0 1992

The Japanese Society of Pathology

Histomorphologica I Characteristics of Chola ngiocellula r Carcinomas in Northeast Thailand, Where a Region Infection with the Liver Fluke, Opisthorchis viverrini is Endemic

Tomoyuki Shirai', Chawalit Pairojku12, Kumiko Ogawa', Hatsumi Naito', Witaya Thamavit3, Watcharabhong Bhudhisawat4, and Nobuyuki Itol

Northeast Thailand has a very high incidence rate of intrahepatic biliary tumors which is believed to closely related to infestation with the liver fluke, Opisthorchis viverrini. This study was conducted to ascertain whether there are any phenotypic differences in such tumors between northeast Thailand and Japan, a country free of liver flukes. Forty one intrahepatic cholangiocarcinomas from patients in northeast Thailand were histopathologically compared with 39 lesions collected i n Japan. The proportions of each type of adenocarcinoma i n the Thailand cases were similar to those of the Japanese cases except that medullary type poorly differentiated tubular adenocarcinoma was only found i n the series from Thailand. Whether the presence of medullary lesions only i n the cases from the area of endemic fluke infection implies differences i n etiology remains i n question. The similarity in the majority of histological types, the inflammatory reactions observed in the bile ducts and the earlier development of tumors i n association with parasites suggests that tumor promotion resulting from liver fluke infection rather than quantitative or qualitative differences in genetic alterations is responsible for the high frequency of cholangiocellular carcinomas in northeast Thailand. Acta Pathol Jpn 42 : 734-739, 1992. Key words : Opisthorchis viverrini, Cholangiocellular carcinomas, Liver fluke

Opisthorchiasis caused by infestation with the liver -




Received May 13, 1992. Accepted for publication August 3, 1992. 'First Department of Pathology, Nagoya, City University, Medical School, Nagoya. 'Department of Pathology, Khon Kaen University, Khon Kaen, Thailand. 3Department of Pathobiology, Faculty of Science, Mahidol University, Bangkok, Thailand. 'Department of Surgery, Khon Kaen University, Thailand. Mailing address : Tomoyuki Shirai, First Department of Pathology, Nagoya City University, Medical School, 1 Kawasumi, Mizuho-ku, Nagoya 467, Japan.

fluke Opisthorchis viverrini (OV) is an endemic parasitic disease in northeast Thailand where approximately seven million people are estimated to be infected (1, 2). This high prevalence due to the habit of eating raw freshwater fish containing the infective metacercariae. The same geographical area is also characterized by a very high incidence of cholangiocellular carcinomas of the liver (3, 4) and many investigations have revealed a direct association between liver fluke infection and the development of cholangiocellular carcinomas (5, 6). Similarly, infestation with Clonorchis sinensis has been linked with intrahepatic bile duct tumors in Hong Kong and Korea (7, 8). Carcinogen contamination of the environment, such as the presence of mycotoxins and nitrosamines as well as nitrosamine precursors in food, is also considered an important contributing factor (9-1 1). Furthermore, Srianujata et a / . (12) reported that salivary nitrate and nitrite levels in northeast Thailand were significantly higher than in Bangkok, which has a low incidence of cholangiocellular carcinomas. This finding suggests that there is a greater possibility of in v i v o formation of N-nitroso compounds in the northeast area which might be associated with tumor induction. Autopsy studies demonstrated that OV infection can induce bile duct proliferation and c holangiofibrot ic changes in the livers. Experimentally, the hamster has also been shown to be susceptible to OV infection and to develop lesions directly analogous to those observed in man (13). Thamavit et a/. (14) and Flavell and Lucas (15) studied the interactions between liver fluke and Nmethylnitrosamine (DMN) in the Syrian golden hamsters and demonstrated that induct ion of chola ng iocellular carcinomas by DMN was significantly enhanced by infection with OV. Thus, it is likely that development of intrahepatic cholangiocarcinomas in northeast Thailand is linked to specific environmental causative factors. This raises

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Acta Pathologica Japonica 42 (1 0) : 1992

the possibility that histopathological features of the tumors may differ from those developing in non-infected area. In the present paper, we describe and compare the histopathological characteristics of cholangiocellular carcinomas obtained in Thailand and Japan.

MATERIALS AND METHODS Forty one cases of intrahepatic bile duct tumors surgically removed in Khon Kaen University (19 8 7 - 1 988) were subjected to this study. Thirty nine cases of cholangiocellular carcinomas obtained by autopsy in Nagoya City University and related hospitals (19791990) were also investigated as parasite-independent controls. Forma lin-fixed paraff i n-embedded tumor tissues were sectioned and routinely processed for hematoxylin and eosin, PAS and Masson trichome staining. In addition, the methods of Grimelius and FontanaMasson were applied to selected materials. Histological categorization of cholangiocellular carcinomas was made according to the classification of the Japanese Society of Biliary Surgery. This includes tubular, papillary, mucinous, signet ring cell, adenosquamous, squamous, anaplastic, undifferentiated, miscellaneous, and unclassified types. Tumors showing bile formation or sinusoidal structures, findings which suggest liver cell origin, were excluded. lmmunohistochemistry of 0fetoprotein and keratin was also applied to selected samples to differentiate cholangiocellular carcinomas from hepatocellular tumors. An 0-fetoprotein antibody (rabbit polyclonal, Nichirei Inc., Tokyo), and P K K l antibody (mouse polyclonal, Labsystems, Helsinki, Finland), recognizing cytokeratins No. 19, 18 and 8 were used. Visualization of proteins was performed by the avidin biotin peroxidase complex (ABC) method (37°C for 30

Figure 1. Thai case of moderately differentiated tubular adenocarcinoma. Note round cell infiltration in the background tissue on the right. HE.

min) with 0.05% diaminobenzidine (for 5 min).

RESULTS The Thailand cases consisted of 24males and 1 7 females, the mean ages being 51.7 and 55.9 years old, respectively. The Japanese controls were 18 males (average age 61.5 years old)and 2 1 females(68.1 years old). Among the cases from Thailand, 88% of the tumors were located a t the peripheral region and 12% a t the hilus, and all were of massive type. 63% of the Japanese cases were located in the hilar region. The differences in these values between Thailand and Japan are statistically significant (P < 0.001). More surgical intervention in peripheral cases than in hilar ones is the major reason for their higher rate in Thailand. Table 1 summarizes data for main histological typing of tumors. They were classified into 7 categories according to the predominant features: tubular adenocarcinoma (well-, moderately- and poorly-differentiated) (Figs. 1 , 2) ; papillary adenocarcinoma (Fig. 3) ; mucinous carcinoma ; squamous cell carcinoma and Table 1. Histological Classification of the Tumors

NE Thailand -

Tubular adenocarcinoma Well-differentia ted Modera tely-diff erent iated Poorly-diff erentiated (medullary type) Papillary adenoca rcinoma Mucinous carcinoma Squamous cell carcinoma Adenosquamous carcinoma a

41 32 (78.0) 5 (12.2) 1 8 (43.9) 9 (22.0) 7 (17.l)a 6 (14.6) 2 ( 4.9) 1 ( 2.4) 0 -


39 32 (82.1) 5 (12.8) 23 (59.0) 4 (10.3) 0 -

2 2 2 1

( ( ( (

5.1) 5.1) 5.1) 2.6)

Significantly different from the Japanese case at P

Histomorphological characteristics of cholangiocellular carcinomas in northeast Thailand, where a region infection with the liver fluke, Opisthorchis viverrini is endemic.

Northeast Thailand has a very high incidence rate of intrahepatic biliary tumors which is believed to closely related to infestation with the liver fl...
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