Shigetaka Sugihara

Hepatocellular carcinoma with sarcomatous change: a special reference to the relationship with anticancer therapy.

SummaryAmong 579 autopsy cases of hepatocellular carcinoma (HCC), 55 cases (9.4%) exhibited a sarcomatous appearance. The incidence of HCC with a sarcomatous appearance has been increasing over the past 17 years. A sarcomatous appearance was found in 20 out of 335 autopsy cases of HCC (5.9%) during the 12 years from 1969 to 1980, and in 35 out of 244 autopsy cases of HCC (14.3%) during the last 6 years, when effective anticancer therapies, such as the one-shot injection of anticancer agents into the hepatic artery (one-shot therapy) and transcatheter arterial embolization (TAE), have become popular. A sarcomatous appearance was found in 20.9% of the cases undergoing anticancer therapy and in 4.2% of the cases not undergoing anticancer therapy. Among the various anticancer therapies, the sarcomatous appearance was most frequent (27.6%) in cases with repeated TAE. Thus, a close relationship between the sarcomatous appearance in HCC and anticancer therapies was suggested. Regarding the development of the sarcomatous appearance, we presume that it may be caused by the pyenotypic change of HCC cells caused by anticancer therapy, or that a number of factors, including anticancer therapy, may accelerate the proliferation of the sarcomatous cells existing in the original tumor as one of the histological components. In order to clarify the true nature of sarcomatous lesions in HCC, further histological and biological studies are required.

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‐Steiners 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.

Small mass lesions in cirrhosis: Transition from benign adenomatous hyperplasia to hepatocellular carcinoma?

Abstract Ten patients with cirrhosis, in whom small mass lesions were detected by imaging techniques and histological diagnosis of the resected specimens was difficult, are described. There were 17 grossly discrete lesions measuring 10 × 8 mm to 27 × 22 mm. Four were compatible with so‐called adenomatous hyperplasia showing no histological features of malignancy, and eight were equivocal as to whether they were benign or malignant. The other five lesions (in four patients) were hepatocellular carcinoma, co‐existing with apparently benign lesions. The eight equivocal lesions were eventually judged to be highly differentiated hepatocellular carcinomas. These benign‐appearing lesions, found by advanced imaging in patients with cirrhosis, create a serious problem in regions where primary liver cancer is endemic among cirrhotics, and hepatic resection is the preferred treatment.

Pathology of Cholangiocarcinoma

Primary liver cancer is roughly divided into hepatocellular carcinoma (HCC) arising from liver cells and cholangiocarcinoma arising from the epithelium of the bile ducts. Of these, the pathological characteristics of cholangiocarcinoma have not yet been elucidated fully because its incidence is low compared with that of HCC and because its differentiation from extrahepatic bile duct cancer is often difficult. Only carcinomas arising from the intrahepatic bile ducts should be classified as cholangiocarcinoma. Carcinomas originating from the right and left hepatic ducts and the area of their junction are generally classified as the hilar type of cholangiocarcinoma, because it is often difficult clinically and pathologically to distinguish the intrahepatic bile duct carcinomas from extrahepatic carcinomas [1–5].

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.

PATHOMORPHOLOGIC STUDY OF PALE BODIES IN HEPATOCELLULAR CARCINOMA

Pathomorphological and immunohistochemical studies were conducted on cases of hepatocellular carcinoma (HCC) with pale bodies (PB). HCC containing PBs was seen in 6 (5.7%) of 106 consecutively resected HCC cases. It was of interest that varying degrees of sclerotic change were found in 4 of the 6 cases and a certain correlation between PBs and sclerotic change of HCC tissue was suggested. Histologically, PBs were identified as a pale amorphous substance with a distinct margin and most of PBs occupied the entire cytoplasm of the cancer cells. PBs were practically negative for periodic acid Schiff, and were also negative for phosphotungstic acid hematoxylin and orcein stains. Ultrastructurally, PBs were found to be a mass of granular or fibrillar materials having a single‐layered limiting membrane, and dilated rough endoplasmic reticula (rER) were also found in the vicinity of PBs, suggesting the presence of a close relationship between rough endoplasmic reticula and PBs. Most PBs were found to be strongly positive for anti‐fibrinogen antibody and some of them were weakly positive for anti‐albumin, but were solely negative for other antibodies such as anti HBs antigen, anti alpha 1 antitrypsin, and anti ferritin. According to those findings, PBs were thought to be fibrinogens accumulating in cystic rER due to a defective intracellular transport or an excretion disturbance.

A Case of Liver Cirrhosis with a Hyperplastic Nodular Lesion

A hyperplastic nodular lesion resembling focal nodular hyperplasia (FNH) was found in the cirrhotic liver of a 50‐year‐old male patient. A nodule was detected by ultrasonography and hepatic angiography conducted as part of a routine follow‐up study for chronic liver disease, and was excised under a diagnosis of suspected hepatocellular carcinoma. Grossly, central stellate scar‐like septa subdividing the nodule ware noted. These fibrous septa contained many small arteries and veins, as well as bile ducts. The parenchyma of the nodule also contained many small arteries. Although these findings were similar to those seen in typical FNH, the present lesion was different in that it was encapsulated, occurred against a background of liver cirrhosis, lacked hepatocyte hyperplasia and showed hemosiderin deposition.

Establishment and characterization of a new human renal cell carcinoma cell line (KRC/Y)

SummaryA new renal cell carcinoma (RCC) cell line (KRC/Y) has been established from a surgical specimen of a 41-yr-old Japanese female patient with RCC composed of both clear cells and granular cells. This cell line has been maintained for more than 15 mo. through 45 passages with a stable growth, KRC/Y cells have clear or eosinophilic polygonal cytoplasm and round to oval nuclei with one or two nucleoli, and proliferate in a pavementlike cell arrangement with a lack of contanct inhibition. By electron microscopy, these cells contain abundant fat droplets and glycogen granules or well-developed organells or both, which were also observed in the original tumor. The doubling time of these cells at the 15th passage was 73 h. The chromosome number was from 37 to 45 with a hypodiploid modal number of 42. Tumorigenicity was identified by tumor formation after subcutaneous injections of KRC/Y cells in nude mice, which showed close resemblance to the original tumor by light and electron microscope observations.

HETEROTRANSPLANTATION OF AN ALPHA‐FETOPROTEIN‐PRODUCING HUMAN GALLBLADDER CARCINOMA INTO NUDE MICE

An alpha‐fetoprotein (AFP)‐producing human gallbladder carcinoma showing direct invasion into the liver was transplanted into BALB/c‐nu/nu nude mice. Although patient serum levels of AFP and carcinoembryonic antigen (CEA) were within normal limits, they were elevated to 1,040 ng/ml and 22.1 ng/ml, respectively, after cholecystectomy. Prominent liver metastasis was demonstrated by diagnostic imaging techniques shortly after the operation. Pathologically, the resected tumor consisted of papillotubular adenocarcinoma and the part which had Invaded the liver showed a solid growth pattern with no papillo‐tubular structure. The transplanted tumor showed both papillo‐tubular and solid growth patterns, in which positive reactions for AFP, CEA, ferritin (FER), carbohydrate antigen 19‐9 (CA 19‐9), albumin (ALB) and fibrinogen (FIB) were confirmed by the avidin‐biotin‐peroxidase complex method. Serum levels of AFP, CEA, CA 19‐9, β2‐microglobulin (BMG) and FER were elevated in the nude mice bearing tumor transplants. Twenty‐five percent of the serum AFP from nude mice with tumor transplants bound with concanavalin A (Con A), suggesting that the tumor was of gastrointestinal rather than hepatic origin.

Eosinophilic Granuloma of Lymph Node

Eosinophilic granuloma confined to the lymph node of a 25‐year‐old Japanese woman is reported. She presented with a low‐grade fever and pain in the left cervical region. A finger‐tip‐sized cervical lymph node was excised for histological study. Microscopically, the normal architecture of the lymph node was distorted, and histiocytoid cells had proliferated mainly in the sinus. Numerous eosinophils and an appreciable number of large multinucleated cells were also observed. Ultrastructurally, Birbeck granules were found in the cytoplasm of the histiocytoid cells. Immunohistochemically, the proliferating cells and multinucleated cells were found to be positive for S 100 protein but negative for lysozyme in the cytoplasm. The patient has been well without recurrence for 10 months after the lymph node biopsy. Acta Pathol Jpn 40: 851‐855, 1990.