A Case of Juvenile Hepatocellular Carcinoma Associated with Liver Cirrhosis in a Family Clustering of HBs Antigen Carriers and Liver Diseases

We describe a case of hepatocellular carcinoma in a 16-year-old boy whose mother, aunts, uncles, and cousins had liver dysfunction associated with HBs-Ag. Postmortem examination in this case revealed a hepatocellular carcinoma with a trabecular and partially pseudoglandular pattern involving the whole left and most of the right lobe, associated with liver cirrhosis of the postnecrotic type. Postmortem examination of the liver revealed numerous HBs-Ag positive hepatocytes demonstrated by Orcein staining in the nontumorous cirrhotic area, but not in the tumorous hepatocytes. Vertical transmission of HBV from his mother to the patient was suspected, and autopsy findings revealed continuous infection of HBV. Hepatocellular carcinoma in a young patient, especially when associated with HBs-Ag positive liver cirrhosis, as described here is rare in the English and Japanese literature.     

Large regenerative nodules and dysplastic nodules in cirrhotic livers: a histopathologic study

In order to reveal the precursor lesion of hepatocellular carcinoma, a histopathologic study was performed on 141 cases of liver cirrhosis with or without hepatocellular carcinoma. Exclusive of primary or metastatic hepatocellular carcinoma nodules, 94 nodular lesions (greater than 5 mm) were detected in 53 cirrhotic livers. They consisted of 83 large regenerative nodules and 11 dysplastic nodules. Besides some common features with those observed in the former type, the dysplastic nodules presented increased cytoplasmic basophilia, nuclear and nucleolar enlargement, nuclear crowding, occasional microacinar formation and proliferation of the hepatocytes within fibrous septa. These changes were not substantial enough to allow the diagnosis of hepatocellular carcinoma. In one case, however, malignant transformation of hepatocytes was suspected because of their pattern of extranodular outgrowth. It is important to recognize these subtle abnormalities in order to define premalignant hepatic lesions. A possible connection between benign large regenerative nodules and dysplastic nodules is also discussed.     

Simultaneous occurrence of malignant fibrous histiocytoma and hepatocellular carcinoma in cirrhotic liver: A case report

Primary hepatic malignant fibrous histiocytoma (MFH) is rarely encountered. There have been no reports to date of hepatic MFH associated with liver cirrhosis. The presence of liver cirrhosis is considered an adjunctive feature favoring sarcomatoid hepatocellular carcinoma (HCC) in the diagnosis of spindle cell tumors in liver. We describe here a 59-year-old man with liver cirrhosis due to hepatitis B virus infection 20 years ago. On abdominal computed tomography scanning, two distinct hepatic masses were identified in the background of cirrhosis, which had different radiological features from conventional HCC. He underwent segmentectomy for removal of the tumors. The pathological examination of surgically resected specimen revealed the large malignant spindle cell tumor and small conventional HCC. Additional tissue sampling and immunohistochemical stainings demonstrated that the spindle cell tumor was consistent with MFH. On the post-operative follow-up for 21 mo, a round mass showing similar radiological findings for the previous MFH was appeared on the surface of resection margin, suggesting the recurrence. Despite its rarity, hepatic MFH should be considered during differential diagnosis, even in cirrhotic patients, and extensive tissue sampling and immunohistochemical analyses are necessary in the diagnosis of hepatic spindle cell tumors.     

Carcinosarcoma of the liver

Herein we present a 73-year-old man with primary carcinosarcoma of the liver, a rare malignant tumor of the liver. The case was followed up due to HBV-related liver cirrhosis. Regular check-up by ultrasound demonstrated a hyperechoic tumor in the left lobe of the liver, and he was referred and admitted to our hospital. Dynamic CT studies revealed a mostly hypoenhancing hepatic mass with a peripheral ring enhancement. Surgical resection was performed, and the resected tumor was macroscopically a simple nodular type, 3 cm in diameter, with a dense fibrous capsule. Microscopically, undifferentiated cells were dominant in the tumor, while moderately differentiated hepatocellular carcinoma (HCC) were also observed. A transitional zone was noted between the undifferentiated tumor and HCC. Tumor tissue with adenocarcinoma, osteosarcoma and chondrosarcoma were also detected. Immunohistochemical studies demonstrated that tumor cells were HepPar 1 positive in hepatocellular carcinoma, and CK19 and partly CK7 positive in adenocarcinoma. Moreover, CD56, chromogranin A and c-kit were occasionally positive in undifferentiated tumor cells. The diagnosis of carcinosarcoma was made based on the concomitant presence of HCC and sarcomatous components, yet it is noteworthy that various types of tumor cells were observed.     

Hepatocellular carcinoma in a patient with liver cirrhosis associated with negative serum HCV tests but positive liver tissue HCV RNA

A 70-year-old woman was admitted to our hospital because of a liver tumor. Laboratory data revealed mild liver dysfunction. Neither serum anti-HCV antibody nor HCV-RNA was detected. Computed tomography revealed a tumor lesion measuring 2 cm in diameter within the liver. Histological examination of the tumor revealed moderately differentiated hepatocellular carcinoma while the non-tumorous liver tissue demonstrated liver cirrhosis. By the RT-PCR method, HCV-RNA was detected from the non-tumorous liver tissue. We herein report a very rare case of hepatocellular carcinoma in a patient with liver cirrhosis associated with negative serum HCV findings, but positive finding for liver tissue HCV RNA.     

Lectin-Reactive Patterns of Markedly Elevated Serum α-Fetoprotein in Patients with Chronic Active Hepatitis

Four cases of chronic hepatitis associated with high serum levels of alpha-fetoprotein (AFP) without hepatocellular carcinoma are reported. All showed transient elevations of serum AFP, with peak levels of 13,500, 8,000, 4,450, and 3,000 ng/ml shortly after aggravation resulting from liver function tests. Liver biopsies revealed severe parenchymal damage in all the cases with piece-meal necrosis, bridging necrosis or bridging fibrosis. In two of four cases, there was a lobular distortion. AFP stain by an immunoperoxidase method showed a positive result in surviving hepatocytes. Lectin affinity electrophoresis of AFP in the four cases, together with an additional 12 patients with chronic hepatitis and cirrhosis and 44 patients with hepatocellular carcinoma, all having AFP levels above 1,000 ng/ml, revealed that the chronic hepatitis patients had a benign pattern of AFP bands, in contrast with the pattern of hepatocellular carcinoma with increased proportions of lentil lectin-reactive AFP-L3 and/or erythroagglutinating phytohemagglutinin-reactive AFP-P4, indicating that the analysis of lectin reactivity of AFP has a great value in differentiating the benign and malignant conditions with increased serum levels of AFP above 1,000 ng/ml.     

Sclerosed hemangioma of the liver: Report of a case and review of the literature.

A sclerosed hemangioma of the liver is an extremely rare type of benign hepatic tumor. A 77-year-old female was referred to Tokushima University Hospital with fever, abnormal liver function tests and a large liver mass. The tumor, 10 x 5 cm in size and located in segment 5-6 of the liver, was depicted as a low density tumor with enhancement by computed tomography (CT). Magnetic resonance imaging (MRI) showed it to be a tumor with a low signal on T1-weighted and a high signal on T2-weighted images. The patient was negative for hepatitis B surface antigen and hepatitis C antibody. She underwent a right hepatectomy for possible malignant liver tumors, including intrahepatic cholangiocarcinoma or fibrolamellar hepatocellular carcinoma. The following histological examination of the surgical specimen revealed the tumor to be a hepatic sclerosed hemangioma with characteristic dense collagenous tissues. We report here on the case of this unusual tumor and review the relevant literature.     

Spontaneous hepatocellular adenoma with marked cystic degeneration

We report a case of spontaneous hepatocellular adenoma with marked cystic degeneration in the non-cirrhotic liver. A 36 year-old Japanese woman with neither history of liver diseases nor use of oral contraceptives and steroids, complained of a 6 kg weight loss over 6 months. Barium meal study revealed an extramural compression along the fornix of the stomach. Abdominal ultrasonography (UC) and computed tomography (CT) demonstrated a mass in the left lateral segment of the liver that measured 11.6x9.5 cm with cystic lesions. Laboratory data on admission showed no significant findings. Celiac angiography revealed a hyper-vascular mass. Surgical exploration revealed a soft mass arising and protruding from the left lateral segment of the liver. Partial resection of the left lateral segment was performed. Histologically, the tumor was surrounded by a thin fibrous pseudocapsule. The neoplastic cells resembling normal hepatocytes around the tumor were large, pale and arranged in thick, irregular cords. Neither mitotic figures nor foci of dysplasia were present. The central portions of the tumor showed marked cystic degeneration. The tumor was histologically diagnosed as hepatocellular adenoma (HCA). HCA with cystic degeneration has been rarely reported.     

Immunohistochemical study on tissue inhibitors of metalloproteinases in normal and pathological human livers

The localization of tissue inhibitor of metalloproteinases (TIMP) in normal and pathological livers was examined by immunohistochemistry using monoclonal antibodies at the light microscopic level. In normal liver, immunoreactive TIMP was detected in smooth muscle cells and endothelial cells of blood vessels, fibroblasts, bile duct cells and Kupffer cells, indicating that TIMP is likely to be a general element of the liver. Immunoreactivity was observed in newly-formed blood vessels, proliferating bile ductules, and fibroblasts in the expanded portal area and fibrous septa of chronic active hepatitis and cirrhosis. TIMP was strongly stained in the capsule of hepatocellular carcinoma. The intensity of the immunoreaction in the capsule was generally greater than that in cirrhotic liver apart from the tumor mass. In three of five cases with hepatocellular carcinoma, endothelial walls in contact with tumor cells were positive.     

A resected case of a small hepatocellular carcinoma developing within the bile duct

We experienced a resected case of a small hepatocellular carcinoma, which required differential diagnosis from intrahepatic cholangiocellular carcinoma. The patient was a 76-year-old man. While his course had been being observed because of hepatitis C antibody-positive liver cirrhosis, ultrasonographic examination of the abdomen revealed dilation of biliary branches in the anterior segment of the liver and a hyperechoic mass 10?mm in diameter at the origin of the branch. A dynamic computed tomography scan showed a high-density tumor in the early phase. After embolization of the right branch of the portal vein, resection of the right lobe of the liver and the extrahepatic bile duct was performed. A resected specimen showed a white-colored mass 8?mm in diameter at the origin of the anterior segmental biliary branch. In the pathological findings, the diagnosis was a poorly differentiated hepatocellular carcinoma with strong nuclear atypia; the tumor filled the bile duct, forming a trabecular structure. The immunohistological stains of the tumor were positive for cytokeratin (CK) 8, CK18, and HepParl and negative for alpha-fetoprotein, carcinoembryonic antigen, CA19-9, CK7, CK19, and CK20. There was atypia in the biliary lining epithelium adjacent to the tumor, and the hepatocellular carcinoma may have developed from the biliary epithelium.     

Fibrolamellar carcinoma of the liver: hepatocellular carcinoma with favourable prognosis

The authors report a case of fibrolamellar carcinoma of the liver in a young woman with bilateral lung metastases. This tumour was surgically unremovable. Presently, after a chemotherapy with adriamycin and mitomycin, this patient is in good health, two years after initial diagnosis. Review of the literature shows that fibrolamellar carcinoma of the liver occurs mainly in young patients. This tumor is characterised by large polygonal eosinophilic hepatocytes and an abundant fibrous stroma. It can be confused with focal nodular hyperplasia. Resection of the tumor and the methodical, repeated resections of metastases must be performed when possible. Prognosis of this tumor is better than that of the other variants of hepatocellular carcinoma.     

Case Report: Fibrolamellar hepatocellular carcinoma in a Japanese woman: A case report and review of Japanese cases

Fibrolamellar hepatocellular carcinoma (FLHCC) is an entity distinct from ordinary hepatocellular carcinoma and is very rare in Oriental countries. We present here a Japanese case of FLHCC in a 25 year old woman, and review Japanese cases of FLHCC. The patient had mild abdominal pain when the hepatic tumour was revealed by ultrasonography. Hepatitis B surface antigen (HBsAg) and anti-hepatitis C antibody were negative and serum alpha-fetoprotein (AFP) was within the normal limit. Ultrasound-guided fine needle biopsy was performed and the tumour was histologically diagnosed as FLHCC. A right lobectomy of the liver was then performed. Macroscopically, the tumour (10 × 10 times 8 cm) was circumscribed, rather hard and yellowish white. Microscopically, neoplastic hepatocytes were polygonal and large with eosinophilic cytoplasm, which contained pale bodies. A number of fibrous stroma were arranged in thin parallel bands. Consequently, the case was diagnosed as FLHCC. In Japan, approximately 18 000 people die of ordinary hepatocellular carcinoma annually, while only nine cases (including the present case; six males, three females) of FLHCC in Japanese subjects have been reported previously. The mean age of the Japanese cases of FLHCC is 20.9 years old. One case with positive HBsAg, liver cirrhosis and high level of AFP was observed of nine cases. The nature of FLHCC in Japanese subjects may not be significantly different from that in Caucasians, except for male predominance.     

Autopsy case of colocalized tumors of hepatocellular carcinoma and malignant lymphoma

We present a rare case of colocalized tumors of hepatocellular carcinoma (HCC) and malignant lymphoma in the liver and bone marrow. A 64-year-old man with hepatitis B virus (HBV)-induced cirrhosis was admitted after detection of elevated serum -fetoprotein level. He was diagnosed as having HCC and treated with chemotherapy and radiotherapy, but the size of the tumors did not diminish. After 11 months' hospitalization, he died due to rupture of esophageal varices. Autopsy revealed two heterogenic malignant tumors, HCC and malignant lymphoma (B cell type), in the liver. These tumors showed colocalization in the liver and bone marrow. The carcinogenetic process of colocalized tumors of HCC and lymphoma was not clarified, but the possibility that persistent HBV infection play a role in promoting hepatocarcinogenic and hematopoietic tumor growths in the reticuloendothelial organs could not be excluded.     

Immunohistochemical study on tissue inhibitors of metalloproteinases in normal and pathological human livers.

The localization of tissue inhibitor of metalloproteinases (TIMP) in normal and pathological livers was examined by immunohistochemistry using monoclonal antibodies at the light microscopic level. In normal liver, immunoreactive TIMP was detected in smooth muscle cells and endothelial cells of blood vessels, fibroblasts, bile duct cells and Kupffer cells, indicating that TIMP is likely to be a general element of the liver. Immunoreactivity was observed in newly-formed blood vessels, proliferating bile ductules, and fibroblasts in the expanded portal area and fibrous septa of chronic active hepatitis and cirrhosis. TIMP was strongly stained in the capsule of hepatocellular carcinoma. The intensity of the immunoreaction in the capsule was generally greater than that in cirrhotic liver apart from the tumor mass. In three of five cases with hepatocellular carcinoma, endothelial walls in contact with tumor cells were positive.     

Malignant Mixed Tumor of the Liver in Adults

An extremely rare case of malignant mixed tumor of the liver in adults is reported. A 60-year-old man was admitted because of abdominal fullness. Abdominal CT-scan demonstrated a low density lesion surrounded by high density ring area in the liver. Liver scintigram and selective hepatic angiography revealed a malignant tumor mass which was indistinguishable from other malignant masses. Postmortem examination disclosed that histology of the liver tumor was Edmondson's grade II hepatocellular carcinoma and cbondrosarcoma. There are no special clinical features of this tumor and the diagnosis is almost always made during exploratory laparotomy or at autopsy. However, abdominal CT-scan findings are somewhat helpful for diagnosis of malignant mixed tumor of the liver in adults.     

Primary Hepatocellular Carcinoma with Hepatitis B Virus Infection in a 16-Year-Old Noncirrhotic Patient

Primary hepatocellular carcinoma metastasizing to abdominal lymph nodes and to the left lung was observed in a 16-year-old male patient. No clinically apparent chronic liver disease preceded the carcinoma and no signs of cirrhosis were detectable in the nonneoplastic liver. Hepatitis B surface antigen, hepatitis B e antigen and antibody to hepatitis B core antigen were found to be positive in the serum. By immunohistochemistry (peroxidase-antiperoxidase technique) hepatitis B surface antigen could be demonstrated in the nontumorous liver parenchyma, but not in the primary hepatocellular carcinoma itself. Serum alpha-fetoprotein was only moderately elevated (75 ng/ml), but immunohistochemically primary hepatocellular carcinoma revealed a considerable number of alpha-fetoprotein-containing cells, whereas nontumorous parenchyma did not. Carcinoembryonic antigen could be demonstrated immunohistochemically in some tumor cells of a lymph node metastasis, but not in the primary tumor or in the nontumorous liver parenchyma. We propose that primary hepatocellular carcinoma developed in this case in a symptomless hepatitis B virus carrier without preceding cirrhosis, an we exclude a simultaneous acute hepatitis B.     

Spontaneous partial regression of hepatocellular carcinoma in a cirrhotic patient

Spontaneous regression of a malignant tumor is an exceptional phenomenon. A 56-year-old woman with liver cirrhosis related to chronic hepatitis C presented with a liver tumor. Partial regression of a hepatocellular carcinoma was diagnosed by imaging studies that showed progressive diminution of the size of the tumor and changes in the tumor markers. However, because of the persistence of the tumor and uncertainty in the diagnosis we recommended surgery. A hepatectomy was performed and a hepatocellular carcinoma moderately differentiated was found. The patient is now doing well and without any evidence of recurrence at 25 months after surgery. We found 61 case reports that have been published from 1982 to September 2006, with apparently spontaneous regression of hepatocellular carcinoma. The precise mechanism regarding the spontaneous regression of this tumor is not fully understood, either ischemia due to rapid growth of the neoplasia or particular inflammatory and immunologic mechanisms may be involved in the regression of the hepatocellular carcinoma.     

Pigmented hepatocellular adenoma with β-catenin activation: case report and literature review

Hepatocellular adenomas (HCAs) are benign liver tumors recently characterized into 4 different types according to genetic, pathological and clinical features. The prognosis is not well established yet and malignant transformation has been recently associated with β-catenin activation. We aimed to describe a case of a pigmented HCA with β-catenin nuclear expression and inflammatory features and to review the cases of pigmented HCAs in the literature. We report a case of a young female patient without contraceptive use, with a liver tumor diagnosis. Liver biopsy revealed diffuse expression of β-catenin and a partial hepatic resection was performed. The histologic analysis revealed a hepatocellular tumor composed of uniform trabeculae of hepatocytes and solid areas, the later with a significant amount of black pigment highlighted by Masson-Fontana stain. Immunohistochemistry showed co-expression of C-reactive protein and serum amyloid A in the tumor. Literature review revealed that pigmented HCAs, previously reported as dark adenomas, are rare tumors. In HCAs, the presence of β-catenin activation should be searched for due to the higher risk of malignant transformation in hepatocarcinoma. We describe a pigmented HCA with β-catenin nuclear expression and inflammatory features being the fifth case reported so far.     

New epidemiological data on liver oncogenesis

The purpose of this review is to address and discuss the following: a) the malignant transformation of hepatocytes may occur, irrespective of the etiologic agent, in the context of increased cellular turnover induced by chronic hepatic damage and regeneration, with genetic mutations being a frequent event prior to the development of this tumor; b) although it is clear that hepatitis B virus-induced chronic liver injury, regeneration and cirrhosis is a major risk factor for hepatocellular carcinoma development, there are also several reports of the direct carcinogenic effects of hepatitis B virus. For instance, integration of hepatitis B virus DNA can directly induce chromosomal rearrangements and viral gene product transactivating properties may influence cellular genes important in the control of the growth process; c) hepatitis C virus and other risk agents, including alcohol, environmental factors and metabolic diseases may operate, mainly through chronic liver damage that progress to liver cirrhosis, a major predisposing factor for the development of hepatocellular carcinoma, regardless of etiology; d) at the molecular level, the interaction between oncogenes, tumor suppressor genes (with or without aflatoxins and hepatitis B virus) and several growth factors may play an additional role in hepatocellular carcinoma development.     

Incidental solitary hepatocellular carcinomas smaller than 1 cm in size found at autopsy: a morphologic study

The morphologic features and growth pattern of single hepatocellular carcinomas less than or equal to 1 cm in size, found incidentally at autopsy, were studied in nine cases. In all but one case, the hepatic parenchyma showed advanced cirrhosis. In three cases, the hepatocellular carcinomas were localized within a regenerative nodule as a form of "nodule within nodule." The carcinoma was rimmed by nonneoplastic hepatic tissue. A fourth carcinoma consisted of an expansile hepatocellular carcinoma nodule enclosed by a fibrous band of cirrhotic stroma. The remaining five cases consisted of hepatocellular carcinomas which infiltrated the surrounding regenerative nodules or hepatic lobules. These observations suggested that hepatocellular carcinomas arise within regenerative nodules, some of which still retain residual nonneoplastic tissue around the tumor. Others invaded the adjacent liver tissue. The grossly visible fibrous capsule, often seen in more advanced hepatocellular carcinomas, was absent in all cases. All of the hepatocellular carcinomas were well-differentiated. Four cases showed a trabecular pattern with slight sinusoidal dilatation, 3 showed a scirrhous pattern and 2 showed a compact pattern. Their histologic features included marked bile production, Mallory body formation by clusters of tumor cells, resistance to hemosiderin deposition in a markedly siderotic background and loss or decrease of reticulin fibers. These features were hallmarks of small hepatocellular carcinomas. Pathologists should study cirrhotic livers carefully so as not to miss small carcinomas. Clinicians should be aware that even small liver nodules may be hepatocellular carcinomas.