Published papers

PURPOSE: To use computed tomography (CT) during arterial portography (CTAP) and CT arteriography to compare the hemodynamic properties of early hepatocellular carcinoma (HCC) with those of small HCC. MATERIALS AND METHODS: Forty-four early HCCs (mean diameter, 1.5 cm) in 37 patients (26 men and 11 women aged 52-74 years; mean age, 59.2 years) were studied. CTAP was performed on 35 early HCCs, CT arteriography on 20, and both studies on 11. CTAP, CT arteriography, or both were performed on 90 small HCCs (mean diameter, 2.0 cm) in 57 patients (44 men and 13 women aged 48-71 years; mean age, 61 years). The findings for small HCC were compared with those for early HCC. RESULTS: CTAP depicted 23 early HCCs as hypoattenuating masses and 12 as isoattenuating. CT arteriography depicted 11 early HCCs as hypoattenuating masses, six as isoattenuating, and three as hyperattenuating. CTAP depicted 85 of 88 small HCCs as hypoattenuating masses and three as isoattenuating. CT arteriography depicted 13 of 14 small HCCs as hyperattenuating masses. CONCLUSION: CTAP, the standard of reference for the detection of small HCC, is not sensitive enough for the detection of early HCC.

The clinical value of radiotherapy for hepatocellular carcinoma (total tumor dose: 50-70 Gy) was evaluated in seven autopsied patients with nine tumors. A partial response as defined by the WHO criteria for chemotherapy was observed in three tumors (33%). Progressive and marked shrinkage of the noncancerous liver tissue within the irradiated field was also observed in all cases. Histological examination revealed viable cancer cells in all cases. These results indicate that local radiotherapy applying 50-70 Gy achieved some clinical benefit, but was not capable of curing hepatocellular carcinoma.

BACKGROUND/AIMS: The survival rate for hepatocellular carcinoma after hepatectomy remains unsatisfactorily low because of the high recurrence rate. The purpose of this study was to elucidate predictive factors for postoperative recurrence of hepatocellular carcinoma. METHODS: Univariate analysis and a multiple regression model were used to retrospectively determine the factors potentially related to recurrence in 98 patients with hepatocellular carcinoma who had undergone curative hepatic resection. RESULTS: DNA diploidy, absence of alcohol abuse, and absence of vascular invasion were determined to be independent favorable predictive factors using a multivariate analysis with Cox's proportional hazards model. A predictive index was developed using these three factors according to the following equation: 1.486 x (O = DNA diploidy or 1 = DNA aneuploidy) + 1.138 x (O = absence or 1 = presence of alcohol abuse) + 0.946 x (O = absence or 1 = presence of vascular invasion). This index was used to classify the patients into two groups with good or poor prognosis. The median time for disease recurrence for the two groups was 24.1 and 9.2 months, respectively (P < 0.001). CONCLUSIONS: The results may be useful in the determination of treatment strategies and postoperative follow-up schedules and in the design and analysis of future clinical trials of therapy for hepatocellular carcinoma.

Human hepatocellular carcinoma (HCC) is characterized by hypervascularity and tumor staining in angiograms, and tumor angiogenesis is considered indispensable for tumor growth. HCC is also characterized by an obvious multistage process of tumor progression. To find out in which stage of human hepatocarcinogenesis angiogenesis occurs, we have carried out a pathological study, of the phenotypic changes in tumor vessels taken from surgically resected liver tumors showing each step of the progression. Eleven early advanced HCCs (advanced HCC component in early HCC nodule, eAd HCC), seven early HCCs (eHCC) and six adenomatous hyperplasias (AH), the non-tumorous liver surrounding each and five normal livers were studied by lectin histochemistry and immunohistochemistry. The sinusoidal endothelial cells from the non-tumorous liver were shown to be negative for UEA-I (Ulex europaeus I), but the endothelial cells from the sinusoidal tumor vessels in advanced HCC components were strongly positive. In AH and eHCC, half the tumors were negative and the other half focally positive. In the early HCC lesion of eAdHCC, the rate of positivity for UEA-I was a little higher than in AH and eHCC but lower than in advanced HCC lesions in eAdHCC. Immunohistochemically, laminin was not detected in the sinusoids in the non-tumorous liver or in the sinusoidal tumor vessels in AH and eHCC. In eAdHCC, however, two early HCC lesions and four advanced HCC lesions were positive. An immunohistochemical examination for muscle actin revealed an increase in arterial tumor vessels in six advanced HCC lesions and one early HCC lesion of eAdHCC. The results indicate the emergence of UEA-I-positive sinusoidal tumor vessels to be most pronounced during the progression from eHCC to advanced HCC, and laminin-positive sinusoidal tumor vessels or actin-positive arterial tumor vessels to emerge mainly in advanced HCC.

Among 92 surgically resected human hepatocellular carcinomas (HCCs) < or = 3 cm in diameter, 23 tumors (25%) grossly showed a nodule-in-nodule appearance indicating stepwise progression of HCC. The central nodules showed destructive growth of HCC, which was less differentiated than the surrounding area histologically, while the surrounding area showed growth of very-well-differentiated HCC with no, or only minimal, destruction of the underlying liver structures. Previously, we proposed the term "early HCC" for HCCs without definite destructive growth, and the nodule-in-nodule lesions described here are considered to be in the transitional stage from early HCC to advanced HCC, and are therefore named early advanced HCC (eAd HCC). DNA cytophotometry was performed in 12 cases of eAd HCC, in which the early HCC component, advanced HCC component and non-tumorous liver tissue showing chronic hepatitis or cirrhosis were analyzed separately. The early HCC component showed a diploid pattern in eight of the 12 cases. The advanced HCC component showed an aneuploid peak in seven cases, and in three of these the peak was detected only in the advanced HCC component and not in the early HCC component. The mean nuclear DNA content was significantly increased from non-tumorous liver to the early HCC component and from the early HCC component to the advanced HCC component. Polyploid cells containing more than 4.8C DNA were exceptional in non-tumorous liver, but were detectable in the early HCC component and increased in number in the advanced HCC component. These findings suggest that DNA instability may have an important role to play in the subclonal progression of human HCC.

All 240 consecutive cases of hepatocellular carcinoma (HCC) that underwent autopsy at the National Cancer Center Hospital (Tokyo, Japan) between September 1962 and August 1986 were reviewed. Among these cases, 162, for which photographs of cut surfaces of the primary tumors were available, were grossly classified using a combination of both Eggel's classification and our own into three major types, i.e., nodular, massive, and diffuse as described by Eggel (Eggel H, Beitr Pathol Anat 1901; 30:506-604), and three subgroups of nodular type, i.e., single nodular type (type 1), single nodular type with extranodular growth (type 2), and contiguous multinodular type (type 3) by our classification (Kanai T et al., Cancer 1987; 60:810-819). Seventy-eight cases were classified as nodular type, comprising seven cases of type 1, 61 cases of type 2, and ten cases of type 3. Sixty-seven and 17 cases were classified as massive and diffuse type, respectively. Of the 78 nodular-type tumors, 59 measured less than 10 cm, whereas 64 of 67 massive-type tumors were 10 cm or more in size. The incidence of intrahepatic and extrahepatic tumor spread of HCC was significantly higher for tumors measuring more than 5 cm. As to the relationship between macroscopic type and tumor spread, the frequency of spread was lowest for type 1 tumors, and high for the other types. Intrahepatic metastasis was detected in 28.6% of type 1, 93.4% of type 2, 100% of type 3, and 98.5% of massive-type tumors. Lymph node metastasis was detected in 14.3% of type 1, 24.6% of type 2, 70% of type 3, 38.8% of massive-type and 52.9% of diffuse-type tumors. Hematogenous extrahepatic metastasis was detected in 14.3% of type 1, 47.5% of type 2, 70% of type 3, 74.6% of massive-type and 82.4% of diffuse-type tumors. It appears that not only primary tumor size but also its macroscopic type has an important influence on the growth and spread of HCC.

To clarify the course of adenomatous hyperplasia (AH) of the liver, 17 patients with 20 biopsy-proven AH nodules were followed clinically for 1-5 years. At the initial biopsy the mean nodular diameter was 10 (SD 4) mm and the relative cellularity [( mean cellularity of AH divided by mean parenchymal cellularity] x 100) 141 (27). The criteria for diagnosis of malignant transformation of AH were both a doubling of nodular volume and changes on imaging. Between 6 and 50 months after biopsy, 9 of the 18 nodules which could still be accurately identified met the criteria for transformation; histological proof of hepatocellular carcinoma (HCC) was obtained later for 7 of these 9 nodules. The product of diameter and cellularity (transformation index) was the strongest predictor of the time to transformation. 9 AH nodules did not undergo transformation--7 did not meet one or both criteria and 2 became undetectable by imaging. Because of the high risk of malignant transformation, it can be concluded that AH is an absolute precursor of HCC. It should therefore be treated as a potential malignant disorder.

Two separate nodular lesions of hepatocellular carcinoma (HCC) were surgically removed from a patient with positive serum hepatitis B surface antigen. Southern blot analysis of DNA from the two separate HCC lesions showed different restriction patterns of integrated hepatitis B virus DNA, indicating their independent origins. The two lesions were composed mainly of poorly differentiated HCC; however, well-differentiated HCC was also observed in the periphery of the lesions. This histological finding is consistent with the multistep and independent development of HCC in each site of the liver.

At the National Cancer Center Hospital in Japan, the total number of surgically treated hepatocellular carcinomas (HCCs) has been increasing steadily and rapidly over the last 10 years, whereas the number of cases positive for hepatitis B surface antigen in sera (HBsAg) has remained almost stable. Thus, the relative percentage of HCC cases with serum HBsAg has shown a marked decrease. In order to examine whether this increased proportion of HBsAg-seronegative patients carries hepatitis B virus (HBV) DNA in the liver, we extracted DNA from the formalin-fixed and paraffin-embedded cancerous and noncancerous liver tissues of 79 patients with HCC. The HCCs examined included 49 specimens resected during a period from 1970 to 1980 and 30 resected in 1986 and 1987. We were able to detect reliably the presence of HBV DNA by dot-blot hybridization. The presence of HBV DNA in liver tissues showed a good correlation with positivity for serum HBsAg in both examined groups. In total, HBV DNA was detected in 81% (21 of 26) of HBsAg-seropositive cases and in only 8% (4 of 53) of HBsAg-seronegative cases, indicating that the increased number of HBsAg-seronegative cases had no HBV involvement. Among these HBsAg-seronegative HCC patients, 89.7% showed a histology of cirrhosis or chronic active hepatitis in the noncancerous liver and 29.1% had a history of blood transfusion. These results suggest an increasing incidence of non-A, non-B hepatitis-associated HCCs in Japan and the possible transmission of factors by means other than blood transfusion.