A Comprehensive Approach to the Management of Benign and Malignant Ampullary Lesions: Management in Hereditary and Sporadic Settings.

PURPOSE OF REVIEW: The purpose of this review was to examine the historical roots of endoscopic management of ampullary lesions and explore emerging data on improved techniques, technologies, and outcomes. Of specific interest was answering whether there exists a reasonable body of data to support one resection technique or strategy above others. RECENT FINDINGS: Review of recent literature suggests the continued use of endoscopic ampullectomy is a safe and effective means of curative treatment of ampullary adenomas. Complications are relatively infrequent and complete endoscopic resection is possible in a majority of cases, with proper patient and lesion selection. Greater than 2 decades of experience with endoscopic ampullectomy have shown this to be a viable, well-tolerated, and highly effective means of treating ampullary adenomas. While few concrete guidelines exist to advise endoscopists on the ideal technique for resection, experience, patient selection, and prior planning can greatly influence the technical and clinical success of endoscopic ampullectomy.

Diffusion-weighted MRI in intrahepatic bile duct adenoma arising from the cirrhotic liver.

A 64-year-old male patient with liver cirrhosis underwent a CT study for hepatocellular carcinoma surveillance, which demonstrated a 1.4-cm hypervascular subcapsular tumor in the liver. On gadoxetic acid-enhanced MRI, the tumor showed brisk arterial enhancement and persistent hyperenhancement in the portal phase, but hypointensity in the hepatobiliary phase. On diffusion-weighted MRI, the tumor showed an apparent diffusion coefficient twofold greater than that of the background liver parenchyma, which suggested that the lesion was benign. The histologic diagnosis was intrahepatic bile duct adenoma with alcoholic liver cirrhosis.

Cystic cholangiomas after transplantation of pancreatic islets into the livers of diabetic rats.

Islet transplantation is increasingly used as a therapy for human type 1 diabetes mellitus. In our study, we investigated the effect of the transplantation of a low number (n = 350) of pancreatic islets into the right liver part on the neighboring portal bile ducts. Male streptozotocin- diabetic Lewis or autoimmune-diabetic BB/Pfd rats (n = 1065) were subdivided into 11 experimental groups. A few days after low-number islet transplantation, cholangiocytes adjacent to the grafts showed an increase in proliferative activity. During the next 12-24 months, many peri-insular ductules progressed via tumor-like cystic lesions to large cystic cholangiomas, accompanied by a translocation of the insulin receptor into the cytoplasm and an increase in expression of insulin-related signaling proteins (Insulin-receptor-substrate-1, Raf-1, Mek-1). After 24 months, 53% of rats with low-number transplantation exhibited at least one cholangioma >10 mm, significantly outnumbering tumor development in the transplant-free left liver part and in any control group. No cholangiocarcinomas emerged. A graft cell origin of the tumors was excluded by Y chromosome in situ hybridization in cross-gender transplantations. Conclusively, low-number intrahepatic islet transplantation, most likely acting by permanent local hyperinsulinism, leads to prolonged cholangiocellular proliferation in streptozotocin- and in autoimmune-diabetic rats, resulting in the development of benign cystic cholangiomas.

Health of lake whitefish (Coregonus clupeaformis) with elevated tissue levels of environmental contaminants.

Lake whitefish (Coregonus clupeaformis) were collected in 1996 from the St. Lawrence River, Quebec, Canada. Histologic examination was performed on major organs of 497 specimens and on the liver of 48 additional individuals. Preneoplastic and neoplastic hepatic changes consisted of vacuolated cell (n = 65), clear cell (n = 17), and acidophilic (n = 16) foci of altered hepatocyte, hepatocellular carcinoma (n = 12), cholangioma (n = 5), and cholangiocarcinoma (n = 28). Six fish were intersexes (1.2%), and 11.7% of the ovaries (26/223) had ducts containing spermatogonia or more differentiated cells of the male germ cell line. Asynchronous nodular maturation of the testes was present in 8.2% of the male fish (22/267). The mean hepatic concentrations of various contaminants, including polychlorinated biphenyls (PCBs), chlorobenzenes, pesticides, and trace metals, were 6 to 8 times higher in lake whitefish than in three other fish species (Ictalurus punctatus, Catostomus commersoni, and Stizostedion vitreum) collected at the same site. Condition factor of lake whitefish from this study was lower than that previously reported 40 to 50 years ago at this site and from contemporary pristine sites in the Great Lakes, USA. The presence of liver neoplasms, gonadal lesions, and a decreased condition factor in lake whitefish from the St. Lawrence River may be etiologically related to elevated tissue concentrations of toxic chemical contaminants.

Primary liver carcinoma in genetic hemochromatosis reveals a broad histologic spectrum.

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.

Colangiocarcinoma / Cholangiocarcinoma

El colangiocarcinoma es una neoplasia de baja prevalencia, pero que representa un gran desafío médico, tanto en el diagnóstico como en el tratamiento, en vista de lo insidioso de sus manifestaciones clínicas. Su aparición se ha asociado en su origen celular con otros tumores hepáticos y relacionado con múltiples factores congénitos o adquiridos (infecciones, medicamentos u otras patologías). La variedad histológica más frecuente es el adenocarcinoma y la ubicación más común en el conducto colédeco; las metástasis regionales son un hallazgo usual al momento de la necropsia. Los hallazgos clínicos más frecuentes son: prurito, pérdida de peso, anorexia, acompañados de ictericia y hepatomegalia. Los avances inmunohistoquímicos en cuanto a los oncogenes (ras y C-er B-1) y marcadores tumorales (factor de crecimiento epidérmico o integrinas, entre otros) permiten hacer diagnóstico diferencial con otros cánceres hepáticos y en un futuro proporcionar información valiosa en relación a su biología celular. La aproximación inicial a los pacientes con esta patología se realiza a través de la ecosonografía, que puede asociarse a doopler, la tomografía axial computarizada y la Resonancia Magnética Nuclear tienen similar sensibilidad y especificidad, y se prefieren la anterior en caso de ancianos con historia de pérdida de peso. La colangiografía transhepática percutánea se prefiere cuando es posible, a la pancreatocolangiografía retrógrada endoscópica ya que permite una mayor visualización de las vias biliares. El tratamiento incluye la resección y la colocación de endoprótesis. El primero, asociado a la radioterapia y la quimioterapia, es el que permite alcanzar la mejor sobrevida; la unión de estas modalidades terapeúticas abre una puerta para nuevas estrategias en cuanto al manejo de ésta patología

Diagnostic role of serum CA 19-9 for cholangiocarcinoma in patients with primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) predisposes to the development of cholangiocarcinoma, a usually fatal complication that is difficult to diagnose. Serum concentrations of CA 19-9, a tumor-associated antigen, are frequently increased in patients with only cholangiocarcinoma. The aim of this study was to assess the value of an increased serum CA 19-9 level for the diagnosis of cholangiocarcinoma in patients with preexisting PSC. We analyzed serum samples from 9 patients with PSC and superimposed cholangiocarcinoma and from 28 patients with only PSC. Serum concentrations of CA 19-9 were measured in a blinded manner with use of an immunoradiometric assay. The serum CA 19-9 concentrations were increased in 8 of 9 patients (89%) with PSC and cholangiocarcinoma (mean +/- SE, 391 +/- 86 U/ml; range, 4 to 677), whereas they were increased in only 4 of 28 patients (14%) with only PSC (mean +/- SE, 61 +/- 16 U/ml; range, 2 to 370). The sensitivity of a CA 19-9 value greater than 100 U/ml for cholangiocarcinoma in PSC was 89%, and the specificity was 86%. The measurement of serum concentrations of CA 19-9 is a promising test for detecting cholangiocarcinoma in patients with PSC.

Late development of cholangiocarcinoma after the treatment of hepatolithiasis.

Although the association of cholangiocarcinoma with intrahepatic calculi (hepatolithiasis) is well recognized, the late development of cholangiocarcinoma after the treatment of hepatolithiasis has not been reported in detail. Of 109 consecutive patients with hepatolithiasis treated during 19 years, eight patients had cholangiocarcinoma, seven of whom had cholangiocarcinoma two to 14 years, with a mean of eight years, after the treatment of hepatolithiasis. Absence of cholangiocarcinoma was confirmed when stones were removed at the time of the initial treatment. The mean age was 56 years, with a female to male ratio of 2:5. At the time of detecting cholangiocarcinoma, three patients had no gallstones and four had gallstones at the corresponding site to the carcinoma. Cystic dilatation of the intrahepatic bile duct was often observed on the direct cholangiogram. The biles were all infected mainly with Escherichia coli and Klebsiella species. Thus, bile stasis and bacteria infection seems to be the important causative factor, causing cholangiocarcinoma rather than the calculi itself. Because the symptoms only mimic those of cholangitis, the possible presence of cholangiocarcinoma should be considered even after the treatment of hepatolithiasis for early detection and curative resection.

The association of malignancy with SLE: an analysis of 150 patients under long-term review.

We describe seven patients who developed malignancy before, after or at the onset of systemic lupus erythematosus (SLE). They comprise three cases of breast adenocarcinoma, two cases of Hodgkin's lymphoma, and one each of cholangiocarcinoma and thymoma. Only one of this group had been treated with cytotoxic agents, and five have subsequently died. They belonged to a group of 150 SLE patients, many of whom had been treated with steroids and cytotoxic agents, under long-term follow-up at a specialized lupus clinic. We discuss the reported association of malignancy in patients with SLE.

Effect of Clonorchis sinensis infection and dimethylnitrosamine administration on the induction of cholangiocarcinoma in Syrian golden hamsters.

The study was carried out to observe the effects of Clonorchis sinensis infection on induction of cholangiocarcinoma in Syrian golden hamsters to which 15 ppm dimethylnitrosamine (DMN) solution was administered for 8 weeks. The histopathological changes of the bile duct and liver cells were observed at the 11th week. In six of 8 hamsters (75%) which were treated with DMN and then infected with C. sinensis, the livers developed cholangiocarcinoma at 10 weeks after the infestation of C. sinensis. The features of cholangiocarcinoma lesions were adenomatous or papillary hyperplasia of the bile duct epithelia showing distinct anaplastic changes with mucinous cell metaplasia and necrotic area. In the hamsters which received either DMN or C. sinensis alone, the livers showed only hyperplastic changes of the bile duct epithelial cells. It was suggested that C. sinensis infection and DMN administration could be a synergism on the development of cholangiocarcinoma in Syrian golden hamsters.

[CT appearance of thorotrast-related and non-thorotrast-related peripheral cholangiocarcinoma].

To assess the differences in CT findings among patients with peripheral cholangiocarcinoma with and without a history of Thorotrast administration, CT studies from 13 Thorotrast patients and eight non-Thorotrast patients were reviewed. Diagnostic and prognostic differences were evaluated between the two groups. Despite periodic imaging surveillance, eight of the 13 (62%) lesions discovered by CT were larger than 6 cm. The prognosis for Thorotrast patients was unfavourable due to difficulties in early detection and complications from associated hepatic fibrosis. The main problem with early detection was that a background of uneven Thorotrast deposits visualized in the liver disguised the tumor as Thorotrast granulations. Although non-Thorotrast patients were not monitored regularly, they had a better chance of undergoing curative resection for the following three reasons: 1) it was easy to detect the tumor (detection rate, 100%); 2) this group rarely had associated liver cirrhosis in noncancerous areas, and 3) non-Thorotrast patients were younger than Thorotrast patients. Early detection of cancer by CA19-9 assay and imaging in asymptomatic subjects without any history of liver disease could be important steps toward the early and radical resection of cancer to achieve a better prognosis.

Precancerous lesions of the biliary tree.

Malignant tumors may arise from any portion of the biliary tree. The term cholangiocarcinoma (CC) applies to both intra- and extrahepatic tumors. More than 95% of these tumors are adenocarcinomas. Differentiation between CC and metastatic adenocarcinoma represents a difficult task for the pathologist. The presence of an intratumoral mini-ductal plate, and in situ carcinoma in bile ducts near the tumor and modulation from the bile duct towards parenchymal liver cells represent the major criteria in assessing the identity of an adenocarcinoma as a primary CC. Primary sclerosing cholangitis and congenital bile duct cysts both put patients at risk of developing CC. Lithiasis, recurrent pyogenic cholangitis, and typhoid infection are suspected but not proven predisposing conditions. Fluke infestations (Clonorchis sinensis and Opisthorchis viverrini) play a role in Far Eastern countries. Bile duct adenoma and multiple biliary papillomatosis may carry a malignant transformation potential. Pseudopyloric metaplasia may be a precursor lesion of CC.

Endogenously formed N-nitroso compounds and nitrosating agents in human cancer etiology.

Humans are exposed to preformed N-nitroso compounds (NOC), but also to a wide range of precursors and nitrosating agents which can react in vivo to form potentially carcinogenic NOC and diazo compounds. Nitrite, nitrate and nitrosating agents can also be synthesized endogenously in enzymic reactions mediated by bacteria, activated macrophages and neutrophils. The latter two cell types generate, via the enzyme nitric oxide synthase, the nitric oxide radical that is involved in cytotoxicity, and is believed to be involved in formation of carcinogenic nitrosamines, DNA base deamination and oxidative damage. Thus endogenous NOC formation, DNA damage and gene mutations in humans could occur at various sites of the body such as the stomach and chronically infected or inflamed organs. Sensitive procedures to estimate the exposure of humans to NOC have been developed and applied in ecological and cross-sectional studies. These have shown that inhabitants of high-risk areas for stomach and esophageal cancer, patients with urinary tract infections (at risk for bladder cancer) and Thai subjects infected with liver fluke (at risk for cholangiocarcinoma) had significantly higher exposure to endogenous NOC. Clinical studies have examined the model of stomach carcinogenesis based on intragastric nitrosation, but the precise roles of bacterial overgrowth and of Helicobacter pylori infection in NOC synthesis and/or inducing oxidative stress in stomach mucosa remain to be clarified. Together these results support the role of NOC and other nitrite-derived mutagens in human cancer etiology, in particular when exposure starts early in life and persists over a long period.(ABSTRACT TRUNCATED AT 250 WORDS)

[A surprising double tumor of the liver 60 years following thoratrast diagnosis]. / Een verrassende dubbeltumor van de lever 60 jaar na thorotrast-diagnostiek.

A 66-year-old man with thorotrastosis of the reticuloendothelial system is described. Post mortem two tumours were found in an enlarged liver: a cholangiocarcinoma and an angiosarcoma. Coincidentally, a hilar neurofibroma was found. The former two tumours most probably developed because of a lifelong endogenous alpha-irradiation by thorium disintegration. The exceptional latency period of 60 years' duration is emphasized.

The combined and separate action of neutron radiation and zirconium dioxide on the liver of rats.

To simulate the chronic alpha radiation of Thorotrast, the liver of female Wistar rats was exposed to fractionated neutron irradiation at 14-d intervals (0.2 Gy per fraction) over 2 y to a total dose of 10.0 Gy. Prior to the start of irradiation, one-half of the animals received 120 microL of non-radioactive Zirconotrast (ZrO2), which is comparable to Thorotrast with regard to all other physical and chemical properties. One year after beginning irradiation, the first liver tumor was detected. At the end of the life-span study, the incidence of irradiated animals with liver tumors was about 40%. In the animals treated additionally with ZrO2, the incidence, time of onset, and overall number of liver tumors was nearly equal, indicating that the fractionated neutron irradiation was the exclusive cause of tumor development. The lifelong-deposited ZrO2 colloid had no stimulating effect. Compared to earlier animal studies dealing with Thorotrast, the same histological types of benign and malignant liver tumors were found.