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We report the imaging of a localized fibrous tumor of the liver, focusing on color Doppler US, CT, MR imaging, and angiographic findings. We discuss the differential diagnosis of such a rare, benign lesion of the liver. Detailed imaging of this tumor has not been reported in the literature previously.

The stroma of hepatocellular carcinomas (HCC) is infiltrated with myofibroblasts (MFs). Preliminary in vivo data have suggested that liver MF express hepatocyte growth factor (HGF), a cytokine that has been implicated in several tumor models. Our aim was to investigate the role of MF and HGF in HCC. Cultured liver MF expressed HGF messenger RNA (mRNA) and secreted HGF in their medium, as shown by Western blot, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA). Addition of MF-conditioned medium to the HepG2 HCC cell line induced cell scattering. This was associated with a decrease in cell proliferation. MF also increased about 100-fold the ability of HepG2 to invade Matrigel. Increased invasiveness was also shown for HuH7 cells, but no scattering was observed and cell proliferation was stimulated. All the effects of MF on both tumor cell types were blocked by addition of an antibody to HGF and they all could be reproduced by adding recombinant HGF to the tumor cells. RT-PCR and Western blot analysis confirmed that both tumor cell lines expressed c-met, the receptor for HGF. The effects of MF-conditioned medium were not reproduced by acidic fibroblast growth factor, basic fibroblast growth factor, epidermal growth factor (EGF), transforming growth factor-beta1 (TGF-beta1), or platelet-derived growth factor (PDGF-BB). Reverse transcription-polymerase chain reaction (RT-PCR) analysis confirmed that HGF was expressed in human HCC. Our data show that human liver MF act on HCC cells to increase their invasiveness and suggest that MF-derived HGF could be involved in the pathogenesis of HCC.

Background/aims: Liver cell dysplasia of large (LLCD) and small (SLCD) cell types may represent a premalignant change. We sought to evaluate their prevalence, relationship with the gross type of cirrhosis, aetiology of liver disease, and the presence of hepatocellular carcinoma in a series of cirrhotic livers., Methods: The presence and pattern of SLCD and LLCD were evaluated by careful histological analysis in 100 consecutive cirrhotic livers of viral (49%) or non viral (51%) aetiology, and with or without hepatocellular carcinoma. Prevalences were compared using Chi-square or Fisher's tests; relative risk for hepatocellular carcinoma was evaluated by the odds ratio., Results: Dysplasia was found in 82/100 of livers. Eighty-one had LLCD, with (n=49) or without (n=32) associated SLCD. SLCD alone was found in only one case. LLCD and SLCD tended to be more frequent and extensive in mixed or macronodular cirrhosis than in micronodular cirrhosis. LLCD was significantly more frequent and extensive in cirrhosis due to hepatitis B, as was SLCD in cirrhosis due to hepatitis B virus or biliary diseases, where it showed a different pattern (focal vs diffuse, respectively). LLCD and SLCD were both significantly associated with the presence of hepatocellular carcinoma, even of small size. Small foci of SLCD and widespread LLCD were the two conditions which showed the strongest association with hepatocellular carcinoma, with odds ratios of: 6.33 and 3.88, respectively. Widespread SLCD was not relevant for hepatocellular carcinoma in biliary diseases., Conclusions: Liver cell dysplasia may be considered an additional risk factor for hepatocellular carcinoma in patients with cirrhosis and should be looked for in biopsies. Widespread LLCD and SLCD with a focal pattern are particularly relevant for hepatocellular carcinoma, whereas widespread small cell changes found in biliary diseases seem to have a different biological significance.

Osteonectin/SPARC is a glycoprotein involved in the regulation of cell shape, adhesion, migration, and proliferation. It also has complex effects on extracellular matrix synthesis and turnover. We found that osteonectin mRNA was very abundant in a human liver myofibroblast library. Using Northern and Western blot, immunoprecipitation, and radioimmunoassay, we found that cultured liver myofibroblasts actively secreted osteonectin. Myofibroblasts are very rare in normal liver but proliferate during liver fibrosis where they synthesize extracellular matrix components. Thus, we studied the distribution of osteonectin in normal and fibrotic human liver using in situ hybridization. Osteonectin mRNA expression was weak in normal liver but very high in fibrotic liver within fibrous septae and scattered sinusoidal cells. Serial sectioning and double staining experiments with an antibody to smooth muscle alpha-actin showed that osteonectin transcripts were mostly co-localized with myofibroblasts. In conclusion, osteonectin is highly expressed in human liver myofibroblasts in culture as well as in human liver fibrosis in vivo. The many biological properties of osteonectin make it a candidate effector of human liver fibrogenesis.

A 60-year-old woman was transplanted for end-stage alcoholic cirrhosis. The diagnosis of cirrhosis was made 13 years earlier on the basis of features of portal hypertension and a wedge liver biopsy. Liver function tests were subnormal except for a low prothrombin time. Unproven possible alcohol abuse was the only aetiological factor. Her condition remained unchanged until transplantation, despite complete abstinence. Histological examination of the explant showed incomplete septal cirrhosis associated with distal obstructive portal venopathy, cirrhotic nodules predominantly in the subcapsular areas and nodular regenerative hyperplasia with septal fibrosis elsewhere. In addition, there were areas of large and small liver cell dysplasia. This observation shows the difficulty in making a diagnosis of incomplete septal cirrhosis and the hypothetical link between liver cell dysplasia (which has never been reported in incomplete septal cirrhosis but is well known to be associated with hepatocellular carcinoma in cirrhosis) and rare cases of liver adenomas and carcinomas reported in patients presenting with liver vascular disorders.

Extracellular matrix (ECM) plays a major role in cell differentiation, proliferation, and gene expression, both in physiological and in pathological conditions. Immunohistochemistry has been used to investigate modifications of ECM and related receptors, the integrins, in 26 small nodular lesions developed in human cirrhotic livers, on the basis that these lesions could represent sequential steps of hepatocarcinogenesis: the lesions were 16 macroregenerative nodules (MRNs), either of ordinary (n = 5) or atypical (n = 11) type, and ten small (< 15 mm) hepatocellular carcinomas (HCCs). Data were compared with those obtained in the surrounding cirrhotic tissue, in large HCCs, and in normal liver. The results indicate similarities between ordinary MRNs and cirrhosis, on the one hand, and between atypical MRNs and small HCCs, on the other. Strong and homogeneous deposition of collagen type IV and laminin in sinusoids and overexpression of alpha 6 integrin by sinusoidal cells and hepatocytes were especially noticeable in dysplastic areas characteristic of atypical MRNs, as in small HCCs. In addition, the staining of alpha 2 and alpha 6 integrins in MRNs revealed the presence of widespread atypical ductular proliferation expanding from periportal and perinodular areas, containing epithelial cells with transitional (hepato-biliary) phenotype. These findings suggest a transition from atypical MRNs to small HCCs and a possible role for liver epithelial precursor cells ('stem cells') in the development and evolution of MRNs.

Immunosuppression is known to favor the development of various types of tumors. After organ transplantation, the risk of lymphoproliferative disease, whether clonal or not, is particularly increased and clearly associated with Epstein-Barr virus infection. We report a case of an unusual large cystic tumor of the liver with satellite hepatic and splenic nodules occurring 4 years after renal transplantation. Radiologic examination showed a rich vascularization of the tumor. Light and electron microscopy of a surgical liver biopsy, completed by an immunohistochemical study, demonstrated a well-differentiated tumor of smooth-muscle origin. Using in situ hybridization, we showed large amounts of Epstein-Barr virus messenger RNAs within the tumor cells. In addition, Southern blot analysis revealed that viral DNA was present in the form of a single monoclonal episome within the tumor. The polymerase chain reaction analysis of the genomic DNA of tumoral cells also indicated a monoclonal pattern. At last, the tumor was shown to be of host origin. Six months later, and despite three courses of chemotherapy, the tumoral lesions were unchanged. This case underlines the role of Epstein-Barr virus infection in the development of unusual and clonal smooth-muscle tumors after organ transplantation. The evolution of these rare tumors is uncertain.

Hepatic stellate cells were studied by immuno-cytochemistry with anti smooth muscle alpha-actin antibody (an activation marker for these cells) and electron microscopy, in eleven patients transplanted for fulminant or subfulminant hepatitis. Numerous smooth muscle alpha-actin positive cells were found in necrotic areas. In both fulminant and subfulminant hepatitis, hepatic stellate cells appeared enlarged, often irregular, with spikes. There were numerous signs of activation and many contained numerous small lipid droplets. In the cases of fulminant hepatitis, hepatic stellate cells presented, at times, some subcellular damage. Hepatic stellate cells processes, often in several layers, displayed numerous cytoplasmic microfilaments with conspicuous dense plaques below the plasma membrane. Hepatic stellate cells were never surrounded by a basement membrane. The extracellular matrix was loose and granulofibrillar. In areas of multiacinar nodules (in cases of map-like pattern), hepatic stellate cells were grossly normal. These results are in agreement with in vitro data showing that acutely damaged hepatocytes activate hepatic stellate cells but do not fully transform them into myofibroblasts.

Objectives and Methods: HCV cirrhosis is one of the major indications for liver transplantation. HCV recurrence rate is high but long term development to cirrhosis seems to be rare. This study included 28 patients with HCV infection (HCV RNA in blood, histologic lesions highly suggestive or compatible with HCV infection)., Results: Twenty-one out of the 28 patients were transplanted for hepatic chronic liver disease associated with HCV infection (reinfection), whereas only 7 out of 94 transplanted patients (7.4%) without pre-transplant HCV infection ("de novo" infection). Patients were followed clinically and histologically for a mean period of 26.8 months (range: 3-56). Of 26 patients with a good histological evaluation, 24 (92.3%) had chronic hepatitis: 7 with mild activity, 17 with moderate activity, 7 of whom had bridging fibrosis. Two patients had unusual features with associated lesions (necrotic hepatitis and chronic rejection in one case, acute hepatitis associated with CMV infection in the other)., Conclusion: This study confirms the high prevalence of HCV recurrence, as well as the "de novo" infection risk, and suggests caution concerning long term prognosis.

We examined 41 consecutive cirrhotic liver explants from French patients for the presence of nodules of adenomatous hyperplasia (AH) and then analyzed these lesions, together with underlying cirrhosis (C) and associated hepatocellular carcinoma (HCC), for various histological parameters, cellular density, and proliferative activity. Thirty-five AHs were identified in 10 livers (prevalence, 24%); seven of 10 were HCV positive. Hepatocellular carcinoma was more frequent in patients with AH than in patients without. The AHs consisted of 17 ordinary (OAH) and 18 atypical (AAH) adenomatous hyperplasia lesions. There was a malignant focus in five of the 18 AAHs. Wide areas of large liver cell dysplasia were frequent in OAH but never found in AAH. Obvious steatosis was frequent in HCC but exceptional in AAH and absent in OAH. There was a significant increase in cellular density in AAH and HCC as compared with C and OAH. Proliferative cell nuclear antigen immunostaining similarly showed an increase in proliferation from OAH or C to AAH and HCC. These data suggest that, in Europe as in Japan, one pathway of hepatocarcinogenesis is a multistep process in which AAH should be considered as a premalignant lesion very close to grade I HCC, while OAH seems to correspond to a regenerative nodule with limited proliferative ability.

We report the case of a 30-year-old male patient suffering from what was initially thought to be end-stage cryptogenic cirrhosis with portal hypertension and liver failure, who underwent liver transplantation. Histological examination of the surgical specimen showed incomplete septal cirrhosis. At the age of 17 this patient had presented pancytopenia and splenomegaly, which were treated by splenectomy. The surgeon discovered portal hypertension. Re-examination of the wedge liver biopsy taken at this time revealed features of idiopathic portal hypertension. This case clearly shows that incomplete septal cirrhosis may be a late manifestation of idiopathic portal hypertension. The presence of sinusoidal dilatation and peliosis as well as early evidence of fibrosis which are already visible on the initial biopsy and are still present on the late specimen, are indirect evidence of a continuous process which ultimately led to incomplete cirrhosis with liver failure.

A previously healthy 25-year-old man developed a spontaneous rupture of the spleen during a cytomegalovirus (CMV) infection. The only other clinical feature was a well tolerated fever of 37.5 degrees C to 39 degrees C during the month before. The diagnosis was confirmed by the presence of IgM antibodies to CMV in the serum and by typical intranuclear inclusions for CMV identified by splenic histopathological findings. The patient recovered completely. Spontaneous splenic rupture is uncommon in primary cytomegalovirus infection.

We report two cases of liver cell adenomatosis associated with granulomatous hepatitis, both developed in white women (52 and 39 years of age) on long-term oral contraceptives (for 18 and 12 years, respectively). The first patient underwent surgery for five hepatic tumors 1-7 cm in diameter; the other patient had a partial segmentectomy for a 4-cm hepatic nodule of the right lobe. In both cases, dissection of the liver showed many other diffuse and smaller nodules. Histologically, all tumors were benign liver cell adenomas, with cellular atypia in the largest tumor and associated in both cases with granulomatous hepatitis, with numerous noncaseating epithelioid and giant cell granulomas located either only in the tumors (case 1) or diffusely in the tumoral and nontumoral hepatic parenchyma (case 2). During follow-up, ultrasound showed new nodular lesions in case 2, whereas in case 1 evolution was uneventful. In estroprogestative-associated liver diseases, adenomas are common, but adenomatosis and granulomas are rare. An association of these latter two conditions would seem to be exceptional. The prognosis for adenomatosis remains uncertain.

The different types of primary hepatic tumors are examined, focusing on their macroscopic and histologic features. A large variety of neoplasms can be observed, derived from the different components of the liver. Benign (adenoma, focal nodular hyperplasia) or malignant (hepatocellular carcinoma) epithelial tumors of hepatocellular origin are very common. Hemangioma is the most common mesenchymatous-derived tumor. However, the frequency of each type of tumor varies considerably in the different age and sex groups. Some special entities recently reported, such as epithelioid hemangioendothelioma or fibrolamellar carcinoma are detailed.

Liver biopsies were taken from ten AIDS patients. Liver architecture was normal in all patients. On 1-micron-thick sections stained with toluidine blue, all ten cases showed lipid overload of perisinusoidal cells (1 massive, 5 moderate and 4 mild) compared to 2/8 in control patients, who had mild lipid overload. Other sinusoidal abnormalities such as hypertrophy of Kupffer cells and inclusions in endothelial cells were also noticed. Some hepatocytes presented evidence of cellular damage. Perisinusoidal cell lipid overload was not associated with hypervitaminosis A. We hypothesize that the abnormal accumulation of lipids in perisinusoidal cells (non-induced by hypervitaminosis A) in patients with AIDS could be due to defective transport of vitamin A from perisinusoidal cells to hepatocytes, and/or from hepatocytes to blood. The cause of the defect is unknown. Since lipid overload occurs in many and diverse conditions (diabetes, cholestasis, primary biliary cirrhosis, etc.), it seems reasonable to propose that the defect is non-specific and limited to functional or structural damage of the liver whether induced by drugs, liver or systemic diseases.

An unusual fracture of the base of the first metacarpal with in contrast with Bennett's fracture displacement of the thumb and avulsion of the Abductor Pollicis Longus tendon is described after a "Rugby" trauma. Immediate repair and stabilization of the injured structures followed by specific rehabilitation, produced a satisfactory result with normal function of the thumb three years after the injury.

The authors present their anatomical and clinical findings concerning fractures and nonunions of the carpal scaphoid. They stress the proximal pole type I et II of the Schernberg (type C of Herbert) classification, and they suggest isolation of an anatomical entity, by the study of blood vessels, the ligament connections, and especially the pathomechanics as well as a clinical entity, by the mechanism of fracture and the surgical treatment, emphasizing the proximo-distal screwing, with excellent results. They present a series of 29 patients, with type I or II proximal fractures, either fresh or non-unions.

We have previously demonstrated increased levels of insulin-like growth factor (IGF)-II mRNAs and protein with re-expression of a fetal pattern of transcripts in human hepatocarcinoma. In the present study, we have investigated IGF-II transcripts and protein in liver tissues from patients with hepatocarcinoma infected with hepatitis B virus, by using in situ hybridization and immunohistochemical techniques. The IGF-II transcripts and protein have been localized to the hepatocytes, be they normal or tumoral with a gradient for IGF-II expression from normal to dysplastic and tumoral tissues. Hepatitis B virus mRNAs and viral surface antigen have only been detected in some hepatocytes in the peritumoral tissues. Therefore, the results show expression of IGF-II in hepatocytes. The increase of IGF-II expression in tumor hepatocytes support the hypothesis that it might represent a marker of hepatocytes differentiation.

In this study, the case of a patient presenting a second hepatocellular carcinoma 13 years after resection of a first tumor of the same type is reported. In this case, etiological investigations remained negative, but an incomplete form of syndromatic Alagille syndrome with paucity of bile ducts in the nontumoral tissue was detected and associated with nodular regenerative hyperplasia and foci of dysplasia. Malignant transformation in Alagille syndrome seems to be extremely rare. The fact that such tumors evolve very slowly could be an argument for partial hepatectomy and, if necessary, liver transplantation.

A 33-year-old heterosexual white man underwent a liver biopsy for determination of mild elevation of aminotransferase levels (aspartate aminotransferase, two times; alanine aminotransferase, three times). The patient had acquired immunodeficiency syndrome (stage IVC2) with tuberculosis of the lymph nodes. Antibody to hepatitis B surface antigen and antibody to hepatitis B core antigen were positive. Syphillis tests were positive. Liver architecture was normal; sinusoids were dilated with perisinusoidal, centrilobular, and portal fibrosis. On a 1-micron-thick section and under electron microscopy, perisinusoidal cells appeared to be massively loaded with lipids, while endothelial cells contained numerous dense bodies. Some hepatocytes presented evidence of cell damage. Sinusoids were infiltrated by an increased number of lymphocytes and macrophages. This patient who had recently been treated for tuberculosis was not taking extra vitamin A. He had no disease so far reported as being associated with perisinusoidal cell hypertrophy. This case and others are evidence that acquired immunodeficiency syndrome represents another cause of perisinusoidal cell hypertrophy in which there is no documented hypervitaminosis A.

Liver sinusoids are special capillaries that are limited by fenestrated endothelial cells, without a genuine basement membrane, surrounded by perisinusoidal cells storing vitamin A, and harbouring Kupffer cells and pit cells, resident macrophages, and large granular lymphocytes, respectively. Each nonparenchymal cell and parenchymal cell of the liver interacts with all others and with the extracellular matrix. Therefore, the functional ability of each cell is constantly being modified by the metabolic activity of the others. Human liver biopsies (132), needle or surgical, perfusion-fixed with glutaraldehyde and processed for transmission electron microscopy (TEM), and occasionally for scanning electron microscopy (SEM), were examined. The study included liver diseases (such as alcoholic liver diseases, benign and malignant liver tumors, cholestasis of various origins, fulminant hepatitis, acute rejection after orthotopic liver transplantation, Budd-Chiari syndrome), as well as general or extrahepatic diseases (such as diabetes, hemochromatosis, hypervitaminosis A, various hematological disorders), and normal controls. Ultrastructural abnormalities are described and illustrated under two different headings: 1) elementary lesions of sinusoidal cells (endothelial, Kupffer, perisinusoidal and pit cells), nonsinusoidal cells (in the space of Disse and/or in the lumen), the extracellular matrix; and 2) the major pathological entities including perisinusoidal fibrosis, capillarization of sinusoids, sinusoidal dilatation, and peliosis. In the discussion, an overview of the major abnormalities reported in the literature is presented, and some specific questions regarding 1) perisinusoidal fibrosis in liver with normal histology, 2) the overload of perisinusoidal cells with lipids in non-hypervitaminosis A intoxication and 3) the etiological relationship of sinusoidal dilatation, peliosis, perisinusoidal fibrosis, or sinusoidal tumors with drugs and toxic compounds are discussed. In the event that lesions are not specific to any diagnosis, the knowledge of the ultrastructure of sinusoids is extremely useful from the perspective of the liver as an ecosystem.

Four patients with liver carcinoma (case 1: hepatocellular carcinoma; cases 2 and 3: metastases; case 4: adenocarcinoma possibly of hepatic origin) underwent a wedge liver biopsy taken at some distance from the tumor. Liver histology was normal in cases 2 and 3. Sinusoids were dilated in case 4. Fibrosis formed bridges between portal tracts in case 1. In all 4 cases, sinusoids contained lymphocytic cells. By electron microscopy (perfusion-fixation with glutaraldehyde) numerous lymphocytes could be identified as pit cells with characteristic dense granules and occasional rod-cored vesicles. The majority of the pit cells were luminal cells in contact with endothelial or Kupffer cells; some were in the Disse space. It is now accepted that pit cells are resident large granular lymphocytes with natural killer activity. The increase in the number of pit cells in liver carcinoma compared to the number observed in the control group (uncomplicated gallbladder lithiasis) could be hypothetically interpreted as a defense mechanism against tumor extension.