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Objective: To review our experiences with surgery for recurrent biliary tract cancer (BTC)., Background: Few studies have reported on surgical procedures for recurrent BTC; therefore, it is unclear whether this surgery has survival benefit., Methods: Between 1991 and 2010, 606 patients had recurrences after resection of BTC (gallbladder cancer, n = 135; cholangiocarcinoma, n = 471); 74 patients underwent resection for recurrence, whereas the remaining 532 did not. The medical records were retrospectively reviewed., Results: Compared with the 532 patients without surgery for recurrence, the 74 patients with surgery had less advanced cancer, and their time to recurrence was significantly longer (1.4 vs 0.8 years; P < 0.001). A total of 89 surgical procedures for recurrence were performed in the 74 patients (1 time in 63 and ≥2 times in 11). Survival after recurrence was significantly better in the 74 patients with surgery than in the 532 without (32% vs 3% at 3 years; P < 0.001). Survival after surgery for recurrence was (1) similar between gallbladder cancer and cholangiocarcinoma; (2) significantly better in patients with initial disease-free interval of 2 or more years; (3) significantly worse in patients with chest or abdominal wall recurrences; and (4) significantly better in patients with pN0 disease in their primary cancer. Nodal status of the primary tumor and the site of initial recurrence were identified as independent prognostic factors after surgery for recurrence., Conclusions: Surgical resection for recurrent BTC can be performed safely and offers a better chance of long-term survival in selected patients.

Objective: To review our 34-year experience with 574 consecutive resections for perihilar cholangiocarcinoma and to evaluate the progress made in surgical treatment of this disease., Background: Few studies have reported improved surgical outcomes for perihilar cholangiocarcinoma; therefore, it is still unclear whether surgical treatment of this intractable disease has progressed., Methods: Between April 1977 and December 2010, a total of 754 consecutive patients with perihilar cholangiocarcinoma were treated, of whom 574 (76.1%) underwent resection. The medical records of these resected patients were retrospectively reviewed., Results: The incidence of major hepatectomies has increased, and limited resections, including central hepatectomies and bile duct resections, were rarely performed. Combined vascular resection was being used more often. Operative time has become shorter, and intraoperative blood loss has also decreased significantly. Because of refinements in surgical techniques and perioperative management, morbidity decreased significantly but was still high, with a rate of 43.1% in the last 5 years. Mortality rate has also decreased significantly (P < 0.001) from 11.1% (8/72) before 1990 to 1.4% (3/218) in the last 5 years. The ratio of advanced disease defined as pStage IVA and IVB has increased significantly from 49.4% before 2000 to 61.4% after 2001. The disease-specific survival for the 574 study patients (including all deaths) was 44.3% at year 3, 32.5% at year 5, and 19.9% at year 10. The survival was significantly better in the later period of 2001 to 2010 than in the earlier period of 1977 to 2000 (38.1% vs 23.1% at year 5, P < 0.001). For pM0, R0, and pN0 patients (n = 243), the survival in the later period was good with 67.1% at year 5, which was significantly better than that of the earlier period (P < 0.001). For pM0, R0, and pN1 patients (n = 142), however, the survival in the later period was similar to that of the earlier period (22.1% vs 14.6% at year 5, P = 0.647). Multivariate analysis revealed that lymph node metastasis was the strongest prognostic indicator., Conclusions: Surgical treatment of perihilar cholangiocarcinoma has been evolving steadily, with expanded surgical indication, decreased mortality, and increased survival. Survival for R0 and pN0 patients was satisfactory, whereas survival for pN1 patients was still poor, suggesting that establishment of effective adjuvant chemotherapy is needed.

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.

Perihilar cholangiocarcinoma is one of the most challenging diseases with poor overall survival. The major problem for anyone trying to convincingly compare studies among centers or over time is the lack of a reliable staging system. The most commonly used system is the Bismuth-Corlette classification of bile duct involvement, which, however, does not include crucial information such as vascular encasement and distant metastases. Other systems are rarely used because they do not provide several key pieces of information guiding therapy. Therefore, we have designed a new system reporting the size of the tumor, the extent of the disease in the biliary system, the involvement of the hepatic artery and portal vein, the involvement of lymph nodes, distant metastases, and the volume of the putative remnant liver after resection. The aim of this system is the standardization of the reporting of perihilar cholangiocarcinoma so that relevant information regarding resectability, indications for liver transplantation, and prognosis can be provided. With this tool, we have created a new registry enabling every center to prospectively enter data on their patients with hilar cholangiocarcinoma (www.cholangioca.org). The availability of such standardized and multicenter data will enable us to identify the critical criteria guiding therapy., (2011 American Association for the Study of Liver Diseases.)

Objective: To outline our experience with hepatectomy with simultaneous resection of the portal vein and hepatic artery for advanced perihilar cholangiocarcinoma, and to discuss the clinical significance of this challenging hepatectomy., Summary Background Data: Only a few authors reported negative results for this surgery in a very limited number of patients., Methods: We retrospectively reviewed medical records of 50 patients with advanced cholangiocarcinoma who underwent hepatectomy (left trisectionectomy in 26, left hepatectomy in 23, and right hepatectomy in 1) with simultaneous resection and reconstruction of the portal vein and hepatic artery, focusing on surgical outcome and survival., Results: The operative time was 776 +/- 191 minutes, and blood loss was 2593 +/- 1890 mL. Time of vessel resection and reconstruction was 25 +/- 19 minutes for the portal vein and 119 +/- 56 minutes for the hepatic artery. A total of 27 (54.0%) patients developed several kinds of complications, including intra-abdominal abscess (n = 13), wound infection (n = 9), bile leakage from liver stump (n = 9), and liver failure (n = 7). Relaparotomy was necessary in 5 (10.0%) patients. One (2.0%) patient died of a postoperative complication. Microscopic cancer invasion of the resected portal vein was found in 44 (88.0%) patients, while that of the resected hepatic artery was found in 27 (54.0%). The distal bile duct margin, proximal bile duct margin, and radial margin were positive for cancer in 2 (4.0%), 4 (8.0%), and 17 (34.0%) patients, respectively. Consequently, R0 resection was achieved in 33 (66.0%) patients. The 1-, 3-, and 5-year survival rates were 78.9%, 36.3%, and 30.3%, respectively. Survival for 30 patients with pM0 disease who underwent R0 resection was better, being 40.7% at the 3- and 5-year time points., Conclusion: Major hepatectomy with simultaneous resection and reconstruction of the portal vein and hepatic artery is technically demanding. However, this surgery can be performed with acceptable mortality by an experienced surgeon and offers a better chance of long-term survival in selected patients.

Objective: To review our surgical experience with hilar cholangiocarcinoma in the "new era.", Methods: The medical records of 428 patients with hilar cholangiocarcinoma who underwent treatment between 2001 and 2008 at the First Department of Surgery, the Nagoya University Hospital, were retrospectively reviewed., Results: Of the 428 patients, 298 (70%) underwent surgical resection (R0, n = 220; R1, n = 70; R2, n = 8). Portal vein resection was performed in 111 (37%) patients, and hepatic artery resection was performed in 53 (18%) patients. Several different types of postoperative complications occurred in a total of 129 (43%) patients and led to 6 (2%) deaths. Of the 298 resected tumors, 206 (69%) were extrahepatic type tumors, and the remaining 92 (31%) were intrahepatic type tumors. Using the Bismuth classification criteria, we identified 15 (5%) type I, 21 (7%) type II, 120 (40%) type III, and 142 (48%) type IV tumors. The overall 1-, 3-, and 5-year survival rates for all 298 patients were 77, 49, and 42%, respectively. The survival rates were highest among the 197 patients with pM0 disease who underwent R0 resection. Patients in this subgroup had a 5-year survival rate of 52%. The 5-year overall survival rate for the 55 patients with pM0 disease who underwent R1 resection was 32%. The survival rate for patients who had pM1 disease and/or underwent R2 resection was the worst of all the subgroups, but was nonetheless significantly better than that of patients with unresectable tumors. The survival rate for patients who underwent vascular resection and reconstruction was unexpectedly better, with 5-year survival of >20%., Conclusions: The surgical approach to hilar cholangiocarcinoma has become more challenging in the new era. Nevertheless, surgical outcomes have been improved, with decreased morbidity and mortality rates being observed. Long-term survival has also steadily improved. These findings indicate that biliary surgeons should use an aggressive surgical strategy to treat this intractable disease.

Background: A few authors have reported the value of multidetector row CT (MDCT) for evaluating the longitudinal extent of cholangiocarcinoma. They have not focused on CT attenuation of a tumor and actual tumor extent along the bile ducts. We designed the present study to analyze attenuation., Methods: Between January 2003 and July 2005, 113 consecutive patients with cholangiocarcinoma underwent a surgical resection following MDCT. Of these MDCT studies, 73 (perihilar cholangiocarcinoma, n = 62; middle and distal cholangiocarcinoma, n = 11) were suitable for analysis, and the patients were enrolled in the study. Patients were divided according to tumor hypoattenuation and hyperattenuation on MDCT. Histologic differentiation, desmoplastic reaction, and vascular density were microscopically compared with the tumor attenuation to differentiate the characteristics of the attenuation. The extent of cancer along the bile duct diagnosed by MDCT was compared with the actual extent determined by the microscopic findings., Results: Hyperattenuated tumor was observed in 40 patients. There was no difference in histologic differentiation, desmoplastic reaction, or vascular density between the hyperattenuated and hypoattenuated cholangiocarcinomas. Neither the proximal nor the distal borders between the normal and thickened bile duct wall could be determined in the 33 patients with hypoattenuated tumor; in contrast, an accurate assessment of extent of tumor was obtained in 76% of the proximal borders and 82% of the distal borders in the 40 patients with hyperattenuated tumor., Conclusions: Although the cause of the difference between the hyperattenuated and hypoattenuated cholangiocarcinoma still is unclear, MDCT can be an alternative to direct cholangiography in selected patients with hyperattenuated cholangiocarcinoma.

Background: Perineural invasion is commonly observed in biliary tract cancer and is an independent prognostic factor. Since intrahepatic cholangiocarcinoma (ICC) develops from biliary epithelia in the liver, ICC may share the same characteristics in terms of the prognostic implications of perineural invasion. The aim of this study was to evaluate the clinical significance of perineural invasion in ICC., Methods: A total of 59 patients with ICC who underwent hepatectomy were retrospectively reviewed. The numbers of nerves with and without tumor involvement were counted. The perineural invasion index (PNI) was calculated as the number of involved nerves divided by the total number of nerves examined. Predictors for perineural invasion and prognostic factors were analyzed., Results: Perineural invasion was observed in 47 of 59 (80%) patients, and the median PNI was 0.082. The macroscopic tumor appearance and tumor location were significantly associated with perineural invasion (p = 0.013 and 0.032, respectively). Univariate and multivariate analyses (excluding seven in-hospital deaths) revealed that histologic grade, the presence of perineural invasion, nodal metastasis, and intrahepatic metastasis were independent prognostic factors. The survival rate of the patients with (n = 42) or without (n = 10) perineural invasion was 17 and 80% at 3 years; and 17 and 70% at 5 years, respectively (p = 0.001)., Conclusion: Perineural invasion is frequently found in patients with ICC and is an independent prognostic factor. ICC is an aggressive tumor similar to other biliary tract cancers. Because perineural invasion is a histologic marker of aggressiveness, it potentially has a role as a determinant of patient selection for adjuvant therapy.

Background: Although knowledge of cancer invasion of the portal bifurcation is vitally important in planning an operation for perihilar cholangiocarcinoma, the diagnostic capability of multidetector-row computed tomography (MDCT) for this purpose has not been assessed. We evaluated how well MDCT could identify cancer invasion of the portal bifurcation by perihilar cholangiocarcinoma., Methods: Between April 2003 and June 2005, perihilar cholangiocarcinoma was resected in 87 patients, 83 of whom underwent MDCT within 1 month before the surgery. Three-dimensional volume-rendered (3DVR) and multiplanar reformation (MPR) images were examined for evidence of portal vein invasion. Agreement with intraoperative and pathologic findings was assessed. Portal bifurcation findings by 3DVR and MPR were classified into no portal vein stenosis, unilateral stenosis, or more extensive stenosis, and also into tumor contact with the bifurcation in no, one of two, or two projections., Results: For macroscopic portal vein invasion, sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy were 81.5, 91.1, 81.5, 91.1, and 88.0% in 3D portography and 96.3, 92.6, 86.7, 98.1, and 94.0% in MPR, respectively. Findings by both 3DVR and MPR were significantly correlated with depth of cancer invasion (p < 0.001)., Conclusion: MDCT is useful in assessing cancer invasion of the portal vein bifurcation by perihilar cholangiocarcinoma.

Background and Aim: To examine associations between lifestyle risk factors and intrahepatic stone (IHS), we conducted a case-control study in Taiwan, which has the highest incidence of IHS in the world., Methods: Study subjects were 151 patients newly diagnosed with IHS at Chang Gung Memorial Hospital between January 1999 and December 2001. Two control subjects per case were selected randomly from patients who underwent minor surgery at the same hospital and from family members or neighbors of the hospital staff. Controls were matched to each case by age and gender. Information on lifestyle factors was collected using a self-administered questionnaire. Strength of associations was assessed using odds ratios derived from conditional logistic models., Results: Female patients were significantly shorter than female controls. Compared to subjects with two or fewer children, odds ratios for those with six or more children were 20.4 in men (95% confidence interval, 1.89-221) and 2.82 (0.97-8.22) in women. Increasing level of education lowered the risk of intrahepatic stone (trend P = 0.004 for men and < 0.0001 for women). Women who had consumed ground-surface water for a long period had a somewhat increased risk (trend P = 0.05)., Conclusion: Lower socioeconomic status and poor hygiene may be involved in the development of intrahepatic stones.

Objective: To clarify the optimal surgical strategy for Bismuth type I and II hilar cholangiocarcinomas., Summary Background Data: Local or hilar resections is often performed for Bismuth type I and II tumors; however, reported outcomes have been unsatisfactory with a high recurrence and low survival rate. To improve survival, some authors have recommended right hepatectomy. However, the clinical value of this approach has not been validated., Methods: Records of 54 consecutive patients who underwent resection of a Bismuth type I or II hilar cholangiocarcinoma were analyzed retrospectively. Through 1996, bile duct resection or the smallest necessary hepatic segmentectomy was performed. Beginning in 1997, choice of resection was based on the cholangiographic tumor type. For nodular or infiltrating tumor, right hepatectomy was indicated; for papillary tumor, bile duct resection with or without limited hepatectomy was chosen., Results: Right hepatectomy was performed in 5 (20.8%) of 24 patients through 1996 and was done in 22 (73.3%) of 30 patients from 1997 (P = 0.0003). In patients without pM1 disease, R0 resection was achieved more frequently in the later period than in the earlier period (23 of 24 = 95.8% vs. 13 of 21 = 61.9%, P = 0.0073), which lead to better survival (5-year survival, 44.3% vs. 25.0%, P = 0.0495). In the 31 patients with nodular or infiltrating tumor, who tolerated surgery and did not have pM1 disease, survival was better in the 18 patients who underwent right hepatectomy than in those who did not (5-year survival, 62.9% vs. 23.1%, P = 0.0030). In cases of papillary tumor, bile duct resection with or without limited hepatectomy was sufficient to improve long-term survival., Conclusions: The surgical approach to Bismuth type I and II hilar cholangiocarcinomas should be determined according to cholangiographic tumor type. For nodular and infiltrating tumors, right hepatectomy is essential; for papillary tumor, bile duct resection with or without limited hepatectomy is adequate.

Objective: We present our experiences with infraportal bile duct of the caudate lobe (B1) and discuss surgical implications of this rare variation., Summary Background Data: Although various authors have investigated biliary anatomy at the hepatic hilum, an infraportal B1 (joining the hepatic duct caudally to the transverse portion of the left portal vein) has not been reported., Methods: Between January 1981 and December 2005, 334 patients underwent hepatectomy combined with caudate lobectomy for perihilar cholangiocarcinoma. Four of them (1.2%) had infraportal B1 and were investigated clinicoanatomically., Results: All infraportal B1 were B1l, draining Spiegel's lobe; no infraportal B1r (draining the paracaval portion) or B1c ducts (draining the caudate process) were found. The infraportal B1l joined the common hepatic duct or the left hepatic duct. Three patients underwent right trisectionectomy with caudate lobectomy; for one, in whom preoperative diagnosis was possible, combined portal vein resection and reconstruction were performed before caudate lobectomy to resect the caudate lobe en bloc without division of infraportal B1. For the other 2 patients, the infraportal B1 was divided to preserve the portal vein, and then the caudate lobe was resected en bloc. The fourth patient underwent right hepatectomy with right caudate lobectomy; the cut end of the infraportal B1 showed no cancer by frozen section, so the bile duct was ligated and divided to preserve the left caudate lobe., Conclusion: Infraportal B1 can cause difficulties in performing right-sided hepatectomy with caudate lobectomy or harvesting the left side of the liver with the left caudate lobe for transplantation. Hepatobiliary and transplant surgeons should carefully evaluate biliary anatomy at the hepatic hilum, keeping this variation in mind.

We investigated the role of Nek2, a member of the serine/threonine kinase family, Nek, in the tumorigenic growth of cholangiocarcinoma cells. Expression of Nek2 is elevated in cholangiocarcinoma in a tumor-specific manner as compared with that of normal fibroblast cells. Expression of exogenous Nek2 did not perturb the growth of cholangiocarcinoma cells, whereas suppression of the Nek2 expression with siRNA resulted in the inhibition of cell proliferation and induced cell death. In xenograft-nude mouse model, s.c. injection of Nek2 siRNA around the tumor nodules resulted in reduction of tumor size as compared with those of control siRNA injection. In peritoneal dissemination model, Nek2 siRNA-treated mice showed statistically longer survival periods in comparison with those of the control siRNA-treated mice. Taken together, our data indicate a pivotal role of Nek2 in tumorigenic growth of cholangiocarcinoma.

Background: Distal bile duct cancer often invades the pancreas and/or duodenum. Invasion of the pancreas is defined as a T3 and that of the duodenum as a T4 tumor in the T classification of the American Joint Committee on Cancer (AJCC). The aim of this study was to assess whether this T classification is rational from the viewpoint of prognostic power., Method: Ninety-five patients with distal bile duct cancer were retrospectively analyzed according to the current T classification of the AJCC., Results: The main determinant of pT3 (n = 32) and pT4 (n = 30) was pancreatic and duodenal invasion, respectively, and the survival rates for patients with pT3 and pT4 are similar (p = 0.595). Duodenal invasion was present in 39% of the patients with pancreatic invasion, whereas pancreatic invasion was observed in 86% of those with duodenal invasion. The survival for patients with pancreatic invasion was not significantly different (p = 0.283) whether or not there was concomitant duodenal invasion (n = 19 and n = 37, respectively). Multivariate analysis identified venous invasion, distant metastasis, histologic grade, and pancreatic invasion as independent prognostic factors., Conclusion: Although duodenal invasion usually occurs after pancreatic invasion, it is not a significant prognostic factor while pancreatic invasion is. The current T classification should be revised since it expresses tumor extension but does not reflect a survival in distal bile duct cancer.

The clinical application of portal vein embolization (PVE) has contributed to improving the postoperative outcome of hilar cholangiocarcinoma. The enlarged nonembolized lobe after PVE protects the patient from postoperative hepatic failure, due to the increased functional reserve, and shortens the hospital stay. Although numerous reports have shown beneficial effects of PVE on postoperative outcome after extended hepatectomy, no randomized controlled study has been performed so far. It is urgent to establish a "gold standard" of PVE, because the indications, approach to the portal vein, types of embolic materials, and methods used to evaluate the function of the future liver remnant are variable among institutions. The indications and procedures of PVE for hilar cholangiocarcinoma may be different from those for hepatocellular carcinoma or colorectal metastasis, because, in many patients with hilar cholangiocarcinoma, biliary cancer is associated with biliary obstruction and cholangitis. This review article summarizes the contribution of PVE to the outcome of postoperative management in patients with hilar cholangiocarcinoma needing extended hepatectomy. We also describe our PVE procedure, which has been established from our experience of more than 240 cases of biliary cancer. Furthermore, the drawbacks of PVE, which may reduce the pool of candidates for surgery, are also discussed.

Objectives: We set out to clarify the clinicopathologic characteristics of colorectal liver metastases with macroscopic intrabiliary tumor growth and to determine optimal surgical management., Methods: Over 15 years, 6 of 103 patients undergoing hepatectomy for colorectal liver metastases had macroscopic intrabiliary tumor growth and were analyzed retrospectively., Results: We performed 11 operations for the 6 patients, consisting of 10 hepatectomies (including 1 hepatopancreatoduodenectomy) and 1 pancreatoduodenectomy. Three patients survived more than 5 years: 1 died of pulmonary emphysema with no sign of recurrence 101 months after initial hepatectomy; the 2 others were alive with no sign of recurrence at 74 and 145 months after initial hepatectomy. Median survival time of all 6 patients was 87.5 months. Histologically, intrabiliary tumor growth had two components: intraluminal and intraepithelial extension. In the proximal direction, distance between these two components ranged from 4-10 mm., Conclusion: Aggressive surgical treatment can improve chances of long-term survival for patients with macroscopic intrabiliary growth of colorectal liver metastasis. Although nonanatomic limited resection is a common procedure for colorectal liver metastasis, anatomic hepatobiliary resection is recommended.

Background: Injury to the duct of Luschka is associated with biliary fistula from the gallbladder bed after cholecystectomy. However, few studies have reported on the detailed anatomy. We elucidated the anatomy and frequency of the duct of Luschka, Methods: A total of 128 specimens from patients who underwent right hepatectomy or more extensive right-sided liver resection between February 1992 and December 2003 were examined. Specimens were fixed in formalin, and serial sections were prepared to trace the course of the bile ducts from the subsegmental branch level., Results: The duct of Luschka was observed in 6 (4.6%) specimens. The sites of confluence were as follows: right anterior inferior dorsal branch (2 patients), right anterior branch (2 patients), right hepatic duct (1 patient), and common hepatic duct (1 patient). The upstream end was located in the liver parenchyma of the right anterior inferior dorsal subsegment (5b) and connective tissue of the gallbladder bed in 4 and 2 specimens, respectively., Conclusions: The duct of Luschka never crosses the segmental (5b) border. Therefore, its upstream region may not be injured by segmentectomy or more extensive liver resection. However, it is possible to injure the duct of Luschka at the common hepatic duct, even if right-sided hepatectomy is performed, as the sites of confluence included the common hepatic duct.

Tumor-stromal interactions are important for the progression of malignant tumors. The purpose of the present study was to examine interactions of cholangiocarcinoma (CC) cells and stromal fibroblasts with respect to stromal-derived factor-1 (SDF-1) and transforming growth factor (TGF)-beta1. Two cell lines of CC (HuCCT-1 and CCKS-1) and WI-38 fibroblast cell line were used for cell culture, and 12 CC tissue specimens for immunohistochemical studies. Invasion of CC cells was increased significantly by the supernatant from fibroblast cultures, but not by the supernatant from fibroblasts cocultured with CC cells. Expression of SDF-1 in cultured fibroblasts was downregulated by TGF-beta1 treatment, and coculture with CC cells and anti-TGF-beta1 neutralizing antibody restored the decreased SDF-1 expression, suggesting that TGF-beta1 secreted from CC cells might have reduced the expression of SDF-1 by fibroblasts and might have reduced the increased invasion of CC cells induced by the supernatant from fibroblasts. Immunohistochemical expression of TGF-beta1 in CC cells was focal or negative and that of SDF-1 was evident in stromal fibroblasts at the invasive front of CC. In conclusion, local mutual influence of TGF-beta1 secreted from carcinoma cells and SDF-1 expressed by stromal fibroblasts may be involved in invasion of CC cells.

Intrahepatic cholangiocarcinoma (ICC) is highly fatal because of early invasion, widespread metastasis, and lack of an effective therapy. We examined roles of CXCR4 and its ligand, stromal cell-derived factor (SDF)-1, in migration of ICC with respect to tumor-stromal interaction by using two ICC cell lines, a fibroblast cell line (WI-38), and 28 human ICC tissues. The two ICC cell lines expressed CXCR4 mRNA and protein, and WI-38 fibroblasts expressed SDF-1 mRNA and protein. Migration of cultured ICC cells in Matrigel was induced by co-culture with WI-38 fibroblasts and by incubation with SDF-1. Anti-SDF-1 antibody suppressed migration, demonstrating that SDF-1 released from WI-38 fibroblasts was responsible for this migration. Tumor necrosis factor (TNF)-alpha pretreatment of ICC cells up-regulated CXCR4 mRNA and protein expression in a concentration-dependent manner. Administration of SDF-1 and TNF-alpha increased synergistically ICC cell migration, which was suppressed by the CXCR4 antagonist AMD3100. In ICC tissue, TNF-alpha was mainly expressed in infiltrated macrophages, CXCR4 in ICC cells, and SDF-1 in stromal fibroblasts. In conclusion, the interaction of SDF-1 released from fibroblasts and CXCR4 expressed on ICC cells may be actively involved in ICC migration, and TNF-alpha may enhance ICC cell migration by increasing CXCR4 expression. CXCR4 could be a therapeutic target to prevent ICC invasion.

Objective: To assess clinical benefit of portal vein embolization (PVE) before extended, complex hepatectomy for biliary cancer., Summary Background Data: Many investigators have addressed clinical utility of PVE before simple hepatectomy for metastatic liver cancer or hepatocellular carcinoma, but few have reported PVE before hepatectomy for biliary cancer due to the limited number of surgical cases., Methods: This study involved 240 consecutive patients with biliary cancer (150 cholangiocarcinomas and 90 gallbladder cancers) who underwent PVE before an extended hepatectomy (right or left trisectionectomy or right hepatectomy). All PVEs were performed by the "ipsilateral approach" 2 to 3 weeks before surgery. Hepatic volume and function changes after PVE were analyzed, and the outcome also was reviewed., Results: There were no procedure-related complications requiring blood transfusion or interventions. Of the 240 patients, 47 (19.6%) did not undergo subsequent hepatectomy. The incidence of unresectability was higher in gallbladder cancer than in cholangiocarcinoma (32.2% versus 12.0%, P < 0.005). The remaining 193 patients (132 cholangiocarcinomas and 61 gallbladder cancers) underwent hepatectomy with resection of the caudate lobe and extrahepatic bile duct (n = 187), pancreatoduodenectomy (n = 42), and/or portal vein resection (n = 63). Seventeen (8.8%) patients died of postoperative complications: mortality was higher in gallbladder cancer than in cholangiocarcinoma (18.0% versus 4.5%, P < 0.05); and it was also higher in patients whose indocyanine green clearance (KICG) of the future liver remnant after PVE was <0.05 than those whose index was >or=0.05 (28.6% versus 5.5%, P < 0.001). The 3- and 5-year survival after hepatectomy was 41.7% and 26.8% in cholangiocarcinoma and 25.3% and 17.1% in gallbladder cancer, respectively (P = 0.011). In 136 other patients with cholangiocarcinoma who underwent a less than 50% resection of the liver without PVE, a mortality of 3.7% and a 5-year survival of 27.6% were observed, which was similar to the 132 patients with cholangiocarcinoma who underwent extended hepatectomy after PVE., Conclusions: PVE has the potential benefit for patients with advanced biliary cancer who are to undergo extended, complex hepatectomy. Along with the use of PVE, further improvements in surgical techniques and refinements in perioperative management are necessary to make difficult hepatobiliary resections safer.

Background/aims: Two types of neoplastic lesions preceding invasive intrahepatic cholangiocarcinoma (ICC) are identified: a flat-type neoplastic lesion called 'biliary intraepithelial neoplasia (BilIN)' and an intraductal papillary neoplasm of the bile duct (IPN-B). Multi-step carcinogenesis has been suggested in both lesions, although phenotypic changes during this process remain unclarified., Methods: We immunohistochemically examined expression patterns of MUC1, MUC2, MUC5AC, cytokeratin 7 (CK7), and CK20 in BilIN, IPN-B, and ICC in 110 cases of hepatolithiasis., Results: Thirty-seven cases of ICC in hepatolithiasis were divided into 18 tubular adenocarcinomas with BilIN, 10 tubular adenocarcinomas with IPN-B and nine colloid carcinomas with IPN-B. Carcinogenesis via BilIN was characterized by MUC2-/CK7+/CK20-with increasing MUC1 expression. IPN-B was characterized by the intestinal phenotype (MUC2+/CK20+), and carcinogenesis leading to tubular adenocarcinoma was associated with increasing MUC1 expression and that to colloid carcinoma with MUC1-negativity. Pathological stages of tubular adenocarcinoma of ICC with BilIN or IPN-B were more advanced than those of colloid carcinoma with IPN-B., Conclusions: Immunophenotypes of MUCs and cytokeratins might characterize three cholangiocarcinogenetic pathways in hepatolithiasis. Increased expression of MUC1 in BilIN and also IPN-B is associated with tubular adenocarcinoma, while colloid carcinoma in IPN-B is characterized by MUC1-negativity and less advanced pathologic stages.

Background: The techniques of right hepatic trisectionectomy are now standardized in patients with hepatocellular or metastatic carcinoma, but not in those with hilar cholangiocarcinoma., Methods: Under preoperative diagnosis of hilar cholangiocarcinoma, 8 patients underwent "anatomic" right hepatic trisectionectomy with en bloc resection of the caudate lobe and the extrahepatic bile duct, in which the bile ducts of the left lateral section were divided at the left side of the umbilical fissure following complete dissection of the umbilical plate., Results: Liver resection was successfully performed, and all patients were discharged from the hospital in good condition, giving a mortality of 0%. All patients were histologically diagnosed as having cholangiocarcinoma. The proximal resection margins were cancer-negative in 7 patients and cancer-positive in 1 patient. Four patients with multiple lymph node metastases died of cancer recurrence within 3 years after hepatectomy. One patient died of liver failure without recurrence 42 months after hepatectomy. The remaining 3 patients without lymph node metastasis are now alive after more than 5 years., Conclusions: Anatomic right hepatic trisectionectomy with caudate lobectomy can produce a longer proximal resection margin and can offer a better chance of long-term survival in some selected patients with advanced hilar cholangiocarcinoma.

Background: A few investigators have evaluated the TNM classification for perihilar cholangiocarcinoma. The new sixth edition of the American Joint Committee on Cancer (AJCC)/Internal Union Against Cancer (UICC) staging system focuses on vascular invasion and regional lymph node metastasis., Methods: For 166 patients with perihilar cholangiocarcinoma undergoing R0 resection, survival curves stratified according to TNM classifications were compared between fifth and sixth editions., Results: The previous T3 now is divided into T3 and T4. Most new pT4 patients had invasion of the portal bifurcation; their survival was poorer than that for new pT3 patients. The 5-, 10-, and 15-year survival rates were worse in the previous stage III than in the previous stage IVA, although the difference fell short of significance. The previous stage IVA (T3 Any NM0) is divided into new stages: IIA (T3N0M0), IIB (T1-3N1M0), and III (T4 Any NM0). All patients in stage III had invasion of the portal bifurcation. Survival was similar between stages IA, IB, and IIA, while patients with T4N0M0 tumors survived longer than those with T4N1M0 tumors and similarly to those with stage IIB tumors., Conclusions: The sixth edition provided improved prediction of survival in patients with perihilar cholangiocarcinoma; for still better prediction, cancer invasion of the portal bifurcation and regional lymph node metastasis should be weighted equally.

Background and Aims: The clinical value of synbiotics in surgical patients remains unclear. The aim of this study was to investigate the effect of synbiotics on intestinal integrity and microflora, as well as on surgical outcome, in patients undergoing high-risk hepatectomy., Methods: Fifty-four patients with biliary cancer were randomly allocated to two groups before hepatectomy. One group received postoperative enteral feeding that included synbiotics; the other received enteral feeding only. Lactulose/mannitol (L/M) ratio, serum diamine oxidase (DAO) activity, and fecal microflora and organic acid concentrations were determined. Postoperative infectious complications were recorded., Results: Of the 54 patients, 44 completed the trial (21 receiving synbiotics and 23 others as controls). Postoperative changes in L/M ratios and serum DAO activities were identical between the two groups. Numbers of beneficial bacteria increased in the synbiotics group after surgery but decreased in controls. Numbers of harmful microorganisms decreased in the synbiotics group but increased in controls. Total organic acid concentrations increased in the synbiotics group but decreased in controls. Incidence of infectious complications was 19% (4/21) in the synbiotics group and 52% (12/23) in controls (P<0.05). All study patients tolerated surgery (mortality 0%)., Conclusions: Synbiotics, combined with early enteral nutrition, can reduce postoperative infections. This beneficial effect presumably involves correction of an intestinal microbial imbalance induced by surgical stress.

Biliary lining epithelia of the bile ducts in biliary diseases are known to have intraepithelial atypical/proliferative lesions related to the development of cholangiocarcinoma. The purpose of the present study was to determine the histological criteria for these lesions based on interobserver agreement. Digital images of 30 intraepithelial atypical/proliferative lesions in the stone-containing intrahepatic bile ducts of hepatolithiasis (30 cases) were sent to 10 pathologists. At first, 10 pathologists made a diagnosis (either of reactive/regenerative change, low-grade or high-grade biliary intraepithelial neoplasia (BilIN-1 and BilIN-2), or in situ carcinoma (BilIN-3)) based on their own criteria. The histological criteria for these four lesions were then determined, and the digital images of the same lesions with proposed criteria were re-distributed. Interobserver agreement on these four lesions was slightly improved (kappa = 0.44, first diagnosis; 0.49, second diagnosis) and intraobserver agreement was 'almost perfect' (kappa = 0.82 at both first and second diagnosis). Interobserver agreement between BilIN-1 and BilIN-2 and that between BilIN-2 and BilIN-3 were 'moderate', although the agreement between regenerative/reactive change and BilIN-1 was 'fair'. In this report, we propose histological criteria for reactive/regenerative change, BilIN-1, BilIN-2 and BilIN-3. Improvement of interobserver agreement suggests their applicability in diagnostic and research fields.

Tumors with clinically recognizable mucin production arising from bile duct, "mucin-producing bile duct tumors (MPBTs)," have not been studied yet for their pathologic features and classification in details. The clinical findings of MPBT have a lot of similarities to those of pancreatic intraductal papillary-mucinous neoplasm. In the present study, we examined 30 MPBTs and classified them into two distinct morphologic categories: 22 cases of "columnar type" composed of pseudostratified columnar cells with basophilic cytoplasm and columnar nuclei and 8 cases of "cuboidal type" composed of pancreaticobiliary and/or oncocytic pattern. Pancreaticobiliary pattern showed abundantly branched papillae lined by acidophilic cuboidal cells with round nuclei, whereas oncocytic pattern was characterized by intraepithelial lumina and cribriform pattern composed of abundant oxyphilic cells with round nuclei, and these patterns overlapped frequently. There were significant differences in the clinicopathologic findings including macroscopic findings, morphometric data, mucin expression profiles (MUC2 expression in columnar type and MUC6 expression in cuboidal type), and cell proliferative activities between columnar type and cuboidal type. Patients with columnar type showed significantly poorer survival than those with cuboidal type. We concluded that columnar type and cuboidal type of MBPTs belong to different lineage of neoplasm and that they are counterparts of "intestinal type" and "pancreaticobiliary type" of pancreatic intraductal papillary-mucinous neoplasm, respectively.

Objective: To better determine the role of portal vein resection and its effect on survival, as well as to appreciate the impact of portal vein invasion on prognosis in hilar cholangiocarcinoma., Summary Background Data: Hepatectomy with portal vein resection is sometimes performed for locally advanced hilar cholangiocarcinoma. However, the significance of microscopic invasion of the portal vein has not been determined., Methods: Medical records of 160 patients with hilar cholangiocarcinoma who underwent macroscopically curative hepatectomy with (n = 52) or without portal vein resection (n = 108) were reviewed. Invasion of the portal vein was assessed histologically on the surgical specimen, and results were correlated with clinicopathologic features and survival., Results: Surgical mortality, including all hospital deaths, was similar in patients who did and did not undergo portal vein resection (9.6% vs. 9.3%), but the primary tumor was more advanced in patients who underwent portal vein resection. Histologically, no invasion was found in 16 (30.8%) of resected portal veins. However, dense fibrosis adjacent to the portal vein was common, and the mean distance between the leading edge of cancer cells and the adventitia of the portal vein was 437 +/- 431 mum. The prognosis was worse in patients with than without portal vein resection (5-year survival, 9.9% vs. 36.8%; P < 0.0001). The presence or absence of microscopic invasion of the resected portal vein did not influence survival (16.6 months in patients with microscopic invasion vs. 19.4 months in those without; P = 0.1506). Multivariate analysis identified histologic differentiation, lymph node metastasis, and macroscopic portal vein invasion as independent prognostic factors., Conclusions: Microscopic invasion of the portal vein may be misdiagnosed clinically in patients with hilar cholangiocarcinoma. However, the distance between tumor and adventitia is so narrow that curative resection without portal vein resection is unlikely to be possible. Gross portal vein invasion has a negative impact on survival, and hepatectomy with portal vein resection can offer long-term survival in some patients with advanced hilar cholangiocarcinoma.

Background & Aims: In hepatolithiasis, chronic proliferative cholangitis may influence the progression of the disease. Prostaglandin (PG) E(2) experimentally causes morphologic changes to intrahepatic bile ducts, analogous to the changes found in cholangitis. This study was designed to gain an understanding of the involvement of PGE(2) and PGE receptor (EP) subtypes in the development of cholangitis., Methods: The expression levels of secretory-type group IIA phospholipase A(2) (sPLA(2)-IIA) and cyclooxygenase (COX)-2 as well as EP subtypes were determined in the bile ducts with change of cholangitis. In in vitro experiments, growth promotion and mucin secretagogue properties of biliary epithelial cells in response to EP-selective agonists or antagonists were studied., Results: The messenger RNA (mRNA) level of sPLA(2)-IIA and the protein and mRNA levels of COX-2 were significantly increased in the bile ducts of patients with hepatolithiasis compared with the levels of the bile ducts of control subjects. These changes were associated with a concomitant increase in PGE(2) and total mucin concentrations in the bile. The mRNAs of EP subtypes EP(2), EP(3), and EP(4) but not EP(1) were amplified in the bile ducts. Treatment with an EP(4)-selective agonist (ONO-AE1-329) caused a dose-dependent increase in DNA synthesis, colony number, and mucin secretion in the cells. Conversely, treatment with an EP(4)-selective antagonist (ONO-AE3-208) abolished the biological effects of PGE(2) on the cells., Conclusions: In hepatolithiasis, an enhanced synthesis of sPLA(2)-/COX-2-derived PGE(2) and its actions mediated via the EP(4) receptor in the bile ducts may be of pathobiological significance for chronic proliferative cholangitis.

Deleted in malignant brain tumor-1 (DMBT1) is a mucin-like molecule participating in mucosal immune defense. Given that bovine gallbladder mucin, which accelerates cholesterol crystallization, is a DMBT1 homolog, DMBT1 expression was examined immunohistochemically in biliary epithelial cells in livers with hepatolithiasis (N = 25), primary sclerosing cholangitis (N = 7), large bile duct obstruction (N = 12), and control normal livers (N = 10). DMBT1 protein was determined in the hepatic bile samples of hepatolithiasis (N = 12) and other hepatobiliary diseases (N = 8) by immunoblot. While DMBT1 was faintly expressed in normal livers (20%), it was significantly augmented in hepatolithiasis (76%) (P < 0.05). DMBT1 was mildly expressed in primary sclerosing cholangitis and large bile duct obstruction. DMBT1 protein was detected frequently in hepatic bile samples of hepatolithiasis (50%) (P < 0.05), but in the other bile samples. The percentage of cholesterol in intrahepatic calculi was significantly higher in the patients with DMBT1-positive bile. Augmented expression and secretion of DMBT1 in intrahepatic large bile ducts in hepatolithiasis suggests its role in lithogenesis.

Background: The dorsal subsegmental intrahepatic bile duct in the right anterior superior segment (B8c) sometimes joins the posterior sectorial duct. In such cases it can be misidentified as the right posterior superior segmental duct (B7). However, there are no published studies on the confluent pattern of B8c., Materials and Methods: We studied B8c in the resected liver of 107 patients (65 with bile duct carcinoma and 42 with gallbladder carcinoma) who had undergone right hepatectomy or more extensive right-sided liver resection., Results: B8c was identified in all cases. It joined the right posterior sectorial duct or B7 in 18 cases (16.8%). In 12 cases B8c joined independently the posterior sectorial duct or B7. In 6 cases B8c joined the posterior sectorial duct after making the common duct with the lateral subsegmental duct in the anterior superior or anterior inferior segment (B8b or B5c)., Conclusions: B8c does not join the anterior sectorial bile duct in every sixth case.

A 63-year-old man was admitted to a community hospital complaining of fever and epigastric pain. He had undergone cholecystectomy and choledocholithotomy with retrograde transhepatic biliary drainage 7 years previously. Referred to our hospital after demonstration of hepatolithiasis by computed tomography, he underwent further imaging that showed a dilated left lateral anterior segmental bile duct (B3) with hepatolithiasis. After he underwent percutaneous transhepatic biliary drainage via the B3 segmental bile duct, cholangiography performed through the drainage catheter revealed a biliary stricture at the confluence of B3 associated with intrahepatic stones. percutaneous transhepatic cholangioscopy showed a stricture and a cholangioscopic biopsy specimen contained no malignant cells. After performing cholangioscopic lithotomy, an endoprosthesis was inserted and connected to a subcutaneously placed reservoir. Repeat percutaneous transhepatic cholangioscopy 10 months later demonstrated a decreased degree of the stricture, so the endoprosthetic catheter could be removed. Retrospective review of computed tomography images obtained just after the first operation indicated that the retrograde transhepatic biliary drainage catheter had passed close to the B3, and that intrahepatic bile duct dilation was not present. Therefore, we suspect that biliary stricture was caused by an old bile duct injury due to retrograde transhepatic biliary drainage catheter placement. Percutaneous transhepatic cholangioscopy effectively managed this stricture and associated hepatolithiasis.

Objective: To investigate whether immunohistochemically demonstrated lymph node micrometastasis has prognostic significance in patients with histologically node-negative (pN0) hilar cholangiocarcinoma., Summary Background Data: The clinical significance of immunohistochemically detected lymph node micrometastasis recently has been evaluated in various tumors. However, no reports have addressed this issue with regard to hilar cholangiocarcinoma., Methods: A total of 954 lymph nodes from surgical specimens of 45 patients with histologically node-negative hilar cholangiocarcinoma who underwent macroscopically curative resection were immunostained with monoclonal antibody against cytokeratins 8 and 18. The results were examined for relationships with clinical and pathologic features and with patient survival., Results: Lymph node micrometastases were detected immunohistochemically in 11 (24.4%) of the 45 patients, being found in 13 (1.4%) of 954 lymph nodes examined. Of the 13 nodal micrometastases, 11 (84.6%) were found in the N2 regional lymph node group rather than N1. Clinicopathologic features showed no associations with lymph node micrometastases. Survival curves were essentially similar between patients with and without micrometastasis. In addition, the grade of micrometastasis showed no effect on survival. The Cox proportional hazard model identified microscopic venous invasion, microscopic resection margin status, and histologic differentiation as significant prognostic factors in patients with pN0 disease., Conclusions: Lymph node micrometastasis has no survival impact in patients with otherwise node-negative hilar cholangiocarcinoma. The authors do not recommend extensive lymph node sectioning with keratin immunostaining for prognostic evaluation.

Background/purpose: We analyzed confluence patterns of intrahepatic segmental bile ducts, seeking to relate hepato-lithiasis to anatomic variation. The comparative study was completed patients with hepatolithiasis in Taiwan and Japan., Methods: Direct cholangiography was performed in 103 hepatolithiasis patients in Taiwan and 77 in Japan. Segmental ducts patterns were classified as type I, normal configuration; type II, "triad" confluence; type III, posterior segmental duct joining left hepatic duct; or type IV, distal confluence of the right posterior segmental duct., Results: Taiwanese patients had only calcium bilirubinate or black stones, and were mostly female. As overall analysis, types I, II, III, and IV were found in 61, 26, 13, and 3 patients, respectively. In Japanese, types I, II, III, and IV were found in 52, 10, 13, and 2, respectively. There was no difference between the two institutes. Since no patients in Taiwan had cholesterol calculi, Japanese patients were reanalyzed including only 58 patients with calcium bilirubinate or black stones. Differences in those populations remained insignificant., Conclusion: Anatomic variations in segmental ducts apparently do not contribute to pathogenesis of hepatolithiasis.

In some patients, bile ducts of segments 2 and 3 (B2 and B3) run caudally to the umbilical portion of the left portal vein (UP)--an infraportal course. We aimed to evaluate the frequency and clinical implications of this variation. Between January 1992 and October 2000, 108 patients underwent resection for hilar cholangiocarcinoma. The records of the 6 patients with infraportal left hepatic ducts were evaluated. An infraportal B3 was diagnosed in 6 patients (6%). No patient had an infraportal B2. An infraportal B3 could be demonstrated by computed tomography (CT) before biliary drainage, percutaneous transhepatic or endoscopic cholangiography, portography after percutaneous transhepatic biliary drainage (PTBD) via B3 and CT after PTBD via B3. Four patients (4/6) had a liver bridge covering Rex's recess (B3 not in the bridge). The incidence of the bridge in 75 comparable patients was 9/75. In conclusion, common radiologic methods are sufficient for diagnosis of abnormal biliary anatomy. The presence of a liver bridge over Rex's recess is suggestive of this variation. Separate biliary reconstruction for an infraportal branch is mandatory in an extended right hepatectomy for biliary tract cancer and may be necessary in liver transplantation with segments 2+3 grafting.

Intraductal papillary neoplasia of the liver (IPN-L) was recently proposed as the name for intraductal papillary proliferation of neoplastic biliary epithelium with a fine fibrovascular stalk resembling intraductal papillary mucinous neoplasm of the pancreas. We histochemically and immunohistochemically examined IPN-L alone or associated with hepatolithiasis, with an emphasis on the gastrointestinal metaplasia, nuclear p53 expression, and histologic progression. A total of 66 cases of IPN-L were divided into 4 groups: group 1, IPN-L with low-grade dysplasia (13 cases); group 2, IPN-L with high-grade dysplasia (20 cases); group 3, IPN-L lined with carcinoma in situ and no or microinvasion (19 cases); and group 4, group 3 with distinct invasive carcinoma (14 cases). It is suggested that IPN-L progresses from group 1 to group 4. As controls, 20 cases of nonneoplastic intrahepatic large bile ducts and 17 cases of nonpapillary invasive intrahepatic cholangiocarcinoma (ICC) were used. Biliary epithelial hypersecretion of sialomucin rather than sulfomucin was prevalent in IPN-L, and this was associated with the progression of INP-L. Immunohistochemically, cytokeratin (CK) 20 and MUC2, a gastrointestinal marker, were expressed more frequently in IPN-L than in nonneoplastic bile ducts and nonpapillary ICC (P <0.01), and their incidence were significantly increased in parallel with the progression of IPN-L (P < 0.01). In contrast, expression of CK 7, a biliary marker, was decreased in IPN-L compared with nonpapillary ICC. Nuclear p53 immunostaining was detected in 30% of IPN-L as a whole and increased in tandem with the progression of IPN-L (P < 0.01). It is suggested that IPN-L forms a spectrum of biliary epithelial neoplasia with frequent gastrointestinal metaplasia, different from the usual nonpapillary ICC, and shows stepwise progression from the perspective of mucin profile, gastrointestinal metaplasia, and p53 nuclear expression., (Copyright 2002, Elsevier Science (USA). All rights reserved.)