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Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are the most common primary liver malignancies. HCC and ICC have characteristic imaging findings, but a number of benign entities can appear similar and can cause diagnostic dilemma. Ideally, accurate and timely diagnosis of these conditions can help the patient to avoid a needle biopsy or even unnecessary treatment. In this article, we present various benign liver lesions that display imaging characteristics that are similar to HCC and ICC on magnetic resonance imaging (MRI) and discuss salient features that may assist in accurate diagnosis.

Purpose We aimed to evaluate the imaging features of bile duct adenoma (BDA) on ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). Methods Retrospective search in our institution database was performed for histologically confirmed BDA. Their imaging studies before histologic confirmation were reviewed. The search identified seven adults (mean age, 52.9 years) with histologically proven single BDA each. US (n=3), CT (n=5), and MRI (n=3) were performed before histologic confirmation. Additionally, a systematic English literature review for BDA and reported imaging findings since 2000 was also conducted using the following search criteria "bile duct adenoma, peribiliary hamartoma, biliary adenoma, CT, ultrasound, MRI" (date range: 01/01/2000 through 08/31/2016). The imaging findings of those cases reported were summarized and compared with our series. Results All seven individual nodules were well circumscribed. Five lesions were located in the right hepatic lobe and two in the left hepatic lobe. On US, lesions appeared hypoechoic (n=2) and hyperechoic (n=1). BDA was hypodense on unenhanced CT images (n=1). On MRI, BDA were hypointense on T1 (n=3), hyperintense on T2 (n=3), and hyperintense on diffusion-weighted images (n=2). On contrast-enhanced CT and MRI, BDAs showed arterial phase hyperenhancement that persisted on portal venous/delayed phase images. Conclusion BDA demonstrates characteristic arterial phase hyperenhancement that persisted into the portal venous and delayed phases on CT and MRI, which may be useful in differentiating from other hepatic lesions.

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.

We present a case of bile duct adenoma that mimicked hepatic metastasis from gastric cancer. The adenoma exhibited prolonged enhancement on dynamic computed tomography, hyperintensity on diffusion-weighted imaging, and diminished uptake of superparamagnetic iron oxide and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid on magnetic resonance imaging, resembling those of adenocarcinomas. Knowledge of the imaging findings of this rare entity may aid correct diagnosis.

Objectives: Hepatocellular carcinoma (HCC) and cholangiolar carcinoma (CC) cell lines are used to analyze the basic mechanisms of carcinogenesis and target therapies. However, it is not yet clear which chromosomal aberrations are to be typically expected in such cell lines. It is also not clear whether there are prerequisites for in vitro growth on the genomic and/or expression level. We therefore analyzed HCC and CC cell lines for typical genetic settings. Methods: The HCC cell lines HLE, HLF, Huh7, HepG2 and Hep3b and the CC cell lines EGI1, MzCha1 and TFK-1 were analyzed using high-density arrays for comparative genomic hybridization (aCGH; 244,000 oligonucleotides). Additional fluorescence in situ hybridization analyses were done to confirm the aCGH results and to add information regarding the aneuploidy of cell lines. Results: The gain of 1q, in particular q21-22, was detected in all HCC cell lines also as a partial loss of 13q. In contrast, a loss of 8p in combination with a relative gain of 8q was seen in all CC but no HCC cell lines. Interestingly, a gain of 17q was seen in all cell lines. These aberrations are also well documented for surgical tumor specimens. Besides these imbalances, the cell lines revealed imbalances for 11p, 12p, 14q, 16p, 16q, 21q and 22q, respectively, only rarely seen in surgical tumor specimens. These aberrations could be of importance for the in vitro cultivation of tumor cells. Structural aberrations were accompanied by aneuploidy in 3 of 5 HCC cell lines and 2 of 3 CC cell lines. Ploidy status was not correlated to any of the imbalances mentioned above. Conclusions: HCC and CC cell lines revealed characteristic chromosomal imbalances similar to those seen in surgical tumor specimens including chromosomes 1, 8, 13 and 17, respectively. These aberrations are characteristic of the histogenetic origin of the tumor cells. However, the chromosomal imbalances that occurred probably led to the ability of tumor cells to grow in vitro.

Intrahepatic bile duct adenoma is a rare benign epithelial hepatic tumor derived from bile duct cells. We report the imaging findings of a patient with bile duct adenoma, which appeared as a small heterogeneously enhancing mass with focal small cystic change on CT and MRI. Follow-up images at seven months showed a slight increase in tumor size, which could be partly explained by intratumoral hemorrhage on pathologic examination. Although rare, bile duct adenoma should be considered as a differential diagnosis of a small hypervascular tumor located in the periphery of liver. Focal cystic change and intratumoral hemorrhage may occur.

Although diagnostic accuracy of imaging techniques for HCC has been improved through recent advances in MR techniques and new hepatocyte-specific contrast agents, misdiagnosis is encountered not uncommonly in real clinical practice. To reduce the rate of misdiagnosis, doctors should be familiar with the clinical manifestation and the imaging findings of false positive and false negative cases. We here report three cases with benign hepatic nodules mimicking HCC: bile duct adenoma, angiomyolipoma and pseudolymphoma.

Hepatocellular carcinoma (HCC) is a well-known complication of genetic hemochromatosis (GH). However, the frequency of primary liver carcinoma (PLC) with biliary differentiation, such as cholangiocarcinoma (CC) and combined hepatocholangiocarcinoma (CHCC), in GH remains unclear. We analyzed the histologic type of 20 PLCs occurring in the background of GH; all patients were homozygotic for the C282Y mutation. Ten were depleted of iron by successive phlebotomies, while the remaining 10 were untreated. Histologically, 13 cases were classified as HCC, 3 as CC, and 4 as CHCC. Immunohistochemical detection of Hep Par 1, cytokeratin 19 (CK19), and MUC1 supported this classification; PLC with biliary differentiation was immunoreactive for MUC1 in 86% (6/7) of cases and for CK19 in 100% (7/7) of cases. The nontumoral liver exhibited no cirrhosis or extensive fibrosis in 6 cases. Von Meyenburg complexes were present in 11 cases and intraparenchymal bile duct adenomas in 3. These data suggest that PLCs in patients with GH present a wide histologic spectrum, with tumors showing frequent biliary differentiation; may arise on a nonfibrotic or a cirrhotic liver; and often are associated with Von Meyenburg complexes and to a lesser extent with bile duct adenomas.

Human liver cancers have been associated mainly with chronic inflammations such as viral hepatitis B or C. This suggests that prolonged cell damage by chronic inflammation is critical in cancer development. Overproduction of nitric oxide (NO-) and its derivative (NO x , peroxynitrite) has been implicated as a cause of tissue damage by inflammation, thus contributing to tumor promotion. We have demonstrated the expression of the inducible isoform of nitric oxide synthase (iNOS) and 3-nitrotyrosine, a marker of peroxynitrite formation, by immunohistochemistry in preneoplastic and neoplastic rat liver tissues induced by continuous infusion of N-nitrosodiethylamine with mini-pumps. The preneoplastic lesions were characterized by proliferation of phenotypically altered hepatic foci (PAHF), dysplastic hepatocytes and oval cells. Histologically, the tumors were hepatocellular carcinomas (HCCs) of trabecular, (pseudo)glandular and solid types with or without cholangiocellular involvement, iNOS was located mainly in oval cells, capillary endothelial and muscular cells, epithelia of cholangiomas and glandular HCCs. 3-Nitrotyrosine was observed in the cytoplasms of PAHF and dysplastic hepatocytes in preneoplasias and in the cytoplasms of some living or apoptotic HCC cells, connective tissues, proteinaceous fluids, sinusoidal endothelia of tumorous hepatocytes and cholangiomas in tumors. From these observations, we suggest that: (i) chronic tissue damage by chemical carcinogens may act to induce iNOS and peroxynitrite formation; (ii) oval cells play a key role in development and/or growth of tumor tissues by producing NO- via iNOS, which may also cause tissue damage by peroxynitrite; (iii) iNOS can be considered as a phenotypic marker in cells of oval cell lineage and neovascularized capillaries in tumor tissues.

As part of a survey of fish diseases, lake whitefish (Coregonus clupeaformis) were collected in fall 1995 from the St. Lawrence River 15 km upstream of Quebec City, Quebec, Canada, to assess the prevalence of liver lesions. A total of 141 fish were captured and necropsied, and three standard sections of liver were taken for histological examination. Prevalences of altered hepatocyte foci, hepatocellular carcinoma, cholangioma, and cholangiocarcinoma were 0.7%, 2.1%, 0.7%, and 2.1%, respectively. Thus, the overall prevalence of liver neoplasia was 4.9% (7/141). Hepatic tumors were only observed in fish 7 years old or older. Fish age was significantly and positively correlated with the index assessing the number and size of macrophage aggregates (p

Published surveys of feline neoplasia have not specifically included biliary cystadenoma, and there is only one case report in the literature. This report is a compilation of 13 feline cases and provides a description of clinical, pathologic, immunohistochemical, and ultrastructural aspects of biliary cystadenoma as well as a discussion of comparative pathology of biliary cystadenoma in human beings and speculative histogenesis.

The fungal toxin fumonisin B1 (FB1) is a potential human carcinogen based on evidence of renal carcinogenicity in rats and hepatocarcinogenicity in mice. The toxicity and carcinogenicity of FB1 is linked to ceramide synthase inhibition. Based on this mechanism of action and on lack of evidence of genotoxicity, FB1 is considered a non-genotoxic carcinogen. The p53 heterozygous (p53+/-) mouse is a cancer-prone model used for carcinogenesis. The effects of chronic dietary FB1 exposure were characterized in p53+/- mice to confirm non-genotoxicity using a model which is more sensitive to genotoxic than non-genotoxic carcinogens and to clarify the relationship between p53 expression, altered sphingolipid metabolism, and FB1-induced carcinogenesis. Responses to FB1 were similar in p53+/- and p53+/+ mice after 26 weeks exposure to 0, 5, 50 or 150 mg FB1/kg diet, supporting a non-genotoxic mechanism of action. Hepatic adenomas and cholangiomas were observed in mice exposed to 150 mg/kg FB1. For a 10% increase in hepatic megalocytosis, the estimated 95% lower confidence limit of the benchmark dose (BMDL10) ranged from 0.15 and 1.11 mg FB1/kg bw/day. Based on similar responses in p53+/- and p53+/+ mice, p53 and related pathways play a secondary role in responses to FB1 toxicity and carcinogenesis.

We report a case of a 53-year-old man who presented with a history of recurrent fever with intermittent jaundice over a few months. Ascending cholangitis was suspected. Abdominal ultrasound showed no gallstone and an only slightly dilated common bile duct (CBD). The patient’s blood tests were normal. The patient was referred for endoscopic ultrasound (EUS). In the endoscopic suite, the patient underwent deep sedation with full anesthetic monitoring. EUS was performed using a curvilinear echoendoscope (GF UC 140P; Olympus, Tokyo, Japan). The EUS findings showed an isoechoic oval shaped mass of 1.1×0.7cm at the distal CBD, without CBD dilation (●" Fig.1). The patient then underwent endoscopic retrograde cholangiopancreatography (ERCP) using the duodenoscope (Olympus TJF-160, Olympus America, Center Valley, Pennsylvania, USA). The ampulla seemed normal on duodenoscopy (●" Fig.2). A cholangiogram revealed a 12-mm CBD with an irregular shaped filling defect, size 11×20mm, at the distal CBD (●" Fig.3). After endoscopic sphincterotomy, a polypoid mass of 1.5×1.0cm popped out (●" Fig.4). The stalk of this polyp was inside the CBD. We decided to take a biopsy from the polyp, and planned for polypectomy later, so a 10-Fr plastic stent (Cotton-Leung biliary endoprosthesis, Wilson-Cook Medical Inc., Winston-Salem, North Carolina, USA) was inserted for biliary drainage (●" Fig.5). Pathological analysis showed a tubular adenoma with low grade dysplasia. The patient was scheduled for polypectomy 2 weeks later. During the second procedure, the polyp had disappeared, thus endoscopic retrograde cholangiography was performed. The cholangiogram showed no residual filling defect at the distal CBD. Overtube-assisted cholangioscopy using an ultraslim gastroscope showed only a residual small ulcer of about 4mm diameter at the distal CBD (●" Fig.6). Our hypothesis for this unexpected event was that the pressure from the plastic stent resulted in stalk necrosis. To our knowledge [1–3], such a case has not been previously reported.

Biliary cystadenoma is a rare tumor of the liver. We describe a biliary cystadenoma of the left lobe of the liver with intracystic gallstone formation. This is the first report of stone formation in biliary cystadenoma of the liver.

Biliary papillomatosis is a rare entity characterized by multiple papillary adenomas involving extensive areas of the biliary tract with a great potential for recurrence and malignant transformation. It has been reported in association with Caroli disease and a choledochal cyst. We report herein a case of malignant intrahepatic biliary papillomatosis associated with cirrhosis secondary to hepatitis C. To the best of our knowledge, this is the first report of this association.

Background. In hepatocellular carcinoma (HCC), a high prevalence of hepatitis C virus antibody (anti-HCV) has been reported, indicating that it may be an important etiologic factor in the pathogenesis of HCC. In this study, the authors investigated the prevalence of anti-HCV in HCC patients, as well as the same prevalence in patients with cholangiocarcinoma (CC) and combined hepatocellular–cholangiocarcinoma (combined HCC-CC), to study the clinicopathologic features of anti-HCV–positive cases. Methods. The authors examined 141 patients with primary liver cancer who were pathologically diagnosed as having HCC (121 cases), CC (13 cases), or combined HCC-CC (7 cases). Hepatitis B surface antigen (HBsAg) and anti-HCV were measured in these patients. Results. Of 121 HCC cases, 85 (70.3%) were found to be anti-HCV positive, 16 (13.2%) were HBsAg positive, and 5 (4.1%) were both anti-HCV and HBsAg positive. In 13 cases with CC and in 7 with combined HCC-CC examined, 4 (30.8%) and 5 (71.4%), respectively, were anti-HCV positive. Conclusions. The anti-HCV–positive rate was high in combined HCC-CC as well as in HCC. These three types of primary liver cancer, which were anti-HCV positive, shared two common features: male dominance and high incidences of complication with liver cirrhosis.

It has been established that loss of tumour suppressor genes is crucial in carcinogenesis. There has been no reported study on searching for tumour suppressor genes in cholangiocarcinomas as yet. In order to investigate the loss of heterozygosity (LOH), which may represent such gene loss, in cholangiocarcinoma, we studied 14 patients with this tumour using restriction fragment length polymorphism analysis. Twenty-two probes assigned to chromosomes 1, 5, 7, 9, 11, 12, 13, 14, 16, 17 and 18 were used. Allelic losses were found in chromosomal regions 5q35-qter and 17p13. Loss of genetic material in these regions in cholangiocarcinoma was shared with hepatocellular carcinoma. Probes for other chromosomes have as yet shown no consistent LOH. In conclusion, this study for the first time showed LOH on chromosomes 5 and 17 in cholangiocarcinoma. Images Figure 1

The development of hepatic neoplasms was histologically characterized in transgenic mice that expressed an albumin enhancer-promotor/SV40 T-antigen fusion gene. At least five transgenic and three control mice were examined at monthly intervals over a 3-month period. At 1 month of age, five transgenic mice (two male, three female) and three controls (one male, two female) were examined. Five transgenic mice (two male, three female) and three controls (one male, two female) were examined at 2 months of age. Fourteen transgenic mice (12 male, two female) and three controls (two male, one female) were examined at 3 months of age. At 1 month of age, liver-to-body weight ratios of transgenic mice were increased nearly twofold as compared with controls. Histologically, livers from transgenic mice were characterized by dysplastic hepatocytes with marked variation in nucleus and cell size. At 2 months of age, livers from transgenic mice were 2.5 times larger than control livers and contained numerous 1–5-mm cystic spaces. Transgenic livers also contained multiple eosinophilic, basophilic, and clear foci, as well as cystic, hyperplastic bile ducts and biliary adenomas. At 3 months of age, transgenic livers were enlarged over eightfold as compared with controls and contained numerous cysts and solid masses up to 2 cm in diameter. Trabecular, glandular, and anaplastic hepatocellular carcinomas, as well as benign and malignant biliary neoplasms, were diagnosed. No metastasis was observed. Subcutaneous trabecular hepatocellular carcinomas developed in two of three syngeneic mice that had received transplants of a solid hepatic neoplasm, confirming the neoplastic behavior of these tumors. These experiments, in which viral oncogene expression is targeted to all hepatocytes, support the multistage hypothesis of tumor development and illustrate the similarities in morphologic response of liver to a variety of carcinogenic insults.

The mortality and morbidity in major hepatic resection is often related to hemorrhage. A high pressure, high velocity water jet has been developed and has been utilized to assist in hepatic parenchymal transection. Sixty-seven major hepatic resections were performed for solid hepatic tumors. The tissue fracture technique was used in 51 patients (76%), and the water jet dissector was used predominantly in 16 patients (24%). The extent of hepatic resection using each technique was similar. The results showed no difference in operative duration (p = .499). The mean estimated blood loss using the water jet was 1386 ml, and tissue fracture technique 2450 ml (p = .217). Transfusion requirements were less in the water jet group (mean 2.0 units) compared to the tissue fracture group (mean 5.2 units); (p = .023). Results obtained with the new water dissector are encouraging. The preliminary results suggest that blood loss may be diminished.

The primary goal in the treatment of malignant obstruction is the relief of jaundice. Although operative biliary bypass is a reliable method of palliation, nonoperative palliation may be desirable in selected patients.We report our experience with forty-eight self expandable metallic biliary endoprostheses (Wallstent) percutaneously placed in 35 patients with irresectable malignant biliary obstruction. In twelve patients more than one stent was necessary to bridge the entire length of the biliary stenosis. The obstruction was due to primary tumors in 14 and to lymph node metastases in 12. In nine patients transanastomotic stents were placed after previous bilioenteric anastomosis because of malignant obstruction. Complications occurred in 11 patients (31.4%), and five patients died within 30 days of stent placement (14.3%). The mean stent patency to date of patients discharged is 6.1 months, and the mean survival 7.2 months. Follow up data is available for 29 patients, and excellent palliation was achieved for more than 75% of the survival time in 22 (76%). Seven patients have had documented stent occlusion requiring further intervention (24%).In this selected group of patients, the results of percutaneous self-expandable stents are encouraging. However, our data does not support the initial reports of self-expandable endoprostheses that suggest an improved result compared to conventional plastic stents. A randomized study using either expandable stents as compared to operative biliary enteric bypass is necessary.

Experience with liver transplantation over a period of 11 years at the University of Pittsburgh is presented. The application of liver transplantation to cases of hepatocellular carcinoma has changed considerably over this 11-year period with the sequential introduction of adjuvant and, more recently, neoadjuvant chemotherapy. Results with the combination of chemotherapy plus surgery appear to be better than results with either agent alone. Moreover, the early results with neoadjuvant therapy appear to be better than those achieved with adjuvant therapy. As a result of this experience, conceptual changes in the approach to the problem of hepatic cancer and the role of both chemotherapy and liver transplantation in its management have changed at the University of Pittsburgh. These changes are identified and discussed.

A case of Cholangitis Glandularis Proliferans (CAGP) in association with a cholangiocarcinoma of the common bile duct as described. This is the eighth case of CAGP described and the second association with cholangiocarcinoma.

The operative management of hilar cholangiocarcinoma has evolved because of advances in diagnostic imaging that have permitted improved patient selection, and refinements in operative techniques that have lowered operative mortality rates. Over a 4-year period, 48 patients with hilar cholangiocarcinoma were managed. Twenty-seven patients were treated by palliative measures. Preoperative investigation identified 29 patients who were judged fit for operation without proven irresectability by radiologic studies, and 21 of the 29 patients had tumor removal (72%). Twenty-three operative procedures were performed: local excision (n = 12) (two had subsequent hepatic resection), and hepatic resection primarily (n = 9). Eight patients had complications (35%), and one patient died (4.3%). The mean actuarial survival after local excision in 36 months, and after hepatic resection, 32 months. Palliation as assessed by personal interview was excellent for more than 75% of the months of survival. A combination of careful patient selection and complete radiologic assessment will allow an increased proportion of patients to be resected by complex operative procedures with low mortality rate, acceptable morbidity rate, and an increase in survival with an improved quality of life.

A 65-year-old man was hospitalized due to an abdominal tumor. Several imaging studies showed multilocular tumors in the right hepatic lobe and in the pancreatic head, 4 and 7 cm in size, respectively. The hepatic tumor rapidly grew to 9 cm in 4 weeks, associated with a rapid increase in the serum carcinoembryonic antigen level from 125 ng/ml to 1,000 ng/ml. The pathologic diagnosis of the resected liver tumor was mucinous cholangiocarcinoma. This hepatic tumor produced a large amount of mucin, but did not secrete mucin into the bile ducts. Therefore, there was no obstructive jaundice. The incidentally accompanied pancreatic tumor was a typical serous cystadenoma. The present case suggested that mucinous cholangiocarcinoma could present rapid growth of the tumor. The clinicopathological features of mucinous cholangiocarcinoma are demonstrated for the first time, and the differences between mucinous cholangiocarcinoma and mucin-producing papillary adenocarcinoma of duct-spreading type are discussed.

Free-floating tumor debris or mucobilia as a cause of intermittent obstruction has been described infrequently. A patient with intermittent jaundice caused by tumor emboli from an intrahepatic polypoid mucinous cholangiocarcinoma is presented. Symptoms of intermittent jaundice and midepigastric pain persisted over 5 years despite an initial cholecystectomy and common bile duct exploration before definitive diagnosis and treatment of an hepatic trisegmentectomy (segments II, III, and IV). Intraductal mucin was confirmed intraoperatively and pathologically as the cause of the obstructive jaundice. The patient remains asymptomatic and without evidence of disease more than 5 years postoperatively. This report of a predominantly mucin-producing intrahepatic cholangiocarcinoma details a rare protracted clinical course of intermittent biliary obstruction from mucus emboli and highlights the possibility of long-term survival after complete resection.

A retrospective analysis of 194 patients who underwent hepatic resection for primary or metastatic malignant disease from January 1962 to December 1988 was undertaken to determine variables that might aid the selection of patients for hepatic resection. Hepatic metastases were the indication for resection in 126 patients. The 5-year survival rate was 17 per cent. For patients with resected metastases from colorectal cancer (n = 104), the survival rate at 5 years was 18 per cent. The 5-year survival rate was 27 per cent when the resection margin was >5 mm compared with 9 per cent when the margin was ≤5 mm (P < 0.01). No patient with extrahepatic invasion, lymphatic spread, involvement of the resection margin or gross residual disease survived to 5 years, compared with a 23 per cent 5-year survival rate for patients undergoing curative resection (P < 0.02). The survival rate of patients with poorly differentiated primary tumours was nil at 3 years compared with a 20 per cent 5-year survival rate for patients with well or moderately diflerentiated tumours (P not significant). The site and Dukes' classification of the primary tumour, the sex and preoperative carcinoembryonic antigen level of the patient, and the number and size of hepatic metastases did not afect the prognosis. The 5-year survival rate for patients with hepatocellular carcinoma (n = 42) was 25per cent. An improved survival rate was found for patients whose α-fetoprotein level was normal (37 per cent at 5 years) compared with those having a raised level (nil at 3 years) (P < 0.01). Involvement of the resection margin, extrahepatic spread and spread to regional lymph nodes were associated with an 8 per cent 5-year survival rate versus 44 per cent for curative resection (P < 0.005). The presence of cirrhosis, the presence of symptoms, and the multiplicity and size of the tumour did not affect the prognosis. The 5-year survival rate of 11 patients with hepatic sarcoma was 25 per cent. No patient with peripheral cholangiocarcinoma survived to 1 year in contrast to patients with hilar cholangiocarcinoma, all four of whom survived for more than 14 months.

Background. Adenosquamous carcinoma and squamous cell carcinoma (SCC) occur rarely in the liver compared with adenocarcinoma, and the histogenesis and biologic behaviors of these tumors remain unknown. The authors addressed these issues in the current article. Methods. A specimen aseptically obtained from the surgically resected cholangiocellular carcinoma (CCC) was cut into pieces and inoculated into the back of a nude mouse, bilaterally. The developed tumors were resected and serially transplanted into nude mice. The morphologic features and growth kinetics of the nude mouse tumors at different passages were compared. Results. The authors established a new human CCC nude mouse strain, designated nuKMC-2, from a 64-year-old woman. The original tumor of the patient showed the features of moderately differentiated tubular adenocarcinoma with small sheet-like arrangement of polygonal cells. The initial tumor developed in a nude mouse showed morphologic features similar to the original tumor. With the serial transplantation to nude mice, the components of tubular adenocarcinoma diminished, and all of the nuKMC-2 was replaced by SCC. Doubling times of nuKMC-2 at the 5th and 11th passages were 9.9 and 7.4 days, respectively, which suggested that the tumor with squamous components were more aggressive biologically than the adenocarcinoma. Conclusions. The results suggested that adenosquamous carcinoma might be a transitional form from adenocarcinoma to SCC and that some of the primary hepatic SCC might originate from adenocarcinomas. Cancer 1992; 70:415–422.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary tumor of the liver. To further define its clinicopathology and surgical management, we reviewed our experience. Clinical presentations of 32 patients with ICC was similar to that with hepatocellular carcinoma. Jaundice occurred in only 27 percent. ICC was unresectable due to advanced disease stage in 81 percent. Six patients had curative resections with two 5 year disease free survivors. Underlying liver disease was associated with ICC in 34 percent of patients.

Hematoxylin and eosin (H-E) stained liver sections of 47 autopsy cases of hepatic malignancies were examined. There were 43 cases of hepatocellular carcinoma (subtypes of 30 trabecular, 7 solid, 5 pseudoglandular, and one scirrhous carcinoma), 3 of cholangiocellular carcinoma and one of mixed carcinoma. After immunohistochemical staining, benign hepatocytes reacted positively with anti-epithelial membrane antigen (EMA). Hepatocellular carcinoma cells reacted more weakly than benign hepatocytes. It was noted that the microtubular structure, which could not be demonstrated even by alcian blue or cationic ferric hydroxide colloid stabilized with cacodylate (Fe-CaC), was clearly detected with anti-EMA. The EMA-positive microtubular structures may indicate terminal cholangiolar differentiation. Based on EMA, seven more cases formerly classified as hepatocellular carcinoma by H-E were reclassified as mixed carcinoma, totaling eight (17.0%). The histologic classification of "mixed carcinoma" has been 1.5 to 2.0% of primary liver cancers in Japan, but we suggest there may be more cases of "mixed carcinoma" identified in the future. In conclusion, we emphasize that EMA staining is useful for more accurate classification of hepatic tumors.

An immunohistochemical study of glutathione S-transferase (GST) expression in hepatocellular carcinoma and cholangiocarcinoma is described. Unlike most animal models of hepatic malignancy pi class GST was not consistently overexpressed in hepatocellular carcinoma. This tumour type either predominantly expressed alpha class GST or failed to express GST. By contrast, cholangiocarcinoma always expressed pi class GST, presumably reflecting the tissue of origin, since in human biliary epithelium pi class GST is the predominant GST. The variable expression of pi class GST which was observed in hepatocellular carcinoma may reflect transformation of hepatocytes damaged by toxins, since this GST can be induced after a chemical insult such as alcohol. As well as indicating the biochemical heterogeneity of hepatocellular carcinoma with respect to GST, this study indicates the need for further study of the nature of inherent drug resistance in these tumour types.

In a 2-yr carcinogenicity bioassay, 0, 2, 4, or 8 mg furan/kg body weight (BW) was administered to male and female Fischer (F344) rats and resulted in an 86-100% incidence of cholangiocarcinomas with occasional metastasis. In a separate but concurrent study, male F344 rats dosed with 30 mg furan/kg BW for 90 days developed marked cholangiofibrosis and cholangiohepatitis and, when subsequently maintained without further treatment for an additional 6, 12, or 18 months, the cholangiofibrosis progressed to yield a 100% incidence of cholangiocarcinomas. Transplantation of 21 primary cholangiocarcinomas into syngeneic recipients resulted in growth from 4 donors. The 4 transplanted lines were successfully transferred through 8 serial passages and resulted in metastases in the recipients. The progressive growth of these proliferative hepatocholangial lesions over time, their transplantability, and the development of metastases in some of the cases provide biological evidence of the malignant potential of the furan-induced liver changes.

This study, aimed at elucidating the epidemiological features of primary liver carcinoma developing in non-cirrhotic livers, was based on 25 103 autopsies performed between 1975 and 1984 in Trieste, Italy. These autopsies correspond to approximately 70% of all deaths that occurred in this area. Various factors allegedly related to carcinomas were analysed in reference to our previous study on cirrhotic livers and in comparison with 5603 autopsies in Kurume, Japan. There were 28 cases of hepatocellular carcinoma (HCC), 16 of cholangiocellular carcinoma (CCC) not associated with cirrhosis in Trieste, and 48 HCC and 19 CCC in Kurume. On the basis of our findings, it was concluded that cirrhosis, regardless of its cause, is the main pathogenetic factor in HCC; it is responsible for a much higher frequency (14.2:1) than in non-cirrhotic livers, as well as for early occurrence of tumours (an average of 6 years earlier in cirrhotic liver) in Trieste. Patients in Trieste were older than those in Japan, and the frequency of HCC among all autopsies was much greater in the latter. By contrast, the influence of cirrhosis on cholangiocellular carcinoma (CCC) was negligible, as such association appeared purely coincidental or absent. The incidence of CCC among autopsies was greater in Japan. Our data on CCC were not sufficient to demonstrate any clear aetiopathogenetic association between this tumour and alcohol abuse and hepatitis B virus (HBV) infection, except for a possible aetiological role of gallstones. The frequency of CCC relative to HCC was greater in Trieste than in Japan; the incidence of HCC was much less in Trieste, whereas CCC was more frequent in Japan.

From 1 January 1983 to 1 January 1989 123 cirrhotic patients with hepatocellular cancer (n = 122) or cholangiocarcinoma (n = 1) were screened using liver function tests, α-fetoprotein determination, ultrasonography with biopsy (and in selected cases computed tomography or nuclear magnetic resonance), laparoscopy and angiography, Child-Pugh classification and urea-nitrogen synthesis rate. Twenty-three patients were selected for surgical resection because the tumour was smaller than 5 cm, not centrally located and at least 1 cm away from main structures; there was no evidence of multicentricity or metastatic disease; and the Child-Pugh classification was A or B and the urea-nitrogen synthesis rate at least 6 g/day. Upper gastrointestinal endoscopy was used routinely to identify oesophageal varices which were present in 17 cases; ten patients with a history of variceal haemorrhage (43 per cent) had preoperative endoscopic sclerotherapy. In cases with recurrent haemorrhage, surgery was used to prevent intraoperative and postoperative bleeding. Tumour resection was carried out using controlled hypotension and hepatoduodenal ligament clamping. Twelve bisegmentectomies, ten segmentectomies and one atypical resection were performed. The operative mortality rate was 13 per cent with liver failure and sepsis as the causes of death. The ‘recurrence rate’ was 26 per cent and the late mortality rate for the whole group up to 1 January 1990 was 30 per cent; 13 patients were still alive. The 12-month survival rate was 77 per cent and after 5 years it was 49 per cent. Thus, surgical resection of small liver tumours is the treatment of choice in this selected group of patients.

The expression of tumour markers CA 19-9 and CA 50, defined by the monoclonal antibodies 1116 NS 19-9 (19-9 antibody) and C 50, was studied by the immunoperoxidase technique in formalin-fixed, paraffin-embedded tissue sections from 11 hepatocellular carcinomas and 10 cholangiocarcinomas of the liver, and from specimens of normal liver and liver cirrhosis. The 19-9 and C 50 antibodies react with sialosylfucosyllactotetraose, corresponding to sialylated blood group antigen Lewis, and the C 50 antibody also with another sugar moiety, sialosyllactotetraose. Neither marker was cancer specific. The CA 19-9 and CA 50 antigens are normal constituents of bile ducts. Nine out of 10 cholangiocarcinomas stained for CA 50, and eight out of 10 for CA 19-9. There was no apparent difference between the staining pattern of CA 19-9 and CA 50. Hepatocellular carcinomas were consistently negative for both markers. Thus, hepatocellular carcinomas and cholangiocarcinomas showed a clear difference in the reactivity for tumour marker antigens CA 19-9 and CA 50. This difference might be of clinical importance in the differential diagnosis between hepatocellular carcinoma and cholangiocarcinoma. Images Figure 1 Figure 2 Figure 3 Figure 4

This study was carried out to clarify the influence of incomplete bile duct obstruction (IBDO) on the occurrence and proliferation of cholangiocarcinoma and to evaluate the effect of release of IBDO at an early stage, using 175 Syrian golden hamsters. These hamsters received 500mg/kg body weight of diisopropanolnitrosamine (DIPN) once weekly for 10 weeks, and then were divided into 3 groups, consisting of the simple laparotomy group (SL group), the IBDO group and 2 week IBDO group, in which IBDO was released after 2 weeks. The occurrence rates of cholangiocarcinoma at 20 weeks were 42% in the SL group, 76% in the IBDO group and 30% in the 2 week IBDO group. The mean numbers of tumors per hamster in the IBDO group were significantly greater than those in other groups (p < 0.05). Both occurrence rates and numbers of tumors in the 2 week IBDO group were similar to those in the SL group. The proliferation of bile ductules and isolation of bacteria from bile in the IBDO group had higher rates at 15, 20 weeks than those found in the other groups. These results suggest that IBDO has an influence, as promoter, on the occurrence of cholangiocarcinoma induced by DIPN, and the disappearance of its promoting effect is caused by release of the obstruction.

Cholangiocarcinoma is more likely to develop in patients with primary sclerosing cholangitis. Our aims were to describe the clinical presentation, course, and management of patients afflicted with both cholangiocarcinoma and primary sclerosing cholangitis and to estimate the prevalence of cholangiocarcinoma in patients with primary sclerosing cholangitis. A retrospective analysis was conducted of 30 patients with both primary sclerosing cholangitis and cholangiocarcinoma managed at our institution during an 8-year period. Development of cholangiocarcinoma was heralded by rapid clinical deterioration with jaundice, weight loss, and abdominal discomfort. Cholangiocarcinoma complicating primary sclerosing cholangitis often was detected at an advanced tumor stage, which precluded effective therapy, and overall median survival was 5 months. Earlier recognition and treatment of cholangiocarcinoma in such patients will be necessary to increase survival rates. Seventy patients with primary sclerosing cholangitis were followed prospectively in a clinical trial of medical therapy for an average of 30 months. Twelve patients died and five were found at autopsy to have cholangiocarcinoma. The potential for cholangiocarcinoma to develop in patients with primary sclerosing cholangitis may indicate that liver transplantation should be considered earlier in the course of the disease.

Renal function in obstructive jaundice in man: Cholangiocarcinoma model. Renal function with respect to water clearance and renal hemodynamics was studied in 15 patients with obstructive jaundice due to cholangiocarcinoma. The results were compared with those of the control normal subjects. There was no change in renal function in the patients with mild to moderate jaundice, with total serum bilirubin from 8.0 to 15.1 mg/dl. Increased urinary sodium excretion and decreased free water and negative water clearances were observed in the patients with severe jaundice with total serum bilirubin from 27.0 to 40.4 mg/dl and normal serum albumin. Renal blood flow was normal, but creatinine clearance was decreased. In severely jaundiced patients with serum bilirubin from 30.5 to 40.1 mg/dl and hypoalbuminemia urinary sodium excretion, free water clearance, negative water clearance, renal blood flow and creatinine clearance were decreased. There was salt and water retention in this group. The findings suggest that in severe jaundice there is inhibition of sodium chloride reabsorption in the thick ascending limb of Henle's loop. ADH and increased hydraulic conductivity of the collecting tubules possibly contribute to decreased free water clearance. In severely jaundiced patients with hypoalbuminemia this salt losing effect is converted to salt retention by increased proximal tubular reabsorption of sodium.

Between January 1982 and April 1989, 134 patients with a suspected liver neoplasm were referred to the liver unit, Queen Elizabeth Hospital, Birmingham. In 105 (78 per cent), a primary hepatic neoplasm was historically confirmed, and 47 patients (45 per cent) proved to have primary hepatocellular carcinoma. Twenty-nine orthotopic liver transplants were performed in 28 of these patients (27 per cent). Twenty patients (71 per cent) survived 30 days or longer (median 11·5 months; range 2–87 months), of whom nine are currently alive. We retrospectively analysed our data to determine the influence of preoperative evaluation, histological type and staging on outcome. Computed tomography proved to be superior to intraoperative assessment (86 versus 58 per cent) in diagnosing tumour positive nodes. Patients with tumour negative lymphadenopathy had a better prognosis. Postoperative stage I/II had a median survival of 16 months (range 3–87 months) compared with 7·5 months (range 2–20 months) for stage III. Non-cirrhotic patients with hepatocellular carcinoma had the best prognosis; cholangiocellular carcinoma and cirrhotic patients with hepatocellular carcinoma had the worst outcome with no survivors beyond 1 year. Because of the advanced stage of disease at the time of presentation, the value of liver transplantation in primary liver cancer is limited. For those presenting with advanced disease confined to the liver (stage I/II) in whom conventional hepatic resection is not possible, significant benefit can be achieved in selected cases.

Inoperable malignant liver tumors have been treated by radiofrequency hyperthermia at Kyoto University Hospital since 1983. In this study, clinical hyperthermia for malignant liver tumor was evaluated for 67 tumors in which we could measure intratumor temperatures. Of the 67 tumors, 41 were hepatocellular carcinomas (HCC), six cholangiocarcinomas, and 20 metastatic tumors. Cholangiocarcinoma and metastatic tumors were more susceptible to this treatment than HCC. Of the three types of HCC, higher intratumor temperatures were achieved in the diffuse type than in the nodular or massive types. The minimum tumor temperature of HCC stayed below 40 degrees C in 46% of cases, especially in larger tumors. The local response rates (complete remission plus partial remission/all) were 28% and 11% for HCC and non-HCC, respectively, for thermochemotherapy; 86% and 33%, for thermoradiotherapy; and 33% and 89%, for thermotherapy with embolization. No apparent relationship was observed between the intratumor temperatures and local response rate.

An extract of cultured human cholangiocellular carcinoma cells (HuCC-T1) was found to contain high mitogenic activity for BALB/c3T3 cells. The growth factor eliciting most of the mitogenic activity was purified and concluded to be identical with basic fibroblast growth factor (bFGF)-like factor on the basis of its molecular weight and heparin-Sepharose elution profile, and the results of immunoblotting and radioimmunoassay. HuCC-T1 cells also secreted bFGF-like factor into serum-free medium. A combination of insulin and transferrin or bovine serum albumin stimulated the growth of HuCC-T1 cells in serum-free medium. However, bFGF did not stimulate their growth in the presence and absence of these supplements. Neutralizing monoclonal antibody against bFGF did not inhibit growth. These results indicate that bFGF-like factor is not a growth factor for this cell line.

Enteroenteric intussusception is a condition in which full-thickness bowel wall becomes telescoped into the lumen of distal bowel. In adults, there is usually an abnormality acting as a lead point, usually a Meckels' diverticulum, a hamartoma or a tumour. Duodeno-duodenal intussusception is exceptionally rare because the retroperitoneal situation fixes the duodenal wall. The aim of this report is to describe the first published case of this condition. A patient with duodeno-duodenal intussusception secondary to an ampullary lesion is reported. A 66 year-old lady presented with intermittent abdominal pain, weight loss and anaemia. Ultrasound scanning showed dilated bile and pancreatic ducts. CT scanning revealed intussusception involving the full-thickness duodenal wall. The lead point was an ampullary villous adenoma. Congenital partial (type II) malrotation was found at operation and this abnormality permitted excessive mobility of the duodenal wall such that intussusception was possible. This condition can be diagnosed using enhanced CT. Intussusception can be complicated by bowel obstruction, ischaemia or bleeding, and therefore the underlying cause should be treated as soon as possible.

The inflammation-associated cytokine interleukin-6 (IL-6) can contribute to tumor growth and resistance to therapy by the activation of survival mechanisms. In several human cancers, IL-6-activated survival signaling involves the signal transducers and activators of transcription (Stat) factors or protein kinase cascades. microRNAs (miRNAs) are endogenous regulators of gene expression that are altered in expression in many cancers. However, the effect of inflammatory cytokines on miRNA expression and the role of miRNA in modulating IL-6-mediated cell survival are unknown. We investigated the involvement of miRNA in malignant cholangiocytes stably transfected to overexpress IL-6, which enhances tumor growth in vivo by inhibition of apoptosis. We provide evidence that (i) miRNA expression both in vitro and in vivo is altered by overexpression of IL-6; (ii) selective miRNAs including let-7a are up-regulated and contribute to the survival effects of enforced IL-6 activity; and (iii) let-7a contributes to the constitutively increased phosphorylation of Stat-3 by a mechanism involving the neurofibromatosis 2 (NF2) gene. These findings reveal a novel mechanism by which IL-6 mediates tumor cell survival that may be therapeutically targeted and emphasize the presence of complex interrelationships between deregulated expression of miRNA and transcription factors in human cancers.

Intrahepatic cholangiocarcinomas are second most common primary tumors of the liver. They are usually seen in 6th to 7th decades of life and at an advanced stage leading to poor prognosis. Their occurrence in the young age group is rare. Histopathological features of this tumor are well documented but literature regarding cytomorphological features on FNA is limited. We describe the cytological features of this tumor in a young woman presenting primarily with a rib metastasis. FNA smears from hard lump in the right chest wall and liver mass showed small round tumor cells arranged in the form of sheets, clusters and occasional tubules. The cells showed mild pleomorphism and bland nuclear morphology. Intimately admixed with tumor cells were spindle shaped fibroblastic cells. Serum alpha-fetoprotein level was within normal limit. Special stain for bile and immunocytochemical staining for NSE, chromogranin and CALLA were all negative. Cholangiocarcinoma was diagnosed based on cytological findings and special stains and this diagnosis was histologically confirmed on biopsy.