Fibrolamellar Hepatocellular Carcinomas Research Articles

HGF, MET, and Matrix-Related Proteases in Hepatocellular Carcinoma, Fibrolamellar Variant, Cirrhotic and Normal Liver

Fibrolamellar variant is an uncommon subcategory of hepatocellular carcinoma with a better prognostic outcome. Proteinases and growth factors that are involved in the remodeling of extracellular matrix may influence the behavior of cancers. To determine whether these factors contribute to the distinct etiologies of fibrolamellar hepatocellular carcinoma and traditional hepatocellular carcinoma, we assayed hepatocyte growth factor, the hepatocyte growth factor receptor, and two hepatocyte growth factor activators, hepatocyte growth factor activator and urokinase-type plasminogen activator, in hepatocellular carcinoma, fibrolamellar hepatocellular carcinoma, cirrhotic liver and normal liver. In addition, we examined the urokinase-type plasminogen activator receptor, the type 1 plasminogen activator inhibitor, plasmin, fibrinogen, and the type IV matrix metalloproteinases. Eighteen hepatocellular carcinomas and 11 fibrolamellar hepatocellular carcinomas were obtained as paraffin embedded sections from the University of Pittsburgh Department of Pathology. Frozen tissues from a subset of cases (9 hepatocellular carcinomas, 4 fibrolamellar hepatocellular carcinomas, 12 cirrhotic livers and 2 normal livers) were also available for analysis. Antibodies against urokinase-type plasminogen activator, urokinase-type plasminogen activator receptor, hepatocyte growth factor and hepatocyte growth factor receptor were used to analyze immunoperoxidase stained slides from the paraffin blocks. Western blot analyses using antibodies against hepatocyte growth factor, hepatocyte growth factor receptor, phosphotyrosine, hepatocyte growth factor activator, urokinase-type plasminogen activator receptor, urokinase-type plasminogen activator, plasminogen activator inhibitor-1, fibrinogen and plasmin were performed on membrane-enriched fractions from the frozen tissue, as was collagen zymography for matrix metalloproteinase-2 and matrix metalloproteinase-9. The most notable findings are as follows: hepatocyte growth factor activator was only detected in malignant tissue but not cirrhotic liver or normal liver. Although hepatocyte growth factor was detected in most samples, it was significantly elevated in 5/9 hepatocellular carcinomas. Furthermore, 8/9 fibrolamellar hepatocellular carcinomas demonstrated hepatocyte growth factor receptor levels similar to normal, whereas 8/9 hepatocellular carcinomas and 11/12 cirrhotic livers exhibited either an increase or decrease. In contrast, active matrix metalloproteinase-2, which was absent in normal liver, was elevated in fibrolamellar hepatocellular carcinoma as compared to cirrhotic liver and conventional hepatocellular carcinoma. Surprisingly, 10/12 cirrhotic livers and 2/4 fibrolamellar hepatocellular carcinomas but only 1/9 hepatocellular carcinomas were enriched for plasmin. The combined data suggest that the hepatocyte growth factor and plasmin systems tend to be operative in hepatocellular carcinoma and cirrhotic liver, more than fibrolamellar hepatocellular carcinoma. Furthermore, matrix turnover appears to be a more prominent feature of fibrolamellar hepatocellular carcinoma. These findings provide insight into the behavioral differences between hepatocellular carcinoma and the fibrolamellar variant.

Fibrolamellar hepatocellular carcinoma: pre- and posttherapy evaluation with CT and MR imaging.

To determine the features of advanced hepatic and extrahepatic fibrolamellar hepatocellular carcinomas (HCCs) and their effects on immediate surgical management and tumor recurrence. Thirty-one patients with fibrolamellar HCC underwent pretherapy computed tomography (CT); 11 underwent pretherapy magnetic resonance (MR) imaging. All 40 patients underwent posttherapy CT; four, follow-up MR imaging. Imaging, surgical, and histopathologic findings were correlated. Twenty-five (81%) patients had solitary tumors (mean maximum diameter, 13 cm). Thirteen (42%) patients had intrahepatic biliary obstruction; 27 (87%) patients had involvement of the portal or hepatic veins. Thirteen (42%) had extrahepatic tumor spread, nine (29%) had distant metastases on pretherapy images, and 20 (65%) had lymphadenopathy. Thirty-two (80%) of 40 patients underwent exploration surgery; curative resection was attempted in 25 (62%), including four patients who underwent liver transplantation. Only 17 patients were considered to have had hepatic and extrahepatic tumors completely excised. Tumor recurred in all eight of the 17 patients who had extrahepatic disease at pretherapy CT and in four of the seven patients who seemed to have tumor limited to the liver. A combination of repeat tumor resection and adjuvant chemotherapy resulted in prolonged tumor-free survival in some cases. Fibrolamellar HCC frequently demonstrates aggressive local invasion and nodal and distant metastases. Pretherapy and follow-up imaging are important for staging, surveillance, and optimal management. Aggressive surgical resection may be helpful to control fibrolamellar HCC and to prolong survival in appropriately selected cases.

Cytologic aspect of fibrolamellar hepatocellular carcinoma in fine-needle aspirates.

This is a review of the cytologic and clinicopathological findings seen in a series of six fibrolamellar hepatocellular carcinomas (FL-HCC) studied by means of fine-needle aspiration (FNA). A comparison of several cellular measurements (cell, nuclear and nucleolar sizes, and N/C ratios) of FL-HCC, ordinary hepatocellular carcinoma (O-HCC), and normal hepatocytes was also carried out in order to find out if these figures could be of help in the cytologic diagnosis. Aspirates were made up of a rather monotonous population of large discohesive cells resembling the morphology of the oncocytes seen in thyroid aspirates; trabecular arrangement of tumor cells was not observed. Cytoplasmic pale bodies and hyaline cytoplasmic bodies were seen in variable quantities. Microbiopsies displaying the fibrolamellar pattern were observed in four cases. FL-HCC individual tumor cells were larger than individual O-HCC tumor cells (P < 0.001), as were nuclear (P < 0.007) and nucleolar sizes (P < 0.001), but N/C ratio of O-HCC was higher than the N/C ratio of FL-HCC (P < 0.005). Based on the findings, a single cell aspirated from an FL-HCC is three times the size of a normal hepatocyte and 1.60 times the size of a single cell aspirated from a well-differentiated O-HCC. The cytologic findings of FL-HCC are very characteristic and permit a correct diagnosis of this liver malignancy, provided the cytopathologist is aware of the clinical, demographic, CT-image, biochemical, and pathological features of this neoplasm. Diagn. Cytopathol. 21:180-187, 1999.

Immunohistochemical expression of metallothionein in resected hepatic primary tumors and colorectal carcinoma metastases.

Metallothionein is a protein with affinity for metals and is present in several tumors. We examined its immunohistochemical expression in 37 resected primary liver tumors and 117 colorectal metastases. The reaction was intense in the two fibrolamellar hepatocellular carcinomas and in many of the hepatocytes of the pseudotumor case of focal nodular hyperplasia. The reaction was low or moderate in 5 of 17 ordinary hepatocellular carcinomas and in 4 of 14 cholangiocellular carcinomas. There was no reaction in one case each of spindle cell hepatocellular carcinoma, oncocytic adenoma and hemangioendothelial sarcoma. In the metastases, the reaction was low or moderate in 14 cases and negative in 103. Surrounding hepatocytes and stromal cells were more or less positive in all cases.

Diagnostic and prognostic value of the determination of the aminopropeptide of type III procollagen in patients with primary liver cancer

Hepatic fibroplasia seems to play an important role in the course of primary liver cancer (PLC) since, for instance, encapsulated and fibrolamellar hepatocellular carcinomas show a definitely better prognosis. In this study, serum procollagen III amino-terminal peptide (PIIIP) levels, which reflect synthesis and release of procollagen type III, were measured with the aim of assessing hepatic fibrogenesis in PLC patients and determining whether serum PIIIP levels play a diagnostic or prognostic role in PLC. Twenty-five patients with PLC, 74 patients with cirrhosis and 38 healthy volunteers were studied. Serum PIIIP levels were determined by a radioimmunoassay (RIA) method. In PLC patients PIIIP serum levels were significantly higher than those of controls and cirrhotic patients (P less than 0.001 and P less than 0.01 respectively) but an analysis of individual values showed an important overlap between PLC and cirrhosis. No correlation was found between serum PIIIP levels and tumour histology, presence or absence of cirrhosis, Child status, possible aetiology of the disease, indices of hepatocellular inflammation, cholestasis and synthesis, or tumour markers. On the contrary, serum PIIIP levels correlated with tumour gross pattern (z = 3, P less than 0.001) and, inversely, with survival (r = 0.659, P less than 0.01), patients with serum PIIIP over 25 ng/mL showing a significantly worse prognosis. These data confirm that hepatic fibroplasia plays an important, but not yet fully understood, role in the course of PLC. From the clinical point of view, PIIIP determination does not add to the differential diagnosis between PLC and cirrhosis but helps to identify patients with larger liver replacements and worse prognoses.

MR imaging of hepatic focal nodular hyperplasia: characterization and distinction from primary malignant hepatic tumors.

Spin-echo MR imaging at 0.35 T was used to image hepatic focal nodular hyperplasia (FNH) and to attempt to distinguish it from primary malignant hepatic tumors. There were six FNH and 10 malignant tumors including seven hepatocellular carcinomas, two cholangiocarcinomas, and one hepatoblastoma. Our results show that FNH has a fairly consistent appearance, dissimilar from that of malignant primary hepatic tumors. Four of six FNH lesions were isointense (except for a central scar in three) and indistinguishable from normal hepatic parenchyma on all pulse sequences, whereas two of six were homogeneous but slightly hyperintense on T2-weighted sequences. Furthermore, a central hyperintense scar was seen in three of six lesions on T2-weighted sequences. In contrast, each of the malignant primary hepatic tumors was hyperintense on T2-weighted sequences and seven of 10 were hypointense on T1-weighted sequences; in nine of 10, heterogeneous areas of intensity were noted. In two fibrolamellar hepatocellular carcinomas a central scar was seen that was hypointense on all pulse sequences. By using quantitative data, the best characterization was obtained by using lesion/normal-liver intensity ratios from a T2-weighted sequence; all FNH had a ratio less than 1.33, while in nine of 10 primary malignant tumors it was greater than 1.41. We conclude that focal nodular hyperplasia may have a consistent appearance on spin-echo MR imaging and probably can be distinguished from primary malignant lesions in most instances.

Role of Liver Transplantation in Cancer Therapy

Fifty-four patients underwent total hepatectomy and liver replacement in the presence of a primary liver malignancy. In 13 recipients in whom the hepatic tumors were incidental to some other endstage liver disease, recurrence was not seen and 12 of the 13 patients are alive after 4 months to 15 1/2 years. In contrast, tumors recurred in 3 of every 4 patients who received liver replacement primarily because of hepatic malignancies that could not be resected by conventional techniques of subtotal hepatectomy and who lived for at least 2 months after transplantation. The most encouraging results were in patients with the fibrolamellar hepatocellular carcinomas that grow slowly and metastasize late, but even with this lesion, the recurrence rate was 57%. In future trials, additional effective anticancer therapy will be needed to improve the results of liver transplantation for primary liver malignancy, but what an improved strategy should be has not yet been defined.

Fibronectin patterns in hepatocellular carcinoma and its clinical significance

Fibronectin, a high molecular weight glycoprotein component of the extracellular matrix, was localized extracellularly and intracellularly in the nuclei and the cytoplasm of hepatocellular carcinomas (HCC) by the use of the biotin-avidin method on paraffin-embedded, pepsin-treated tissue. The specificity of the staining was confirmed by absorbing the antibodies with purified fibronectin. Twenty HCC were investigated (7 were autopsy specimens and 13 biopsy and surgical specimens). The fibronectin was either increased or decreased. When increased the fibronectin consisted of thin or thick feathery strands and was either pericellular, sinusoidal, periglandular, or stromal. Marked increase of fibronectin was seen in fibrolamellar HCC, clear cell HCC, and encapsulated HCC, correlating with the better prognosis. Decreased fibronectin was seen in two undifferentiated HCC. HCC obtained at autopsy displayed nuclear and cytoplasmic fibronectin staining. Nuclear fibronectin may be an expression of the DNA binding ability of fibronectin which becomes demonstrable in cells with increased membrane permeability.