Kunio Okuda

Natural history of hepatocellular carcinoma and prognosis in relation to treatment. Study of 850 patients

A total of 850 patients with hepatocellular carcinoma seen during the last 8 years were analyzed retrospectively for survival in relation to treatment and disease stage. A new staging scheme based on tumor size, ascites, jaundice and serum albumin was used. Clearly, the prognosis depended on disease stage. The median survival of 229 patients who received no specific treatment was 1.6 months, 0.7 month for Stage III patients, 2.0 months for Stage II, and 8.3 months for Stage I. The median survival of Stage I patients who had hepatic resection (n = 115) was 25.6 months and Stage II patients with resection (n = 42) was 12.2 months. In patients who had a small cancer (≤25% of liver area in size) the median survival was 29.0 months. Survival of the surgically treated patients, which represented a highly selected group, was better than that of medically treated patients of a comparable stage. Median survival of Stage I medically treated patients (n = 124) was 9.4 months, for Stage II (n = 290) 3.5 months, and for Stage III (n = 50) 1.6 months. Medical treatment prolonged survival in Stage II and III patients, but not in Stage I. Transcatheter arterial embolization gave a better survival compared with chemotherapy, whether intra‐arterial bolus administration of mitomycin C, systemic mitomycin C, or oral/rectal tegafur, in Stage II. Among various chemotherapeutic modalities, intra‐arterial bolus injection was superior to systemic chemotherapy in survival in Stage II. In Stage III, chemotherapy improved survival as compared with no specific treatment. The major causes of death were hepatic failure and gastrointestinal bleeding, probably due to the coexistent advanced cirrhosis. These results in survival are much improved over the past reports, and the differences are probably a result of earlier diagnosis and frequent hepatic resections.

Pathology of hepatocellular carcinoma in Japan. 232 Consecutive cases autopsied in ten years.

The pathologic findings of 232 consecutive cases of hepatocellular carcinoma (HCC) autopsied during the past ten years at Kurume, Japan, were analyzed from the point of view of global epidemiology, in relation to clinical feature, and in regard to incidence, age, sex, etiologic factors, size of liver, changes in noncancer parenchyma, gross type of tumor, extrahepatic metastases, intravascular and intraductal growths, cancer cell histology, hepatitis B surface antigen (HBsAg) in hepatocytes and cancer cells, liver cell dysplasia, and frequency and clinicopathologic characteristics of minute HCC. Furthermore, postmortem hepatic arteriography and portography were done in 152 livers for comparison with gross anatomy and celiac angiograms. It was found that: (1) epidemiologicall), HCC in Japan is distinct from that in the West that it is frequently encapsulated, livers are generally small because of frequent and advanced cirrhosis and small cancer, minute HCC, is not uncommon at autopsy, cirrhosis most commonly associated is the one with thin stroma and medium size nodules, and micronodular cirrhosis is very rare despite frequent alcohol abuse; (2) HCC is increasing in incidence; (3) HBsAg is frequently found in parenchyma; (4) liver cell dysplasia is indirectly related to HBsAg with no evidence for premalignancy; (5) the lung is the most frequent site of metastasis but peritoneal dissemination is unusual; (6) intraportal tumor growth is very common and the hepatic vein is less frequently affected; (7) growth in the major bile duct is frequently associated with intraportal growth and clinically presents as obstructive jaundice; and (8) tumor is supplied solely by arteries and celiac arteriograms are closely correlated with gross pathologic findings.

Treatment of gastric fundal varices by balloon-occluded retrograde transvenous obliteration

Although less common than oesophageal varices in portal hypertension, gastric fundal varices carry a higher mortality rate when they rupture. They are less amenable to sclerotherapy. We have developed a minimally invasive balloon‐occluded retrograde transverse obliteration (B‐RTO) procedure to treat gastric fundal varices. B‐RTO involves inserting a balloon catheter into an outflow shunt (gastric‐renal or gastric‐vena caval inferior) via the femoral or internal jugular vein. Blood flow is then blocked by inflating the balloon, and 5% ethanolamine oleate iopamidol is injected in a retrograde manner. The embolized gastric varix subsequentlyl disappears. B‐RTO was performed in 32 patients with gastric varices. Follow‐up endoscopies were performed at intervals of 2–4 months for an average observation period of 14 months. Eradication of the varices has been confirmed in 31 of 32 patients. No recurrence occurred in any patients in the follow‐up period. There were no significant changes in liver function after the procedure. We conclude that B‐RTO is a safe and effective procedure for the treatment of gastric fundal varices.

Natural History of Minute Hepatocellular Carcinoma Smaller Than Three Centimeters Complicating Cirrhosis

Twenty-two patients with cirrhosis and minute hepatocellular carcinoma less than 3 cm in diameter were followed for periods of 6-37 mo without specific treatment. The survival curve drawn by the Kaplan-Meier method showed a 1-yr survival of 90.7%, a 2-yr survival of 55.0%, and a 3-yr survival of 12.8%. The ultrasonic patterns of these masses in the liver were correlated with the size and showed a tendency to change from a low echo pattern to a low periphery and, finally, to a massive pattern. The growth speed calculated from the doubling time for tumor volume varied considerably from case to case with an average of 6.5 +/- 5.7 mo; it also changed in some cases during the observation period. Serum alpha-fetoprotein levels were generally low, rarely assisted in diagnosis, but tended to increase when the mass attained a diameter of greater than 3 cm; sudden acceleration in the rate of increase in alpha-fetoprotein level often coincided with a change of ultrasonic pattern to the massive one.

Percutaneous ethanol injection for the treatment of small hepatocellular carcinoma : study of 95 patients

Abstract Percutaneous ethanol injection (PEI) was applied to 120 lesions in 95 patients with hepatocellular carcinomas (HCC) smaller than 3 cm in the past 6 years. All main target tumours, in 67 patients who had been followed by sonography for more than 6 months after PEI, decreased in size; 28 tumours (41.8%) became undetectable and have remained so until now. The 1‐, 2‐, 3‐, 4‐ and 5‐year survival rates calculated by the Kaplan‐Meier method were 93%, 81%, 65%, 52% and 28% respectively. These survival rates were better than those of patients with HCC smaller than 3 cm who did not receive anticancer treatment (P <0.01). The survival of patients of the Childs A or Childs B status was better than that of those with Childs C disease. Recurrence occurred in areas within the liver different from the original lesion in 34% in one year, 61% in two years and 66% in three years after PEI. PEI was then repeated in 61% of such patients.

Primary liver cancers in Japan

Statistical analyses have been made by the Liver Cancer Study Group of Japan of 4031 cases of primary liver cancers diagnosed at 155 institutes during the period of Jan. 1, 1968–Dec. 31, 1977, based on the questionnaire in the form of individual file. They comprised 2411 cases of hepatocellular carcinoma, 268 of cholangiocellular carcinoma, 58 of the mixed type, 69 of hepatoblastoma, 23 of others, and 1202 cases with only clinical diagnosis. The survey and analyses mostly based on the histology‐proven cases included gross anatomical and histological features of tumors, grades of anaplasia and growth patterns of tumor cells, pathology of noncancerous liver portion, frequency of accompanying cirrhosis or fibrosis, distant metastases, past history, frequency of hepatitis in the past history, frequency of positive HBsAg and anti‐HBs, familial clustering of positive HBsAg tests, age distribution, subjective symptoms, objective signs, serum alpha‐fetoprotein, celiac angiography findings, number of operations performed, kinds of surgical approaches made, extents of hepatic resection, prognosis in terms of survival in relation to various surgical treatments, chemotherapeutic agents used and routes of administration, prognosis as related to the accompanying parenchymal liver disease, and overall survival.

Diagnosis and Clinical Features of Small Hepatocellular Carcinoma With Emphasis on the Utility of Real-Time Ultrasonography: A Study in 51 Patients

The clinical features and usefulness of various methods for diagnosis of small hepatocellular carcinoma, no greater than 5 cm in diameter, were studied in 51 patients. The diagnosis was verified in 28 patients by hepatic resection and in 4 patients at autopsy. The tumor was less than 3 cm in diameter in 23 patients. In 37 patients (72.5%), the tumor was first discovered by real-time linear scan ultrasonography, generally during a routine periodic follow-up examination of patients with chronic liver disease, mostly cirrhosis. Clinically, 62.7% of the patients were asymptomatic, and symptoms in the remainder were not suggestive of carcinoma. Most patients showed only mildly abnormal liver function tests that did not suggest the diagnosis. Serum alpha-fetoprotein level was normal in 25.5%, and it was elevated above 200 ng/ml in only 33.3%. Among the various imaging modalities, ultrasonography had the highest detection rate (92.2%) for these small hepatocellular carcinomas compared with computed tomography (73.2%), scintigraphy (50.0%), and angiography (86.0%). False-positive lesions, however, were also found frequently by ultrasonography, requiring ultrasonography-guided biopsy for differential diagnosis in some of the patients. Routine examination at regular intervals of patients with chronic liver disease using a combination of real-time ultrasonography and alpha-fetoprotein measurement is currently the most effective approach to detecting small hepatocellular carcinoma.

Association of gallbladder carcinoma and anomalous pancreaticobiliary ductal union

A total of 96 patients with gallbladder carcinoma in whom direct cholangiography clearly opacified the pancreaticobiliary ductal union and the common channel, and 65 patients with an anomalous union of these two duct systems at a distance greater than 15 mm from the papilla of Vater (normally less than 4.6 +/- 2.2 mm, mean +/- SD) were studied. It was found that this anomalous ductal union occurred in 16.7% of the patients with gallbladder carcinoma in comparison with an incidence of 2.8% among 641 consecutive patients with various hepatobiliary and pancreatic diseases studied by endoscopic retrograde cholangiopancreatography who did not have gallbladder carcinoma. It was also found that gallbladder carcinoma occurred in 24.6% of the 65 cases of anomalous ductal union in comparison with a 1.9% incidence of this cancer among 635 consecutive patients similarly studied and found to have normal ductal union (p less than 0.001). Thus, a close etiologic association was suggested between this anomaly in the terminal segment of the biliary tract and gallbladder carcinoma. Of the 65 patients with anomalous ductal union, 50 had the so-called congenital cystic dilatation of the common bile duct and 15 did not. Five of the 50 (10%) and 11 of the 15 (73.3%) had gallbladder carcinoma (p less than 0.01), and this carcinoma seems to be related to anomalous ductal union rather than to cystic dilatation of the common bile duct. As a tumorigenic factor in this anomaly, regurgitation of pancreatic juice has been stressed.

Nonsurgical, percutaneous transhepatic cholangiography—Diagnostic significance in medical problems of the liver

Percutaneous transhepatic cholangiography has been carried out from the right flank on 314 patients with hepatobiliary disease, using a very thin needle. Practically no complication has been encountered in 80 cases with medical problems of the liver. In contrast, such complications as bile leakage, bleeding, shock, fever, and blood pressure drop were experienced in patients with biliary obstruction and stones, though less frequently than reported. The intrahepatic bile ducts were visualized in 67.5% of the patients with no to minimal dilatation, and this high success rate is accounted for by the policy of injecting contrast medium instead of suctioning bile in search of an intrahepatic duct. This technique has proved of value in the diagnosis of intrahepatic cholestasis, inflammation or infection of the bile ducts, space-occupying lesions of the liver, and in elucidating the cause of biliary colics. It sometimes provides unexpected information. It may also serve the same purpose as portography and hepatic arteriography, since these vessel systems run together with the bile duct.

Incidence of portal vein thrombosis in liver cirrhosis

Portal vein thrombosis was thought to be a common complication of liver cirrhosis in the past. The incidence of angiographically demonstrable portal vein thrombosis was studied in 708 consecutive patients with unequivocal cirrhosis seen in the past 10 yr in whom either transhepatic portography or superior mesenteric arterial portography clearly delineated the major portal vein system. Excluding 2 cases that were thought to be associated with past splenectomy, there were 4 cases of portal vein thrombosis related to cirrhosis, all in a decompensated stage. The calculated incidence of portal vein thrombosis was 0.573% of all cirrhotic patients without splenectomy in the past. They constituted 23.5% of the 17 cases of extrahepatic portal vein obstruction encountered during the same period. There were 78 cases of idiopathic portal hypertension similarly studied angiographically, and the incidence of portal vein thrombosis unrelated to splenectomy was 2.86%. A statistical survey based on 247,728 necropsies recorded in the Japan Autopsy Registries of 1975-1982 showed a 0.05489% incidence of portal vein thrombosis and a 6.58857% incidence of cirrhosis of all types among them, suggesting that portal vein thrombosis is not a common complication of cirrhosis in Japan in recent years.