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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.

Hepatobiliary cystadenoma is a rare hepatic lesion characterized by a multiloculated cyst lined by cuboidal or columnar epithelial cells. Four cases of hepatobiliary cystadenoma with mesenchymal stroma (HCMS) and one case of hepatobiliary cystadenoma with intracystic epithelial component were studied by light microscopy, immunohistochemical methods, and electron microscopy. Similar studies were conducted on six fetal gallbladder tissues, representing the biliary tree, and two adult ovarian tissues. By light microscopy, the columnar epithelium of the five cases of hepatobiliary cystadenoma was similar to the epithelium of the developing gallbladder. The spindle cell stroma of the HCMS and the subepithelial spindle cells of the developing gallbladders showed similar reactivity to smooth-muscle actin. Vimentin reactivity was strongly positive in the stroma of the HCMS, and in the fetal gallbladders it was only noted in the subepithelial spindle cells of the 15-week gestation fetal gallbladder tissues. By electron microscopy, the epithelium lining the hepatic lesions showed characteristic gastrointestinal features and was identical to the epithelia lining the embryonic gallbladders. Furthermore, the mesenchymal stroma of the HCMS recapitulated the features found in subepithelial tissues in developing gallbladders. Although the ovarian stroma resembled the stroma of the HCMS by light microscopy, the immunohistochemical reactions and the electron microscopic studies showed dissimilarities. This study supports the hypothesis that the hepatobiliary cystadenomas arise from ectopic embryonic tissues destined to form the adult gallbladder.

Neoplastic transformation occurs in the intrahepatic biliary tree in hepatolithiasis. The present study aimed to clarify the neoplastic processes by correlating the histological features of the bile duct lesions with counts of interphase argyrophilic nucleolar organizer regions (AgNORs), which reflect cell proliferative activity. We studied 55 cases of hepatolithiasis and 25 normal autopsy livers. The biliary epithelial lesions in hepatolithiasis were divisible into hyperplasia, dysplasia and neoplasia. These lesions were found in bile ducts containing calculi. All cases of hepatolithiasis showed a varied degree of hyperplasia. Additionally, eight cases showed dysplasia, five non-invasive intraductal adenocarcinoma and 10 invasive adenocarcinoma. Cases of non-invasive and invasive carcinoma frequently harboured areas of dysplasia, and areas of dysplasia and non-invasive carcinoma, respectively. The mean and standard deviation of the number of interphase AgNORs in the normal and abnormal biliary epithelium showed a step-wise increase in the following order: normal (1.32 +/- 0.36), hyperplasia (1.52 +/- 0.37), dysplasia (2.28 +/- 0.56), non-invasive carcinoma (3.23 +/- 1.00), and invasive carcinoma (3.72 +/- 0.77). These histological and cell kinetic observations suggest that, in hepatolithiasis, carcinogenesis in bile duct epithelial cells progresses in a multi-step manner, through hyperplasia, dysplasia, non-invasive adenocarcinoma and invasive adenocarcinoma.

Little is known about the genetics and biology of cholangiocarcinoma (intrahepatic bile duct carcinoma). Only three human bile duct carcinoma cell lines have been described in the literature. We present the first detailed cytogenetic analysis of two cell lines; a new cell line designated PCI:SG231, established in our laboratory, and RPMI-7451, a previously established cell line. Both lines had highly aneuploid karyotypes with complex rearrangements including marker chromosomes. PCI:SG231, harvested after 50 days in culture, had a modal and median chromosome number of 65, and many cells contained double-minute chromosomes. RPMI-7451 had a modal and median chromosome number of 67. C-banding confirmed the presence of dicentric chromosomes in PCI:SG231. Q-banding confirmed the absence of the Y chromosome in PCI:SG231 and the presence of a der(1)t(Y;1)(q11;p11) chromosome in RPMI-7451. Numerical abnormalities common to both lines included trisomies 2, 5, 11, and 20. Chromosomes 1, 5, 7, and 12 were most commonly involved in structural abnormalities in both lines. Consistent chromosomal breakpoints included 7q22 and 12p11-12. PCI:SG231 was tumorigenic in immunosuppressed nude mice and was histologically similar to the original tumor. Additional cholangiocarcinoma cell lines are being developed to continue the study of the genetics and cell biology of this disorder.

A silver colloid technique to identify argyrophilic nucleolar organizer region associated protein (AgNOR) was applied to 43 cases of intrahepatic bile duct carcinoma (cholangiocarcinoma, CC), 2 with bile duct adenoma (BDA), 5 with focal duct epithelial hyperplasia (FEH) associated with hepatolithiasis, 15 with posthepatitic ductular proliferation (PHDP) associated with massive or submassive hepatic necrosis and 20 of normal liver. In the present study, only discrete, easily counted black dots within nuclei and silver-stained nucleolus were counted under a magnification of x 400 without oil-immersion objectives. The mean AgNOR count of CC was significantly higher than those of BDA, FEH, PHDP and normal controls (P less than 0.05, P less than 0.001, P less than 0.01, and P less than 0.001, respectively). Among CCs the mean AgNOR numbers of papillary adenocarcinoma (pap), moderately (tub2) and poorly differentiated (por) adenocarcinoma, and adenosquamous carcinoma (as) were significantly higher than that of normal controls (P less than 0.01, P less than 0.001, P less than 0.001 and P less than 0.001, respectively), and those of tub2, por and as were also significantly higher than those of BDA, FEH and PHDP, whereas that of well differentiated tubular adenocarcinoma (tub1) was not different from those of BDA, FEH, PHDP and normal controls, and that of pap was not different from those of BDA, FEH and PHDP. The mean numbers of AgNORs of BDA and FEH were not different from that of normal controls, whereas that of PHDP was significantly higher than that of normal controls (P less than 0.01). Interestingly, the mean AgNOR counts of tubular adenocarcinoma were increased with histologic tumor grades.(ABSTRACT TRUNCATED AT 250 WORDS)

N-diethylnitrosamine (DEN) was simultaneously administered with diazepam (DZP) or thiouracil (TU) once weekly for life to gerbils (Meriones unguiculatus). Additional DZP or TU treatment increased significantly average survival time and inhibited the development of cholangiocarcinomas, although cholangiomas were still observed in these groups. Tumor type and incidence in the nasal cavities were not influenced by DZP or TU. However, in comparison to DEN alone tumor latencies were prolonged.

Antibodies against constitutive proteins of different types of intermediate-sized filaments were used in immunofluorescence microscopy on frozen sections of normal rat liver and various rat liver tumors induced by treatment with nitrosamines. Antibodies to tonofilament prekeratin stained bile duct epithelia and hepatocytes of normal liver and hepatocellular carcinoma cells and ductal cells of cholangiofibromas. These cells were not significantly stained by antibodies to vimentin. By contrast, antibodies to vimentin stained mesenchymal cells of normal liver and cells of early and advanced angiosarcomas and of undifferentiated spindle cell sarcoma. These mesenchymal tumor cells were not stained with antibodies to prekeratin. The presence of intermediate-sized filaments in these tumors, often in large whorl-like aggregates, was also demonstrated by electron microscopy. The results show that immunofluorescence microscopy with antibodies to cytoskeletal proteins is a powerful tool for the classification and differential diagnosis of mesenchymal and epithelial liver tumors. We propose that staining with antibodies to proteins of different types of intermediate filaments can be used to improve the identification of tumors of other organs, including metastases, as well as non-neoplastic proliferative lesions.

Liver tumors induced in F344 rats by methapyrilene were studied by electron microscopy. The tumor cells constituting hepatocellular carcinomas showed a pronounced increase in the number of mitochondria and conformational changes of these organelles while the content of lipid, glycogen and smooth endoplasmic reticulum was greatly reduced. The cholangiocarcinomas consisted of bile duct epithelia at varying stages of squamous metaplasia.

A morphological, cytophotometrical and autoradiographical study was carried out on the early liver cell lesions present after one month of thioacetamide (TAA) exposure. We wanted to determine the extent of cell damage in the hepatocytes in relation to the later occurring cholangiocarcinoma. Cytoplasmic and nuclear alterations were present in the hepatocytes. They were mainly due to the toxic influence of the metabolites of TAA. No Feulgen-DNA changes have been observed in the hepatocytes in any of the studied zones. The increased TdR H3+ uptake and mitotic activity in the periportal and midzonal areas represented regenerative activity. In addition to these hepatocytic changes, the centrolobular area was infiltrated by oval cells. These cells appeared at first singly, later on they formed clusters. The electron microscopy of these cells revealed phenotypic characteristics, which were different from the hepatocytes. When separately, these cells resembled undifferentiated cells with cytoplasmic extensions and absent basement membrane. When arranged in clusters, a definite canalicular arrangement was present with characteristics of bile canalicular cells with microvillous extensions at the apical border of the cytoplasm and the presence of a basement membrane. A transition from the first oval cell type to the second oval cell type was suggested. This transition might represent a differentiation process of cells, which are regarded as the target cell and the precursor cell in the development of the cholangiocarcinoma. This is the first study reporting oval cell proliferation in the centrolobular area in a multistep model of livercarcinogenesis in rats.

During the past few years several laboratories investigated the occurrence of cytoskeletal components in epithelial and mesenchymal cells by electron microscopy and/or immunocytochemical methods in a number of tumor types growing in vitro or in the body. Since it is well established that antibodies to different intermediate-sized filament proteins can distinguish cells and tissues of epithelial, mesenchymal, muscle, astrocytic and neural origin special attention has been paid to the behaviour of these filaments in neoplastic cells recently. While the organisation of the cytoskeleton in tumor cells growing in vitro is very variable, regularities relevant for the diagnosis and the determination of the histogenetic origin of tumors have been observed in tumor cells growing in the body. In general, ultrastructural and immunological features of intermediate filaments are maintained during neoplastic transformation in the body. Thus immunofluorescence microscopy with antibodies to cytoskeletal proteins is a powerful tool for the classification and differential diagnosis of tumors, especially for the distinction between epithelial and mesenchymal tumors, including metastases. The concept that presence of an excess of contractile proteins such as actin is an important prerequisite for the metastatic spread of malignant cells has not been unequivocally supported by more recent results. However, an accumulation of various types of intermediate filaments (e.g. prekeratin, vimentin, acidic glial fibrillar protein) has been shown in different tumor types. The further elucidation of this alteration could contribute to a better understanding of the molecular mechanisms of neoplastic cell transformation.

An electron microscopic study was carried out on eleven surgical liver biopsy specimens obtained from patients with cholangiocarcinoma associated with opisthorchiasis. The tumor cells of histologically well differentiated cholangiocarcinoma had few cytoplasmic organelles. They contained relatively large nuclei, abundant free ribosomes and numerous groups of fine fibrils. Each cell was surrounded by a basement membrane. Numerous long microvilli were seen projecting into the glandular lumen. The moderately differentiated cholangiocarcinomatous cells exhibited increased organelle content, marked variation in the shape of the nuclei with deep cytoplasmic invagination into the nuclear membrane; there were small intranuclear pseudoinclusions, and shorter microvilli. The tumor cells showed intracellular microvillus-lined spaces, abundant free ribosomes, many fine fibrils and their surrounding basement membranes were incomplete. The ultrastructure of the poorly differentiated cholangiocarcinoma was similar to that of the moderately differentiated tumor, except for fewer microvilli, abundant cytoplasmic organelles, and ill-defined or absent basement membrane.

A 66-year-old man developed two distinct primary malignant hepatic neoplasms (leiomyosarcoma and cholangiocarcinoma) 50 years after Thorotrast administration. This is the first case report of Thorotrast-associated primary hepatic leiomyosarcoma. Ultrastructural and immunohistochemical studies are discussed.

A patient with an unresectable well-differentiated bile duct tumor who survived for 15 yr after biopsy diagnosis is presented. Histologic examination of the tumor revealed bland features of bile duct adenoma despite extensive spread within the liver. Over its subsequent course, the tumor progressively replaced the liver, achieving huge size, although there was no evidence of metastases until shortly before the patient's death. This clinical course was very unusual for either bile duct adenoma or cholangiocarcinoma, but would be more characteristic of another tumor of intrahepatic bile duct origin, the biliary cystadenoma. However, this latter diagnosis was excluded with both gross and microscopic pathologic criteria. Evidence is presented to support classification of this tumor as an unusual varient of peripheral cholangiocarcinoma which requires correlation of the clinical and pathologic findings for correst diagnosis.

A comparative study of the ultrastructure of human and experimental hepatocellular carcinoma is made. The histogenesis and morphopathology of human and chemically induced experimental liver tumors in Wistar rats and golden hamsters are similar.

The results of the study of ten cholangiocarcinomas from intrahepatic or extrahepatic origins are reported. Using both light microscopic immunohistochemistry and transmission electron microscopy the scirrhous stroma of the tumour showed clear evidence for the production of its collagenous, elastic and possibly other fibrillar elements by the neoplastic cells. Our findings refute the view that the occasional spindle cells (i.e. fibroblasts, myofibroblasts or even smooth muscle cells) could play a major role in the production of such a voluminous amount of the various connective tissue elements. Therefore, it seems reasonable to suggest that the scirrhous stroma of cholangiocarcinomas is produced by the malignant cells similar to those of the breast, oesophagus, stomach and ureter.