expression status of programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) in occupational cholangiocarcinoma. Immunostaining of PD-1, PD-L1, CD3, CD8, and CD163 was performed using tissue sections of occupational cholangiocarcinoma (n = 10), and the results were compared with those of control cases consisting of intrahepatic (n = 23) and extrahepatic (n = 45) cholangiocarcinoma. Carcinoma cells expressed PD-L1 in all cases of occupational cholangiocarcinoma, whereas the detection of PD-L1 expression in cholangiocarcinoma cells was limited to a low number of cases (less than 10%) in the control subjects. In cases of occupational cholangiocarcinoma, occasional PD-L1 expression was also noted in precancerous/preinvasive lesions such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct. Additionally, tumor-associated macrophages and tumor-infiltrating T cells expressed PD-L1 and PD-1, respectively. The number of PD-L1-positive mononuclear cells, PD-1-positive lymphocytes, and CD8-positive lymphocytes infiltrating within the tumor was significantly higher in occupational cholangiocarcinoma compared with that in control cases. These results indicate that immune escape via the PD-1/PD-L1 axis may be occurring in occupational cholangiocarcinoma., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

Background: Cholangiocarcinoma caused by exposure to 1,2-dichloropropane and/or dichloromethane is recognized as occupational cholangiocarcinoma. The aim of this study was to investigate the outcomes after resection of occupational cholangiocarcinoma to establish a treatment strategy for this disease., Methods: Clinicopathological findings and outcomes after surgical intervention in 20 patients with occupational cholangiocarcinoma were investigated., Results: Of 20 the patients, curative resection was performed in 16 patients. Three patients underwent radiation at the stump of the bile ducts. Adjuvant chemotherapy was performed in 12 patients. Biliary intraepithelial neoplasia, intraductal papillary neoplasm of the bile duct, and/or chronic bile duct injury was detected in most subjects. Intraabdominal infection developed after surgery in nine patients. Cholangiocarcinoma recurred in 12 of the 20 patients. The recurrent tumors in five patients developed at a different part of the bile duct from the primary tumor and a second resection was performed in four of these five patients., Conclusions: The incidence of postoperative complications including intraabdominal infection was high in patients with occupational cholangiocarcinoma. Multicentric recurrence occurred not infrequently after surgery because the bile ducts had a high potential for the development of carcinoma. The aggressive treatment including second resection for the multicentric recurrence appeared to be effective., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Objectives: This study aimed to evaluate the relationship between cumulative exposure to 1,2-dichloropropane (1,2-DCP) and incidence risk of cholangiocarcinoma among workers in the offset proof-printing section of a small printing company in Osaka, Japan., Methods: We identified 95 workers of a printing company (78 men and 17 women) who had been exposed to 1,2-DCP between 1987 and 2006, and calculated the standardised incidence ratio (SIR) of cholangiocarcinoma from 1987 to 2012. We estimated cumulative exposure to 1,2-DCP and calculated SIRs in four exposure categories. We also calculated incidence rate ratios (RRs) adjusted by sex, age, calendar year and dichloromethane (DCM) exposure for three exposure categories using Poisson regression analysis., Results: Cumulative exposures to 1,2-DCP ranged from 32 to 3433 ppm-years (mean, 851 ppm-years) and the SIR was 1171 (95% CI 682 to 1875). In the analysis of the four exposure categories, SIRs increased significantly in the three highest exposure categories, but not in the lowest category. Adjusted RRs in the middle and high exposure categories were 14.9 (95% CI 4.1 to 54.3) and 17.1 (95% CI 3.8 to 76.2), respectively, in the analysis without lag time, and were 11.4 (95% CI 3.3 to 39.6) and 32.4 (95% CI 6.4 to 163.9), respectively, in the analysis with a 5-year lag. The trend analysis revealed a significant increase in RR in association with increasing cumulative exposure to 1,2-DCP. DCM exposure was not significantly associated with the development of cholangiocarcinoma., Conclusions: The present study demonstrated an exposure-response relationship between exposure to 1,2-DCP and the development of cholangiocarcinoma., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: An outbreak of cholangiocarcinoma has been reported among workers of an offset color proof-printing department at a printing company in Japan. In this study, we compared the clinicopathological findings of this type of intrahepatic cholangiocarcinoma (occupational ICC) and non-occupational ICC., Methods: The clinical records of 51 patients with perihilar-type ICC who underwent liver resection, including five patients with occupational ICC were retrospectively reviewed. The clinicopathological features were compared., Results: In the occupational group, the patients were significantly younger (P < 0.01), while serum γ-glutamyl transpeptidase activity and the proportions of patients with regional dilatation of the bile ducts without tumor-induced obstruction were significantly higher (P = 0.041 and P < 0.01, respectively); the indocyanine green retention rate at 15 min was significantly lower (P = 0.020). On pathological examinations, precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct, were observed at various sites of the bile ducts in all occupational ICC patients; such lesions were observed in only six patients in the control group (P < 0.01)., Conclusions: The clinicopathological findings including age, liver function test results, diagnostic imaging findings, and pathological findings differed between the occupational and control groups., (© 2016 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: This study aimed to investigate the association between non-alcoholic steatohepatitis (NASH) and intrahepatic cholangiocarcinoma (ICC)., Methods: This was a case control study of patients who underwent surgical resection either for ICC or for a metastatic liver tumor (the control group). We assessed their clinical characteristics, pathological findings, and the prevalence of known ICC risk factors. For patients without known risk factors, we compared other factors including the prevalence of NASH., Results: In the patients without known risk factors, 15 of 34 patients in the ICC group and 13 of 69 patients in the control group were diagnosed with NASH. Univariate analysis showed significantly higher values in the ICC group for age (P = 0.0478), prevalence of obesity (P = 0.0365) and NASH (P = 0.0078), and serum levels of albumin (P = 0.0051), and gamma-glutamyl transpeptidase (γ-GTP) (P = 0.0006) compared with the control group. Multivariate analysis showed that age and serum levels of γ-GTP and NASH were independent risk factors for ICC. In patients with NASH, the proportion of patients with hepatic fibrosis was significantly higher in the ICC group than in the control group (P = 0.0014)., Conclusion: NASH is a possible risk factor for ICC development. J. Surg. Oncol. 2016;113:779-783. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: This study aimed to establish an efficient strategy for screening and surveillance for occupational cholangiocarcinoma., Methods: We evaluated the consecutive changes in laboratory findings during regular health examinations and in abdominal ultrasonography findings before the diagnosis of occupational cholangiocarcinoma in nine patients. The results of laboratory tests and abdominal ultrasonography at the time of diagnosis were also examined., Results: In all patients, the serum γ-glutamyl transpeptidase (γ-GTP) activity increased several years before the diagnosis of cholangiocarcinoma. The serum alanine aminotransferase (ALT) activity also increased several years before the diagnosis, following an increase in the serum aspartate aminotransferase (AST) activity in most patients. Abdominal ultrasonography before the diagnosis revealed regional dilatation of the bile ducts, which continued to enlarge. At the time of diagnosis, the γ-GTP, AST, and ALT activities were increased in nine, seven, and seven patients, respectively. The regional dilatation of bile ducts without tumor-induced stenosis, dilated bile ducts due to tumor-induced stenosis, space-occupying lesions, and/or lymph node swelling were observed. The serum concentrations of carbohydrate antigen 19-9 (CA 19-9) and/or carcinoembryonic antigen (CEA) were increased in all patients., Conclusions: Regular health examinations with a combination of ultrasonography and laboratory tests including the γ-GTP, AST, ALT, CA 19-9, and CEA levels are useful for screening and surveillance for occupational cholangiocarcinoma.

Background: We aimed to identify the pathological characteristics of occupational cholangiocarcinoma., Methods: We examined the location and distribution of the carcinomas: atypical epithelium including biliary intraepithelial neoplasia (BilIN) and intraductal papillary neoplasm of the bile duct (IPNB); and chronic bile duct injuries in operative or autopsy liver specimens from 16 patients. We examined the detailed pathological findings and diagnostic imaging of three patients. Immunohistochemical analysis using primary antibodies against γH2AX and S100P was performed., Results: BilIN and chronic bile duct injury were observed in 16 patients, and IPNB or invasive IPNB was observed in 11 patients. BilIN, IPNB, and/or chronic bile duct injury were observed in almost all the large bile ducts. Regional dilatation of the bile ducts without tumor-induced obstruction revealed such pathological changes. Highly positive results for the γH2AX and S100P markers were noted in invasive carcinoma, BilIN, and IPNB, whereas positive results for γH2AX and negative results for S100P were noted in non-neoplastic biliary epithelium., Conclusions: The carcinogenic process of occupational cholangiocarcinoma comprised chronic bile duct injury and DNA damage in almost all the large bile ducts, along with induction of precancerous lesions and development of invasive carcinoma. Such pathological findings reflected radiological changes on diagnostic imaging., (© 2015 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma (HCC) are liver originated malignant tumors. Of the two, ICC has the worse prognosis because it has no reliable diagnostic markers and its carcinogenic mechanism is not fully understood. The aim of this study was to integrate metabolomics and transcriptomics datasets to identify variances if any in the carcinogenic mechanism of ICC and HCC. Ten ICC and 6 HCC who were resected surgically, were enrolled. miRNA and mRNA expression analysis were performed by microarray on ICC and HCC and their corresponding non-tumor tissues (ICC&#95;NT and HCC&#95;NT). Compound analysis was performed using capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS). Principle component analysis (PCA) revealed that among the four sample groups (ICC, ICC&#95;NT, HCC, and HCC&#95;NT) there were 14 compounds, 62 mRNAs and 17 miRNAs with two distinct patterns: tumor and non-tumor, and ICC and non-ICC. We accurately (84.38%) distinguished ICC by the distinct pattern of its compounds. Pathway analysis using transcriptome and metabolome showed that several pathways varied between tumor and non-tumor samples. Based on the results of the PCA, we believe that ICC and HCC have different carcinogenic mechanism therefore knowing the specific profile of genes and compounds can be useful in diagnosing ICC.

A 42-year-old man working at a printing company was referred to our hospital for examination and treatment of icterus. We diagnosed resectable hilar cholangiocarcinoma and provided neoadjuvant chemoradiotherapy, extended right hepatectomy, and extrahepatic bile duct resection. A detailed history revealed that he had used 1,2-dichloropropane as part of his work as an offset colour proof-printer, and he has subsequently been recognized as having occupational cholangiocarcinoma. He has survived without recurrence for more than 2 and half years since the liver resection. In the present report, we describe our valuable experience of neoadjuvant chemoradiotherapy for occupational cholangiocarcinoma.

Background: Since seventeen employees of an offset printing company in Osaka, Japan developed cholangiocarcinoma it has become recognized as an occupational cancer. This study investigated the differences of clinical features between occupational cholangiocarcinoma and sporadic young-onset cholangiocarcinoma., Materials and Methods: Thirty-four young adults (<50 years old) with sporadic cholangiocarcinoma were extracted from the Rosai Hospital Group database (sporadic group) and their clinical features were compared with those of 17 patients with occupational cholangiocarcinoma (occupational group)., Results: The 34 patients in the sporadic group were treated for cholangiocarcinoma at 16 different Rosai hospitals. There were significant differences of age (p<0.01), gender (p<0.01), abnormal laboratory tests (p<0.01), and tumor location (p<0.01) between the two groups. The percentage of patients with abnormal laboratory tests was significantly higher in the occupational group than in the sporadic group (p<0.001). Regional dilation of bile ducts, which is a characteristic of occupational cholangiocarcinoma, was not observed in the sporadic group., Conclusions: No cluster of cholangiocarcinoma cases was identified in the Rosai Hospital database. There were differences of clinical features between occupational and sporadic cholangiocarcinoma, which might be helpful for diagnosing occupational cholangiocarcinoma in the future.

Objective: This study aimed to identify the chemicals used by five printing workers and one coating worker who developed cholangiocarcinoma and estimate the workers' levels of chemical exposure., Methods: We obtained information on chemicals from the Ministry of Health, Labour and Welfare, Japan, and estimated working environment concentrations of the chemicals in printing and coating rooms and exposure concentrations during the ink and dirt removal processes. We also calculated shift time-weighted averages of exposure concentrations., Results: All five printing workers were exposed to both 1,2-dichloropropane (1,2-DCP) and dichloromethane (DCM). The estimated maximum exposure concentrations for each of the five workers were 190 to 560 ppm for 1,2-DCP and 300 to 980 ppm for DCM, and the estimated shift average exposure concentrations were 0 to 230 ppm for 1,2-DCP and 20 to 470 ppm for DCM. The coating worker was exposed to 1,2-DCP, but not DCM. He did not use ink, and thus was subjected to different conditions than the printing workers. The estimated maximum exposure concentration of 1,2-DCP was 150 ppm, and the estimated shift time-weighted average exposure concentration was 5 to 19 ppm., Conclusions: Our findings support the notion that 1,2-DCP contributes to the development of cholangiocarcinoma in humans and the notion that DCM may also be a contributing factor. The finding that the coating worker was exposed to 1,2-DCP at a lower exposure concentration is important for determining the occupational exposure limit. Furthermore, the subject did not use ink, which suggests that ink did not contribute to the development of cholangiocarcinoma.

Background: Cholangiocarcinoma has been reported in workers exposed to chlorinated organic solvents and has consequently been classified as an occupational disease (occupational cholangiocarcinoma) by the Japanese Ministry of Health, Labour and Welfare. This study aimed to identify the characteristics of nine workers newly diagnosed with occupational cholangiocarcinoma., Methods: This study was a retrospective study conducted in 13 hospitals and three universities. Clinicopathological findings of nine occupational cholangiocarcinoma patients from seven printing companies in Japan were investigated and compared with 17 cholangiocarcinoma patients clustered in a single printing company in Osaka., Results: Patient age at diagnosis was 31-57 years. Patients were exposed to 1,2-dichloropropane and/or dichloromethane. Serum γ-glutamyl transpeptidase activity was elevated in all patients. Regional dilatation of the intrahepatic bile ducts without tumor-induced obstruction was observed in two patients. Four patients developed intrahepatic cholangiocarcinoma and five developed hilar cholangiocarcinoma. Biliary intraepithelial neoplasia and/or intraductal papillary neoplasm of the bile duct was observed in four patients with available operative or autopsy specimens., Conclusions: Most of these patients with occupational cholangiocarcinoma exhibited typical findings, including high serum γ-glutamyl transpeptidase activity, regional dilatation of the bile ducts, and precancerous lesions, similar to findings previously reported in 17 occupational cholangiocarcinoma patients in Osaka., (© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Recently, cholangiocarcinoma has epidemically developed among young adult workers of a printing company in Japan. Exposure to organic solvents including 1,2-dichloropropane and/or dichloromethane is supposed to be associated with the carcinoma development. The metabolism of dichloromethane proceeds through a Theta-class glutathione S-transferase (GST) T1-1-catalyzed pathway, where its reactive intermediates have been implicated in genotoxicity and carcinogenicity. This study examined features of the carcinogenic process of the cholangiocarcinoma developed in the printing company. Surgically resected specimens of the cholangiocarcinoma cases were analyzed, where all cases were associated with precursor lesions such as biliary intraepithelial neoplasia (BilIN) and/or intraductal papillary neoplasm of the bile duct (IPNB). Immunohistochemical analysis confirmed constitutional expression of GST T1-1 in normal hepatobiliary tract. Immunostaining of γ-H2AX, a marker of DNA double strand break, showed that its expression was significantly increased in foci of BilIN, IPNB and invasive carcinoma as well as in non-neoplastic biliary epithelial cells of the printing company cases when compared to that of control groups. In the printing company cases, immunohistochemical expression of p53 was observed in non-neoplastic biliary epithelial cells and BilIN-1. Mutations of KRAS and GNAS were detected in foci of BilIN in one out of 3 cases of the printing company. These results revealed different carcinogenic process of the printing company cases, suggesting that the exposed organic solvents might act as a carcinogen for biliary epithelial cells by causing DNA damage, thereby contributing to the carcinoma development.

Background: Recently, the Liver Cancer Study Group of Japan (LCSGJ) staging system for intrahepatic cholangiocarcinoma (ICC) was followed by a proposal of the American Committee on Cancer (AJCC)/International Union Against Cancer (UICC) system. The present study aimed to assess the accuracy of both systems to predict survival after curative resection for mass-forming ICC and to establish a new staging system based on survival analysis results. The present study was conducted as a project study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery., Methods: Clinical data from 233 patients who underwent curative resection for mass-forming ICC were retrospectively reviewed. Survival analysis was performed to identify predictors of postoperative outcomes, and a new staging system was established. The survival stratification of our proposed system was compared with two previous staging systems., Results: A N0M0 cohort analysis demonstrated that tumor size, tumor number, and vascular invasion were independently associated with survival after curative resection for mass-forming ICC, whereas serosal and periductal invasion were not. Of patients with nodal metastases, patients with T4 tumor had significantly lower overall survival rate than patients with T1, T2, or T3 tumor. Thus, we proposed a new staging system as follows: serosal invasion was excluded from the LCSGJ T categories, and patients with nodal metastases were divided into stage IVA or IVB according to T classification. The new system better stratified survival after curative resection for mass-forming ICC than the two previous systems., Conclusions: The AJCC/UICC staging system failed to stratify the Japanese patients with mass-forming ICC. The new staging system provided better survival prediction in the patients who underwent curative resection for mass-forming ICC, although further studies are necessary to evaluate the impact of tumor size on survival., (© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: An outbreak of cholangiocarcinoma occurred among workers in the offset color proof-printing department at a printing company in Japan. The aim of this study was to clarify the characteristics of the patients with cholangiocarcinoma., Methods: This was a retrospective study conducted in 13 Japanese hospitals between 1996 to 2013. The clinicopathological findings of cholangiocarcinoma developed in 17 of 111 former or current workers in the department were investigated. Most workers were relatively young., Results: The cholangiocarcinoma was diagnosed at 25-45 years old. They were exposed to chemicals, including dichloromethane and 1,2-dichloropropane. The serum γ-glutamyl transpeptidase activity was elevated in all patients. Dilated intrahepatic bile ducts without tumor-induced obstruction were observed in five patients. The cholangiocarcinomas arose from the large bile ducts. The precancerous or early cancerous lesions, such as biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile ducts, as well as non-specific bile duct injuries, such as fibrosis, were observed in various sites of the bile ducts in all eight patients for whom operative specimens were available., Conclusions: The present results showed that cholangiocarcinomas occurred at a high incidence in relatively young workers of a printing company, who were exposed to chemicals including chlorinated organic solvents., (© 2014 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Despite surgical treatment for intrahepatic cholangiocarcinoma (ICC) becoming more widely available, the prognosis after hepatic resection for ICC remains poor. Because ICC is relatively rare, the TNM staging system for ICC was finally established in the 2000s. Resection margin status and lymph node metastases are important prognostic factors after surgery for ICC; however, the true impact of wide resection margins or lymph node dissection on postoperative survival is unclear. Although adjuvant chemotherapy can improve the postoperative prognosis of patients with various types of cancer, no standard regimen has been developed for ICC. Over 50 % of patients suffer postoperative recurrence, even after curative resection, and no effective treatment for recurrent ICC has been established. Therefore, despite advances in imaging studies and hepatobiliary surgery, significant challenges remain in improving the prognosis of patients with ICC.

Objectives: A cholangiocarcinoma outbreak among workers of an offset color proof-printing department in a printing company was recently reported. It is important to understand the clinical course leading to occupational cholangiocarcinoma development for investigation of the carcinogenesis process and for surveillance and early detection. We evaluated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma., Methods: We investigated the changes in laboratory test results and diagnostic imaging presentation before the detection of cholangiocarcinoma in 2 patients because the data were available. Results The clinical courses observed in the 2 participating patients showed persistent elevation of serum γ-glutamyl transpeptidase levels with or without elevated serum levels of alanine aminotransferase and/or aspartate aminotransferase before cholangiocarcinoma detection. Dilatation of the bile ducts without tumor-induced stenosis was observed several years before cholangiocarcinoma detection and progressed gradually in both patients. The serum concentration of carbohydrate 19-9 also increased prior to cholangiocarcinoma detection in both patients. Eventually, observation of stenosis of the bile duct and a space-occupying lesion strongly suggested cholangiocarcinoma. Pathological examination of the resected specimens showed chronic bile duct injury and neoplastic lesions, such as "biliary intraepithelial neoplasia" and "intraductal papillary neoplasm of the bile duct" in various sites of the bile ducts, particularly in the dilated bile ducts., Conclusions: The changes in laboratory test results and diagnostic imaging might be related to the development of cholangiocarcinoma. It is important to monitor diagnostic imaging presentation and laboratory test results in workers with extended exposure to organic solvents.

Background/purpose: The aim of this study was to clarify the prognostic factors of intrahepatic cholangiocarcinoma (ICC) following hepatectomy and to examine the impact of lymph node metastasis on survival. This study was therefore carried out as a Project Study of the Japanese Society of Hepato-Biliary-Pancreatic Surgery., Methods: Three hundred and forty-one patients who underwent hepatectomy for ICC between 1995 and 2004 at the 9 institutions of the Medical University Hospitals were analyzed retrospectively. Multivariate regression analyses and a Kaplan-Meyer analysis were performed to identify prognostic factors., Results: Pathological lymph node metastasis was one of the significant factors affecting overall survival (hazard ratio 2.10, p < 0.001) based on the multivariate analysis. Among the patients who underwent extended lymphadenectomy beyond the hepatoduodenal ligament, the median survival of 121 patients with nodal involvement was 12.2 months. Only seven patients with nodal involvement have survived for more than 4 years., Conclusions: In the present study, preoperative carbohydrate antigen (CA) 19-9, intrahepatic metastasis, and nodal involvement were the significant independent predictors of poor prognosis by multivariate analysis. Further prospective studies may thus be needed to confirm these findings, because this study has a limitation in that it was a retrospective study with multicenter data collection.

Background: A high serum cytokeratin 19 fragment (CYFRA21-1) concentration in patients with various cancers is associated with poor prognosis. This study aimed to establish the clinical significance of preoperative serum CYFRA21-1 in patients with intrahepatic cholangiocarcinoma., Methods: CYFRA21-1, carcinoembryonic antigen (CEA), and carbohydrate antigen (CA) 19-9 concentrations were measured in sera from 71 patients with intrahepatic cholangiocarcinoma. The prognostic significance of serum CYFRA21-1 levels was assessed by univariate and multivariate analyses., Results: Analysis of the areas under the receiver operator characteristic (ROC) curves clearly showed better discrimination between intrahepatic cholangiocarcinoma and benign liver diseases for CYFRA 21-1 than for CEA or CA 19-9. Based on the maximization of the Youden's index, the optimal cut-off value was 2.7 ng ml(-1) for CYFRA 21-1 (sensitivity, 74.7%; specificity, 92.2%). The serum CYFRA21-1 concentration was related to tumor stage, since the CYFRA21-1 concentrations varied according to tumor size, vascular invasion, and number of tumors. The 3-year recurrence-free survival rates for patients with high and low concentrations of CYFRA21-1 were 25.0% and 76.2%, respectively (log-rank test, p < 0.01). The 3-year overall survival rates for patients with high and low concentrations of CYFRA21-1 were 39.4% and 63.6%, respectively (p = 0.01). On multivariate analysis, a high concentration of CYFRA21-1, nodal metastases, and a microscopic resection margin involvement were independent prognostic factors associated with both tumor recurrence and postoperative death., Conclusions: A high serum CYFRA21-1 concentration is associated with tumor progression and poor postoperative outcomes in patients with intrahepatic cholangiocarcinoma.

Background/purpose: The postoperative outcome of patients who have intrahepatic cholangiocarcinoma with lymph node metastases is extremely poor, and the indications for surgery for such patients have yet to be clearly established., Methods: The demographic and clinical characteristics of 133 patients who underwent lymph node dissection during hepatic resection of intrahepatic cholangiocarcinoma were retrospectively analyzed., Results: Multivariate analysis identified three independent prognostic factors: intrahepatic metastasis, nodal involvement, and tumor at the margin of resection. Of the patients with tumor-free surgical margins, none of the 24 patients who had both lymph node metastases and intrahepatic metastases survived for 3 years. In contrast, the survival rates for the 23 patients who had lymph node metastases associated with a solitary tumor were 35% at 3 years and 26% at 5 years., Conclusions: Surgery alone cannot prolong survival when both lymph node metastases and intrahepatic metastases are present, while surgery may provide a chance for long-term survival in some patients who have lymph node metastases associated with a solitary intrahepatic cholangiocarcinoma tumor.

Background/aims: Combined hepatocellular and cholangiocarcinoma of the liver is relatively infrequent, and its pathogenesis remains obscure. The aim of this study is to investigate its clinical and pathological features and proliferative activity., Methodology: In this study, we investigated the histopathological features, Ki-67 labeling index, and p53 immunohistochemistry of 18 surgically resected cases of combined hepatocellular and cholangiocarcinoma among 1102 consecutive cases of surgically resected primary liver cancers. All tumors were compatible with the WHO definition of this tumor. Microscopically, we classified the cases into the following three categories according to the arrangement of the hepatocellular carcinoma and cholangiocarcinoma components; (1) Type I in which hepatocellular carcinoma and cholangiocarcinoma formed nodules that could easily be distinguished from each other, (2) Type II in which the both components were finely mixed, so that the two components were almost indistinguishable, and (3) Type III in which the tumors had lobular structures with hepatocellular carcinomas existing centrally and cholangiocarcinomas existing peripherally., Results: Microscopically, the tumors were classified into type I 7 tumors, type II 5 tumors, and type III 6 tumors. In one case of type I, well differentiated hepatocellular carcinoma demonstrated cholangiocarcinoma in "nodules-in-nodules" fashion. The average of Ki-67 labeling index of hepatocellular carcinoma component of combined hepatocellular and cholangiocarcinoma was 4.4 +/- 3.4% and the index of cholangiocarcinoma component was 11.0 +/- 8.5%, which is significantly higher than that of the hepatocellular carcinoma component. On p53 immunohistochemistry, 5 of 18 cases (29.4%) were positive. In one case, the cholangiocarcinoma component was positive for p53, but the hepatocellular carcinoma component was negative. In the other 4 cases, both the hepatocellular carcinoma and cholangiocarcinoma components were positive., Conclusions: Microscopically, type III seems to be a feature of metaplasia or proliferation of bipotential progenitor cells. Metaplasia of hepatocellular carcinoma to intrahepatic cholangiocarcinoma is assumed to be one of the pathogenic pathways of combined hepatocellular and cholangiocarcinoma.

We report an unusual case of adenomyoma of the common hepatic duct mimicking bile duct cancer. A 50-year-old woman was referred to our hospital for the investigation of general fatigue. Laboratory data showed abnormal liver test results and computed tomography showed a mass lesion in the hepatic hilum and dilatation of the intrahepatic bile ducts. These findings led to a preoperative diagnosis of hilar bile duct carcinoma, and we performed a left lobectomy with resection of the extrahepatic bile duct. Macroscopically, an elevated lesion was found in the common hepatic duct, which was confirmed histologically to be an adenomyoma. Bile duct strictures are rarely caused by benign tumors of the biliary tract, such as adenomyoma. Surgical resection of the bile duct should be considered for all bile duct strictures because it is often difficult to differentiate malignant from benign lesions in this location preoperatively, and malignant cells may be present in the lesion.

Recently, it has been suggested that hepatitis C virus infection plays a role in the pathogenesis of some intrahepatic cholangiocarcinomas (ICC). We describe two patients with small ICC detected after interferon therapy for chronic hepatitis C. Case 1 was diagnosed with ICC by preoperative biopsy and underwent anterior segmentectomy of the liver, while Case 2 was diagnosed with hepatocellular carcinoma preoperatively and the tumor was diagnosed as ICC after biopsy and microwave coagulonecrotic therapy. Both patients are in good health six months and five months, respectively, after operation. It is important to monitor carefully for ICC as well as hepatocellular carcinoma in patients with chronic hepatitis C, even when interferon therapy has been carried out, since the outcome of treatment for small ICC is favorable.

Background/purpose: The Liver Cancer Study Group of Japan established a tumor-nodule-metastasis (TNM) staging system for mass-forming intrahepatic cholangiocarcinoma, with T determined by tumor number and size and vascular or serosal invasion. Serosal invasion is not considered in the designation established by the International Union Against Cancer., Methods: Sixty-three patients who underwent hepatic resection for mass-forming intrahepatic cholangiocarcinoma were investigated retrospectively, with the investigation including univariate and multivariate analyses of potential prognostic factors., Results: By log-rank test, tumor size more than 3.0 cm, vascular invasion, lymph node metastasis, intrahepatic metastasis, and involved resection margin, but not serosal invasion, were associated significantly with poor prognosis. Even in patients with serosal invasion, the postoperative outcome was much better in those without than in those with vascular invasion. Multivariate analysis identified vascular invasion, lymph node metastasis, and an involved resection margin as independent prognostic factors. When serosal invasion was excluded from tumor staging, the 5-year survival rates became more clearly stratified: 100% in those with stage I disease, 62% in those with stage II, 25% in those with stage III, and 7% for patients with stage IV., Conclusions: Serosal invasion showed no survival impact after hepatic resection for mass-forming intrahepatic cholangiocarcinoma. When serosal invasion was omitted from the TNM staging proposed by the Liver Cancer Study Group of Japan, stratification of postoperative survival between stages was more effective.

Background: Although hepatitis C virus (HCV) infection is a possible pathogenetic factor for intrahepatic cholangiocarcinoma (ICC), clinicopathologic features of ICC patients with HCV infection remain unclear., Patients and Methods: Of 50 patients with ICC treated, 19 were infected with HCV (HCV-positive group) and 38 underwent surgical treatment. Clinicopathologic features and postoperative outcome were compared between patients with and without HCV infection., Results: In 15 patients in the HCV-positive group, ICC was detected during follow-up for chronic hepatitis C. The proportion of patients who underwent curative resection was significantly higher in the HCV-positive than in the HCV-negative group, and tumors were significantly smaller in the HCV-positive than in the HCV-negative group. In the HCV-positive group, tumors were significantly smaller in patients who were followed up for chronic hepatitis C than in patients who were not followed up. Although cumulative survival rates did not differ significantly between groups, prognoses of patients with small ICC were significantly better than those with large ICC., Conclusion: Follow-up for patients with chronic hepatitis C by imaging series at regular intervals is important and provides the possibility to detect a small ICC as well as a hepatocellular carcinoma. Resection should be guided by liver function and the tumor stage in patients with HCV-associated ICC., (Copyright (c) 2005 S. Karger AG, Basel.)

A 5-cm lesion in the right hepatic lobe was detected in a 61-year-old man with chronic hepatitis C by ultrasonography. Contrast-enhanced computed tomography showed a low-density lesion with wide peripheral enhancement. Hepatic angiography revealed that the tumor had partial hypervascularity. Although serum concentrations of alpha-fetoprotein and carcinoembryonic antigen were within normal limits, an elevated concentration of carcinohydrate antigen 19-9 was detected in serum. A definitive diagnosis was not made although we strongly suspected mixed hepatocellular carcinoma and cholangiocarcinoma. Since intraoperative frozen-section examination revealed adenocarcinoma, a right hepatic lobectomy with regional lymph node dissection was performed. A histologic diagnosis of mixed hepatocellular carcinoma and cholangiocarcinoma was made because the hepatic tumor consisted of components of both hepatocellular carcinoma and cholangiocellular carcinoma, with a transitional area. Additionally, immunohistochemical examination revealed that some tumor cells in the transitional area were immunoreactive for both cytokeratin 19 and hepatocyte paraffin 1.

A 57-year-old man, who had undergone hepatic arterial infusion chemotherapy with right portal occlusion for hepatocellular carcinoma was admitted to our hospital because of severe abdominal pain. Contrast-enhanced computed tomograms revealed that most areas of the liver were not enhanced, a finding suspicious for perfusion disturbance in the liver. Angiography revealed an interrupted right hepatic artery. Arterial portograms revealed complete obstruction of the right portal vein and a small left branch of the portal vein. Despite anticoagulant therapy with urokinase for portal vein thrombosis, the patient died from hepatorenal failure. Autopsy revealed that cholangiocarcinoma occupied almost the entire parenchyma of the right lobe, although the treated hepatocellular carcinoma lesion was completely necrotic. The right hepatic artery was obstructed due to direct invasion of tumor. There were diffuse thrombi in the left portal branches surrounded by tumor infiltrating along Glisson's sheath to the peripheral portion of the left lobe.