Juei-Low Sung

Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.

The growth rate of 31 asymptomatic hepatocellular carcinomas (diameter less than or equal to 5 cm) discovered in 28 patients by a prospective screening program was determined by real-time ultrasonography over 36-860 days. Except for one tumor that shrank on follow-up, the doubling time ranged from 29 to 398 days, with a median of 117 days, an arithmetic mean of 136 days, and a geometric mean of 110 days. In 17 tumors with more than two measurements, the growth rate remained exponential in nine, declined in growth in seven, and showed an initial lag period in one. Doubling time correlated with initial tumor diameter but was independent of the patients age, sex, hepatitis B surface antigen status, tumor location, liver function tests, stage of liver cirrhosis, histologic type, or grade of malignancy. Although initial alpha-fetoprotein levels did not correlate well with growth rate, in 14 patients with an exponential increase of serum alpha-fetoprotein, the alpha-fetoprotein doubling time was closely related to the tumor doubling time. Based on the above data, the median detectable subclinical period of hepatocellular carcinoma was deduced to be 3.2 yr, and the suitable screening interval for its early detection in our area was 4-5 mo.

Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion.

T cell proliferative responses to hepatitis B virus-encoded envelope antigen (S + preS2 + preS1), recombinant core antigen (HBcAg), and natural hepatitis B e antigen (HBeAg) were examined in 22 HBeAg-positive patients with chronic type B hepatitis and 17 healthy hepatitis B surface antigen (HBsAg) carriers. The results showed that HBeAg-positive patients had (a) higher levels of T cell responses to HBcAg/HBeAg than those of healthy HBsAg carriers (P less than 0.001 and P less than 0.01, respectively); (b) a further increase in these T cell responses during acute exacerbations (P less than 0.05 and P less than 0.05, respectively); (c) subsidence in the T cell responses to HBcAg/HBeAg after recovery from acute exacerbations and HBeAg seroconversion, whereas the responses would persist at high levels if the patients did not enter a clinical remission; and (d) low levels of T cell responses to S + preS2 + preS1 either before or after HBeAg seroconversion. The appearance of increasing T cell responses to HBcAg/HBeAg usually occurred in the early phase of acute exacerbations. These findings imply that HBcAg/HBeAg-specific T cells play an important role in the exacerbations of chronic hepatitis B and in HBeAg seroconversion. HBcAg/HBeAg-specific precursor T cell frequencies were serially studied in selected cases by limiting dilution assay. Elevation (two- to fourfold) of HBcAg/HBeAg-specific precursor T cell frequencies contributed to the increase of HBcAg/HBeAg-specific T cell proliferation during acute exacerbations.

Early detection of hepatocellular carcinoma by real-time ultrasonography. A prospective study

For early detection of hepatocellular carcinoma (HCC), real‐time ultrasonography (US) was performed prospectively in 528 patients, including 236 with cirrhosis, 81 with chronic hepatitis, 168 asymptomatic hepatitis B surface antigen carriers, and 43 with a family history of HCC. Simultaneous measurement of serum alpha‐fetoprotein (AFP) level was also done. In addition, 233 patients had regular controls at 3‐ to 6‐month intervals, with an average follow‐up period of 1.4 years. On initial screening, a total of 17 patients were found to have HCC: 13 in the cirrhotic group, 3 in the HCC family group, and 1 in the asymptomatic carriers. Of these HCCs, 7 were smaller than 3 cm, 6 were between 3 to 5 cm, and 4 were larger than 5 cm. In patients with tumors smaller than 5 cm, the AFP levels were normal in 46.2%, between 20 to 400 ng/ml in another 46.2%, and only 7.6% were over 400 ng/ml. On follow‐up, another seven patients, all in the cirrhotic group, were found to have HCCs varying from 1.6 to 4.7 cm; three of them had normal serum AFP level. The authors conclude that real‐time US is more sensitive than AFP assay in early detection of HCC, and the high‐risk subjects should receive this procedure at regular intervals.

Estimation of Seroprevalence of Hepatitis B Virus and Hepatitis C Virus in Taiwan from a Large-scale Survey of Free Hepatitis Screening Participants

BACKGROUND/PURPOSE Taiwan is a hyperendemic area of liver diseases. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the two major etiologies of liver diseases in Taiwan. This study investigated the seroprevalence of HBV and HCV in Taiwan. METHODS Since 1996, a series of outreach community-based screening programs for liver diseases have been available to the general population aged > or = 18 years. Blood samples were obtained from the subjects and sent for hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) tests. RESULTS The prevalence of HBsAg(+) was 17.3% (27,210/157,720), while the prevalence of anti-HCV(+) was 4.4% (6904/157,720). Geographic variation in HBV and HCV seroprevalence was found, with the highest anti-HCV positive rate in Miaoli County, Chiayi County, Chiayi City, and Yunlin County, and the highest HBsAg positive rate in Keelung City and Yilan City. The HBsAg positive rate progressively decreased after the age of 50 years, while the anti-HCV positive rate progressively increased after the age of 20 years. The estimated total number of HBsAg carriers in the general population > 20 years old is 3,067,307, while the estimated number of anti-HCV positive patients is 423,283. CONCLUSION This study estimated a 17.3% seroprevalence of HBV and a 4.4% seroprevalence of HCV in Taiwan. Significant geographic variations in the seroprevalence of HBV and HCV were found. These data suggest the importance of modifying programs for the prevention and treatment of chronic viral hepatitis in Taiwan to reflect its varying prevalence and epidemiology.

Serum α-Fetoprotein in the Early Stage of Human Hepatocellular Carcinoma

The serum alpha-fetoprotein levels of 17 patients with cancers less than or equal to 3 cm in size were studied using radioimmunoassay to determine alpha-fetoprotein response in the early stage of human hepatocellular carcinoma. The levels were normal in 6 patients (35%), and elevated to 645 +/- 1140 micrograms/L (mean +/- SD) in the remaining patients. The levels were not correlated with tumor size. In 10 surgically resected patients, 5 had elevated levels of alpha-fetoprotein that returned to normal after surgery. The levels and tumor sizes were serially observed for 3-26 mo in the remaining 7 patients not surgically treated. In 1 patient alpha-fetoprotein levels were persistently normal and in the other 6 patients, the levels tended to increase with a median doubling time of 60-75 days (range 30-223 days). Despite continued tumor growth, a spontaneous fall in serum alpha-fetoprotein levels was encountered in 4 patients; in 2 patients the levels even fell within the normal range. After this fall, the levels increased drastically in 4 patients. We concluded that in the early stage of hepatocellular carcinoma, serum alpha-fetoprotein level is frequently normal, and thus determination of serum alpha-fetoprotein levels only is not a reliable indicator in the early detection of human hepatocellular carcinoma. A spontaneous fall in the level of alpha-fetoprotein is not an uncommon finding in the early stages of this cancer and cannot be used to rule out the diagnosis of hepatocellular carcinoma.

Local radiotherapy with or without transcatheter arterial chemoembolization for patients with unresectable hepatocellular carcinoma

PURPOSE To evaluate the treatment outcome, patterns of failure, and prognostic factors for patients with unresectable hepatocellular carcinoma (HCC) treated with local radiotherapy alone or as an adjunct to transcatheter arterial chemoembolization (TACE). METHODS AND MATERIALS From March 1994 to December 1997, 25 patients with unresectable HCC underwent local radiotherapy to a portion of the liver. Twenty-three patients were classified as having cirrhosis in Child-Pugh class A and 2 in class B. Mean diameter of the treated hepatic tumor was 10.3 cm. Mean dose of radiation was 46.9 +/- 5.9 Gy in a daily fraction of 1.8-2 Gy. Sixteen patients were also treated with Lipiodol and chemotherapeutic agents mixed with Ivalon or Gelfoam particles for chemoembolization, either before and/or after radiotherapy. Percutaneous ethanol injection therapy (PEIT) was given to one patient. All patients were monitored for treatment-related toxicity and for survival and patterns of failure. RESULTS In a median follow-up period of 23 months, 11 patients were alive and 14 dead. The median survival duration from treatment was 19.2 months with a 2-year survival of 41%. Only 3 of 25 patients had local progression of the treated hepatic tumor. The recurrences were seen within the liver or extrahepatic. The 2-year local, regional, and extrahepatic progression-free survival rates were 78%, 46%, and 39%, respectively. The local control ranked the highest. Patients with Okuda Stage I disease had significantly longer survival than those with Stage II and III (p = 0.02). Patients with T4 disease (p = 0.02) or treated with radiotherapy alone (p = 0.003) had significantly shorter survival. T4 disease (p = 0.03) and pretreatment alpha-fetoprotein level of more than 200 ng/ml (p = 0. 03) were associated with significantly worse regional progression-free survival. A significant difference was observed in both regional progression-free survival (p = 0.0001) and extrahepatic progression-free survival (p = 0.005) between patients with and without portal vein thrombosis before treatment. The presence of satellite nodules had a significantly worse impact on regional progression-free survival (p = 0.04) and extrahepatic progression-free survival (p = 0.03). Patients with hepatic tumor more than 6 cm in diameter or portal vein thrombosis tended to have shorter survival. Radiation-induced liver disease (RILD) and gastrointestinal bleeding were the most common treatment-related toxicities. CONCLUSION Radiotherapy is effective in the treatment of patients with unresectable HCC. Its effect appeared to be more prominent within the site to which radiation was given. The combination of TACE and radiation was associated with better control of HCC than radiation given alone, probably due to the selection of patients with favorable prognosis for the combined treatment. A dose-volume model should be established in the next phase of research in the treatment of unresectable HCC.

Serum alphafetoprotein in hepatocellular carcinoma.

The serum alphafetoprotein level (AFP) was studied in 125 histologically verified cases of hepatocellular carcinoma, 66 other malignancies, 74 cases of cirrhosis of the liver, 60 of chronic aggressive hepatitis, 12 of chronic persistent hepatitis, 16 of subacute hepatitis, 36 of acute viral hepatitis, and 13 healthy hepatitis B‐surface antigen (HBsAg) carriers. Double immunodiffusion and radioimmunoassay (RIA) were used in all cases. AFP greater than 10 ng‐ml appeared in 90% of the cases, and was above 400 ng/ml in 69%. In 80% of those above 400 ng/ml, AFP could also be demonstrated by immunodiffusion. The AFP level in hepatocellular carcinoma was discovered to decline as the age increased. It also appeared to be related to the tumor cell type; the relatively immature cell type was more frequently associated with a higher AFP level. The presence of HBsAg did not influence the AFP level. Although the AFP in other malignancies and liver diseases ranged abnormally from 14 to 69%, the level did not exceed 400 ng/ml as in our cases of hepatocellular carcinoma (except in one case). Thus, this figure provides a diagnostic serum level of AFP for the identification of hepatocellular carcinoma. Cancer 40:779–783, 1977.

Small Hepatocellular Carcinoma—A Clinicopathological Study in Thirteen Patients

Abstract To investigate the diagnosis and clinicopathological features of hepatocellular carcinoma at its early stage, 13 patients with carcinoma ≤3.0 × 3.0 cm in size (small hepatocellular carcinoma) were studied with radionuclide scan, celiac arteriography, computed tomography, ultrasonography, and peritoneoscopy. Most of the patients were found from prospective studies in hepatoma high-risk subjects and were asymptomatic, with liver tests showing only mild abnormalities. Hepatitis B surface antigen was positive in all except one who was hepatitis B core antibody positive. Serum α-fetoprotein level was normal in 3 patients and in the remaining patients it increased to an extent far lower than in patients with advanced hepatocellular carcinoma. For detecting small tumors, ultrasonography, computed tomography, and celiac arteriography were superior to radionuclide scan or peritoneoscopy (detection rate: 95%, 94%, 89% vs. 16%, 12%, respectively). Small hepatocellular carcinoma was characterized as a hypoechoic shadow with weak internal echoes on ultrasonography, hypodense lesion on computed tomography, and hypervascular stain in angiography. None of these three examinations detected all the tumors in every patient and thus at least two of the three examinations should be done to avoid missing any tumor. Among them, the real-time ultrasonography was most practical for localizing small hepatocellular carcinoma and the diagnosis could be confirmed by ultrasound-guided biopsy. Ultrasonography was indispensable for identifying the small tumor during laparotomy in 3 patients. Ten patients had a single tumor. The small tumors were resected successfully in 10 patients. The tumor was frequently surrounded by a thin fibrous capsule and the most common cell type was of the trabecular pattern.

Clonal origin of recurrent hepatocellular carcinomas.

Recurrence of hepatocellular carcinoma after treatment is frequent. To study the clonal origin of the recurrent tumors, we examined five pairs of hepatocellular carcinomas resected from individual hepatitis B surface antigen carriers. Using integrated hepatitis B virus DNA as a marker, tumor clonality was determined by Southern blot analysis. In 2 cases the second tumor contained the same integrated viral DNA as the first one. In the other 3 cases, the clonality of the second cancer differed. We conclude that recurrent hepatocellular carcinomas originate from the first tumor in some cases but represent de novo neoplasms in others.

Transplacental leakage ofHBeAg-positive maternal blood as the most likely route in causing intrauterine infection with hepatitis B virus

Thirty-two HBeAg-positive carrier mothers and their 32 babies were investigatedto elucidate the mechanism involved in intrauterine infection with HBV. Five mothers had symptoms and signs of threatened abortion and/or threatened preterm labor. Three mothers gave birth more than 6 weeks after the episodes, and their babies were those infected in utero. The other two gave birth within 1 week after the episodes, and the two babies were treated with HBIG immediately after birth; HBV infection was successfully prevented. Therefore we suggest that transplacental leakage of HBeAg-positive maternal blood, which is induced by uterine contractions during pregnancy and the disruption of placental barriers, is the most likely route to cause HBV intrauterine infection.