Liver fibrosis is potentially reversible after removal of the injurious agent. Fibrosis resolution is characterized by apoptosis of hepatic myofibroblasts and degradation of extracellular matrix components. Matrix metalloproteinase-2 (MMP-2) is involved in matrix remodeling. In the liver, it is synthesized by myofibroblasts, secreted as a proenzyme, and activated by membrane type-MMPs (MT-MMP) such as MT1-MMP. The goal of this work was to determine whether apoptosis induction in human hepatic myofibroblasts modulates the gene expression of MMP-2 and/or its activation by MT1-MMP. Induction of apoptosis by cytochalasin D or C-2-ceramide did not modulate MMP-2 mRNA expression. In contrast, apoptosis was associated with marked activation of pro-MMP-2, as shown by gelatin zymography, which revealed the presence of the 59-kd active form, whereas untreated cells only expressed the 66-kd proform. SB-203580, a specific inhibitor of p38(MAPK), selectively abrogated both C-2-ceramide-induced apoptosis and pro-MMP-2 activation. Apoptosis-induced pro-MMP-2 activation was inhibited by the tissue inhibitors of metalloproteinases (TIMP)-2 but not by TIMP-1, implying involvement of an MT-MMP-mediated process. Induction of apoptosis by cytochalasin D and C-2-ceramide upregulated MT1-MMP protein expression and MT1-MMP mRNA expression. In conclusion, apoptosis of hepatic myofibroblasts induces pro-MMP-2 activation through increased MT1-MMP expression.

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.

We recently identified activating mutations of fibroblast growth factor receptor 3 (FGFR3) in bladder carcinoma. In this study we assessed the incidence of FGFR3 mutations in a series of 132 bladder carcinomas: 20 carcinoma in situ (CIS), 50 pTa, 19 pT1, and 43 pT2-4. Ah 48 mutations identified were identical to the germinal activating mutations that cause thanatophoric dysplasia, a lethal form of dwarfism. The S249C mutation, found in 33 of the 48 mutated tumors, was the most common. The frequency of mutations was higher in pTa tumors (37 of 50, 74%) than in CIS (0 of 20, 0%; P < 0,0001), pT1 (4 of 19, 21%; P < 0.0001) and pT2-4 tumors (7 of 43, 16%; P < 0,0001), FGFR3 mutations were detected in 27 of 32 (84%) G1, 16 of 29 (55%) G2, and 5 of 71 (7%) G3 tumors. This association between FGFR3 mutations and low grade was highly significant(P < 0.0001)FGFR3 is the first gene found to be mutated at a high frequency in pTa tumors. The absence of FGFR3 mutations in CIS and the low frequency of FGFR3 mutations in pT1 and pT2-4 tumors are consistent with the model of bladder tumor progression in which the most common precursor of pT1 and pT2-4 tumors is CIS.

Purpose: To determine the incidence of trocar site spill age, local recurrence, and metastatic disease associated with retroperitoneal laparoscopic tumor resection.Methods: From 1994 to 1999, 228 retroperitoneal laparoscopic procedures were performed at our institution. Fifty-six procedures (24.6%) were for malignancies and comprised 41 radical nephrectomies and 8 partial nephrectomies for renal tumors, and 7 nephro-ureterectomies for renal pelvis tumors. The pathological stage and the status of surgical margins were noted according to the 1997 TNM classification. Postoperative follow-up data were obtained by means of physical and radiological examinations after 1 and 3 months, and then half-yearly. Trocar site seeding, local recurrence and metastatic disease were recorded. Kaplan-Meier actuarial analysis was used to determine the disease-free survival likelyhood.Results: The mean follow-up was 24.9 +/- 13.85 months. All the patients had tumor-free surgical margins. No laparoscopic trocar site recurrences were identified. For laparoscopic radical nephrectomy: one patient had a local recurrence with hepatic metastasis of a pT(3)G(2) tumor after 9 months and died 19.7 months after the procedure. One patient with a pT(3a)G(3)M+ tumor died 23.1 months after radical nephrectomy without any sign of local recurrence. For laparoscopic nephro-ureterectomy: one patient with a pT(3)G(3) tumor had a local recurrence 12.1 months after the procedure and died 26.6 months after surgery. One patient with a pT(1)G(2) renal pelvis tumor had bone metastasis at 9 months and died 29 months after the procedure. The Kaplan-Meier actuarial disease-free survival rate was 91% at 54 months for radical nephrectomy, 61% at 30 months for nephro-ureterectomy and 100% at 49 months for partial nephrectomy.Conclusion: Malignancies of the upper urinary tract can be managed by means of retroperitoneal laparoscopy. Short-term results suggest that this procedure is not associated with an increased risk of portsite or local recurrence, and that disease-free survival is equivalent to that obtained with open surgery. Copyright (C) 2000 S. Karger AG, Basel.

Hepatocellular carcinoma (HCC) occurring in nonfibrotic liver represents a rare, ill-defined subgroup of HCC without cirrhosis in which mechanisms of hepatocarcinogenesis remain unclear. The aim of our study was to assess epidemiological factors and detailed histopathologic changes in the nontumoral liver of patients developing such tumors. Of 330 HCCs resected in our institution between 1985 and 1998, we retrospectively analyzed 80 cases (53 men, 27 women; mean age, 51 +/- 16 years) in which the nontumoral liver showed no (n = 28) or minimal (n = 52) portal fibrosis without any septal fibrosis. In the group with no portal fibrosis there was no male predominance, and patients were significantly younger (44 +/- 19 years vs. 54 +/- 14 years) than those with minimal portal fibrosis. Sixty-seven tumors were typical HCCs, 8 were of fibrolamellar type, and 5 were hepatocholangiocarcinomas. Mean tumor size was 10 +/- 5 cm. Risk factors for HCC development were found in 30 patients: hepatitis B (n = 17) or C (n = 2) virus infections, alcohol consumption (n = 11), and hemochromatosis (n = 1). In the nontumoral liver, periportal and lobular necrosis, mild portal inflammation, steatosis, and iron overload were present in 15%, 57%, 52%, and 54% of cases, respectively. Liver cell changes were noted in 6%. This study emphasizes the need for strict criteria to classify HCC without cirrhosis. HCC in nonfibrotic liver is a distinct subgroup in which nontumoral liver shows nonspecific minimal changes without regeneration or premalignant lesion. Etiologic factors are often unidentified, although presence of HBV infection in 21% suggests a direct oncogenic role of this virus.

The role of liver biopsy in hepatitis C viral infection is diagnostic and prognostic. It states diagnoses of chronic hepatitis, cirrhosis and hepatocellular carcinoma. The association of portal lymphoid nodules, inflammatory bile duct lesions and steatosis suggests an hepatitis C viral etiology. Liver biopsy allows grading (extent of necro-inflammatory lesions) and staging (amount of fibrosis) of the disease using scoring systems proposed by Knodell et al. and (or) by METAVIR group. It can be helpful in confirming (or refuting) the presence of secondary diagnoses such as alcohol-induce liver disease or haemochromatosis and in assessing the efficacy of antiviral treatments.

HepatologyVolume 32, Issue 6 p. 1411-1412 CorrespondenceFree Access Occurrence of hepatocellular carcinoma in nonfibrotic livers Paulette Bioulac-Sage M.D., Paulette Bioulac-Sage M.D. Laboratoire de Pathologie/GREF, Université Bordeaux II, Bordeaux, FranceSearch for more papers by this authorBrigitte Le Bail M.D., Ph.D., Brigitte Le Bail M.D., Ph.D. Laboratoire de Pathologie/GREF, Université Bordeaux II, Bordeaux, FranceSearch for more papers by this authorMaria Winnock Ph.D., Maria Winnock Ph.D. Laboratoire de Pathologie/GREF, Université Bordeaux II, Bordeaux, FranceSearch for more papers by this authorCharles Balabaud M.D., Charles Balabaud M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this authorPierre Henri Bemard M.D., Pierre Henri Bemard M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this authorJean Frederic Blanc M.D., Jean Frederic Blanc M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this authorJean Saric M.D., Jean Saric M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this author Paulette Bioulac-Sage M.D., Paulette Bioulac-Sage M.D. Laboratoire de Pathologie/GREF, Université Bordeaux II, Bordeaux, FranceSearch for more papers by this authorBrigitte Le Bail M.D., Ph.D., Brigitte Le Bail M.D., Ph.D. Laboratoire de Pathologie/GREF, Université Bordeaux II, Bordeaux, FranceSearch for more papers by this authorMaria Winnock Ph.D., Maria Winnock Ph.D. Laboratoire de Pathologie/GREF, Université Bordeaux II, Bordeaux, FranceSearch for more papers by this authorCharles Balabaud M.D., Charles Balabaud M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this authorPierre Henri Bemard M.D., Pierre Henri Bemard M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this authorJean Frederic Blanc M.D., Jean Frederic Blanc M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this authorJean Saric M.D., Jean Saric M.D. Fédération, d'Hépatologie-Gastroentérologie, Hôpital St. André CHU Bordeaux, Bordeaux, FranceSearch for more papers by this author First published: 30 December 2003 https://doi.org/10.1053/jhep.2000.20819Citations: 1AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume32, Issue6December 2000Pages 1411-1412 RelatedInformation

A 68-year-old woman who had been treated for non-insulin-dependent diabetes mellitus for the past 20 years was admitted to hospital because of abdominal pain and weight loss. Radiological investigation revealed a tumour in the body of the pancreas and numerous intraductal calcifications in both the tail and the head of the pancreas. Left-sided pancreatectomy was performed to remove the tumour. The resection specimen showed fatty enlargement of the parenchyma and numerous intraductal calcifications in the tissue adjacent to the tumour, which was 7 cm in diameter and was found to be a primary squamous cell carcinoma with a spindle cell component. There was also lipomatous pseudohypertrophy.

Malignant vascular neoplasms of the liver are uncommon. We report the case of a young woman who developed an epithelioid hemangioendothelioma of the liver associated with multiple focal nodular hyperplasias and hepatic cavernous hemangiomas. Such an unusual association is probably not fortuitous and could support the theory that focal nodular hyperplasia is a reaction to an abnormal vascular supply rather than a true neoplasm.