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Morphometric, immunohistochemical, and electron-microscopic studies were undertaken in an attempt to identify the types of hepatoblastoma cellular elements responsible for the synthesis of alpha-fetoprotein (AFP), and to see how they may relate to serum AFP levels and the metastatic spread and prognosis of the hepatoblastoma. Morphometric studies of 21 hepatoblastomas with statistical treatment of the results revealed a moderately strong reliable correlation of the AFP serum titer with the volume ratio of embryonal tumor cells and with that of those tumor elements of endodermal hepatic diverticulum which are similar to the latter cells with regard to degree of differentiation. Also, a consistent, reliable negative correlation was demonstrated between serum AFP titer and the volume of fetal hepatoblastoma cells. The volume ratio of stromal elements was found to be subject to chance variations and not to correlate with serum AFP level. Immunohistochemical and electron-microscopic studies confirmed the morphometric findings and showed AFP synthesis to be effected by poorly differentiated hepatoblastoma cells--by endodermal hepatic diverticulum elements at first and by embryonal and intermediate tumor cells later--and to decrease as the liver tumor cells differentiate further. It is concluded that a high serum AFP level is, generally, an indication that the hepatoblastoma is an extensive one and consists of poorly differentiated cells so that the prognosis is unfavorable.

The value of ultrasonography and serum alpha foetoprotein assay in the detection of hepatocellular carcinoma was evaluated in a retrospective study of 217 patients, (135 men and 82 women; mean age 58 years) who had been hospitalized for 18 months. Cirrhosis was of alcoholic origin in 76 per cent of the cases and complicated by ascites in 54 per cent. Twenty-four patients (11 per cent) had hepatocellular carcinoma diagnosed at ultrasonography in 20 cases. The carcinoma was diffuse in 7 cases, focal in 13 cases and less than 3 cm in diameter in 3 cases. A second ultrasonography diagnosed hepatocellular carcinoma in 4 cases. In 25/217 patients (11.5 per cent) the focal lesion seen at sonography was obviously not a carcinoma. Among the 207 patients who had a serum alpha foetoprotein assay, the result was normal in 167 (81 per cent) and 4 of these had a carcinoma. Among the 40 patients with an abnormal level of alpha foetoprotein, 19 had a carcinoma. This study confirms the good sensitivity of ultrasonography in the detection of hepatocellular carcinoma, but it also shows its low specificity, especially in cases with focal lesions. Ultrasonography and serum alpha foetoprotein assay should be used to detect hepatocellular carcinomas in cirrhotic patients who may benefit from surgical treatment. In the other patients, ultrasonically-guided biopsy should provide a firm diagnosis of carcinoma before undertaking other treatments, such as chemoembolization.

Of the 118 patients with primary liver cancer treated in our clinic during a 6 year 7 month period, 11 patients had cholangiocellular carcinoma of the liver. Ten (90.9 percent) of the 11 patients underwent surgery, and 9 (90 percent) had major hepatic resection with no operative deaths. Seven were still alive at the time of the study 2 months to 4 years 1 month after surgery. Three patients died from recurrence 9 months, 11 months, and 1 year 4 months after surgery. The 1 and 3 year actuarial survival rates after hepatic resection were excellent (85.7 and 61.2 percent, respectively) compared with the 1 and 3 year rates of 58.8 and 0 percent in the Japanese series. Even though the cholangiocellular carcinomas in our 11 patients were in the advanced stages, good results were obtained by hepatic resection. If they were detected at a much earlier time, an even more remarkable survival rate could be expected.

Des-gamma-carboxy prothrombin [DCP], a protein induced by vitamin K absence or antagonist-II and also abbreviated PIVKA-II, was evaluated as a serologic marker for hepatocellular carcinoma (HCC). Its plasma levels were measured by enzyme immunoassay (E-1023) using an anti-DCP monoclonal antibody in 514 patients with various diseases. Of 120 patients with HCC, 76 (63%) had abnormal DCP levels greater than 0.1 arbitrary unit (AU)/ml and 58 (48%) showed levels greater than 0.3 AU/ml. When a diagnostic minimum level of 0.3 AU/ml was applied for DCP, false-positive cases of HCC were virtually eliminated. In some patients with HCC, plasma DCP levels normalized after surgical resection of the tumor. However, they rose again later with recurrence of the disease. The sensitivity of DCP in the diagnosis and monitoring of HCC was increased by serial and simultaneous determinations of alpha-fetoprotein (AFP), because high DCP levels were observed more often in low AFP-producing HCC patients. Elevated plasma DCP levels were not related to low vitamin K concentration in the serum. In fact, in many patients vitamin K administration resulted in only a moderate reduction of DCP levels. These results suggested strongly that DCP was synthesized by the hepatoma cells.

The incidence of epi-cirrhotic liver carcinoma is apparently on the increase. Between 1969 and 1973 there were 84 cases of primary liver carcinoma and 467 of cirrhosis among 10211 autopsies. In 74 (16%) the carcinoma had developed in a cirrhotic liver. Clincally the diagnosis of carcinoma had been made in only 14 cases. The mean survival time after the diagnosis was seven weeks, after onset of the terminal symptoms 13 weeks. Typical clinical features were decompensated, hypertrophic, often coarsely granular, liver cirrhosis. The best diagnostic method was apparently laproscopy and determination of alpha 1-fetoprotein and cholestatic enzymes.

Right hemi-hepatectomy was performed in two patients because of metastases in one and a malignant hepatoma in the other. After five and six months, respectively, a right hepatic lobe was again demonstrated, at first by ultrasound, then by isotope scanning. Further studies by coeliacography, 99Tc hepatobida, CT scan and liver-biopsy histology from the regenerated lobe revealed a functionally and morphologically normal picture of a right hepatic lobe, the external form of the regenerated right lobe being identical with the original one. A histologically and functionally unchanged residual liver is considered the prerequisite for satisfactory regeneration after resection. Liver regeneration, as far as regulating factors are concerned, seems to be under similar hormonal control mechanism as external wound healing.

By means of polyacrylamide gel stage electrophoresis designed by us, serum gamma-glutamyl transferase (GGT) and alkaline phosphatase (ALP) were separated into 9 (I to IX) and 7 (I to VII) isoenzyme bands. The GGT II and ALP I were found only in the sera of patients with primary hepatic carcinoma showing positive rates of 29.5% and 8.5%, respectively. The combined positive rate of the two kinds of isoenzymes was 36.2% which is lower than that of alpha-fetoprotein (AFP) in the liver cancer but it has a higher specificity compared to the latter test. Furthermore, positive GGT II and ALP I may also be present in patients with liver cancer who were negative for AFP. It is obvious that the simultaneous determinations of GGT II, ALP I and AFP are mutually supplementary in the diagnosis of liver cancer.

Five children with primary hepatic malignancies were treated with continuous infusions of doxorubicin administered as a single agent every 3-4 weeks. Four of five children showed positive response to therapy, manifested by decreasing tumor size and/or tumor markers; the fifth child had stable disease for 4 months. Side effects included mild nausea and vomiting and myelosuppression. No evidence of cardiotoxicity was seen with cumulative doses up to 720 mg/m2.

The appearance and clinical significance of an atypical fraction of serum alkaline phosphatase called "biliary" have been evaluated in patients with primary liver cancer (PLC) and control subjects. The "biliary" fraction was present in all 42 PLC patients and proved to be the most sensitive of the biochemical parameters utilized. The association with alpha-fetoprotein determination allowed us to identify patients affected by hepatic pathology of neoplastic type, with a diagnostic efficiency of 92%.

Increasing attention has been focused recently upon those factors in carcinogenesis that are responsible for the proliferation of initiated cells and the increasingly aberrant phenotype that they progressively manifest. The agouti locus allele Avy (viable yellow) has been shown to be associated with conditions which favor promotion of cells that have been initiated by a wide variety of causes, in many organs, but has not been previously associated with tumor progression in those systems. In the current study, the presence of the Avy gene in a strain of mice not normally predisposed to hepatocarcinogenesis, C57BL/6N was, for the first time, associated not only with much earlier appearance, but with progression of the histiotype of hepatic tumors, following neonatal administration of diethylnitrosamine. At 52 weeks, 28 C57BL/6N mice demonstrated 7 mouse liver tumors 0.5 cm or greater in diameter, all of more benign histiotype, without associated metastasis. The 31 C57BL/6N-Avy demonstrated 194 mouse liver tumors at that time, 22% of which were of malignant histiotype, 19% of which were associated with metastasis. This system would appear to offer the possibility of identifying the underlying mechanisms for components of the carcinogenic process. In addition, the C57BL/6N-Avy mouse appears to offer advantages as a test animal in bioassay procedures that use the liver as a target organ. Thus, it represents a mouse with little or no spontaneous predisposition to hepatocarcinogenesis, with a predicted short lag period toward response to hepatocarcinogens.

This paper describes a 50-year-old woman with an unusual malignant tumour of the liver. Poorly differentiated liver cells, tubular structures and spindle cells in abundant intercellular ground substance characterized the tumour. Extremely high serum concentration of alpha-fetoprotein was present. The spindle cells showed strong immunoreactivity against this antigen and vimentin. Both the spindle and epithelial cells showed negative immunoreactivity against desmin, epithelial membrane antigen and keratin. Markers for low molecular cytokeratin (MAK-6, CAM 5.2) were demonstrated in both cell types. Ultrastructurally the neoplastic epithelial cells showed frequent intercellular spaces and well-formed brush borders suggestive of differentiation towards hepatocytes and bile duct epithelium. The immunohistological findings established the epithelial nature of the spindle cells thus distinguishing the tumour from hepatoblastoma.

Transcatheter embolization of the hepatic artery for hepatomas was performed with the use of Gelfoam and Lipiodol-ADM in 98 patients (Gelfoam 63 patients; Lipiodol-ADM 35 patients). The cumulative one-year survival rate was 52.9% for the Gelfoam group and 28% for the Lipiodol-ADM group. Response to hepatic embolization was most remarkable in the nodular type; CR was obtained in five patients and PR in 31 patients (response rate: CR + PR = 57.1%) in the Gelfoam group, with no CR and six PRs (response rate, 17.6%) in the Lipiodol-ADM group. Alfa-feto protein (AFP) decrease of more than 50% was observed in 78.1% of the Gelfoam group and 40% of the Lipiodol-ADM group. The side effects were transient and controlled with conservative treatment. Gelfoam seemed to be more effective in the treatment of hepatoma, but the damage to normal tissue was more severe with this embolic material.

During hepatocarcinogenesis by N-2-fluorenylacetamide, the hormonal status of male Sprague-Dawley rats is modified. The testes present a reduced activity which is evidenced by a decreased spermatogenetic activity accompanied by a drastic decrease of the plasma testosterone level. In contrast, plasma progesterone and estradiol-17 beta levels were not modified despite the 80 fold augmentation of alpha-fetoprotein, an estrogen binding protein synthesized during liver carcinogenesis.

In two children with hepatoblastoma, response to chemotherapy permitted subsequent surgical resection. Initially, in both patients, the tumor was thought to be unresectable because of size and/or extent. Chemotherapy with vincristine sulfate and cyclophosphamide resulted in substantial reduction in tumor size, and laparotomy for excision was performed after nine months and four months of therapy, respectively. In case 1, the tumor was localized in the right hepatic lobe and the right hepatic lobectomy was performed. In case 2, the tumor was located in both right and left lobes, but was encapsulated and it was possible to enucleate the tumor with complete gross excision. Both children are living and well without evidence of recurrence of tumor 11 and 23 months after operation.

The selective and long-term deposition of iodized oil in the hepatocellular carcinoma (HCC) and its gradual drainage were clinicopathologically analyzed in 13 cases. All patients were Japanese and had an intrahepatic arterial injection of Lipiodol (LIP) mixed with Mitomycin C. The comparison among the follow-up computerized tomography (CT) findings, the observation of the soft x-ray radiogram, and histopathologic studies of the surgical or autopsy materials revealed that the selective deposition of LIP in HCC lasted for a long term, particularly in cases treated by LIP combined with transcatheter arterial embolization (TAE). Also revealed was an extremely gradual decrease of LIP from the HCC. It was thus postulated that, mainly, the accumulated macrophages surrounding LIP around the necrotic cancer tissue and, partially, the intrahepatic lymphatic system itself contributed to this drainage. Further, in histologic sections with lipid staining, x-ray microanalysis proved that the lipid droplets in the cancer tissue included highly concentrated iodine, as a deposition of LIP.

Membranous obstruction of the inferior vena cava has been incriminated as a risk factor for hepatocellular carcinoma in South African Blacks and in Japanese. However, the frequency with which this anomaly is found in patients with hepatocellular carcinoma, and hence its numerical importance as an etiological association of the tumor, has not been ascertained. Using radionuclide and contrast venography as well as necropsy and laparotomy examination, we investigated 162 unselected southern African Blacks with hepatocellular carcinoma together with appropriate controls for the presence of membranous obstruction of the inferior vena cava. Membranous obstruction of the inferior vena cava was detected in six of 162 (3.7%) hepatocellular carcinoma patients, compared with one of 279 subjects (0.36% p = 0.011) dying a violent death, none of 55 patients (p = 0.169) with malignant disease other than hepatocellular carcinoma and eight of 150 patients (5.3%; p = 0.336) being investigated for conditions which might have been associated with membranous obstruction of the inferior vena cava. Six of the 15 individuals (40%) found to have membranous obstruction of the inferior vena cava had concomitant hepatocellular carcinoma, confirming that membranous obstruction of the inferior vena cava constitutes a risk factor for the development of the tumor. However, only a very small proportion of hepatocellular carcinoma patients have this abnormality, so that it is a minor causal association of the tumor only.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors describe two cases of hepatocellular carcinoma presenting with the initial manifestations of an intracranial mass lesion without any symptoms or signs suggestive of the primary hepatic site of the tumor. The only clue of hepatic dysfunction was mild elevation of the SGOT and SGPT. The diagnosis could not be made until operation. It is unusual for the initial clinical presentation to be related to intracranial metastasis without evidence of hepatic involvement. Measurement of the serum alpha-fetoprotein and liver ultrasound examination are the most helpful screening tools for diagnosing hepatocellular carcinoma. The literature of hepatoma with cranial metastasis is reviewed.

The clinical significance of serum ferritin as a serological marker of hepatocellular carcinoma (HCC) was studied. Fasting serum ferritin levels were measured in 343 patients with diseases of the liver, using a radioimmunoassay ferritin kit. Elevated ferritin levels were obtained in various liver diseases but hyperferritinemia could be more clearly interpreted by classifying ferritin levels according to serum iron or transaminase values. Significantly higher values were obtained in HCC than liver cirrhosis. Sensitivity for diagnosis of HCC increased by serial and simultaneous determinations of ferritin and alpha-fetoprotein because high ferritin levels were observed more often in low alpha-fetoprotein-producing HCC and also in HBsAg negative, alcohol related, small-sized HCC. Therefore, simultaneous determination of alpha-fetoprotein and ferritin seems to be useful for detection of HCC in high risk patients such as those with liver cirrhosis.

The expression of the alpha-fetoprotein (AFP) gene in hepatocellular carcinoma (HCC) and liver cirrhosis by in situ hybridization analysis of AFP mRNA in cryostat and paraffin-embedded tissue sections was studied. In HCC sections the majority of tumor cells showed positive hybridization with a 3H-labeled AFP complementary DNA probe. The number of radioactive hybrid grains detected in HCC sections generally paralleled the level of serum AFP in the patient. In liver cirrhosis sections a small number of cells showed positive hybridization. These cells were dispersed in the tissue and morphologically indistinguishable from surrounding hepatocytes. Each of these cells contained a high level of hybridization signals to permit easy identification. In situ hybridization analysis of AFP mRNA may be of use in detecting preneoplastic cells in liver cirrhosis that cannot be defined on the morphologic and immunohistochemical basis.

To determine the frequency of hepatocellular cancer in corticosteroid-treated severe autoimmune chronic active hepatitis and to identify risk factors for its development, 124 patients who were selected by uniform criteria, treated comparably and followed systematically for 111 +/- 6 months were evaluated. Hepatocellular cancer was diagnosed in three patients (2%) after 66, 99 and 174 months of observation, respectively. The incidence of hepatocellular cancer was 1 per 350 patient-years of follow-up. All three patients with hepatocellular cancer had cirrhosis for at least 5 years. The frequency of neoplasm in patients with cirrhosis of at least 5 years' duration was 7%. The incidence of hepatocellular cancer in these patients with cirrhosis was 1 per 182 patient-years of follow-up, and the probability of tumor was 29% after 13 years. Late elevation of the serum alpha-fetoprotein level was associated with the presence of neoplasm but normal levels did not exclude the diagnosis. We conclude that patients with corticosteroid-treated severe autoimmune chronic active hepatitis are at risk for hepatocellular cancer. This risk is greatest in patients with cirrhosis for at least 5 years. Such patients are candidates for cancer surveillance.

Following reports that specific estrogen receptors could be detected in samples of hepatocellular carcinoma tissue, a prospective randomized controlled trial was undertaken in 59 patients, half of whom received doxorubicin (60 mg/m2 at 3-week intervals) and half doxorubicin and tamoxifen (10 mg twice per day). Response occurred in three (11%) of those patients receiving doxorubicin alone and in four (16%) of those given both drugs. This difference was not statistically significant nor was the difference in survival when compared by life-table analysis. One patient treated with both drugs achieved complete remission for 30 months which was maintained (on tamoxifen alone) for 18 months before death from a non-tumor-related condition. Tamoxifen may have a role in maintenance of doxorubicin-induced remissions.

The accuracy of ultrasound (US) and alpha-fetoprotein (AFP) in the diagnosis of hepatocellular carcinoma (HCC) in 363 patients with cirrhosis (C) and a clinical suspicion of HCC was assessed. The ultrasonographic patterns of HCC and their relationship with AFP values were analyzed. Echographic patterns were distributed as follows: 47 patients had sonodense lesions; 30 patients had hypoechoic lesions; 47 had mixed-pattern lesions, and in four patients focal dilated intrahepatic bile ducts were demonstrated. The sensitivity of US was 90%; specificity was 93.3%. Serum AFP level greater than or equal to 500 ng/ml (RIA) was the first clue to the diagnosis in 71 patients (48.6%); specificity was 100%. In 28 patients AFP levels became significantly elevated during follow-up after US detection of HCC. No relationship between echo pattern and serum AFP levels was demonstrated. An algorithm for diagnosis of HCC is proposed.

Geographic area, age and sex influence the epidemiology of hepatoma. Aetiological factors are aflatoxins, sex hormones, thorotrast, alpha 1-antitrypsin deficiency, immunosuppression, vinylchloride, parasites, cirrhosis of the liver, and the hepatitis-B virus. Early diagnosis of the tumour is possible using alpha 1-fetoprotein estimations and modern morphological methods, particularly scintiscanning. Tumour resection is therapeutically desirable, while selective chemotherapy remains palliative and liver transplantation failed to prolong survival.

Seric alfa-FP has been studied in acute and chronic hepatitis and in hepatocellular carcinoma. Sixty five normal subjects, 62 cirrhoses, 10 active chronic hepatitis, 12 chronic persistent hepatitis, 4 primary biliary cirrhoses and 9 hepatomas have been examined for seric alfa-FP. Abnormal seric alfa-FP (> 10 ng/ml) values agree with literature data. It is likely that hepatocellular regeneration due to viral or inflammatory disorders, can produce formation of alfa-FP and other abnormal proteins fro a depression mechanism of sue regulator gene.

During chemical carcinogenesis by N-2-fluorenylacetamide, the hormonal status of female Sprague Dawley rats is largely modified. Thyroids present a modified activity which is evidenced by the histological study as well as T4 and T3 assays. In hypophysis, thyrotropic cells were found in an hyperactive state, a fact which is in agreement with the changes observed in thyroid follicles size and epithelial cells demonstrating an hyperactivity of thyroid glands. Despite this histological result, T4 serum level was lowered. T3 level was also decreased but to a lesser extent. We suggest that the low thyroid hormone level play a role in the relative protection of females versus males toward liver cancer induction by chemicals.

During the last 5 years, radical hepatic resection was performed in 91 patients with hepatocellular carcinoma (HCC). Thirty-one of them had tumour recurrence in the remaining liver during the follow-up period. Second hepatic resection was carried out on nine of them 4-38 months after the first hepatectomy. The ages of these patients ranged from 39 to 65 years with an average of 53.7. There were six men and three women. Eight patients had underlying cirrhosis of the liver and one chronic active hepatitis. Six patients are alive, four being free of HCC and two with disease, for 15-45 months after the first operation. Two patients died of systemic cancer dissemination. The remaining patient had tumour recurrence in the liver again and died of hepatic failure after the third laparotomy. The survival rate of these nine patients was significantly better than that of twenty-two patients who were treated by other palliative methods. The present result shows that a second hepatic resection is a possible and meaningful method of treatment for the patients with recurrent HCCs in the liver remnant.