Pearls and pitfalls in magnetic resonance imaging of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the most common primary hepatic malignancy, which usually arises in cirrhotic liver. When the typical enhancement pattern, consisting of late arterial hyperenhancement followed by washout, is present in nodules larger than 1 cm, HCC can be confidently diagnosed without the need for tissue biopsy. Nevertheless, HCC can display an atypical enhancement pattern, either as iso or hypovascular lesion, or hypervascular lesion without washout. Not only the enhancement pattern of HCC could be atypical, but also a variety of histological types of HCC, such as steatotic, scirrhous, fibrolamellar, or combined hepatocellular-cholangiocellular carcinoma could raise diagnostic dilemmas. In addition, distinct morphological types of HCC or different growth pattern can occur. Awareness of these atypical and rare HCC presentations on magnetic resonance imaging is important for accurate differentiation from other focal liver lesions and timely diagnosis, which allows optimal treatment of patients.     

Hepatocellular carcinoma in the youth. A comparative analysis with hepatocellular carcinoma in adulthood

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is a very rare disease among young individuals. Epidemiological, clinical and histopathological features of this malignancy in the youth have not been thoroughly studied. METHODOLOGY: A review of the clinical files of patients with HCC younger than 40 years of age, who were treated between May 1990 and July 2002, was performed. RESULTS: Seventeen patients were included for analysis; nine were female and eight male. The mean age at diagnosis was 24 years (range 12-39 years). Abdominal pain was the main symptom, followed by vomiting and nausea. Enlargement of the liver was observed in 11 patients (65%). In seven patients (41%), an etiological factor was not found. Five of these cases were of the fibrolamellar variant (29%). Only four patients were resected (23%) two of which belonged to the fibrolamellar type. Three patients (18%) are still alive after 64.9 months of follow-up. CONCLUSIONS: HCC is a very uncommon disease in the youth and affects similarly both genders. It is discovered at an advanced stage. Hepatitis B and C are uncommon etiological factors. The frequency of fibrolamellar carcinoma is higher in this age group. Though resection is more feasible, the overall survival rates remain low.     

A resected case of fibrolamellar hepatocellular carcinoma with chronic hepatitis (type B)]

We report a case of a 34-year-old woman who tested positive for HBs Ag with fibrolamellar hepatocellular carcinoma of the liver. The sister of this patient, who was also positive for HBs Ag, died of hepatocellular carcinoma (HCC). The patient showed elevation of alpha-fetoprotein. Abdominal CT scan showed a tumor in the posterior segment of the liver and hepatic angiography revealed marked neovascularity in the tumor. Partial resection of the liver was performed, and the histological diagnosis was fibrolamellar hepatocellular carcinoma. The patient is now tumor free and doing well 20 months after the operation.     

Hepatocellular carcinoma in women: probable lack of etiologic association with oral contraceptive steroids

To investigate the possibility of an association between oral contraceptive steroids (CS) and hepatocellular carcinoma (HCC), we reviewed 128 cases of HCC in women collected between 1953 and 1980. There were 48 cases under the age of 40, and 13 of these (27%) had used CS. However, 62% of HCC associated with CS and 58% of HCC in women under 40 not using CS were classified histologically as "fibrolamellar" carcinoma. This subtype of HCC occurs predominantly in young people, both male and female. The apparent increase in HCC in young women can be explained by the presence of cases of fibrolamellar carcinoma in this age group, an the apparent association with CS is probably coincidental.     

alpha-1-Antitrypsin phenotypes in hepatocellular carcinoma

alpha-1-Antitrypsin deficiency due to homozygous Pi ZZ state is reported to be associated with cirrhosis and hepatocellular carcinoma (HCC); however, the role of heterozygous Pi Z state is not definitely known. In order to investigate the possible association, we studied the phenotypic distribution of alpha-1-antitrypsin variants (Pi) in 124 cases of HCC. Two thousand ten normal American Red Cross blood donors were studied as controls. Twelve patients with HCC had aberrant phenotypes, an incidence of 9.67% as compared to 8.36% among normal controls. Nine of 12 patients with HCC with aberrant Pi type had cirrhosis; 5 of the 9 had cirrhosis due to hepatitis B virus; 2 of the 9 had alcoholic liver disease with cirrhosis, and 2 had cryptogenic cirrhosis. The three patients with HCC arising in noncirrhotic livers who also had aberrant Pi phenotypes, had a relatively rare variety of HCC called fibrolamellar type. Z gene was found in five patients: all five were MZ. Incidence of MZ phenotype in HCC was similar to that of the normal control population (4.0% in HCC and 2.9% in the controls). However, 3 of 5 MZ were associated with fibrolamellar HCC. Another aberrant phenotype found among the patients with HCC was MF (fast moving) which occurred with an incidence of 2.41% as compared to none in the control group. In conclusion, we found no significant increase in the incidence of Z gene among 124 patients with HCC as compared to the normal population.     

Fibrolamellar Hepatoma

Primary hepatocellular carcinoma (HCC) has a high incidence rate worldwide with an extremely grave prognosis, but, fortunately, accounts for only 2% of all cancers in the United States. Yet, a unique subset of HCC fibrolamellar hepatocellular carcinoma (FLHC) is reported only from the United States. Five cases of FLHC from the University of Minnesota's 17 years of experience are reported and compared with the literature reports for FLHC, as well as contrasted to reports of HCC. The review of the literature is addressed for data evaluating FLHC as a distinct entity from HCC.     

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.     

Fibrolamellar carcinoma: a review with focus on genetics and comparison to other malignant primary liver tumors

Fibrolamellar carcinoma is a rare primary malignant liver neoplasm that usually affects adolescents and young adults with no underlying liver disease. Morphologically, the tumor cells resemble oncocytic hepatocytes arranged in cords with a stroma of lamellated collagen fibers. Immunohistochemical studies have found that fibrolamellar carcinomas express markers associated with both biliary (CK7 and epithelial membrane antigen) and hepatocytic (heppar-1and glypican-3) differentiation, as well as markers associated with hepatic progenitor cells (CK19 and EpCAM) and stem cells (CD133 and CD44). Genetic studies show fewer alterations compared with classic hepatocellular carcinoma. Pooled data from comparative genomic hybridization studies show that fibrolamellar carcinomas have fewer and less frequent genomic alterations when compared with classic hepatocellular carcinoma, cholangiocarcinoma, and hepatoblastoma. Of the alterations seen in fibrolamellar carcinoma, the most frequent are gains in 1q and 8q (also frequently seen in other hepatic tumors) and loss of 18q. Fibrolamellar carcinoma also has less frequent methylation of tumor suppressor promoters compared with hepatocellular carcinoma and minimal alterations in mitochondrial DNA. Fibrolamellar carcinoma is associated with better survival than hepatocellular carcinoma and cholangiocarcinoma, presumably due to the young age of the patients and the lack of cirrhosis. These features make more aggressive surgical therapy possible. There is currently very little information on the effectiveness of chemotherapy for fibrolamellar carcinoma.     

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.     

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.     

Liver resection in advanced hepatocellular carcinoma

BACKGROUND/AIMS: The aim of this study was to assess the results of major liver resection in patients with advanced hepatocellular carcinoma in terms of safety and survival. METHODOLOGY: The subjects of this study are 19 patients that underwent 24 resections for advanced (stage IV) hepatocellular carcinoma. Eighteen of these resections were performed for primary tumor and 6 were repeat resections. Nine patients presented without cirrhosis, 5 with cirrhosis, and 5 patients had the fibrolamellar variant of hepatocellular carcinoma. RESULTS: Hospital mortality was recorded in 1 case (5%). Morbidity was noted in 7(37%) cases. All patients with fibrolamellar variant of hepatocellular carcinoma are alive at 78, 41, 24, 12 and 9 months (P = 0.008), compared with a median survival of 18 and 9 months for the noncirrhotic hepatocellular carcinoma and cirrhotic hepatocellular carcinoma groups, respectively (P = 0.24). CONCLUSIONS: We conclude that an aggressive policy of major liver resection with vascular reconstruction was justifiable in patients with advanced fibrolamellar variant of hepatocellular carcinoma and in selected patients with noncirrhotic hepatocellular carcinoma, and of doubtful value in patients with cirrhosis.     

Fibrolamellar hepatocellular carcinoma: report of a case

We report a case of fibrolamellar hepatocellular carcinoma, which occurred in a 58-year-old man with normal liver function. Preoperative ultrasonography, computed tomography and magnetic resonance imaging depicted a large tumor in the left lateral segment, which was compatible with the typical radiological features of fibrolamellar hepatocellular carcinoma. He underwent left lobectomy and no lymphadenopathy or distant metastasis was demonstrated. Macroscopic findings of the resected liver demonstrated a well-defined whitish-yellow tumor with a central scar. Microscopic findings of the tumor showed cords of tumor cells, which were surrounded by abundant collagenous fibrous tissue arranged in a lamellar distribution. He has been doing well for approximately one year since the surgery without any signs of recurrence. In addition, we discuss the clinicopathological features of fibrolamellar hepatocellular carcinoma based on a review of 22 Japanese patients who have been previously reported.     

Fibrolamellar hepatocarcinoma: clinical, radiologic, and pathologic features

Three new cases of an unusual subtype of hepatocellular carcinoma (HCC) referred to as fibrolamellar hepatocarcinoma (FLHC) recently seen at our institution are described. This report focuses on the clinical, radiologic, and pathologic features of this rare subset of HCC. All three patients were under 30 years of age with no previous history of hepatitis or cirrhosis. Each had had subacute symptoms for 5 months to 1 year before medical attention was sought and/or diagnosis of FLHC was established. There was no reliable correlation with oral contraceptive use in the 2 female patients. Serum alpha-1-fetoprotein levels were normal with only mild elevation of liver enzymes. The CT features, although not specific, were suggestive of an aggressive tumor with amorphous calcification in 2 of the 3 cases. Angiographically all tumors were hypervascular without any evidence of arterioportal shunting or venous invasion of major vessels. The clinical and radiologic recognition of these tumors is important since the surgical resectibility rate and 2- and 5-year survival rates are higher than those applicable to conventional HCC.     

Immunohistochemical study of HBV antigens in 338 liver cell carcinomas.

Tumor tissue (n = 338) and liver parenchyma (n = 276) from patients of Asian (n = 31) and European descent (n = 307) with hepatocellular carcinoma (HCC, n = 299), cholangiocellular carcinoma (CCC, n = 16) and combined HCC/CCC (n = 23) were screened with immunohistochemical methods for HBV antigens (HBs, preS1, preS2, HBc, HBe and HBx). Of the HCC cases nine were of the fibrolamellar type (FLC). All cases of HCC/CCC and CCC were from Western European patients. HBV antigens could be demonstrated more frequently in HCC cases of Asian descent (59.09% in liver parenchyma and 66.67% in tumor tissue) compared to Western European HCC cases (23.11% and 30.77%; chi-square test, p = 0.0003 and p = 0.0001, respectively), HCC/CCC (26.32% and 30.43%), CCC (7.14% and 20%) and FLC (0% and 25%). Results for HBx were not considered here due to questionnable HBV specificity of the antibodies employed. Immunohistochemical detection mainly HBs, whereas HBc, HBe and preS antigens played only a minor part. Comparing the results obtained with a rabbit and a goat polyclonal HBs antibody and a cocktail of seven monoclonal HBs antibodies showed statistically significant superior sensitivity for the goat antibody. Reactivity of tumor tissue for HBc and/or HBe as observed in twelve cases is suggestive of virus replication within tumor tissue. These data plus the demonstration of HBV antigens within so-called proliferated bile ducts, which represent metaplastic hepatocytes, underscore the nature of CCC as malignant counterpart of proliferated bile ducts. Consequently, it is proposed to divide the entity liver cell carcinoma (LCC) into the subcategories HCC and CCC in contrast to adenocarcinomas arising from bile ducts or peribiliary glands. In conclusion, HBV seems to play a part in the pathogenesis of LCC in Asian and in Western European patients. Further factors like HCV and other chronic inflammatory processes may be employed here.     

Hepatocellular carcinoma occurring in nonfibrotic liver: epidemiologic and histopathologic analysis of 80 French cases

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.     

Glutathione treatment of hepatocellular carcinoma

ABSTRACT— This prospective study was undertaken to substantiate observations that glutathione (GSH) inhibits or reverses tumor growth in humans with hepatocellular carcinoma (HCC), a neoplasm with an extremely poor prognosis. Eight patients with biopsy-proven HCC not amenable to surgery were given 5 g of GSH daily from the time of diagnosis. Two patients withdrew shortly after receiving GSH due to intolerable side-effects. Of the six eligible patients, two had mildly advanced tumors and four moderately advanced tumors. At 1–2-month intervals the liver was CT and ultra-sound scanned to assess the growth status of the tumor (progression, stagnation or regression). All the patients, except a male with a fibrolamellar type of HCC, died within 1 year after diagnosis. Two women with moderately advanced tumors survived almost 1 year, tumor growth stopped or regressed and in one of the women an initially abnormal alfa-1-fetoprotein (AFP) returned to normal after GSH treatment. AFP remained normal throughout the treatment period in the other woman. These observations indicate that GSH may have a sex-dependent effect on HCC. However, further studies involving more patients are required to pursue this hypothesis.     

Histopathology of liver cancers

Recently, new pathomorphologic information about early-stage small hepatocellular carcinoma (HCC) and the multi-step process of human hepatocarcinogenesis has been obtained, along with advances in the development of diagnostic modalities. The most valuable information is that in the majority of cases HCC arises as a very well differentiated cancer and proliferates with a stepwise process of dedifferentiation. In addition, it has been suggested that many HCCs seem to arise from dysplastic nodules (DNs) on the basis of the following evidence: the presence of DNs containing HCC foci, frequent association of DNs in the vicinity of HCC, and clinical progression from DN to HCC. However, as many HCCs are still detected at an advanced stage, it is also important to understand not only the classical pathologic features of HCC but also unusual features such as scirrhous change, sarcomatous change, fibrolamellar variant, and intra-bile duct or intra-atrial tumor growth.     

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.     

Combined hepatocellular-cholangiocarcinoma: A clinicopathological study

Combined hepatocellular-cholangiocarcinoma (HCC-CC) is an uncommon form of primary liver cancer having features of both hepatocellular and biliary epithelial differentiation. We reviewed 21 cases of this tumour diagnosed between 1972 and 1996 (patient age range 16–79 years; mean patient age 49.7 years; 18 male and three female patients). Histologically, the majority (n= 18) of tumours were ‘mixed’ tumours, in which areas of hepatocellular and biliary epithelial differentiation were intimately mixed within the same tumours. Two patients had separate tumours in which discrete nodules of HCC and CC occurred in the same livers. One patient had a ‘fibrolamellar’ tumour that histologically simulated the fibrolamellar variant of HCC, but some of the tumour cells were mucin-producing cells. Of the 21 cases, mucin was demonstrable in 16 and, in the few mucin-negative tumours, electron microscopic studies confirmed the presence of the dual differentiation. The tumours frequently exhibited an invasive character with frequent venous permeation, direct invasion into adjacent liver parenchyma and tumour microsatellite formation, similar to that of ordinary HCC. Histological evidence of cirrhosis or chronic hepatitis was present in 77.8% of patients and 75% of patients were hepatitis B surface antigen positive. Raised serum α-fetoprotein (AFP) levels (above 300 ng/mL) were present in 61.5% of patients and AFP was detected immunohistochemically in 55% of tumours. The overall survival times of patients with HCC-CC were short. In conclusion, HCC-CC showed clinical and pathological features more akin to those of ordinary HCC than to CC.     

Copper and hepatocellular carcinoma

The presence of copper and copper-binding protein (CBP) within tumor cells was searched by histochemical methods (rhodanine, rubeanic acid and Shikata's orcein) in a group of 39 autopsies, all consecutive cases of hepatocellular carcinoma (HCC) associated with cirrhosis (HCC + C). In 2 cases, fibrolamellar carcinoma (FLC) not associated with cirrhosis was observed at surgery. Considerable amounts of copper and CBP were found within tumor cells only in the 2 FLC cases and in 1 HCC + C case, in a portion of the tumor showing FLC-like features. Copper-positive tumor cells had an oncocytic appearance, which was confirmed by ultrastructural examination. In 64% of the HCC + C cases (25 out of 39), copper and CBP deposits were found in nonneoplastic hepatocytes mainly distributed along the periphery of cirrhotic nodules. The present study indicates that the storage of copper inside tumor cells is a peculiarity of the FLC type of HCC with a close relationship to the oncocytic nature of neoplastic hepatocytes. The significance of copper deposits in nonneoplastic cirrhotic hepatocytes remains a matter for further investigations.