LOCALIZATION OF HEPATITIS B SURFACE ANTIGEN IN HEPATOCELLULAR CARCINOMA

The author respectively examined the localization of hepatitis B surface antigen (HBsAg) in 150 autopsy cases of hepatocellular carcinoma (HCG) with particular attention to growth pattern of HCG. Varying numbers of orcein-positive cells were observed In 42 cases (28.0%) with various distribution patterns, and all the 42 cases were confirmed with immunoperoxidase technique for HBsAg. HBsAg-positive cells were detected in HCG tissue In 10 cases (6.6%) among the 150 cases. Regarding the growth pattern of HCG in the 10 cases, many HBsAg-positive cells were seen In HGGs of the sinusoidal and replacing types, in which the hepatocytes were frequently retained in the cancerous tissue, particularly around the tumor-nontumor boundary. On the other hand, there was no HBsAg-positive cell in the encapsulated type HGC which was the most common (approximately 50%) in the present study and in which the retained hepatocytes were hardly seen. Meticulous histological observation after decoloration of the positive reaction to HBsAg in the sections treated with immunoperoxidase technique and subsequent eosin stain disclosed that HBsAg-positive cells in HGC tissue were retained hepatocytes in 9 cases, and the possibility of HCC cell was not denied in one case. Moreover, HBsAg-positive cells were never detected in tumor thrombi of the portal vein branches and pulmonary metastases.     

HEPATOCELLULAR CARCINOMA WITH CHONDROSARCOMATOUS VARIATION

An autopsy case of hepatocellular carcinoma with a sarcomatous component in a 63-year-old woman was described. A massive tumor measuring 15 times 15 times 10 cm almost replaced the left lobe of the liver and extended to the right atrium of the heart. Histologically the tumor was a typical hepatocellular carcinoma of adult type, except in the central portion where there was gradual replacement of the carcinoma by spindle-shaped atypical cells with areas of chondrosarcomatous tissue. Some of the spindle cells were immunohisto-chemically positive for keratin, and the sarcomatous component was not found in the metastatic foci of liver and lungs. Reported cases of mixed hepatic tumor of adults in the literature were reviewed, and discussion was made concerning the nosology of the present tumor. ACTA PATHOL. JPN. 37:1165 -1173, 1987.     

COMBINED HEPATOCELLULAR AND MUCINOUS CARCINOMA

A rare autopsy case of combined liver cell and bile duct carcinoma (CLBC) occurring in a 51-year-old male with alcoholic liver cirrhosis is presented. Histologically, while the primary lesion was solely composed of well differentiated hepatocellular carcinoma (HCC), intrahepatic metastases consisted of a variable admixture of HCC and cholangiocarcinoma (CC) with excessive mucin production. Interestingly, the tumor cell cluster showing a trabecular growth pattern produced both bile and mucin, thus converting from HCC to mucinous CC. It is concluded that this liver malignancy is principally HCC with a marked tendency to transform into CC. The importance of the findings, especially the simultaneous production of bile and mucin within the same cell cluster, is emphasized in terms of the classification of CLBCs.     

ULTRASTRUCTURE OF HUMAN HEPATOCELLULAR CARCINOMA

Twelve human hepatocellular carcinomas (HCC) were studied ultramicros-copically. In the aspects of development of cytoplasmic organelles, well differentiated cancer cells were similar to the normal hepatocytes. On the other hand, poorly differentiated HCC cells contained little cytoplasmic organel-le except for relatively developed rER and ribosomes. HCC cells showed not only several differentiations but also many degenerative changes, such as fatty metamorphosis, "dark" and "clear" cells, "fingerprint" formation and myelin-like figure, and the ultrastructural alterations of the vessels among HCC cells could play one of the most important roles in causing these degenerative changes in human HCC cells.     

HEPATOCELLULAR CARCINOMA COMBINED WITH HEPATIC SARCOMA

An autopsy case of hepatocellular carcinoma combined with hepatic sarcoma was presented. There were three main tumor nodes in the liver. They showed necrosis due to therapeutic embolization of the hepatic artery. Histologically, one of the three was of hepatocellular carcinoma, and the other two were of spindle cell sarcomas. Extrahepatic metastases all showed characteristics of sarcoma. In the present case report, some problems concerning hepatic sarcoma and sarcomatous representation of hepatocellular carcinoma were proposed in reviewing the literatures.     

HEPATOCELLULAR CARCINOMA PRESENTING EXTRAHEPATIC BILIARY OBSTRUCTION

An autopsy case of hepatocellular carcinoma presenting extrahepatic obstructive jaundice was reported. The patient was a 68-year-old man with 5-year history of chronic liver disease and markedly jaundiced, and died of gastrointestinal hemorrhage. Autopsy revealed hepatocellular carcinoma associated with liver cirrhosis and metastatic polypoid growth in the common bile duct and cystic duct which completely obstructed the duct lumen. Obstructive jaundice secondary to complete obstruction of the common bile duct was a rare complication of hepatocellular carcinoma. The other 85 cases of hepatocellular carcinoma presenting extrahepatic biliary obstruction are reviewed.     

PATHOLOGIC FEATURES OF SMALL HEPATOCELLULAR CARCINOMA

Twenty-one nodules of small hepatocellular carcinoma (HOC) were examined. Hlstologically, the nodules often presented formation of plump trabeculae, marked nuclear atypism, or aggressive growth comprising capsular invasion, vascular invasion, and replacement of adjacent pseudolobules. Aside from these characteristic findings of HCC, it was important to reveal the following features for the diagnosis of well differentiated type of small HCC: (1) variable thickening or distortion of trabecular structure in association with nuclear crowding, (2) acinar formation, (3) selective cytoplasmic accumulation of Mallory bodies, (4) nuclear abnormalities consisting of thickening of nuclear membrane, irregularities in shape, and enlargement of nucleus or nucleolus, (5) hepatic cords in close contact with bile ducts or blood vessels, and (6) hepatocytes growing in a fibrous environment. During the invasive growth, the tumor cells may well be subtly blended with benign hepatocytes, giving rise to a pattern of "mixed cellularity". It is also emphasized that connective tissue septa of pseudolobules could be a route of rapid tumor spreading.     

HEPATOCELLULAR CARCINOMA AND CHRONIC PERSISTENT HEPATITIS

The morphologic type of cirrhosis that is followed most frequently by hepatocellular carcinoma is posthepatitic cirrhosis. Furthermore, HB Ag is detected in a high rate among cases with hepatocellular carcinoma suggesting the intimate causal relationship between hepatitis B virus and hepatocellular carcinoma. It has been considered that hepatocellular carcinoma might develop during destruction and regeneration of fully developed liver cirrhosis. However, hepatocellular carcinoma is combined with not only liver cirrhosis but also with mild liver fibrosis. An attempt was made to determine HBs Ag in the liver tissue of liver fibrosis with hepatocellular carcinoma. HBs Ag was found in non-cancerous liver tissue of 40% of those cases. Therefore, it may be concluded that, at least some of those fibrosis is caused by chronic viral hepatitis and hepatocellular carcinoma may develop not only on posthepatitic cirrhosis but also on chronic persistent hepatitis. This evidence also suggests the carcinogenicity of hepatitis B virus.     

肝癌病人天然杀伤细胞活性的观察

本文测定了42例正常人和62例疗前不同病期原发性肝癌病人和18例非癌肝病患者外周血淋巴细胞对 K_562靶细胞的天然杀伤(NK)活性。结果表明,肝癌病人平均 NK 活性明显低于正常人和非癌病人,经统计处理有显著性差异(P<0.01和P<0.02),而非癌肝病患者的 NK 活性与正常人相比无明显差异(P>0.05)。按临床病状分组进行各组间方差分析显示,有转移或肝破裂的肝癌病人 NK 活性明显低于无转移者(P<0.01);在无转移的病人中,肝癌肿块负荷与 NK 活性无关。比较 AFP 阳性和阴性的肝癌病人 NK 活性时,发现两组间 NK 活性有明显的差异(P<0.02)。     

ULTRASTRUCTURAL STUDY OF HEPATOCELLULAR CARCINOMA WITH REPLACING GROWTH PATTERN

The replacing growth of hepatocellular carcinoma (HCC) has been considered as a basic growth pattern at the tumor- nontumor boundary. In order to clarify the ultrastructural characteristics of HCC with the replacing growth, we have studied 59 surgical cases of HCC. At the tumor-nontumor boundary of HCC with the replacing growth pattern, the tumor cells grow to replace the hepatocytes along the liver cell cord, but oppress and distort the adjacent liver cell cord with varying degrees of aggregation of reticulin fiber. Hepatocytes and cancer cells are in direct contact, but some of the hepatocytes are compressed by cancer cells. The sinusoid in the non-cancerous area is continuous with the blood space in the cancerous tissue, and several layers of endothelial cells are often observed. Accordingly, it is predicted that sinusoidal blood through the portal vein and arterial blood through arterial tumor vessels may mix at the tumor-nontumor boundary. ACTA PATHOL. JPN. 35:549-559, 1985.     

原发性肝癌端粒酶活性的检测及临床意义

为探讨端粒酶活性化在原发性肝癌发生发展中的作用，本文采用ＴＲＡＰ技术，对４２例手术切除的原发性肝细胞癌及癌旁组织的端粒酶活性进行检测。结果发现：４２例肝癌组织有３４例检出端粒酶活性，阳性率为８１．０％，４２例癌旁组织有１２例检出端粒酶活性，阳性率为２８．８％，端粒酶活性与肿瘤大小，组织学分级及肿瘤转移无显著相关，以上结果提示，检测原发性肝癌组织端粒酶活性对阐明原发性肝癌的发病机理，癌变危险性的预测     

CAVERNOUS STRUCTURES COMPOSED OF HEPATOCYTES IN EXPERIMENTALLY INDUCED HEPATOCELLULAR CARCINOMA

Cavernous structures composed of hepatocytes were observed for the first time in trabecular-patterned hepatocellular carcinomas by light, scanning and transmission electron microscopy. The carcinomas were induced by a single dose of diethylnitrosamine combined with subsequent administrations of 2-acetylaminofiuorene and partial hepatectomy. The cavernous structures had numerous cavities walled by flat hepatocytes. In the cavities, dendritic hepatocytes, connected with each other by their long and slender processes, formed a network and were attached to the fenestrated sinusoidal endothelium via intercellular spaces between the flat hepatocytes. Dendritic hepatocytes had smooth surfaces, prominent nucleoli, decreased glycogen, and well organized cisternae. Dilated bile canaliculi were sometimes seen among flat and dendritic cells. Dendritic cells showed more morphological dearrangement than flat cells. Blood cells were observed in the cavities. Kupffer cells were not seen in the sinusoids among the cavernous structures. The cavernous structures in the hepatocellular carcinomas resembled the hepatocyte arrangement in fetal liver in which intercellular spaces of hepatocytes are extremely widened.     

MULTICENTRIC HEPATOCELLULAR CARCINOMA FOLLOWING PHOSPHATE DIETHYLSTILBESTROL THERAPY FOR PROSTATIC CANCER

This paper reports an autopsy case of a 78-year-old male with multiple nodules in the liver developed after longtermed administration of phosphate diethylstilbestrol (PDES) for prostatic cancer. Large part of these nodules were suspected to be well differentiated hepatocellular carcinoma with high level of serum alpha-fetoprotein (AFP) up to 3,400 ng/ml, but a part of them was evaluated to be a borderline between hepatocellular carcinoma and adenoma with mild cellular atypism. The liver other than the nodules showed liver fibrosis associated with liver cell dysplasia and peliosis hepatis-like change. This is a unique autopsy case of hepatocellular carcinoma closely related to diethylstilbestrol (DES) therapy for prostatic cancer.     

HEPATOCELLULAR CARCINOMA COMBINED WITH HEPATIC MESENCHYMAL CELL TUMOR AND SARCOMA

An autopsy case of hepatocellular carcinoma combined with sarcoma and mesenchymal cell tumor or cholangiole cell carcinoma is presented. The main tumor nodes in the liver consisted of hepatocellular carcinoma and sarcoma. Extrahepatic metastases showed characteristics of monocytic or reticulum cells and hemangioendothelial sarcomas. In this report, some problems concerning hepatocellular carcinoma and sarcomatous representation of the liver tumor are proposed. Differentiation to the monocytemacrophage-like cells and a reticulum cell pattern were present in the metastatic locations. Thus strongly suggesting that the sarcoma may have arisen from mesenchymal cells, particularly from the Kupffer cells or endothelia consisted of the sinusoid. However, mesenchymal tumor from cholangiole cells might be associated in a part of the sarcomatous cells.     

HEPATOCELLULAR CARCINOMA AND MYOCARDIAL SARCOIDOSIS—AN AUTOPSY CASE—

An autopsy case of a 65-year-old male who died of hepatocellular carcinoma superimposed on liver cirrhosis complicated with systemic sarcoidosis is presented, No organ metastasis of hepatocellular carcinoma was found except for a minute tumor embolus in the left upper lobe of the lung. Involved organs by sarcoidosis were the lymph nodes, lungs, heart, liver and spleen, but its presence was not noticed before death. Its cardiac involvement coincide with his clinical symptom of exertional dyspnea and the ECG finding of A-V block.     

FIBRONECTIN IN HUMAN HEPATOCELLULAR CARCINOMA (HCC) and HCC CELL LINES

The localization of fibronectin (FN) in human hepatocellular carcinoma (HCC) was studied in thirty-six HCC tumors (19 autopsy and 17 surgical specimens), two xenografted tumors of HCC to BALB/c mice and three HCC cell lines. The synthesis of FN was also examined in three HCC cell lines. FN was demonstrated on the endothelial surface of the blood spaces of cancerous tissue. Cytoplasmic and intercellular localization of FN was also observed. But there was no correlation between the localization pattern of FN and metastasis. In the two xenografted HCC tumors, FN was found in association with the blood vessels of the tumor tissue and between the HCC tumor cells. In all 3 HCC cell lines, FN was localized on the surface and in the cytoplasm of some HCC cells. FN was detected in the serum-free culture media of three HCC cell lines by immunoelectroblotting. The electrophoretic pattern of FN synthesized by these cell lines was different from that of plasma-FN and resembled that of cellular-FN synthesized by normal liver fibroblasts.     

STUDIES ON THE PATHOGENESIS OF HEPATOCELLULAR CARCINOMA IN HBV-NEGATIVE ALCOHOLIC CIRRHOTICS

Ninety five cases of HBV marker-negative cirrhosis with excess alcohol intake were examined clinicopathologically to obtain some clues and insights into the pathogenesis of hepatocellular carcinoma (HCC). The following data were obtained: (1) cases were divided morphologically into 37 cases of macronodular cirrhosis (MacCir), 16 mixed cirrhosis (MixCir), and 42 mi-cronodular cirrhosis (MicCir), (2) the mean age at death was the oldest in MacCir (61 yrs), the youngest in MicCir (51 yrs), and intermediate in MixCir (59 yrs), (3) association of HCC was common both in MacCir and MixCir (78 and 63%, respectively) but infrequent in MicCir (17%), (4) all livers of MicCir with HCC had broad collapse and a small number of macronodules in noncancerous areas and the mean age of them was older than that of MicCir without both the collapse and macronodules (56 vs 48 yrs), (5) in total cases, the mean age at death of patients with HCC was 7 years older than that without HCC (60 vs 53 yrs), (6) the mean liver weight was the largest in MicCir (1,211 g), the smallest in MacCir (829 g), and intermediate in MixCir (1,022 g), (7) the incidence of MacCir was significantly higher in patients who had given up alcohol for more than one year before death than those without abstinence, and (8) neither the subtypes of cirrhosis nor the incidence of HCC was significantly related to the total amount of alcohol intake. These data indicate that the development of HCC in HBV-negative alcoholics with cirrhosis occurs in relation to the development of macronodules and loss of liver weight, most likely along with the prolongation of the life span. ACTA PATHOL. JPN. 36: 1297–1305, 1986.     

PALE EOSINOPHILIC INCLUSIONS SIMULATING GROUND-GLASS APPEARANCE OF CELLS OF HEPATOCELLULAR CARCINOMA

Pale eosinophilic inclusions simulating ground-glass appearance were observed in cells of hepatocellular carcinoma. They were round or elliptical in shape, and their size was about 14 μm in diameter. Light eosinophilia and fine granulation with homogeneous appearance were delineated from other cellular materials. They were negative for HBsAg blood plasma proteins including α1-antitrypsin, and α-fetoprotein by immunohistochemical stainings. Ultrastructurally, they were well-demarcated and consisted of homogeneous finely granular matrix. Histological, histochemical and ultrastructural features were different from several intracellular inclusions hitherto reported on hepatocellular carcinoma. These changes may represent a deposition of secretory proteinous materials in cells of hepatocellular carcinoma, but their chemical and antigenetical content could not be identified.     

A NEW HUMAN PLEOMORPHIC HEPATOCELLULAR CARCINOMA CELL LINE, KYN-2

A new human hepatocellular carcinoma (HCC) cell line, KYN-2, has been established from a surgical specimen obtained from a 52-year-old Japanese male HCC patient. The originally resected HCC was classified as pleomorphic HCC corresponding to Edmondson-Steiner's grade III with a thick trabecular to solid arrangement. The cell line has been maintained for 17 months through 35 passages. Morphologically, the KYN-2 cells have retained the characteristics of the original HCC, being pleomorphic and composed of various types such as cells with relatively small, polygonal, eosinophilic cytoplasm and oval-shaped nuclei with a marked tendency to pile up, flat cells with abundant clear cytoplasm and oval-shaped nuclei, and many multinucleated giant cells, proliferating in a pavement-like cell arrangement. Some junctional complexes and a number of microvilli are evident between the cells by electron microscopy. Functionally, these cells were found to secrete albumin, α,-acid glycoprotein, α₁-antitrypsin, ceruloplasmin, transferrin, complement C, fibrinogen, fibronectin, prothrombin, retinol-binding protein (serum type), α-fetoprotein (AFP), carcinoembryonic antigen (CEA), ferritin and β₂-microglobulin in chemically defined medium (CDM). The secretion of AFP and CEA is apparently dependent upon culture medium and passage. The doubling time of cells growing in serum-containing medium at the 14 th passage was 84 h, and those of cells in serum-containing medium, HB101 (serum-free medium) and CDM at late passage were 28,68, and 42 h, respectively. Chromosome analysis revealed that the chromosome number ranged from 56 to 69 without a mode, and the presence of marker chromosomes. HB virus DNA sequence was not detected by hybridization analysis. The tumorigenicity of KYN-2 cells was identified by development of tumors in nude mice after subcutaneous injection of the cells; the tumors showed an appearance basically similar to that of the original HCC. Thus, these findings suggest that the KYN-2 cell line is available as a new human HCC cell line and should be useful for various studies on HCC. ACTA PATHOL JPN 38: 953-966, 1988.     

HEPATOCELLULAR CARCINOMA WITH METASTATIC GASTRIC CANCER SIMULATING BORRMANN TYPE 2 AND HYPERLIPIDEMIA

A case of hepatocellular carcinoma with metastasis to the stomach and hyperlipidemia as a paraneoplastic syndrome was presented. The patient, a 69-year-old man, was admitted to Kurobe City Hospital with a complaint of eplgastralgia. He was diagnosed as having hepatocellular carcinoma by an increased plasma AFP and the abnormalities of hepatic scintigram and abdominal angiography. Endoscopic examination of the stomach revealed an ulcerative lesion suggesting Borrmann type 2 gastric cancer and the gastric mucosal biopsy was interpreted as tubular adenocarcinoma. At autopsy, the liver was enlarged and weighed 4,170g without liver cirrhosis. Histologic finding of the liver tumor was hepatocellular carcinoma of Edmondson's grade 2 and the gastric tumor with bile production was identical to that of liver tumor. The tumor architecture of the stomach, however, was mixed with trabecular pattern and tubular pattern near the site of gastric mucosa, and was concordant with the findings of gastric mucosal biopsy. Multiple tumor thrombi in the portal system suggested that hepatocellular carcinoma retrogradely metastasized to the stomach through the portal system.