Fibrolamellar hepatocellular carcinoma

Fibrolamellar hepatocellular carcinoma is an uncommon malignancy seen in young adults without underlying liver disease. Physical signs are minimal and laboratory values are noncontributory. Diagnosis is suggested by clinical history, supported by radiographic studies, and confirmed by histologic examination. Individuals with fibrolamellar carcinoma generally have a greater survival than those with hepatocellular carcinoma. Although most patients with fibrolamellar carcinoma undergo curative surgery, two of the three patients we report had inoperable tumors.     

Expresion of cell adhesion molecule CD44 in primary tumors of the liver: an immunohistochemical study

Abstract: CD44, a widely distributed integral membrane protein, has been implicated in tumor invasion and metastatic spread in some human carcinomas and lymphomas. In this study, 35 cases of hepatocellular carcinoma from 32 patients (11 cholangiocarcinomas, 9 hepatic adenomas, and 5 cases of focal nodular hyperplasia, a non-neoplastic lesion) were examined by imunohistochemical methods for expression of CD44. The mouse monoclonal antibody A3D8 was used on formalin-fixed, paraffin-embedded tissue; this antibody does not distinguish between standard CD44 and splice variants. Positive membrane staining was seen in 13 of 35 cases of hepatocellular carcinoma (12 of 32 patients), 8 of 11 cases of cholangiocarcinoma, and 1 of 9 cases of hepatic adenoma. The strongest staining for CD44 was seen in two cases of fibrolamellar carcinoma, but CD44 expression was otherwise not related to degree of tumor differentiation. All five cases of focal nodular hyperplasia were negative for CD44. In non-neoplastic liver, hepatocytes were negative; sinusoidal lining cells and portal lymphocytes were positive; bile ducts and proliferating bile ductules were focally positive in some cases. Anatomic stage at time of presentation was similar in both groups of patients, with most patients presenting with stage III or IV disease. A trend towards slightly longer survival in patients whose hepatocellular carcinomas were CD44 negative was noted. These results show that aberrant CD44 expression is present in a subset of hepatocellular carcinomas and in most cholangiocarcinomas. The relationship between CD44 expression and tumor spread is unclear in this group of tumors, but is unlikely to be a simple association between CD44 expression and metastatic potential.     

Semi-automated quantitative method for detecting the loss of heterozygosity at the long arm of chromosome 4 in hepatocellular carcinoma

OBJECTIVES: Chromosomal deletions are the most frequent genetic alterations observed in hepatocellular carcinoma. Loss of heterozygosity on chromosome 4q has been observed in 40% of hepatocellular carcinomas suggesting the presence of a tumor suppressor gene which has not yet been identified. METHODOLOGY: We developed a semi-automated quantitative genotyping method which allowed us to characterize 119 hepatocellular carcinomas with 22 fluorescent microsatellite markers distributed on chromosome 4q. RESULTS: 4q loss was observed in 40% of cases. Among these deletions, 19 cases of partial or interstitial loss made it possible to define two common minimal regions of deletion of 25.1 and 37.6 centimorgans localized between markers D4S414 and D4S430 and between markers D4S3033 and D4S408, respectively. CONCLUSION: This work represents the first step towards the identification and characterization of new genes involved in hepatic carcinogenesis.     

Hepatic progenitor cells in human liver tumor development

INTRODUCTION The traditional view that adult human liver tumors arise from mature cell types has been challenged in recent decades. The results of several studies suggest that some types of human liver tumors can be derived from hepatic progenitor cells (…     

Carcinoma, a fibrolamellar variant--immunohistochemical analysis of 4 cases

BACKGROUND/AIMS: To analyze, by means of immunocytochemistry, the cases of fibrolamellar variant of hepatocellular carcinoma (FLC), diagnosed in our Department. METHODOLOGY: The material comprised 4 FLC cases of tumors resected surgically. Besides the routine morphological assessment, we used a panel of immunohistochemical stainings including: hepatocellular cytokeratin, CK7, CK19, Ki67, PCNA, chromogranin A, synaptophysin, NSE, insulin, calcitonin, parathormon, CD34, EBV (LMP), Bcl2, cyclin D1. RESULTS: In 3 out of 4 cases, we observed co-expression of CK7 with hepatocellular CK. In addition, there was positive staining with some endocrine markers in the majority of patients. In one case, we found strong cyclin D1 immunoreactivity which correlated with EBV (LMP) immunoreactivity, in the same patient. The score of PCNA positivity varied between 15 and 90%. In all cases Ki67 was negative. CONCLUSIONS: The incidence of FLC, among all hepatocellular carcinomas diagnosed in our Department was 5.1%. In accordance with other reports, all our FLC cases were young patients without underlying liver disease. We were unable to find a correlation between FLC cellular immunophenotype, and histological and clinical markers of malignancy. In addition, it appears that PCNA is a better marker of cell-proliferation in FLC than Ki67. The significance of EBV infection in FLC requires further study.     

Recurrent fibrolamellar hepatocellular carcinoma with biliary invasion: Successful resection

A jaundiced 17-year-old man was diagnosed as having a local recurrence of fibrolamellar hepatocellular carcinoma 2 years and 4 months after left hepatic trisegmentectomy with total caudate lobectomy had been performed. The patient had a tumor occupying the upper part of the extrahepatic and intrahepatic bile ducts. Complete resection of the recurrent tumor was carried out. The patient remains well 3 years after the second surgery. Fibrolamellar hepatocellular carcinoma, a rare type of liver cancer, is a well defined disease entity with distinct clinical and histopathological features and a favorable prognosis. The good prognosis seems to warrant aggressive surgical intervention in patients with recurrences. Therefore, additional surgery for tumor recurrence should be considered. To our knowledge, this is the first report of a case in which a recurrent tumor of fibrolamellar hepatocellular carcinoma invaded the entire bile duct wall was successfully resected.     

Endothelial cell marker expression in dysplastic lesions of the liver: an immunohistochemical study

BACKGROUNDS/AIMS: Hepatocellular carcinoma usually contains continuous capillary vessels lacking the differentiation markers specific for normal sinusoidal endothelial cells. We therefore aimed to search for alterations in endothelial cell marker expression in precancerous liver lesions. METHODS: Expression of the endothelial cell markers CD31, CD34 and BNH9 was analyzed in 138 dysplastic lesions from 40 cirrhotic patients (20 with and 20 without hepatocellular carcinoma). RESULTS: No expression of the three endothelial cell markers was detected in cirrhotic nodules and in non dysplastic regenerative macronodules. The three markers were detected in 29.8% of dysplastic lesions and 47% of hepatocellular carcinomas. At least one marker was detected in 75% of dysplastic lesions and 100% of hepatocellular carcinomas. The three markers were more frequently expressed in areas of small cell than of large cell change (34 vs 10%). No correlation was found with the grade of dysplasia, the occurrence of arterialization and the association with hepatocellular carcinoma. CONCLUSIONS: Alterations in the hepatic microcirculation comparable to those observed in hepatocellular carcinoma are present in a significant proportion of dysplastic lesions of the liver and may be indirect markers of the process of liver carcinogenesis.     

Fibrolamellar liver cell cancer. A case report

Fibrolamellar hepatocellular carcinoma of the liver is a rare variant of hepatocellular carcinoma with characteristic morphological patterns and a good prognosis. Preoperatively the tumor is rarely diagnosed. Surgical treatment is resection, hemihepatectomy or transplantation of the liver. We report a case of a 51 years old patient with fibrolamellar hepatocellular carcinoma of the liver.     

Primary combined hepatocellular-cholangiocellular sarcoma: An unusual case

Primary liver carcinosarcoma is rare. Here we report an unusual case of liver carcinosarcoma containing combined hepatocellular cholangiocarcinoma. A mass in the right liver lobe of a 45-year-old man was accidentally discovered by ultrasonic inspection and computed tomography (CT) scan. Surgical resection was performed following a diagnosis of primary liver cancer. Micropathologically, both carcinomatous and sarcomatous elements were present, and diagnosis of liver carcinosarcoma was confirmed. The carcinomatous element consisted of hepatocellular carcinoma and foci of cholangiocellular carcinoma. The sarcomatous element was composed of spindle cells and bizarre cells, as well as foci of osteosarcoma and chondrosarcoma. Hepatocellular carcinoma cells diffusely expressed both hepatocyte specific markers cytokeratin (CK) 8/18 and cholangiocyte specific markers CK19, and sarcoma cells were positive for vimentin. Interestingly, both carcinomatous and sarcomatous cells expressed epithelial membrane antigen. CD117-positive ductular reactions and small undifferentiated cells were observed. A liver progenitor cell origin of the liver carcinosarcoma was proposed.     

Fibrolamellar hepatocellular carcinoma with a recurrence of classic hepatocellular carcinoma: a case report and review of Oriental cases

A 72-year-old Chinese male, hepatitis B carrier, received a right hepatic trisegmentectomy in 1997 for fibrolamellar hepatocellular carcinoma. Serum alpha-fetoprotein was in the normal range until two years after the operation, a rapid increase to 241 ng/mL occurred and computed tomography showed a 2-cm-sized recurrent nodule in the caudate lobe. Because computed tomography arterioportography showed additional multifocal nodules in the residual liver, transarterial embolization was performed. Four months after the first transarterial embolization, the caudate tumor grew to 6 cm and serum alpha-fetoprotein increased to 6090 ng/mL. Prior to the second transarterial embolization, this new hepatic lesion received a biopsy and showed a characteristic feature of classic hepatocellular carcinoma, which was different from the previous one. Four months after the second transarterial embolization, computed tomography showed no recurrent tumor and serum alpha-fetoprotein subsequently normalized. Twenty-two months after the first transarterial embolization, a 2.5-cm-sized tumor recurred again at the lateral segment. At this time, serum alpha-fetoprotein (3.6 ng/mL) was not elevated. He received the third transarterial embolization and is still alive. Recurrence of fibrolamellar hepatocellular carcinoma after hepatic resection has been reported to be high, but a case report with a character of muticentric, multifocal, and metachronous recurrences of fibrolamellar and classic type hepatocellular carcinoma is very rare. This is the second case report in the literature.     

Hepatic neoplasms: computed tomography and magnetic resonance features

Over the last decade, major advances in computed tomography and magnetic resonance technology have occurred. These advances enable accurate, noninvasive detection and characterization of many hepatic neoplasms. This article illustrates the role of imaging in the evaluation of hepatic neoplasms and reviews the typical imaging features of both benign and malignant hepatic tumors. Benign tumors discussed include hemangiomas, focal nodular hyperplasia, hepatocellular adenoma, and simple cysts, as well as cysts associated with polycystic liver disease. Malignant neoplasms reviewed include metastases and conventional hepatocellular carcinoma as well as less common tumors such as fibrolamellar hepatocellular carcinoma, intrahepatic cholangiocarcinoma, angiosarcoma, and epithelioid hemangioendothelioma.     

Genomic stability prevails in North-African hepatocellular carcinomas

The molecular pathogenesis of hepatocellular carcinoma, a tumour characterized by a vast clinical heterogeneity, remains unexplored outside Europe and Eastern Asia. We analysed by direct sequencing or loss of heterozygosity assay, the common targets of genomic alterations in 42 hepatocellular carcinomas collected in western North-Africa. Overall, genomic instability was uncommon, allelic losses affecting mostly chromosomes 1p, 4q, 8p and 17p (24-28% of cases). CTNNB1 and TP53 were infrequently mutated (9 and 17% of cases, respectively). Surprisingly, TP53 mutation R249S, diagnostic of aflatoxin B1 exposure, usually frequent in Africa, was exceptional (one case), indicating that in western North-Africa, hepatocellular carcinoma genetics differs markedly from that of the remainder of the continent.     

Primary liver carcinoma of intermediate (hepatocyte-cholangiocyte) phenotype

BACKGROUND/AIMS: Recent evidence of hepatic progenitor cells with the bipotential to differentiate into hepatocytes and cholangiocytes gives rise to the suggestion that primary hepatic carcinomas with features intermediate between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) may originate from hepatic progenitor cells. METHODS: Fifty-four cases of primary liver carcinomas were selected and an immunohistochemical analysis was performed using hepatocytic markers (alpha-fetoprotein, hepatocyte), cholangiocytic markers (carcinoembryonic antigen, cytokeratin 19) and progenitor cell marker (c-kit). RESULTS: Thirteen cases designated 'intermediate' carcinomas demonstrated strands/trabeculae of small, uniform, round-to-oval cells with scanty cytoplasm and hyperchromatic nuclei embedded within a thick desmoplastic stroma. Six were designated transitional type combined hepatocellular-cholangiocarcinoma (CHC). Ten were named HCC small cell type, demonstrating similar features to typical HCC, but composed of smaller cells. Simultaneous expression of hepatocytic and cholangiocytic markers was demonstrated in 8/13 (61.5%), 4/6 (66.7%), and 3/10 (30%) cases of intermediate carcinomas, transitional CHCs, and HCC small cell type, respectively, and c-kit expression was noted in 10/13 (76.9%), 4/6 (66.7%) and 7/10 (70%) cases, in the same order. CONCLUSIONS: Intermediate carcinoma may be a distinct type of primary liver carcinoma, morphologically and phenotypically intermediate between HCC and CC, which originates from transformed hepatic progenitor cells.     

Potentiality of combined hepatocellular and intrahepatic cholangiocellular carcinoma originating from a hepatic precursor cell: Immunohistochemical evidence.

Hypothesizing that combined hepatocellular and intrahepatic cholangiocellular carcinoma originates from hepatic stem cells, we conducted a series of immunohistochemical studies using hepatic stem cell markers to better understand the origin of the tumor. Specially, we investigated 15 combined tumors confirmed to be immunoreactive to anti-hepatocyte paraffin 1, and anti-cytokeratin 7 and 19 antibodies. Macroscopic investigation revealed cancer cells morphologically intermediate between neoplastic hepatocytes and cholangiocytes (combined tumor with intermediate morphology) in 11 of 15 tumors. The remaining four tumors lacking these cells were considered ordinary combined tumors. We used 20 hepatocellular carcinomas and 10 cholangiocarcinomas as controls. Immunohistochemical analysis was performed using stem cell markers (c-kit and CD34). Of the 15 combined tumors, 8 stained for c-kit (2 of the 4 ordinary tumors and 6 of the 11 intermediate morphologic tumors). Both of the tumor cell types in both of the ordinary combined tumors stained for c-kit. The c-kit staining was present in cells of all three morphologic types, including the intermediate cells, in all six of the intermediate combined tumors. None of the cells in the combined tumors showed immunoreactivity for CD34. None of the 30 control tumors expressed CD 34 or c-kit. The present study suggests that combined hepatocellular and intrahepatic cholangiocellular carcinomas originate not from a hepatic stem cell, but from a hepatic precursor cell, such as the canal of Hering cell. Alternatively, these tumors might show up-regulation of c-kit in relation to angiogenesis.     

Primary liver cancer with bidirectional differentiation into hepatocytes and biliary epithelium

A 70-year old Japanese man with hepatitis B infection developed a 4.8-cm liver tumor in the right lobe. Computed tomographic findings suggested hepatocellular carcinoma or combined hepatocellular and cholangiocarcinoma. After right hepatectomy, the cut surface of the resected specimen showed a whitish tumor with indistinct borders. Microscopically, the tumor consisted of pleomorphic, eosinophilic cells forming thickened trabeculae, suggesting hepatocellular carcinoma, and also tumor cells forming glandular structures, suggesting adenocarcinoma. Cells comprising both the trabeculae and the glands were immunoreactive for cytokeratin (CK) 19. In some gland-forming cells, varying immunoreactivity for CK7 and carcinoembryonic antigen (CEA) was observed. In the cytoplasm of cells in the thickened trabeculae, hepatocyte paraffin (HepPar) 1 and alpha-fetoprotein (AFP) were focally reactive. Some of these tumor cells were also reactive for CK19. Accordingly, we concluded that this tumor was a combined hepatocellular and cholangiocarcinoma whose cells had undergone divergent differentiation into hepatocytes and biliary epithelium. Because the tumor expressed markers of both phenotypes, it may have originated from cells intermediate between hepatocytes and biliary epithelium. A few reported cases have shown similar histologic features.     

A novel diagnostic marker,p28<Superscript>GANK</Superscript> distinguishes hepatocellular carcinoma from potential mimics

Purpose To investigate the sensitivity, specificity, and spatial distribution of the product of p28 gene (p28^GANK protein) in human hepatocellular carcinoma (HCC) and nonhepatocellular carcinomas in relation to immunostaining with Cytokeratin 18 (CK18), -fetoprotein (AFP), and Hepatocyte paraffin 1 (HepPar1).Method In this retrospective study, formalin-fixed paraffin-embedded tissues from 24 HCCs, five intrahepatic cholangiocarcinomas (ICC), five combined hepatocellular cholangiocarcinomas (C-HCC-CC) and mine metastatic hepatic carcinomas (MHC) were immunostained for p28^GANK as well as CK18, AFP and HepPar1. Only cases with more intensified staining in carcinoma contrast to the adjacent liver tissues were accepted as positive.Result In HCC, p28^GANK was expressed restrictively in hepatocytes of both para-lesion and carcinoma liver tissues, while absent in the bile duct epithelial cells, Kupffer cells, and other interstitial cells. The positive staining of p28^GANK was noted in 16 (66.7%) specimens of HCC and three (60.0%) specimens of C-HCC-CC, and no specific lesion staining was found in all tested specimens of ICC and MHC. Sensitivity and specificity for hepatocyte-originated carcinoma were, respectively, 65.5% and 100% for p28^GANK, 79.3% and 85.2% for CK18, 20.7% and 100% for AFP, 79.3% and 92.0% for HepPar1.Conclusion The hepatocytic staining for p28^GANK is clearly useful in differentiating hepatocyte-originated carcinoma from non-HCC. p28^GANK may be used as an ancillary marker for the diagnosis of HCC.Abbreviations HCC Hepatocellular carcinoma - ICC Intrahepatic cholangiocarcinoma - C-HCC-CC Combined hepatocellular cholangiocarcinoma - MHC Metastatic hepatic carcinoma - HepPar1 Hepatocyte paraffin 1 - CK18 Cytokeratin 18 - AFP -fetoprotein - IHC Immunohistochemistry This work was supported by the Chinese National Key Project of Basic Research (No. 001CB510205), the Hi-Tech Research and Development Program of China (No. 2002BA711A02-3), and the Shanghai Science and Technology Committee Grant (No. 03DJ14007).     

Prognostic factors in patients with hepatocellular carcinoma receiving systemic chemotherapy. Identification of two groups of patients with prospects for prolonged survival

Among 37 patients with hepatocellular carcinoma given systemic chemotherapy, 12 (32 percent) lived 14 to 37 months from initiation of treatment whereas the remainder died within five months. Individual factors associated with improved survival included fully ambulatory performance status, lack of jaundice, response to chemotherapy, the fibrolamellar carcinoma pathologic variant, absence of cirrhosis, and normal serum alpha-fetoprotein levels. Patients living longer than 12 months fell into two groups. Seven patients with fibrolamellar carcinoma lacked evidence of hepatitis B serum markers or cirrhosis and had normal alpha-fetoprotein levels and surprisingly frequent extrahepatic metastases. All but one were Caucasians aged 25 years or less. The other five "long-term" survivors were all fully ambulatory without jaundice, and the majority were older non-Caucasians with tumor confined to the liver at the time of diagnosis and with hepatitis B markers, elevated alpha-fetoprotein levels, or cirrhosis. All patients without fibrolamellar carcinoma who were less than fully ambulatory or who had jaundice died quickly. Patients with fibrolamellar carcinoma have homogeneous clinical features, and their disease follows a relatively indolent course. In other patients with hepatocellular carcinoma, assessment of ambulatory status and serum bilirubin determination can identify those with some prospect of prolonged survival.     

Lymphoepithelioma-like cholangiocarcinoma:A mimic of hepatocellular carcinoma on imaging features

Primary lymphoepithelioma-like carcinoma in the liver is extremely rare. A few cases of lymphoepithelioma-like cholangiocarcinoma have been reported, but few radiologic features were described. We reviewed 23 cases of lymphoepithelioma-like cholangiocarcinoma reported between 1996 and 2014 and describe a rare case of a 35-year-old woman in our hospital who was diagnosed with lymphoepithelioma-like cholangiocarcinoma of the liver and was a hepatitis B carrier. The tumor(1.6 cm) in our patient appeared to be hypoechoic in sonographic images and hypodense in computed tomography(CT) images. In addition, it was homogeneous hypointense in T1-weighted magnetic resonance(MR) images(MRI) and hyperintense in T2-weighted MRI. Dynamic gadolinium-enhanced MRI showed typical image pattern of hepatocellular carcinoma(HCC). The patient underwent a laparoscopic left hepatic lobectomy, and the resected tumor consisted of well-differentiated glandular cells with extensive lymphocytic infiltration that were immunoreactive to CK(AE1/AE3), CD3, and CD20. In addition, the tumor was positive for Epstein-Barr virus-encoded RNA in situ hybridization. Finally, lymphoepithelioma-like cholangiocarcinoma was diagnosed. In previous studies, the incidence is highest among middle-aged people. Most tumors appeared to be hypodense with either hypovascular or hypervascular patterns in CT images. This case report is the first study to address sonography, CT, and MRI observations and delineate pathologic correlations. We suggest that the imaging pattern of lymphoepithelioma-like cholangiocarcinoma, either the typical cholangiocarcinoma pattern or a mimic of HCC, should be considered in the differential lists for HCC.     

Genomic instability of murine hepatocellular carcinomas with low and high metastatic capacities

AIM: To investigate the frequency of genomic instability in murine hepatocellular carcinoma (HCC) cell lines Hca/A2-P(P) and Hca/163-F(F) with low and high metastatic capacity, and to explore its association with the occurrence and metastasis of hepatocellular carcinomas. METHODS: Forty microsatellite markers were randomly selected to examine P and F cells for genomic instability using PCR-simple sequence length polymorphism (PCR-SSLP) analysis. RESULTS: Allelic genes on the chromosomes of P cell line with thirty informative microsatellite loci were paralleled to those of inbred strain C(3)H mouse, while those of F cell line with 28 loci were paralleled to those of inbred strain C(3)H mice. The frequency of microsatellite alterations was 37.5% and 42.5% in P cell line and F cell line, respectively. There were different alterations of allelic band 9 at loci between P and F cells, among which, the frequency of microsatellite alterations was most commonly seen on chromosomes 3, 7, 11 and 16. CONCLUSION: Genomic instability in mouse chromosomes 3, 7, 11 and 16 may play a more important role in the development and progression of HCC in mice. It is suggested that these two sub-clones derived from a same hepatic tumor in homozygous mouse present different genetic features.