Toshiro Nakashima

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.

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.

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.

Hepatocellular carcinoma presenting as intrabile duct tumor growth. A clinicopathologic study of 24 cases

We describe the features of 24 cases of hepatocellular carcinoma (HCC) with prominent intrabile duct tumor growth seen among 238 autopsy and 21 surgical cases of HCC. Progressive obstructive jaundice occurred during the course of most cases and was the presenting sign in nine. A fluctuating rise and fall of the total bilirubin was seen in two cases. The average survival time of the cases was significantly shorter than that of HCC patients without intrabile duct tumor growth (Mann‐Whitneys U‐test, onetailed, P < 0.05). The average survival time after the development of severe jaundice (total bilirubin over 10 mg/dl) was only 16 days. Intrabile duct tumor casts were located in the hepatic and/or the common bile ducts in 19 cases (79%) and in five cases were seen in the peripheral (medium to small‐sized) bile ducts. Hemobilia developed in five cases (21%) and was regarded as the immediate cause of death in one. Grossly all the cases presented infiltrative or mixed (infiltrative and nodular) growth pattern. Intrabile duct tumor growth and associated marked obstructive jaundice may frequently herald the terminal phase of HCC in certain patients. In our series, approximately 40% of patients with HCC and significant jaundice had gross evidence of extensive intraductal tumor growth. In the absence of intraductal tumor growth, jaundice in HCC usually was seen in a setting of progressive terminal hepatic failure.

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.

Hepatocellular carcinoma with sarcomatous change. Clinicopathologic and immunohistochemical studies of 14 autopsy cases

Among 355 autopsy cases of hepatocellular carcinoma (HCC), 14 cases exhibited sarcomatous appearance (incidence, 3.9%). A clinicopathologic study was performed in these 14 cases, and the immunohistochemical localization of keratin (KRT), vimentin (VMT), albumin (ALB), fibrinogen (FBG) and alpha‐fetoprotein (AFP) was also examined using the avidin—biotin complex method. Clinically, the HCCs with sarcomatous appearance were characterized by negative or low serum AFP levels and high incidence of extrahepatic metastasis. Grossly they were of infiltrative, mixed expansive and infiltrative, and pedunculated types. Histologically, the tumor consisted mainly of spindle‐shaped cells and partly of multinucleated cells, and showed a sinusoidal growth pattern at the tumor—nontumor boundary. Immunohistochemically, tumor cells in the regions showing sarcomatous appearance were frequently found to be positive to KRT and VMT, whereas the percentage of positivity to ALB, FBG, and AFP were not significantly different from those in ordinary HCC. These results strongly suggest that the lesion showing sarcomatous appearance represents the sarcomatous change of HCC rather than being regarded as the complication of HCC and sarcoma. Cancer 59:310–316, 1987.

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.

Pathomorphologic characteristics of 102 cases of thorotrast-related hepatocellular carcinoma, cholangiocarcinoma, and hepatic angiosarcoma

The pathomorphologic characteristics of 102 autopsy cases of Thorotrast (Th)‐related hepatic malignancies were described and compared to the features of non‐Th‐related cases. Among the 102 Th‐related hepatic malignancies, 44 (43.1%) were cholangiocarcinoma (CHC), 39 (38.3%) were angiosarcoma (AGS), 16 (15.7%) were hepatocellular carcinoma (HCC), and 3 (2.9%) were double cancer. In the non‐Th‐related cases approximately 90% were HCC, and AGS was very rare. Grossly, the majority (91.7%) of Th‐related CHC was located in the middle‐peripheral portion of the liver. In contrast, 77.8% of the non‐Th‐related cases were located in the hilar portion. Th‐related AGS was classified into four types: diffuse micronodular, multi‐nodular, massive, and mixed multi‐nodular and massive. Histologically, AGS was characterized by two cell types (spindle‐shaped cells and polyhedral cells) and three growth patterns (sinusoidal, carvernous, and solid). In noncancerous areas foci of varying degrees of sinusoidal dilatation with hyperplastic changes of sinusoidal lining cells were observed in all AGS cases and in some of the cases of Th‐related CHC and HCC cases. In many (80%) of the non‐Th‐related HCC, mixed macronodular and micronodular cirrhosis was associated. By contrast, in Th‐related HCC cases cirrhosis was superimposed on varying degrees of hepatic fibrosis related to Th deposition in only four cases (21.1%). Taken together, these findings suggest that Th influences are more carcinogenic to epithelial cells of the bile duct and sinusoidal lining cells than hepatocytes.