Yasuhiko Kubo

Clinical aspects of intrahepatic bile duct carcinoma including hilar carcinoma. A study of 57 autopsy‐proven cases

The clinical features of 57 autopsied cases of intrahepatic bile duct carcinoma including 28 cases of the peripheral type (cholangiocarcinoma in the narrow sense) and 29 cases of the hilar type are described in comparison with those of hepatocellular carcinoma, with a review of the literature on the clinicopathological aspects of intrahepatic bile duct carcinoma. As compared with hepatocellular carcinoma, the average age of the patients was older; the male predominance was not obvious, chronic parenchymal liver disease was infrequent in the past history, association of primary cirrhosis was seldom, cholestatic features were frequently the early signs and more pronounced during the course, the liver was enlarged to a lesser extent, ascites was less common, signs of portal hypertension were absent or minimal, and extrahepatic metastases were less frequent. In many respects, the hilar type resembled extra‐hepatic bile duct carcinoma, and the peripheral type was somewhat between it and hepatocellular carcinoma. Although the overall survival was not much different from that for hepatocellular carcinoma, early diagnosis is emphasized; this would make surgical management possible. Differential diagnosis from hepatocellular carcinoma may be possible in the majority with direct cholangiography, liver scan, celiac angiography, determination of α‐fetoprotein and hepatitis B antigen, and blood chemistry such as SGOT, SLDH, serum bilirubin and alkaline phosphatase. Illustrative cases are given including one patient with a hilar carcinoma who survived for more than 2 years after transhepatic biliary drainage.

Clinicopathologic features of encapsulated hepatocellular carcinoma. A study of 26 cases

The clinicopathologic features of 26 cases of hepatocellular carcinoma (HCC) surrounded by a grossly distinct capsule‐like fibrous tissue were studied. The frequency of this type was 10.3% among autopsy cases of HCC. The mean age of the patients was 64.1 years, which was significantly older compared with that of 143 cases of nonencapsulated HCC. Hepatitis‐B surface antigen in serum was positive in 18.7% of the cases studied, the positivity rate being lower than that of HCC in general. Histologically, the tumor was relatively well differentiated and the capsule was the product of slow expanding growth. Intravenous tumor invasion was less frequent compared with other types of HCC. Clinically, celiac angiography proves to be a most useful diagnostic method; a thick capsule may be demonstrated as a thin radiolucent rim around the mass. The clinical course from the early stage is protracted and, if detected early, this type of HCC may be removed surgically.

Angiographic demonstration of intrahepatic arterio-portal anastomoses in hepatocellular carcinoma.

Hepatic angiograms of 114 patients with hepatocellular carcinoma (HCC) were studied, particularly changes in the portal vein branches. Arterio-portal shunts of varying sizes, evidenced by opacification of intrahepatic portal branches, were seen in 72 cases (63.2%), with retrograde opacification of the portal vein trunk in 29 (25.4%). At least four types of shunts were found: (a) through a tumor thrombus in the portal branch, (b) in a retrograde direction via a peripheral tumor nodule, (c) through a small tumor invading or amputating an artery, and (d) through a tumor located near a major portal vein branch and supplied by a large, coiling artery. Postmortem angiography of the liver in 50 patients with HCC suggests that arterio-portal shunts are the result of the special vasculature in HCC and are highly diagnostic when accompanied by other angiographic changes.

Angiographic Assessment of Gross Anatomy of Hepatocellular Carcinoma: Comparison of Celiac Angiograms and Liver Pathology in 100 Cases1

Of 190 sets selective celiac and/or hepatic angiograms obtained in patients with hepatocellular carcinoma (HCC), comparison with gross anatomy of the liver was subsequently made by autopsy in 77 and by surgery in 23. It was found that the gross anatomy of HCC can be assessed with certain accuracy by careful interpretation of the angiograms, because tumor vasculature and vascular alterations in the noncancerous parenchyma are closely related to the mode of tumor growth, size of tumor nodules and their distribution. Even a fibrous capsule of the tumor may be discerned as a radiolucent zone around the tumor contour. Diagnosis of the gross anatomical type of HCC is important to the selection of therapeutic measure and assessment of prognosis.

Hepatocellular carcinoma arising in noncirrhotic and highly cirrhotic livers: A comparative study of histopathology and frequency of hepatitis B markers

Hepatocellular carcinoma (HCC) associated with cirrhosis and HCC developing in a noncirrhotic liver may have differing pathogeneses. To study this possibility, 426 autopsied cases of HCC were investigated. Of these, 45 livers were not cirrhotic, 50 were highly cirrhotic (liver weight less than 99 g), and the remaining 331 were cirrhotic but not so highly. The average age was significantly older in the highly cirrhotic group, suggesting a longer premalignant period of chronic liver disease. The liver weight in the noncirrhotic group was about 3.5 times that in the highly cirrhotic group. Hepatitis B surface antigen was positive in serum in only 9.3% and in liver tissue in 10% in the noncirrhotic cases, the positivity rate being much lower compared with other groups (P < 0.005–0.01), yet antibody to HB core was positive in 90%. The antibody titers were low, however, indicating that these noncirrhotic patients had in the past had HB virus (HBV) infection with no residual chronic B hepatitis. Analysis of the grades of anaplasia of cancer tissue demonstrated an inverse correlation between the degree of fibrosis and grade of anaplasia, i.e., the more advanced the fibrosis, the less anaplastic the cancer. These data suggest that HCC arising in highly cirrhotic livers and in noncirrhotic livers have different pathogenetic backgrounds, and that HBV infection, even though transient, has a certain role in hepatocarcinogenesis. The generally held conjecture that HCC in a noncirrhotic liver is caused by nonviral carcinogens and HCC arising on the ground of cirrhosis is due to HBV seems untenable in such a simple concept.

Antibody To Hepatitis B Core Antigen In Patients With Hepatocellular Carcinoma

Hepatitis B surface antigen (HBsAg), anti-HBs, and anti-HB core (HBc) were measured in 124 patients with hepatocellular carcinoma (HCC) in comparison with 299 control subjects of comparable ages, and in 48 cases of chronic hepatitis and 52 cases of hepatic cirrhosis. It was found that 72.6% of the HCC patients were positive for anti-HBc, and 80.6% were positive for at least one test, whereas in the control, anti-HBc was positive in 30.1% and 34.1% were positive for at least one test, the differences between the two groups being significant (P less than 0.01). The frequencies of positive tests for HBsAg and anti-HBc were the highest in HCC followed in decreasing order by cirrhosis, chronic hepatitis and the control group. A possible role of HB virus infection in hepatocellular carcinoma is discussed in relation to other factors.

Serum glutamic oxalacetic transaminase/glutamic pyruvic transaminase ratios in hepatocellular carcinoma.

Serum enzyme activities were studied in 131 cases of hepatocellular carcinoma (HCC), 76 cases of metastatic liver carcinomas (MLC) and 234 cases of hepatic cirrhosis. SGOT was elevated above SGPT in most of the time in these patients, SGOT/SGPT was greater in HCC compared with other groups, and that this ratio increased during the preterminal period more markedly in patients with HCC because of the significant increase of SGOT in the face of relatively stable SGPT. Preterminal rises of alkaline phosphatase and LDH activities were more pronounced in MLC. Leucine aminopeptidase activity exhibited no characteristic feature of diagnostic value. Of the five enzymes, SGOT changes were more closely correlated with the growth of HCC; SGPT reflected more of the liver parenchymal damage while SGOT was probably accounted for in part by tumor‐derived GOT. Other clinical and pathological implications are discussed. Cancer 40:319–324, 1977.

Localized submassive liver cell necrosis as a terminal event of liver carcinoma.

Six cases of hepatocellular carcinoma (HCC) and one case of metastatic liver carcinoma in which SGOT, SGPT, and SLDH were suddenly and markedly elevated immediately before death are described. All had a large blood loss and systemic hypotension in the preterminal period; autopsy disclosed irregularly shaped, patchy necrotic areas or infarcts, often clearly demarcated by hemorrhagic rims, in the noncancerous liver parenchyma. Tumor growths in the intrahepatic portal branches were extensive in all six cases with HCC; in the metastatic case, invasion and narrowing of the portal branches were extensive. The incidence of this terminal catastrophe was 3.3% (6 of 184 cases) for HCC and 1.15% (1 of 87) for metastatic carcinoma. The terminal liver necrosis was probably a result of sudden reduction in portal perfusion which had been inadequate because of tumor thrombosis, combined with hypotension of hepatic arteries.

Hepatitis B Surface Antigenemia in Patients with Hepatocellular Carcinoma in Relation to Clinical Course and α-Fetoprotein

Hepatitis B surface antigen was determined in sera of 122 cases of hepatocellular carcinoma seen in Japan, using both the counterimmunoelectrophoresis and radioimmunoassay (RIA) techniques. It was positive in 49.2% of the patients with RIA, but the level of antigen in serum was relatively low since positivity rate by counterimmunoelectrophoresis was only 10.7%. The degree of antigenemia as assessed from the count relative to the cut-off value in RIA, was increased during the clinical course in 75% of the patients. The antigen tended to rise in concentration when the tumor grew at a rapid rate, when damage to liver parenchyma was extensive, or in patients receiving chemotherapy. There was also a tendency for less frequent positive antigen tests in patients with higher α-fetoprotein levels. Illustrative cases are presented with discussion on the possible explanation for the change in the degree of antigenemia.

SERUM α‐FETOPROTEIN IN THE RELATIVELY EARLY STAGES OF HEPATOCELLULAR CARCINOMA AND ITS RELATIONSHIP TO GROSS ANATOMICAL TYPES

The early expectations that serum a-fetoprotein (AFP) would make it possible to detect small, operable hepatocellular carcinomas (HCC) have not yet been met. In the majority of patients, when AFP is found to be positive the HCC is already so large as to defy surgery. Furthermore, a mildly positive test for AFP is not uncommon when it is carried out in a variety of liver diseases and, particularly in acute and chronic hepatitis, AFP rises temporarily. Before this fact was known, we had to mobilize every possible means such as celiac angiography, operative portography and even laparotomy in chronic hepatitis patients who showed elevated AFP, in search of HCC. Through these experiences, we have come to realize that the only way to detect HCC in its resectable stage is to check AFP regularly, at monthly intervals if feasible, in patients with chronic hepatitis and cirrhosis, to carry out liver scanning at intervals to assess speed of the disease progress, and celiac angiography when AFP has started rising sharply without evidence of preceding parenchymal damage, which is followed by a transient rise of AFP. We have so far been able to detect relatively early HCC in 4 cases, in 2 of which lobectomy was carried out (FIGURE 1 ) .