CASE REPORT Annals of Nuclear Medicine Vol. 14, No. 6, 485-488, 2000 Discordant uptake of Tc-99m PMT and Tc-99m GSA by two hepatocellular carcinoma lesions Yoshio TANABE, Masayuki HASHIMOTO, Yasufumi OHUCHI, Fumiko KODAMA and Toshihide OGAWA Department of Raidiology, Faculty of Medicine, Tottori University Tc-99m PMT and Tc-99m GSA can be taken up by hepatocellular carcinoma (HCC), but there has been no report concerning HCC showing accumulation of both of Tc-99m PMT and Tc-99m GSA. In this paper we describe a case of two simultaneously developed HCCs, one of which took up both tracers but the other took up neither of them. Key words: Tc-99m PMT, Tc-99m GSA, hepatocellular carcinoma INTRODUCTION SCINTIGRAPHY with Tc-99m-Sn-N-pyridoxyl-5-mcthyl-tryptophan (Tc-99m PMT) or Tc-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin (Tc-99m GSA) is used for the evaluation of liver function.1-4 It is important to know the entire or regional hepatic function for treating hepatocellular carcinoma (HCC) and this significantly relates to the choice of the therapy. In addition, as these tracers are thought to be taken up by HCC in association with the degree of differentiation, they make it possible to estimate the grade of malignancy of HCC and the involvement of extrahepatic sites, and to use them in evaluating the efficacy of therapy.5-7 We routinely perform Tc-99m PMT and Tc-99m GSA studies combined with other radiographical examinations of the liver when HCC is suspected, and several kinds of therapies are taken into consideration. This report describes a patient with two HCCs. The findings of radiographical studies other than scintigraphy for the tumors were similar, but the results of Tc-99m PMT and Tc-99m GSA studies were quite discordant. CASE REPORT A 76-year-old woman was referred to our hospital for Received August 17, 2000, revision accepted October 23, 2000. For reprint contact: Yoshio Tanabe. M.D., Department of Radiology. Faculty of Medicine, Tottori University, 36-1, Nishicho, Yonago 683-8504, JAPAN. further examination of liver tumors suspected of being HCC, which had been detected by abdominal ultrasonography performed as a periodic workup for liver cirrhosis caused by hepatitis C virus infection. On admission, the laboratory evaluation was remarkable for a GOT level of 108 IU/L (normal 0-40 IU/L), and a GPT level of 97 IU/ L (0-47 IU/L), and retention of indocyanine green in plasma after 15 min (ICGR-15) was 26% (0-10%). The serum protein induced by the vitamin K absence-II (PIVKA-II) level had increased to 2.2 AU/mL (<=0.1 AU/mL), whereas the level of the serum a-fetoprotein (AFP) was normal. Dynamic CT imaging revealed two well-enhancing tumors in contact with each other in the anterior superior segment of the liver. Tc-99m PMT scintigraphy showed no intrahepatic bile stagnation on sequential images for 60 minutes. But a solitary high uptake was found in the hepatic dome, which became more apparent on the planar abdominal image obtained 3 hours later (Fig. 1). Tc-99m GSA SPECT images of the liver obtained after sequential upper abdominal imaging for 20 minutes identified a humpy uptake in the area corresponding to high accumulation of Tc-99m PMT and a cold area adjacent to it (Fig. 2). CT during arterial portography (CTAP) showed the two tumors as filling defects and CT arteriography (CTA) depicted them as well enhancing masses (Fig. 3). On hepatic angiogram, the tumors accompanied irregular vessels and stains (Fig. 4). According to the radiological results and the laboratory data, the two liver tumors was diagnosed as HCC and transcatheter arterial embolization therapy (TAE) was performed. On dynamic MRI performed later to evaluate the effect of TAE, it was clearly seen that of the two tumors the supero-medial one showed signs of considerable accumulation of Tc-99m PMT and Tc-99m GSA, and the other which was located right infero-laterally to it showed no sign of accumulation of these tracers (Fig. 5). DISCUSSION Tc-99m PMT is taken up by hepatocytes and excreted into bile, and therefore allows us to assess hepatobiliary function of the liver.8 It has also been reported to concentrate in HCC in liver and its metastatic sites,5,9 Its mechanism of uptake by HCC is thought to be due to the hepatocytic function remaining in the tumor. The uptake of hepatobiliary imaging agents is correlated with the degree of histologic differentiation of HCC.10 Tc-99m GSA is one of the synthetic radioligands which bind specifically to asialoglycoprotein receptors (ASGP-R) on the membrane of hepatocytes. After binding, the ligand-receptor complex is transported to hepatic lysosomes where the ligand is catabolized.11 Due to this characteristics, Tc-99m GSA can be used for evaluating a normally functioning hepatocyte mass.3,4,12 Receptor-mediated binding with subsequent cellular endocytosis usually does not occur in HCC, because surface asialoglycoprotein receptors are lost during malignant dedifferentiation.13 But it has also been pointed out that some well-differentiated HCCs contain ASGP-R,14 and such tumors take up ASGP-R binding radiopharmaceutical.6 By keeping this characteristic in mind, it is possible to diagnose hepatic tumors qualitatively. The patient had developed two HCCs in the anterior superior segment of the liver. Progressive increase in the arterial supply and parallel decrease in the portal supply are pointed out as the grade of malignancy increases in various types of hepatocytic nodules in the experimental and clinical investigation.15,16 According to the CTAP and CTA, both of the tumors in this patient had the same kind of blood supply with decreased portal and increased arterial blood flow, which was consistent with dedifferentiated HCC,15 but the tumors showed quite different findings in Tc-99m PMT and Tc-99m GSA scintigraphy. One of the tumors took up Tc-99m PMT and Tc-99m GSA, but the other took up neither of them. Although the reason for this discordance cannot be fully explained, it may be due to a cellular functional difference between the two HCCs which was not demonstrable by other radiological examination including CTAP and CTA. The differentiation of HCC is related to the response to TAE or percutaneous ethanol injection therapy and the chemosensitivity.17,18 In addition, HCC can be composed of tumor cells of more than one cellular differentiation,19 so that evaluation of cellular differentiation of HCC appears to be essential for treating HCC. The hepatocytic function of HCC is closely associated with the degree of differentiation of the tumor cells.7 Although there is need for further investigation into the correlation with histopathology, scintigraphical study with Tc-99m PMT or Tc-99m GSA, which can noninvasively demonstrate the characteristics of HCC on the basis of the hepatocytic function of tumor cells as in this patient, may play a role in the management of HCC. ACKNOWLEDGMENT The authors thank Ken-ichi Endou, B.S. and Tsuyoshi Nishio, B.S. for their technical assistance. REFERENCES 1. Shimomura O, Takahashi M, Tsuji A, Takagi Y, Tomiguchi S, Koga Y, et al. Evaluation of hepatic function by hepatobiliary scintigraphy using factor analysis. KAKUIGAKU (Jpn J Nucl Med) 26: 145-153, 1989 2. Gon J, Nakagawa T, Maeda H, Nakamura H, Tashiro T, Matsuoka Y, et al. Evaluation of postoperative hapatobiliary function by deconvolution analysis of hepatobiliary image data by 99mTc-N-pyridoxyl-5-methyltryptophan. Radioisotopes 37: 7-14, 1988. 3. Sasaki N, Shiomi S, Iwata Y, Nishiguchi S, Kuroki T, Kawabe J, et al. Clinical usefulness of scintigraphy with 99mTc-galactosyl-human serum albumin for prognosis of cirrhosis of the liver J Nucl Med 40: 1652-1656, 1999. 4. Kudo M, Todo A, Ikekubo K, Hino M. Receptor index via hepatic asialoglycoprotein receptor imaging: correlation with chronic hepatocellular damage. Am J Gastoenterol 87: 865-870, 1992. 5. Hasegawa Y, Nakano S, Ishiguro S, Imaoka S, Sasaki Y, Tanaka S, et al. Comparison of delayed hepatobiliary imaging using 99mTc-Sn-N-5-methyltryptophan and 67Ga-citrate imaging for diagnosis of hepatocellular carcinoma Eur J Nucl Med 14: 414-418, 1988. 6. Saito K, Koizumi K, Abe K, Goto Y, Seki T. Potential for qualitative diagnosis of tumors and tumorous lesions in the liver with Tc-99m-GSA SPECT-correlation with pathological evaluation and MRI findings. Ann Nucl Med 12: 275-280, 1998. 7. Hasegawa Y, Nakano S, Hiyama T, Sobue T, Yoshida H, Sasaki Y, et al. Relationship of uptake of Technetium-99m(Sn)-N-pyridoxyl-5-methyltryptophan by hepatocellular carcinoma to prognosis. J Nucl Med 32: 228-235, 1991. 8. Azuma-Kato M. Tc-99m(Sn)-N-Pyridoxylaminates: A new series of hepatobiliary imaging agents. J Nucl Med 23: 517-524, 1982. 9. Hasegawa Y, Nakano K, Ibuka T, Hashizume Y, Sasaki S, Imaoka S, et al. Concentration of 99mTc-Sn-N-pyridoxyl-5-methyltryptophan, a biliary agent, in distant metastases of hepatoma. Eur J Nucl Med 10: 255-258, 1985. 10. Cavlet X, Pons F, Bruix J, Bru C, Lomena F, Herranz R, et al. Technetium-99m DISIDA hepatobiliary agent in diagnosis of hepatocellular carcinoma: relationship between detectability and tumor differentiation J Nucl Med 29: 1916-1920, 1988. 11. Stadalnik RC, Vera DR, Woodle ES, Trudeau WL, Porter BA, Ward RE, et al. Technetium-99m NGA functional hepatic imaging: preliminary clinical experience J Nucl Med 26: 1233-1242, 1985. 12. Wu J, Ishikawa N, Takeda T, Tanaka Y, Pan XQ, Sato M, et al. The functional hepatic volume assessed by 99mTc-GSA hepatic scintigraphy. Ann Nucl Med 9: 229-235, 1995. 13. Kurtaran A, Li S-R, Radere M, Leimer M, Muller C, Pidlich J, et al. Technetium-99m-galactosyl-neoglycoalbumin combined with iodine-123-try-(A14)-insulin visualizes human hepatocellular carcinomas. J Nucl Med 36: 1875-1881, 1995. 14. Hyodo I, Mizuno M, Yamada G, Tsuji T. Distribution of asialoglycoprotein receptor in human hepatocellular carcinoma. Liver 13: 80-85, 1993. 15. Matsui O, Kadoya M, Kaneyama T, Yoshikawa J, Takashima T, Nakamura Y, et al. Benign and malignant nodules in cirrhotic livers: distinction based on blood supply. Radiology 178: 493-497, 1991. 16. Conway JG, Popp JA, Thurman RG. Microcirculation of hepatic nodules from diethylnitrosamine-treated rats. Cancer Res 45: 3620-3625, 1985. 17. Yamashita Y, Matsukawa T, Arakawa A, Hatanaka Y, Urata J, Takahashi M. LTS-guided liver biopsy: predicting the effect of interventional treatment of hepatocellular carcinoma. Radiology 196: 799-804, 1995. 18. Shimada M, Takenaka K, Kawahara N, Yamamoto K, Shirabe K, Maehara Y, et al. Chemosensitivity in primary liver cancers: evaluation of the correlation between chemosensitivity and clinicopahological factors. Hepatogastroenterolgy 43:1159-1164, 1996. 19. Kenmochi K, Sugihara S, Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC. Liver 7: 18-26, 1987.