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We used a novel diagnostic Fourier transform (FT) algorithm of the entire extrahepatic bile duct (EHBD) measured by magnetic resonance cholangiography (MRC) to evaluate subtle deformation of bile duct lumen, indicating the malignant potential of EHBD, in patients with pancreaticobiliary maljunction (PBMJ) and in a comparative group of controls without PBMJ. From the workstation, the EHBD lumen was traced automatically and a 2D diagram cross section was measured at 0.5 mm-longitudinal intervals. The FT-based integrated power spectral density function value (FTPSDI) of the diameter or area (mm2 or mm4/Hz) and the phase value distribution entropy (PVDE) were also measured. There were 16 patients with undilated PBMJ and 7 with dilated PBMJ. The control group comprised 10 patients with a normal bile duct, 20 with bile duct carcinoma (BDC), and 1 with primary sclerosing cholangitis. Both the diameter and area of the dilated bile ducts and the ducts with early- or advanced-stage BDC were significantly greater than those of the normal duct (p

Background: Neuroma of the biliary tree is extremely rare with no more than 100 cases reported so far. They mostly present with obstructive jaundice and have been commonly described after surgery or abdominal trauma. Although involvement of the extrahepatic bile duct is far more common, occurrence in the intrahepatic ducts has not so far been reported. Case Report: We describe 3 cases of diffuse biliary tree neuroma affecting 3 females aged 53–68 years. None had a history of neurofibromatosis type1. All presented with progressive obstructive jaundice with no evidence of gallstones. A history of previous surgery was noted in 2 patients. Initial impression on clinical and imaging examination was highly suspicious for bile duct carcinoma in 2 patients. Histology showed diffuse neuromatous proliferation replacing and thickening the bile duct walls. The third patient had concurrent neuroma and recurrent cholangiocarcinoma causing great clinical confusion as initial biopsy showed only benign neuroma, but CA 19-9 was steadily increasing, necessitating a second biopsy which then confirmed recurrent carcinoma. Conclusion: This uncommon cause of long-distance bile duct stenosis and progressive jaundice should be included in the differential diagnosis of bile duct neoplasms, in particular when there is a previous surgical history in this abdominal region.

Background: Cholangiocarcinoma (CCA) is a cancer that emerges from the biliary epithelium neoplastic transformation and has a steadily increasing incidence and prevalence. It is the 2ndmost prevalent primary hepatic cancer, accounting for around 15% of cases and 3% of GITcancers. Objectives: are to determine risk factors and prevalence for various forms of Cholangiocarcinoma (CCA). Method: A prospective study was conducted at Qena university hospital on 62 patients with cholangiocarcinoma proved by imaging, cytological or pathological evidence. Complete full history was taken, then full clinical examination and laboratory study were done. Result: Prevalence of distal cholangiocarcinoma was 56.5%, but hilar cholangiocarcinoma was 43.5% (n=27). A significant relation between gender and type of cholangiocarcinoma, where hilar type was more common among females P value= 0.02. Also, a significant relation between smoking and obesity and type of cholangiocarcinoma where distal type was more common among smokers and obese patients (P = 0.05 and P=0.03 respectively). Conclusion:Gender variation, smoking and obesity are the most important risk factors of cholangiocarcinoma, with hilar type more common among females, distal type more common among smokers and obese patients. Distal cholangiocarcinoma is more prevalent than hilar cholangiocarcinoma (56.5% and 43.5% respectively).

Introduction: Although primary hepatic neuroendocrine carcinomas, whose prognostic mechanisms remain unclear, are rare, coexistence of neuroendocrine carcinomas and other tumors is rarer. In this report, we describe a unique case of coexistence between primary hepatic neuroendocrine carcinoma and a distal cholangiocarcinoma in the pancreas. Patient concerns: A 64-year-old woman with a history of diabetes, but none of hepatitis, was admitted to hospital because of intermittent epigastric distension and pain discomfort for more than 1 month aggravated 1 day. A contrast-enhanced computed tomography (CT) scan of the upper abdomen and abdominal magnetic resonance imaging (MRI) revealed a thickening of the bile duct wall in the middle and lower segment of common bile duct and the corresponding lumen is narrow and low-density tumors with ring enhancement (1.83 cm × 1.9 cm) in lobi hepatis dexte. Diagnosis: Primary neuroendocrine carcinoma of the liver was diagnosed to be coexisting with a distal cholangiocarcinoma, which had invaded the pancreas. Immunohistochemical examination revealed that the neoplastic cells strongly expressed chromogranin A, synaptophysin, and CD56 proteins. The tumor cells did not express HepPar-1, glypican-3, S-100, CK7, and CK19 in the liver tumor. A distal bile duct in pancreatic tissues shows the characteristics of typical bile duct carcinoma, as an invasion of carcinoma is also seen in the pancreatic tissues. Gastrointestinal endoscopy, chest and abdominal CT, abdominal MRI, and positron emission tomography (PET)-CT were used to exclude metastatic neuroendocrine tumors of the liver. Interventions: Resection of the pancreas-duodenum, the right anterior lobe of the liver, and regional lymph nodes was performed in patients. Outcomes: The patient had survived for 5 months after the operation. Conclusion: A unique case of a coexistence of primary hepatic neuroendocrine carcinoma and a distal cholangiocarcinoma, which had invaded the pancreas. No treatment guidelines are established for the treatment of the unique case.

Contains fulltext : 229851.pdf (Publisher’s version ) (Open Access) BACKGROUND AND AIMS: Patients with a choledochal malformation, formerly described as cysts, are at increased risk of developing a cholangiocarcinoma and resection is recommended. Given the low incidence of choledochal malformation (CM) in Western countries, the incidence in these countries is unclear. Our aim was to assess the incidence of malignancy in CM patients and to assess postoperative outcome. METHODS: In a nationwide, retrospective study, all adult patients who underwent surgery for CM between 1990 and 2016 were included. Patients were identified through the Dutch Pathology Registry and local patient records and were analysed to determine the incidence of malignancy, as well as postoperative mortality and morbidity. RESULTS: A total of 123 patients with a CM were included in the study (Todani Type I, n = 71; Type II, n = 10; Type III, n = 3; Type IV, n = 27; unknown, n = 12). Median age was 40 years (range 18-70) and 81% were female. The majority of patients (99/123) underwent extrahepatic bile duct resection, with additional liver parenchyma resections in eight patients, only exploration in two, and a local cyst resection in eight patients. Postoperative 30-day mortality was 2% (2/123) and limited to patients who underwent liver resection. Severe morbidity occurred in 24%. In 14 of the 123 patients (11%), a malignancy was found in the resected specimen. One patient developed a periampullary malignancy 7 years later. CONCLUSIONS: In a large Western series of CM patients, 11% were found to have a malignancy. This justifies resection in these patients, despite the risk of morbidity (24%) and mortality (2%).

Background/Aims: Bile duct cancer, although not among the most common tumors, still accounts for more and more worldwide deaths each year. By attempting to verify an overexpression of ALDOA in cholangiocarcinoma tissues and cells and explore the underlying molecular mechanism regulated by miR-122-5p, this study was designed to provide a potential molecular target in bile duct cancer treatment. Methods: Western blot and immunohistochemistry were performed to detect the ALDOA protein level in duct carcinoma tissues. The transfection efficiency was confirmed by western blot and/or RT-qPCR assay. The proliferation of bile duct carcinoma cells was determined by MTT and colony formation assay. The invasion ability of bile duct carcinoma cells was evaluated with Transwell invasion assay. Flow cytometry detected cell apoptosis of bile duct carcinoma cells. The miRNAs which modulate ALDOA were filtrated from bioinformatics software and clinical specimens. The target relationship was confirmed by dual luciferase reporter assay. Furthermore, a xenograft model was completed to verify the impact of miRNA on inhibition growth of bile duct carcinoma cells. Results: ALDOA was found up-regulated in bile duct carcinoma tissues and cells. Knockdown of ALDOA promoted the apoptosis of cells and inhibited the proliferation and invasion of bile duct carcinoma cells. Bioinformatics and clinical specimens indicated the negative correlation and targeted regulation between miR-122-5p and ALDOA. By down-regulating ALDOA, overexpression of miR-122-5p appeared to promote cell apoptosis and significantly inhibit cell proliferation, invasion in vitro and suppress the tumor growth in vivo. Conclusion: miR-122-5p inhibited proliferation and invasion of bile duct carcinoma cells and promoted cell apoptosis by targeting ALDOA expression.

Pancreaticobiliary maljunction (PBM) is the anomalous union of the main pancreatic duct and common bile duct outside the Oddi-sphincter, allowing the reflux of pancreatic juice to the gallbladder. There is only limited awareness and understanding of the pathologic correlates of this condition, mostly from Japan; this entity is largely unrecognized in the West. In this study, 76 gallbladders from patients with PBM (64 from Japan; 12 from the United States) were analyzed and contrasted with 66 from non-PBM patients. These were predominantly females (54 vs. 22), mean age, 53 (range: 14 to 81). Cholelithiasis was uncommon (16% vs. 80% in non-PBM, P

Highlights • Mixed adeno-neuroendocrine carcinoma arising primarily in the bile duct is very rare neoplasm. • The patient with mixed adeno-neuroendocrine carcinoma in the bile duct indicates a poor prognosis. • On imaging studies, a hypervascular tumor is suspicious of mixed adeno-neuroendocrine carcinoma. • Curative resection is the only way to obtain the long-term prognosis, even if these patients have lymph node metastasis., Introduction Neuroendocrine tumors arising primarily in the bile duct are rare. And among these tumors, mixed adeno-neuroendocrine carcinoma (MANEC) is quite uncommon. We report a patient with MANEC who achieved long-term recurrence-free survival. And our case report includes analysis previous case reports. Presentation of case A 66-year-old man underwent investigation for persistent anorexia and fatigue. Laboratory tests showed that the values of hepatobiliary enzymes were increased. On CT, a 10 mm × 8 mm hypervascular tumor was observed in the distal bile duct and the proximal bile duct was markedly dilated. Endoscopic retrograde cholangiography (ERC) also showed a stenosis with a long diameter of 10 mm. Examination of a biopsy specimen obtained from the narrow site of the bile duct at the time of ERC revealed tubular adenocarcinoma. Therefore, pylorus-preserving pancreaticoduodenectomy was performed under a preoperative diagnosis of distal bile duct carcinoma. Postoperative pathologic examination revealed alveolar structures and a mixture of moderately differentiated adenocarcinoma with synaptophysin-positive and chromogranin-A-positive neuroendocrine carcinoma. Therefore, the final diagnosis was MANEC, pT3, pN1, M0, pStage II B (TNM classification of the UICC). Curative resection was achieved and there has been no recurrence after 30 months. Discussion In the previous reports, only five patients (14.7%) survived for 24 months or longer. Median survival was longer (14 months) in the curative resection group and shorter (6 months) in the non-curative resection group. Conclusion Curative resection is essential to achieve long-term survival in patients with bile duct MANEC, even if these patients have lymph node metastasis.

Extrahepatic biliary atresia, paucity of intrahepatic bile ducts, viral hepatitis, and malformations of bile ducts are the main causes of neonatal cholestasis. Biliary atresia occurs due to inflammation and destruction of extrahepatic bile duct systems in utero and during the perinatal period. Malformations of bile ducts are associated with abnormal remodeling of embryonic bile duct plate and fibrocystic lesions are developed, and they include congenital hepatic fibrosis [1], Caroli’s disease [2], microhamartoma [3], and choledochal cyst, and they carry an increased risk of bile duct carcinoma. Differing from other cystic lesions, ciliated hepatic cyst arising from embryonic foregut is detected incidentally in adults and should be differentiated from bile duct lesions [4]. Infantile and adult types of hereditary polycystic disease cause renal failure, and hepatic failure is rare [5, 6].

Summary Distal extrahepatic bile duct (EBD) carcinoma is a rare but highly aggressive malignant neoplasm. Some in vitro studies have shown that EGFR and PI3K-Akt pathway play an important role in the carcinogenesis of bile duct carcinoma. The aim of the present study is to investigate the expression of EGFR, p-AKT, and COX-2 and the mutation of PIK3CA in distal EBD carcinoma and evaluate the association with clinicopathological factors. Ninety cases of distal extrahepatic bile duct (EBD) carcinoma specimens were studied. Immunohistochemistry (IHC) using antibodies against EGFR, p-AKT, and COX-2 was performed on TMA blocks. The PIK3CA mutation was evaluated using the PNAClamp Detection Kit from DNA samples extracted from formalin fixed, paraffin embedded tissue. EGFR expression of distal EBD carcinomas was 61.9%, 26.2%, 6.0% and 6.0% in the negative, weakly positive, moderately positive, and strongly positive groups, respectively. Positive EGFR expression showed significant relationships with high T stage ( p = 0.024). In Kaplan–Meier analysis, EGFR expression was associated with shorter cancer-specific overall survival ( p = 0.005). Multivariate analysis also showed that moderate or strong (2+ or 3+) EGFR expression was a significant prognostic factor in distal EBD carcinoma: HR 5.286; p = 0.001. Ninety cases of EBD carcinoma tissue were analysed for hotspot mutations (exon 9 and 20) in the PIK3CA gene. Only one mutation was detected: a missense mutation of H1047 at exon 20. The expression levels of p-AKT and COX-2 showed no association with any clinicopathological parameters, including survival rate. Moderate and strong EGFR expressions demonstrate a direct link to poor prognosis. Although further study is warranted to understand the clinicopathological significance, our finding suggests EGFR is a useful prognostic marker of patients with distal EBD carcinoma. A low prevalence of PIK3CA mutation exists in the distal EBD carcinoma of Korean patients, indicating that mutation screening may not be useful in determining prognosis or in formulating a treatment response to targeted inhibition in Korea.

Background: Aquaporins (AQPs) are important in controlling bile water secretion. AQP is related to the invasion and metastasis of cancer. However, the relationship of biliary tract cancer is not clear. The role of AQP-1 in cancer cell is also unknown. Methhods: We analyzed AQP-1 expression using tissue microarray (TMA) in 99 samples immunohistochemically (50 gallbladder carcinoma, 39 bile duct carcinoma and 10 Papilla Vater carcinoma patients who underwent surgery at our department from 1997 to 2011). Gene expressions were evaluated by the combination of the immunohistological intensity and distribution. The expression level is compared to the clinico-pathological data of the patients. Results: In the TMA, depth of tumor invasion and histological type are associated with AQP-1 expression. The group of patients with high AQP-1 expression is associated with higher rates of disease specific survival (log-rank p = 0.013). Cox’s proportional hazard model reveals that AQP-1 expression is an independent prognostic factor (RR, 0.324; p = 0.001) in multivariate analysis. There is a correlation between AQP-1 expression and tumor invasion. Conclusions: These observations of this study suggest that AQP-1 expression may be favorable biomarkers associated with prognosis and tumor invasion in biliary tract carcinoma.

Increasing discoveries of the molecular alterations underlying pancreatic and biliary lesions have led to the utilization of cytology samples for molecular testing. Currently in pancreaticobiliary cytology, routine molecular testing has limited diagnostic utility except in the preoperative evaluation of pancreatic cysts and the detection of malignancy in biliary duct brushings. Because of the significant morbidity and mortality associated with pancreatic surgeries, it is of paramount importance to distinguish benign from premalignant/malignant cystic lesions preoperatively. In some institutions, molecular testing is being routinely performed on pancreatic cyst fluid to improve the detection of mucinous cysts, where the detection of a KRAS and/or GNAS mutation is highly specific for a mucinous etiology, and GNAS mutations are diagnostic of intraductal papillary mucinous neoplasm. The addition of molecular testing can be particularly helpful in cases where cytology and/or CEA are noncontributory and thus significantly improves the sensitivity of pancreatic cyst fluid analysis. With bile duct brushings, the addition of fluorescence in situ hybridization (FISH) to cytology is an established ancillary test for the diagnosis of bile duct carcinoma, and next-generation sequencing has also shown promise as a valuable ancillary tool. Late mutations in the progression to malignancy such as p16 (CDKN2A/INK4A) and SMAD4 deletions support a high-risk lesion in both pancreatic cyst fluids and bile duct brushing specimens.

Liver disease has always been one of the key concerns of the medical community. In recent years, liver diagnostic techniques such as serology have been continuously developed, but the pathological diagnosis of the liver, especially the advancement of liver biopsy technology, is still the most reliable basis for the diagnosis and treatment of liver diseases. In this paper, pathological sections of rat bile duct carcinoma were used as experimental samples to identify and analyze liver tumor by microscopic hyperspectral imaging (MHSI)technique. The proposed method combines the Otsu (OTSU)algorithm with the support vector machine (SVM)algorithm to segment the liver tumor, and comparing with SVM segmentation results. Experimental results show that the OTSU-SVM method has an accuracy of 94.59%, which provides a potential reference value for the pathological diagnosis of liver tumors.

IgG4-related disease is characterized by lymphoplasmacytic inflammation and fibrosis, often leading to mass-forming lesions in different organs. When IgG4-related disease affects the bile ducts, it is called IgG4-related sclerosing cholangitis. A 74-year-old male complained of dysphagia and abdominal pain. Endoscopic retrograde cholangiography and magnetic resonance cholangiography revealed bile duct changes suspicious of a bile duct carcinoma or cholangitis. Liver biopsy showed storiform fibrosis, lymphoplasmacytic infiltration, obliterative phlebitis, and a portal-based inflammatory nodule with expansion of a portal tract. Hot spots revealed 339 IgG4-positive cells per high power field (HPF) and an IgG4/IgG ratio of 72%. Eight months earlier, an inguinal lymph node had been removed, showing expanded interfollicular zones and increased plasma cells. Hot spots revealed 593 IgG4-positive cells and an IgG4/IgG ratio of 92%. The serum IgG4 of the patient was elevated nearly 10 times upper limit of normal. The diagnosis of IgG4-related sclerosing cholangitis associated with IgG4-related lymphadenopathy was made. There was good response to treatment with prednisolone and azathioprine. The differentiation of IgG4-related sclerosing cholangitis from primary sclerosing cholangitis and bile duct carcinoma is often difficult. Liver biopsy only rarely contributes to this setting, but we describe and report in detail a case where liver biopsy showed a portal-based inflammatory nodule with the characteristic features of this disease.

Pancreaticobiliary maljunction (PBM) and congenital biliary dilatation (CBD) are important risk factors of biliary cancers. According to the nationwide survey in Japan, the biliary cancer incidence of PBM was 21.6% in patients with CBD and 42.4% in patients without CBD. In patients with PBM and CBD, resection and reconstruction of the extrahepatic bile duct (flow-diversion surgery) is a basic surgical procedure for preventing the high occurrence of bile duct and gallbladder cancer. On the contrary, in patients with PBM but without CBD, no consensus has been reached about whether it is better to perform cholecystectomy alone or flow-diversion surgery. After surgery, a reported 0.5–2.0% of patients who undergo cyst excision develop bile duct carcinoma. Although the incidence of cancer after surgery is lower than that before surgery, it is 120–200 times higher than that of the entire population. Therefore, long-term follow-up is needed in patients with PBM and/or CBD.

Background In 2008, the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) launched the clinical practice guideline for the management of biliary tract cancers. JSHBPS decided to revise these guidelines for distribution of updated points concerning the treatment of biliary tract cancers. Methods To make clearer recommendations, we introduced the concepts of Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, in which the strength of recommendations are decided considering not only quality of evidence, but also balance of benefits and harms/burdens, patients’ preferences, and cost benefits. Results We emphasize the importance of the dynamic contrast enhanced multiple row detector CT (MDCT) in the diagnosis of biliary tract and gallbladder carcinomas. For biliary drainage, we suggest to perform endoscopic approaches instead of percutaneous approach to avoid complications. Regarding the surgical treatments, we included new clinical questions about the importance of combined vascular resection, intraoperative histological examination of the bile duct resection margin, and the combined extrahepatic bile duct resection for the gallbladder carcinoma. We also discussed details about premalignant lesions and non-neoplastic lesions in pathology section. Conclusion With this major revision, we expect that the Japanese standards of treatments of these diseases are recorded and reported in the universal language.

Photodynamic therapy (PDT) is an effective local treatment modality as a cancer-specific laser ablation in malignancy of some organs including digestive tracts or bile duct. In Japan, PDT has been applied at the early period after the first clinical induction in 1980’s. Although the useful efficacy was clarified, PDT has not been fully applied because of the phototoxicity of the porfimer sodium. The next generated talaporfin-sodium was used for PDT, in which phototoxicity was reduced and, however, the clinical efficacy for digestive tract malignancy has not yet been clarified. By proceeding the experimental and clinical trials, it is necessary to clarify the evidence of efficacy as a local powerful treatment with the conventional surgery, brachiotherapy and chemotherapy in the future step.

Background As an induced enzyme, COX-2 expression is elevated under stimuli from inflammatory mediator or growth factor product. Ki-67, a cell cycle-related proliferative antigen, reflects the tissue proliferative activity. This study analyzed the expressional profile of cyclooxygenase-2 (COX-2) and Ki-67 in hepatolithiasis and bile duct carcinoma tissues, in an attempt to provide evidence for diagnosis and prognosis prediction of disease. Material and methods A cohort of tissue samples from hepatolithiasis with bile duct carcinoma (N=47) patients were analyzed using immunohistochemical (IHC) staining method for the expression of COX-2 and Ki-67, in parallel with hepatolithiasis (N=44) and normal bile duct tissues (N=30). The relationship between expression pattern of COX-2 and Ki-67 and pathological conditions was also analyzed, in addition to the correlation with positive expression in hepatolithiasis samples. Results The positive expression rate of COX-2 and Ki-67 in bile duct carcinoma was 76.6% and 80.9%, respectively, and was significantly higher than those in the hepatolithiasis group, which was also higher than the control group. Expression of both COX-2 and Ki-67 is closely related to TNM staging, lymph node metastasis, and differentiation stage. They were also correlated with the mortality rate of patients. Conclusions Both COX-2 and Ki-67 are abundantly expressed in hepatolithiasis and bile duct carcinoma tissues and may play an important role in the disease occurrence, progression, and metastasis.

Conventional pancreatoduodenectomy (PD) for bile duct and papilla carcinoma is associated with a risk of surgical site infection and peritoneal tumor seeding because of the timing of bile duct removal. In our modified PD procedure, transection of the ligament of Treitz was performed, followed by resection of the jejunum and duodenum. Pancreatic tunneling was performed from the caudal side. Finally, the tumor was removed by cutting the bile duct. To prevent bile exposure, all anastomoses other than choledochojejunostomy were performed before bile duct removal. We retrospectively compared the effectiveness of our modified PD technique by comparing data from seven patients who underwent modified PD with 19 patients who underwent conventional PD. The rate of surgical site infection was 28.6% in the modified PD group and 73.6% in the conventional PD group (P = 0.04). The cumulative and recurrence-free survival rates were not significantly different between the two groups. Thus, modified PD may reduce the risk of surgical site infection. We conclude that modified PD may reduce the risk of surgical site infection.

Our recent work revealed that elevated expression of claudin-18 is involved in bile duct neoplasia. In the present study, we found that wound generation of a cell sheet de novo induced claudin-18 expression in its leading edge, coincident with high mitotic activity. We also found that the suppression of claudin-18 expression significantly reduced cell growth and invasiveness of bile duct cancer cell lines and tumorigenicity in vivo. In addition, an antibody specific to an extracellular loop of claudin-18 showed similar effects on the cells such as cell proliferation. Interestingly, treatment with epidermal growth factor (EGF) and overexpression of RAS oncogene induced claudin-18 expression by activation of extracellular signal-related kinase (ERK)1/2. Furthermore, enhanced claudin-18 expression activated ERK1/2. These findings provide evidence for an oncogenic property of claudin-18 in bile duct carcinoma cells via modulation of EGFR/ERK signaling, indicating that claudin-18 is a possible therapeutic target for this malignancy.

A 73-year-old woman was admitted because of obstructive jaundice. Computed tomography revealed a stricture in the lower bile duct with enhanced bile duct wall. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a tapering stenosis at the lower bile duct. Transpapillary histological biopsy using biopsy forceps through ERCP was performed; the diagnosis of signet ring cell carcinoma (SRCC) of the bile duct was established. Regional lymph node enlargement and distant metastases were not detected on diagnostic imaging. Pancreaticoduodenectomy with pylorus preservation was performed. Histological examination of the resected specimen confirmed SRCC of the extrahepatic bile duct coexisting with adenocarcinoma (ADC) of the extrahepatic bile duct with negative resection margins. However, tumor cells directly invaded the pancreatic parenchyma and the muscle layer of the duodenum, prompting us to administer adjuvant chemotherapy to the patient, with no sign of tumor recurrence at 1-year follow-up. Almost all tumors originating from the extrahepatic bile duct are ADC and other histological variants are rare. Of these, SRCC is extremely rare and only four cases have been reported. Furthermore, to the best of our knowledge, this is the first case report regarding the preoperative diagnosis of SRCC of the bile duct. Current reports indicate that younger age and Asian ethnicity are the clinical features of SRCC of the extrahepatic bile duct. Immunohistochemical staining of CK7, CK20 and MUC2 may be useful for predicting prognosis. Chemotherapy has not resulted in increased survival rates and only surgical resection currently serves as a curative treatment.

ROS1 rearrangements have been detected in a variety of tumors and are considered as suitable targets of anticancer therapies. We developed a new, quick, specific, and sensitive PCR test to screen for the FIG-ROS1 fusion and applied it to a series of Italian patients with bile duct carcinoma (BTC). Formalin-fixed, paraffin-embedded tissues, derived from 65 Italian BTC patients, and six cell lines were analyzed by nested PCR to investigate the prevalence of a previously reported FIG-ROS1 fusion. The specificity and sensitivity of nested PCR were investigated in FIG-ROS1 positive U118MG cells in reconstitution experiments with peripheral blood mononuclear cells. We found that six out of 65 (9%) BTC patients were positive for the FIG-ROS1 fusion, comprising two out of 14 (14%) gallbladder carcinoma (GBC) patients and four out of 25 (16%) extrahepatic cholangiocarcinoma (ECC) patients. None of the 26 intrahepatic cholangiocarcinoma cases harbored the FIG-ROS1 fusion. All the cell lines were negative for this variant. In conclusion, 14-16% of GBC and ECC were positive for FIG-ROS1. This may have clinical implications, since these patients will potentially benefit from the treatment with specific ROS1 inhibitors.

Biliary tract cancer occurs frequently in patients with pancreaticobiliary maljunction (PBM), although no details of its clinicopathological characteristics have been reported. Here we describe a case of bile duct (BD) cancer that developed in association with PBM. This BD cancer involved the common channel, extended to the main pancreatic duct (MPD) via the common channel, and invaded the pancreatic parenchyma, where its growth and spread, and features of its recurrence, were similar to those of ductal carcinoma of the pancreas. We assumed that MPD extension of BD cancer via the common channel was the reason for its deep spread to the pancreas, since BD cancer usually spreads along the BD and rarely reaches the common channel of the ampulla of Vater. During the follow-up of patients with PBM, attention should be paid to involvement of the common channel by BD cancer and also to cancer developing silently in the pancreas after extrahepatic BD resection.

A cholangiocarcinoma is reported in an 18-yr-old, female African lion (Panthera leo). The primary tumor consisted of multifocal to coalescing, hepatic, white–yellow masses distributed throughout the liver lobes. Metastases were present in regional lymph nodes, peritoneal surface, and lungs. Histologically, the tumor was characterized by a tubular pattern with alcian- and periodic acid–Schiff–positive secretory material in cystic spaces. The neoplastic cells were positive to broad-spectrum cytokeratins. Histochemical and immunohistochemical stains were consistent with bile duct carcinoma. Biliary tumors arising from the gallbladder have been reported in lions. However, to the authors' knowledge, this is the first case of intrahepatic bile duct carcinoma reported in an African lion.

OBJECTIVE:The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. SUMMARY BACKGROUND DATA:Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over-expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. METHODS:Bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, linear regression, multiple regression, and receiver operating characteristic (ROC) curve analysis. RESULTS:Bile from 83 patients was analyzed: 42 with benign disease and 41 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower median biliary CEACAM6 levels than patients in the malignant cohort (7.5 ng/ml vs. 40 ng/ml; p = 14 ng/ml associated with 87.5% sensitivity, 69.1% specificity, and a likelihood ratio of 2.8 (AUC 0.74). Multiple regression analysis suggested elevated alkaline phosphatase and the presence of biliary endoprostheses may influence CEACAM6 levels. CONCLUSION:Biliary CEACAM6 can identify patients with extrahepatic cholangiocarcinoma with a high degree of sensitivity and should be investigated further as a potential screening tool.

Purpose To quantitatively analyse the pancreaticobiliary duct changes of periampullary carcinomas with volumetric interpolated breath-hold examination (VIBE) and true fast imaging with steady-state precession (true FISP) sequence, and investigate the value of these findings in differentiation and preoperative evaluation. Materials and methods Magnetic resonance (MR) images of 71 cases of periampullary carcinomas (34 cases of pancreatic head carcinoma, 16 cases of intrapancreatic bile duct carcinoma and 21 cases of ampullary carcinoma) confirmed histopathologically were analysed. The maximum diameter of the common bile duct (CBD) and main pancreatic duct (MPD), dilated pancreaticobiliary duct angle and the distance from the end of the proximal dilated pancreaticobiliary duct to the major papilla were measured. Analysis of variance and the Chi-squared test were performed. Results These findings showed significant differences among the three subtypes: the distance from the end of proximal dilated pancreaticobiliary duct to the major papilla and pancreaticobiliary duct angle. The distance and the pancreaticobiliary duct angle were least for ampullary carcinoma among the three subtypes. The percentage of dilated CBD was 94.1%, 93.8%, and 100% for pancreatic head carcinoma, intrapancreatic bile duct carcinoma and ampullary carcinoma, respectively. And that for the dilated MPD was 58.8%, 43.8%, and 42.9%, respectively. Conclusion Quantitative analysis of the pancreaticobiliary ductal system can provide accurate and objective assessment of the pancreaticobiliary duct changes. Although benefit in differential diagnosis is limited, these findings are valuable in preoperative evaluation for both radical resection and palliative surgery.

Intraductal papillary neoplasm of the bile duct (IPNB) is a variant of bile duct carcinoma characterized by intraductal growth and better outcome compared with the more common nodular-sclerosing type. IPNB is a recognized precursor of invasive carcinoma, but its pathogenesis and natural history are ill-defined. This study examines the clinicopathologic features and outcomes of IPNB. A consecutive cohort of patients with bile duct cancer (hilar, intrahepatic, or distal) was reviewed, and those with papillary histologic features identified. Histopathologic findings and immunohistochemical staining for tumor markers and for cytokeratin and mucin proteins were used to classify IPNB into subtypes. Survival data were analyzed and correlated with clinical and pathologic parameters. Thirty-nine IPNBs were identified in hilar (23/144), intrahepatic (4/86), and distal (12/113) bile duct specimens between 1991 and 2010. Histopathologic examination revealed 27 pancreatobiliary, four gastric, two intestinal, and six oncocytic subtypes; results of cytokeratin and mucin staining were similar to those of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Invasive carcinoma was seen in 29/39 (74%) IPNBs. Overall median survival was 62 months and was not different between IPNB locations or subtypes. Factors associated with a worse median survival included presence and depth of tumor invasion, margin-positive resection, and expression of MUC1 and CEA. Conclusion: IPNBs are an uncommon variant of bile duct cancer, representing approximately 10% of all resectable cases. They occur throughout the biliary tract, share some histologic and clinical features with IPMNs of the pancreas, and may represent a carcinogenesis pathway different from that of conventional bile duct carcinomas arising from flat dysplasia. Given their significant risk of harboring invasive carcinoma, they should be treated with complete resection. (HEPATOLOGY 2012)

Pancreaticobiliary reflux may occur either as a result of an anatomically abnormal pancreaticobiliary junction or because of a functionally impaired sphincter despite a normal radiological appearance. It is associated with a wide spectrum of biliary diseases, including gall bladder and bile duct carcinoma. Pancreaticobiliary maljunction and related biliary reflux have been studied extensively in Southeast Asian populations and associations with choledochal cyst and biliary malignancy defined. However, reflux in the absence of ductal malunion has only been described relatively recently and its significance with respect to biliary malignancy requires clarification. We present four cases of pancreaticobiliary reflux to demonstrate the varied associations of this under-recognized disorder and review the related management issues.

門脈が膵実質に完全に包まれる膵形態異常は国内外合わせ，ごく少数だが存在し“portal annular pancreas”または“circumportal pancreas”として報告されている．今回，膵鈎部が膵体部背側と癒合し門脈を輪状に巻き込んだまれな膵形態異常を伴う下部胆管癌症例を経験し，膵頭十二指腸切除術を施行したので若干の考察を加え報告する．症例は84歳の女性で，閉塞性黄疸を呈し下部胆管癌の診断にて膵頭十二指腸切除術を施行した．術中に膵鈎部が背側より門脈を包み込んで膵体部と癒合する形態異常を認めた．改めて主膵管が門脈腹側を通過していることを確認し，門脈のトンネリング後に主膵管が露出するまで膵実質を鋭的に切離し，さらに背側の膵実質は自動縫合器にて切離した．術後にInternational Study Group on Pancreatic Fistula（ISGPF）分類でGrade Aの膵液漏を認めたが保存的治療にて改善した．

Primary liver cancer is uncommon and is generally classified as hepatocellular carcinoma (HCC), bile duct carcinoma, neuroendocrine (or carcinoid) tumor, and mesenchymal tumor (sarcoma). Here we describe the gross and histopathology characteristics of a rare HCC in a captive Arabian sand cat (Felis margarita harrisoni) held at Al Ain Zoo, United Arab Emirates. The description of this case in the Arabian sand cat adds to the current knowledge of hepatocellular carcinoma in captive nondomestic felids.

Extensive intraepithelial spread of bile duct carcinoma is a common feature, seen in approximately 18% of all cases. However, this spread is rarely accompanied by bile duct strictures. We herein describe three cases of bile duct carcinoma with multiple bile duct strictures due to extensive intraepithelial spread. In all three cases, the spread of intraepithelial cancer extended into the epithelium of the peribiliary glands along the intrahepatic bile ducts with marked fibrosis on histopathological examination. It is speculated that peribiliary gland involvement by superficially spreading bile duct cancer and subsequent obstructive glandular inflammation with fibrosis might cause intrahepatic bile duct strictures even without interstitial cancer invasion.

Adenomyomatous hyperplasia is rarely found in the extrahepatic bile duct. A 54-year-old man was referred to our center with a diagnosis of extrahepatic bile duct stenosis which had been detected by endoscopic retrograde choloangiopancreatography. Abdominal computed tomography revealed thickening of the wall of the middle extrahepatic bile duct, however no malignant cells were detected by cytology. Since bile duct carcinoma could not be ruled out, we performed resection of the extrahepatic duct accompanied by lymph node dissection. Histopathologically, the lesion was diagnosed as adenomyomatous hyperplasia of the extrahepatic bile duct. Present and previously reported cases showed the difficulty of making a diagnosis of adenomyomatous hyperplasia of the extrahepatic bile duct preoperatively or intraoperatively. Therefore, when adenomyomatous hyperplasia is suspected, a radical surgical procedure according to malignant disease may be necessary for definitive diagnosis.

BACKGROUND: It is difficult to diagnose lymph node metastasis in biliary and pancreas carcinomas before surgery. AIM: The aim of this study was to assess the utility of the combination of multi-detector computed tomographic (MDCT) findings and serum carbohydrate antigen (CA)19-9 level in the diagnosis of lymph node metastasis in biliary and pancreas carcinomas. METHODS: The subjects were 139 patients with biliary and pancreas carcinomas who underwent surgical resection. We calculated the positive predictive values (PPV), sensitivities, specificities, positive likelihood ratios (PLR) and accuracies of diagnosis by MDCT alone, serum CA19-9 level alone, and their combination. RESULTS: The PPV and sensitivity were higher for node metastasis in hepatoduodenal ligament than in common hepatic artery (CHA) or para-aortic region (PAR). Specificity, accuracy and PLR were highest for CHA in biliary carcinoma. With pancreatic carcinoma, PLR was slightly higher in PAR compared to other regions. The sensitivity of CA19-9 for node metastasis was higher than that of MDCT, while the PPV, specificity, accuracy and PLR were low for both biliary and pancreas carcinoma. The combination of positive CT findings and high CA19-9 level had the highest positive rate for node metastasis for both types of carcinomas. Nodes around the supra-mesenteric vein could not be fully observed on CT. CONCLUSION: The combination of high-resolution MDCT and CA19-9 is useful for the diagnosis of lymph node metastasis in biliary and pancreas carcinomas., The original publication is available at www.springerlink.com, Digestive diseases and sciences, 55(12), pp.3617-3626; 2010

AIMS: To study the relevance of periostin, known to be involved in epithelial-mesenchymal transition (EMT), in hepatocellular and bile duct cancer. METHODS AND RESULTS: Immunohistochemical periostin expression was semiquantitatively analysed in normal liver tissue (n = 20), hepatocellular carcinoma (HCC; n = 91), liver-cell adenoma (n = 9), focal nodular hyperplasia (n = 13) and bile duct carcinomas (BDC; n = 116) using tissue microarrays. Normal bile ducts, gallbladder epithelium and hepatocytes showed weak cytoplasmic periostin expression. In HCC, there was strong epithelial periostin expression in 19/91 (20.9%) and strong stromal periostin expression in 10/91 cases (11%). Epithelial expression in tumour cells was significantly associated with a higher tumour grade (P > 0.05) and hepatitis B virus infection (P = 0.007). Importantly, there was no strong periostin expression in benign liver tumours. Strong stromal periostin expression was detected in 78/116 (67.2%) BDC and strong epithelial expression in 39/116 (33.6%) BDC. pT stage, differentiation grade and proliferation rate in primary BDC were independent of periostin expression. Epithelial periostin expression was associated with reduced overall survival on univariate and multivariate analysis. CONCLUSIONS: The EMT protein periostin is expressed in the stroma and epithelium of a subset of BDC and HCC. Epithelial periostin expression is a marker for malignant transformation of hepatocytes and a novel prognostic marker in BDC

We previously reported an inoperable jaundiced woman and man with bile duct carcinoma who underwent cholangioscopic MTC and survived longer than 13 and 15 years, respectively. Here, we report another jaundiced patient with bile duct carcinoma with survival longer than 10 years after cholangioscopic and X-ray image-guided MTC.A 56-year-old man was referred to our institution because of right hypochondric pain and constipation with suspected postoperative intestinal stenosis. Three years previously, he had undergone a non-curative resection of carcinoma in the transverse colon, in which both the second group of regional lymph nodes and pelvic tumor were histologically metastatic (Schnitzler's metastasis).Besides abdominal pain, he had bulbar jaundice, increased serum bilirubin and amylase, and leucocytosis. Percutaneous transhepatic cholangial drainage (PTCD) was performed for biliary decompression with improvement of jaundice, followed by fluorographically complete obstruction of the common bile duct (CBD) suggestive of a neoplastic lesion. Percutaneous transhepatic cholangioscopy (PTCS) revealed a papillary tumor in the terminal portion of the CBD, with a histological diagnosis of papillary adenocarcinoma.Given his previous non-curative resection of colon cancer, he did not wish to undergo pancreatoduodenectomy (PD) as radical surgery. Therefore, cholangioscopic and X-ray image-guided MTC using Microtaze® (Heiwa Electronic Industrial Co. Ltd., Osaka Japan), a 1.8 mm φ spherical antenna, and a 5 mm φ bullet-shaped antenna covering a thin guide wire (0.028 inch, Cook Co. Ltd., USA) was carried out under radiation of 45 watts and repetitions of 3-5 seconds in duration.The patient lived for 11.5 years after the onset of pain and jaundice.For malignant neoplasms in the early stage of progression in the bile duct, cholangioscopic methods including MTC may be a treatment option aimed at cure, as are bronchoscopic methods for lung cancer in the early stage of progression.

Aim: To clarify the features of biliary carcinomas and pancreatic disorders associated with pancreaticobiliary maljunction (PBM). Method: A total of 107 PBM patients with biliary dilatation were reviewed (52 with and 55 without PBM). Clinicopathological findings of biliary carcinomas, and acute or chronic pancreatitis were examined in association with PBM. We also investigated pancreatographic findings in PBM patients and the relationship to their clinical findings in view of pancreatic juice flow. Results:Gallbladder and bile duct carcinomas were seen in 11 (21%) and 8 (15%) of the 52 patients with PBM and biliary dilatation, respectively. In patients with PBM without biliary dilatation (n = 55), only gallbladder carcinoma was detected in 36 (65%) patients. At diagnosis, patients with gallbladder or bile duct carcinoma associated with PBM were younger than those without PBM (p < 0.01). Gallstones were detected only in 6% of the patients with PBM-associated gallbladder carcinoma. Multiple biliary carcinomas were detected in 3 patients (38%) with PBM-associated bile duct carcinoma. While 48 patients (60%) with biliary carcinoma and PBM had a normal pancreatic duct system, only 2 gallbladder carcinomas occurred in 11 dorsal pancreatic duct (DPD)-dominant patients (p < 0.05). Amylase concentration in the bile of DPD-dominant patients was significantly lower than that of patients with a normal pancreatic duct system (p < 0.05). Ten PBM patients had pancreatic disorders: acute pancreatitis (n = 3), chronic pancreatitis (n = 5), and pancreatic carcinoma (n = 2). Conclusions: In PBM patients, pancreatobiliary reflux frequently leads to biliary cancer, and biliopancreatic reflux often leads to acute or chronic pancreatitis. The biliary tract of PBM patients can be considered premalignant.

Background: Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) are the two most common primary liver cancers, yet there have been no significant advances in effective therapeutics. Mesothelin has been reported as a new therapeutic target in various types of cancer. Here, we investigated the expression of mesothelin in liver cancer and its potential role as a novel therapeutic target for immunotherapy. Methods: HCC and CCA specimens were examined by immunohistochemistry for mesothelin expression. Protein expression was assessed by immunoblotting and flow cytometry. The SS1P immunotoxin targeting mesothelin was evaluated in the well-established CCA cell lines HuCCT1, HuH-28, KMBC, KMCH, Mz-ChA-1 and OZ. Results: We showed strong immunochemical mesothelin staining in 33% of the surgically resected CCA specimens and 3 of 6 CCA cell lines (OZ, KMBC and KMCH). No mesothelin staining was found in HCC or normal liver tissue. Mesothelin was primarily localized to the cellular plasma membrane and the mature form (molecular weight, ~40 kDa) was expressed at a high level in CCA tissues. Moreover, 22% of CCA specimens had a high mesothelin expression level which was comparable to the CCA cell line models. Interestingly, SS1P showed very high and specific growth inhibition when added to mesothelin-expressing CCA cells with IC50 values ranging from 0.5 to 11 ng/mL. Conclusions: Mesothelin is overexpressed in one-third of CCA tissues. SS1P targeting mesothelin reveals a remarkable single agent activity against CCA in vitro. These findings indicate a potential for SS1P in the immunotherapeutic treatment of CCA.

The oncofetal protein IMP3 (insulin-like growth factor II mRNA binding protein 3) is expressed during embryogenesis and carcinogenesis. Various tumor types have been analyzed for IMP3 expression, which was exclusively found in tumor cells and correlated with increased tumor aggressiveness and reduced overall survival. To our knowledge, IMP3 expression has not been investigated in bile duct carcinomas. Using large tissue sections from resection specimens of the extrahepatic biliary tract, we analyzed IMP3 in normal bile ducts (n = 36), bile ducts with acute inflammation and reactive epithelial changes (n = 26), low-grade dysplasia (n = 9), and high-grade dysplasia (n = 11). Furthermore, IMP3 expression was assessed in bile duct carcinoma (n = 115) using clinically well-characterized tissue microarrays. The findings were correlated with clinical-pathologic parameters including survival. High-grade dysplasia was strongly positive for IMP3 in all cases studied compared with no or weak expression in normal, inflamed, and low-grade dysplastic bile ducts. Of the bile duct carcinomas 58.3% (67/115) were strongly positive for IMP3, which was associated with a higher proliferation rate (P = .004) and p53 positivity (P = .022). Patients with strong IMP3 expression had significantly reduced overall survival (P = .037) similarly to the subgroup of pT3 carcinomas (P = .007). In multivariate analysis, IMP3 expression was an independent prognostic factor for overall survival (P = .040, RR = 1.809). This comprehensive study shows that IMP3 is an independent prognostic biomarker in bile duct carcinoma. In addition, it may be a marker for high-grade dysplasia in the extrahepatic biliary tract.

The American Joint Committee on Cancer (AJCC) T classification system for cholangiocarcinoma does not take into account the unique pathologic features of the bile duct. As such, the current AJCC T classification for distal cholangiocarcinoma may be inaccurate.A total of 147 patients with distal cholangiocarcinoma were identified from a single institution database. The prognostic importance of depth of tumor invasion relative to the AJCC T classification system was assessed.The AJCC T classification was T1 (n = 11, 7.5%), T2 (n = 6, 4.1%), T3 (n = 73, 49.7%), or T4 (n = 57, 38.8%). When cases were analyzed according to depth of tumor invasion, most lesions wereor =5 mm (5 mm, 9.5%; range, 5-12, 51.0%;12 mm, 39.5%). The AJCC T classification was not associated with survival outcome (median survival, T1, 40.1 months; T2, 14.8 months; T3, 16.5 months; T4, 20.2 months; P = .17). In contrast, depth of tumor invasion was associated with a worse outcome as tumor depth increased (median survival,5 mm, not reached; range, 5-12, 28.9 months;12 mm, 12.9 months; P = .001). On multivariate analyses, tumor depth remained the factor most associated with outcome (5 mm; hazard ratio [HR] = referent vs 5-12 mm; HR = 3.8 vs12 mm; HR = 6.7 mm; P = .001).The AJCC T classification for distal cholangiocarcinoma does not accurately predict prognosis. Depth of the bile duct carcinoma invasion is a better alternative method to determine prognosis and should be incorporated into the pathologic assessment of resected distal cholangiocarcinoma.

BACKGROUND: Longitudinal tumor extension from the main tumor involves intramural or superficial spread along the bile duct, which influences surgical curability. Identifying the range of superficial extension is difficult by preoperative imaging. To clarify specific characteristics of bile duct carcinoma (BDC) with superficial extension of epithelium in the bile duct, we examined clinicopathologic features and patient outcomes in BDC patients with or without superficial extension who underwent surgical resection. METHODS: Between 1994 and 2008, we retrospectively examined clinicopathologic findings and outcomes for 42 BDC patients who underwent surgical resection and divided them into two groups: (1) superficial extension (SE) group (n = 10); and (2) non-SE group (n = 32). RESULTS: In terms of macroscopic growth of the main tumor, the papillary type was more common in the SE group than in the non-SE group, whereas the nodular type was dominant in the non-SE group. The prevalence of cancer-positive findings at the cut end of the bile duct was higher in the SE group. Portal vein invasion was not observed in the SE group, and the prevalence of regional lymph node metastasis was significantly greater in the non-SE group than in the SE group. No patients died of cancer in the SE group, who tended to show better survival than the non-SE group. CONCLUSIONS: The present results suggest that a good prognosis may be achieved in BDC patients with SE when complete resection is accomplished., The original publication is available at www.springerlink.com, World journal of surgery, 33(6), pp.1255-1258; 2009

Neoplasms appear very rare in pelicans. Few cases are described within the literature including 8 chondrosarcomas, 1 bile duct carcinoma, 1 bronchial carcinoma, 1 pheochromocytoma, 1 ganglioneuroma, and 1 case of a recurring squamous cell carcinoma. The present study describes the clinical and histopathological features of an epithelial neoplasm arising from the upper bill of a Dalmatian pelican (Pelecanus crispus) at Tierpark Berlin. The article deals with the surgery, the patients’ recovery and the pathology of such a neoplasm in detail.

Intraductal papillary neoplasm of the bile duct (IPNB) represents biliary papillary tumors mainly growing and is considered to be of relatively low-grade malignancy. Here we report a case of IPNB in whom the poorly differentiated component deeply infiltrated the bile duct wall. A 77-year-old male had an invasive carcinoma of the bile duct 3 cm in size. He underwent right hemihepatectomy with combined resection of the extrahepatic bile duct. Papillary growing tumor was observed in the common bile duct and the right posterior Glisson’s pedicle was invaded. Histologic finding showed papillary adenocarcinoma in the surface layer superficially extending to the epithelium of the surrounding bile duct. In the subserosal layer, the tumor represented poorly differentiated adenocarcinoma. The tumor was diagnosed as invasive bile duct carcinoma arising from IPNB.

Carcinoma of the distal bile duct is associated with poor prognosis. Surgical resection remains the only potentially curative treatment. We conducted a retrospective study to identify prognostic factors determining longterm survival. From 1990 to 2006, 95 patients with distal and/or middle bile duct carcinoma had resections. Fifty-four patients underwent pylorus-preserving pancreaticoduodenectomy (57%) and 41 patients underwent standard Kausch-Whipple pancreaticoduodenectomy (43%). Nine patients underwent pancreaticoduodenectomy including portal vein resection (9%). Overall 1-, 3-, and 5-year survival rates were 60%, 36%, and 29%, respectively. Five-year survival after R0 resection was 34%, and after R1 resection it was 0%. Four patients died during their hospital stay (4%). Multivariate analysis showed negative resection margins (P = 0.040), lymphatic vessel invasion (P = 0.036), and portal vein infiltration (P = 0.027) as strong predictors for survival, whereas the location of the tumor (distal bile duct vs middle bile duct) and lymph node status were not identified as independent prognostic factors. Five-year survival depends strongly on negative resection margins, independent of nodal status. Portal vein resections in patients with portal vein involvement fail to ameliorate long-term survival. Primary tumor site — middle bile duct or distal bile duct — did not determine prognosis.

Extrahepatic bile duct carcinoma occasionally presents with intraepithelial spread for a considerable area around the main tumor. In this study, we compared clinicopathological features of extrahepatic bile duct carcinoma with and without extensive intraepithelial spread (or=20 mm from the main tumor). Out of 117 cases of extrahepatic bile duct carcinoma, 21 (18%) were found to have extensive intraepithelial spread. Those cases were pathologically characterized by a papillary or nodular main tumor, a more differentiated histological grade, less deep invasion, and infrequent portal vein or hepatic invasion in comparison with cases without intraepithelial spread. Areas of intraepithelial spread histologically consisted of low-papillary growth (17 cases, 81%) and completely flat growth (4 cases, 19%) of carcinoma cells. The former histology corresponded to a macroscopic granular mucosa, whereas the latter growth was hardly detected by gross examination. Immunohistochemically, in 16 of 21 cases (76%), at least one of p53, CEA, and MUC1 was expressed in both the main tumor and the spreading area. Interestingly, patients with intraepithelial spread had a better postoperative prognosis than those without intraepithelial spread (P=0.009). However, three patients had anastomotic recurrence 54-130 months after surgery. In conclusion, intraepithelial-spreading bile duct carcinoma is characterized by papillary or nodular main lesions, a more differentiated histological grade, and less invasiveness. The presence of intraepithelial spread was not an indicator of a poor prognosis, but carcinoma in situ at the bile duct stump could cause late anastomotic recurrence after surgery.