å¡ CASE REPORT å¡ Hepatocellular Carcinoma Producing Carcinoembryonic Antigen and Carbohydrate Antigen 19-9 Yutaka Usui, Hirotaro Miura, Yuji Kimura*, Shigemitsu Takayama and Morito Nakayama A case of hepatocellular carcinoma producing carcinoembryonic antigen and carbohydrate antigen 19-9 is reported. The serum level of carcinoembryonic antigen was 26,800 ng/ml and carbohydrate antigen 19-9, 5,500 U/ml on the final day. Immunohistochemical study revealed positive monoclonal antibodies for these two antigens within the cytoplasm of the hepatocellular (Internal Medicine carcinoma cells. 31: 791-793, 1992) Key words: tumor marker, immunohistochemical staining, monoclonal antibody

Intr oduction Carcinoembryonic antigen (CEA) is a glycoprotein which is frequently detected in the serum of patients with digestive tract malignancies (1). Carbohydrate antigen 19-9 (CA19-9) is also a cancer-associated antigen which may increase in the serum of patients with gastrointestinal, pancreatic, or biliary tract adeno carcinoma (2, 3). In patients with hepatocellular car cinoma (HCC), the serum CEA as well as CA19-9 may be elevated in some instances. However, the levels are usually mild to moderate (4-8). We describe a case of HCC with extremely high serum CEA and CA19-9 levels, which ultimately reached 26,800 ng/ml and 5,500 U/ml, respectively. Monoclonal antibody staining of the HCC for CEA and CA19-9 revealed evidence that the tumor Case Report cells produced these two antigens. In September 1989 a 71-year-old female was admitted to the hospital because of loss of appetite, right upper abdominal pain, and bilateral lower extremity edema. She had been diagnosed with a well-differentiated adeno carcinoma of the lung, Clara cell type, in February 1987 (Fig. la). A right upper lobectomy was performed at that time. The serum CEA titer was 6.1ng/ml (normal range: below 5.0 ng/ml) before surgery. It fell to 1.6 ng/ml after the1988 lobectomy. In June she was found to have an elevated serum CEA of 10.5 ng/ml. At that time the serum CA19-9 was

51 U/ml (normal range: below 37 U/ml). Full screening for tumor recurrence revealed a solitary mass in the liver. This had not been seen in the previous study. The CEA increased to 79.2ng/ml and the CA19-9, 82U/ml in August 1988. Liver metastasis of the lung cancer was strongly suspected. Chemotherapy with cis-platinum, vindesin, and mitomycin C was initiated. The CEA titer fell to 22.7ng/ml and the CA19-9, 70U/ml. However, both subsequently increased. In May 1989, an abdominal CT showed multiple low-density areas in the liver. At that time the serum CEA titer measured 3,420ng/ml and the CA19-9,and 783U/ml. Loss of appetite pedal edema had been present one month prior to admission. She noted right upper abdominal pain during the previous week. She had no history of excess intake of alcohol, blood transfusion, or exposure to toxic agents. Laboratory data were as follows: total protein 5.0g/dl, albumin 2.9g/dl, asparate amino transferase 89U/1, alanine aminotransferase 135 U/l, lactate dehydrogenase 1 ,135 U/l, gamma-glutamyltrans peptidase 1,570 U/l, alkaline phosphatase 684 U/l, total bilirubin 3.5mg/dl. Serum CEA was 15,600ng/ml, CA19-9 3,200U/ml, and serum alpha-fetoprotein was below 10 ng/ml. Hepatitis B surface antigen and antibody After were admission negative. she was not given any anti-cancer therapy because of poor performance status. She died of peritonitis secondary to perforation of a duodenal ulcer on the ninth hospital day. At that time the serum CEA measured and the CA19-9, 5,500U/ml. An autopsy26,800ng/ml was performed.

From the Department of Internal Medicine and ^Pathological Anatomy Service, Yokosuka Kyosai Hospital, Yokosuka Received for publication August 17, 1991; Accepted for publication February 18, 1992 Reprint requests should be addressed to Dr. Yutaka Usui, the Department of Internal Medicine, Hiratsuka Kyosai Hospital, 9-ll Oiwake, Hiratsuka 254, Japan Internal

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Fig. 3. CA19-9 staining of the liver, showing positive CA19-9 Fig. 1. a) Lung cancer in the right upper lobe showed a well differentiated adenocarcinoma mimicking bronchiolar Clara cell within the cytoplasm of the HCC cells as well as on the surface of the (hematoxylin-eosin, x l40). b) The liver tumor showed hepatocellular bile duct (peroxidase-antiperoxidase technique counterstained by hematoxylin, x70). carcinoma, Edmondson type IV (hematoxylin-eosin, X 140). At autopsy, multi focal nodules up to 5 cm in diameter occupied the liver. Microscopic examination of the liver (Fig. lb) revealed hepatocellular carcinoma, Edmondson type IV, small cell type without a component of chol angiocarcinoma. The liver did not havetocirrhotic change. There were lymphogenous metastases the celiac and pancreatic nodes. There was no evidence of lung adeno carcinoma or other malignancies. CEA staining of the liver, using monoclonal antibody (DAKO-CEA, A5B7: DAKO, which shows no cross reactivity with normal components of the liver) by the peroxidase-antiperoxidase method (Fig. 2) showed that CEA was present only within the cytoplasm of the tumor cells. CA19-9 staining by monoclonal anti-CA19-9 antibody (Centocor, Toray Fuji Bionichs) showed that CA19-9 was detected within the cytoplasm of the neo plastic hepatocytes as well as on the surface of the bile duct (Fig. 3).

Discussion Immunohistochemical studies have revealed that CEA may be present among neoplastic hepatocytes, showing a bile canalicular pattern as seen in non-neoplastic parts of the liver (9, 10). In those reports, polyclonal unabsorbed rabbit anti-CEA immunoglobulins was used for staining. Hirohashi et al (10) utilized a murine monoclonal anti CEA antibody, which stained neither neoplastic nor non-neoplastic hepatocytes. They concluded that the CEA which may be detected by polyclonal antibody was a CEA cross-reactive differentiation antigen, and that CEA of an oncofetal nature was not produced by HCC. A glycoprotein called biliary glycoprotein I (BGP-I) which cross-reacts with CEA (ll) was first described by Svenberg et al in 1979. This glycoprotem is detected in normal human bile and may be considered to be the one which accounts for the elevated serum level of CEA in liver diseases, including HCC. Recently, Koelma et al (12) reported an immuno histochemical study on 26 cases of HCC. Using polyclonal unabsorbed anti-CEA, polyclonal absorbed anti-CEA, and monoclonal anti-CEA which cross-reacts with BGP I, they clearly demonstrated that positive CEA staining seen as a bile canalicular pattern is due to cross-reactivity with BGP-I. There are only a few well-documented reports of

HCC producing CEA. Amano et al (13) described a case of70-year-old male with a serum CEA of7,368 ng/ml and Maeda et al (14) reported a 78-year-old female with a serum CEA of 940ng/ml. They verified positive CEA staining within the cytoplasm of HCC cells. However, Fig. 2. CEA staining ofthe liver, showing CEA present within thethe antibody used for CEA detection was polyclonal in cytoplasm of the HCC cells. There was no CEA on the inner surface bothof cases and the CEA was detected also on the surface the acinar structure, so called "bile canalicular pattern" (peroxidase of the bile canaliculus of the tumor tissue (bile canalicular antiperoxidase technique counterstained by hematoxylin, x70). pattern) as well as on that of the normal liver. Therefore, 792

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Usui et al they could not differentiate the HCC producing CEA from CEA cross-reacting substance. Using monoclonal anti-CEA antibody, we have firstly verified CEA which is produced by HCC cells. CA19-9 is regarded to be less useful as a tumor marker than alpha-fetoprotein in cases of HCC (7, 8). Serum CA19-9 titer in patients with HCC has been reported to increase at most three- to four-fold (8) above the normal level. The mechanism of this elevation is not known (7). To our knowledge, there is no report of HCC with an extremely high titer such as thisstudies case. In addition, there are fewCA19-9 immunohistochemical

diseases, comparison with carcinoembryonic antigen. Cancer 56: 277, 1985. 4) Khoo SK, Mackay IR. Carcinoembryonic antigen in serum in diseases of the liver and pancreas. J Clin Pathol 26: 470, 1973. 5) Macnab GM, Urbanobicz JM, Kew MC. Carcinoembryonic antigen in hepatocellular cancer. Br J Cancer 38: 51, 1978. 6) Richart C, Ruibal A, Monne J, Vilaseca J, Guardia J. Car cinoembryonic antigen in liver disease. Lancet i: 447, 1979. 7) Kew MC, Berger EL, Koprowski H. Carbohydrate antigen 19-9 as a serum marker of hepatocellular carcinoma: comparison with alpha-fetoprotein. Br J Cancer 56: 86, 1987. 8) Leandro G, Zizzari S, Fabris C, et al. Do CA19-9 and TPA play a minor role as compared to AFP in diagnosing primary hepatocellular carcinoma? Oncology 46: 381, 1989. 9) Balaton AJ, Nehama-Sibony M, Gotheil C, Callad P, Baviera of HCC for CA19-9 reported. Atkinson et al (15) EE. Distinction between hepatocellular carcinoma, cholangio reported that CA19-9 was focally positive in only one carcinoma, and metastatic carcinoma based on immunohisto chemical staining for carcinoembryonic antigen and for cytokeratin out of ll cases of clearly HCC by immunoperoxidase assay. The present case demonstrated that CA19-9 19 on paraffin sections. J Pathol 156: 305, 1988. 10) Hirohashi S, Shimosato Y, Ino Y, Kishi K, Ohkura H, Mukojima was produced by the neoplastic hepatocytes. Although T. Distribution of alpha-fetoprotein and immunoreactive car the true nature of CEA and CA19-9 in HCC remain to cinoembryonic antigen in human hepatocellular carcinoma and be determined, it is important to be aware of this rare hepatoblastoma. Jpn J Clin Oncol 13: 37, 1983. ll) Svenberg T, Wahrn B, Hammarstrom S. Elevated level of a tumor when treating intrahepatic mass with a high serum biliary glycoprotein (BGP I) in patients with liver or biliary tract CEA and/or CA19-9 titer. disease. Clin Exp Immunol 36: 317, 1979. 12) Koelma IA, Nap M, Huitema S, Krom RAF, Houthoff HJ. Acknowledgments: We are indebted to Dr. Randall Sellers, Yokosuka U.S. Naval Hospital for a critical reading of this manuscript. Hepatocellular carcinoma, adenoma, and focal nodular hyper plasia: comparative histopathologic study with immunohisto chemical parameters. Arch Pathol Lab Med 110: 1035, 1986. References 13) Amano S, Kataoka H, Hazama F, Nakatake M, Maki A. Alpha fetoprotein and carcinoembryonic antigen producing hepatocel Gold P, Freedman SO. Demonstration of tumor-specific antigens lular carcinoma: a case report studied by immunohistochemistry. Acta Pathol Jpn 35: 969, 1985. in human colonic carcinomata by immunological tolerance and 14) Maeda M, Tozuka S, Kanayama M, Uchida T. Hepatocellular absorption techniques. J Exp Med 122: 467, 1965. Del Villano BC, Brennan S, Brock P, et al. Radioimmunometric carcinoma producing carcinoembryonic antigen. Dig Dis Sci 33: 1629, 1988. assay for a monoclonal antibody-defined tumor marker, CA19-9. 15) Atkinson BF, Ernst CC, Herlyn M, Steplewski Z, Sears HF, Clin Chem 29: 549, 1983. Gupta MK, Arciaga R, Bocci L, Tubbs R, Bukowski R, Debdhar Koprowski H. Gastrointestinal cancer associated antigen in SD. Measurement of a monoclonal-antibody-defined antigenimmunoperoxidase assay. Cancer Res 42: 4820, 1982. (CA19-9) in the sera of patients with malignant and nonmalignant

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Hepatocellular carcinoma producing carcinoembryonic antigen and carbohydrate antigen 19-9.

A case of hepatocellular carcinoma producing carcinoembryonic antigen and carbohydrate antigen 19-9 is reported. The serum level of carcinoembryonic a...
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