Sipple'sSyndrome with Liver Tumors Examined by Iodine- 13 1 MIBG and Technetium-99m(V)-DMSA

Hitoya Ohta, Keigo Endo, Toru Fujita, Mitsuru Koizumi, Junji Konishi, Atsuhiko Maki, Keiichirou Mori, Kazue Ozawa, Gen Inoue, and Yutaka Nakano Department ofNuclear Medicine and Surgery, Kyoto University School ofMedicine, Kyoto; and Shinkori Hospital, Osaka, Japan

This case report describes the localization and categorization of tumors using @“Tc(V) dimercaptosuccinicacid and [131l]metaiodobenzylguanidinescans ina veryuncommoncase of medullary thyroid carcinoma associated with pheochromocytoma (Sipple's syndrome) and hepatocellular carcinoma. Technetium-99m(V)-dimercaptosuccinic acid showed accumulation only in medullary thyroid carcinoma, but [131l]metaiodobenzylguanidine scans were positive in both medullary thyroid carcinoma and pheochromocytoma. In advanced Sipple's syndrome, combined use of [@Tc(V)Jdimercaptosuccinic acid and 11311]metaiodobenzylguanidine may be useful for the categorization of tumor mass lesions and planning appropriate therapy.

J Nuci Med 29:1130—1135, 1988

edullary thyroid carcinoma (MTC) is a unique METhODS cancer of the thyroid, accounting for 2% to 9% of all thyroid malignancies. It secretes calcitonin and CEA [@mTC(V)JDMSAand [‘311]MIBGwere preparedas prey and is associated with pheochromocytoma also known ously reported(1,6). Purityof[@mTc(V)]DMSAwas analyzed as Sipple's syndrome. by thin layer chromatography(TLC) [Merck silica gel, devel Iodine-131 metaiodobenzylguanidine ([1311]MIBG), aped with n-butanol/acetic acid/H20 (3:2:3)], and no free first reported as the imaging agent for the pheochro pertechnetateor other @mTcderivatewas detected. [@mTc(V)J DMSA imaging was performed at 2 hr after 10 mCi i.v. mocytoma, has been found to be taken up in other injection, using a large field-of-view gamma camera with a neuroectodermally derived tumors, such as neuro low-energy,highresolution,parallelholecollimator.At 7days blastoma, carcinoid tumors, and MTC (1—5).Tech following [@mTC(V)]DMSAscans, [‘311]MIBGimaging was netium-99m(V)-dimercaptosuccinic acid ([Tc(V)] obtained at 24 and 48 hr after 0.5 mCi i.v. injection,usinga DMSA) specifically accumulates only in MTC among largefield-of-viewgammacamerawitha high-energy,parallel various thyroid cancers (6,7). However, uptake of both hole collimator. Single photon emission computed tomogra radiopharmaceuticals in MTC have been shown to be phy (SPECT)using [@mTc(V)1DMSAwas performedwith 64 variable (8,9). Recently, we had the opportunity to different views over 360°and 15 sec, each view for a 5.6- examine a very uncommon case where recurrent Sip degree rotation of the gamma camera with no attenuation plc's syndrome associated with hepatocellular carci correction.Computerizedtomography(CT)wasperformed2 noma using [‘3IJMIBGand [@mTc(V)]DMSAwas pres wk before [99mTc(V)]DMSAscans. ent. The obtained images suggested that scintigraphic examinations are useful not only for the localization, CASE REPORT but also for categorization of tumors. A 66-yr-oldmalewasadmittedto the hospitalbecauseof paroxysmalhypertensiveattackand righthypochondrialpain. His healthwasgood until he was43 yrold, when he underwent an operationforbilateraladrenalpheochromocytomas. At age ReceivedSept. 30, 1987;revision accepted Feb. 23, 1988. 55 yr, total thyroidectomy was performed because of MTC. Forreprintscontact:HitoyaOhta,Dept. ofNuclear Medicine, His son also had pheochromocytoma accompanied with MTC Kyoto UniversityHospital,54 Shogoin-Kawaharacho,Sakyoku and diagnosed as familiar Sipple's syndrome. On this admis Kyoto 606 Japan. sion, physical examination revealed three hard masses of his

1130 Ohta,Endo,Fujitaetal The Journal of Nuclear Medicine , I

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FIGURE 1 A, B, C, D: CT scans of abdomen. CT revealed multiple liver tumors (arrow) and bilateraladrenal tumors (arrowhead). Histologyrevealed that tumors in A and C were metastatic livertumors from medullarythyroid carcinoma and tumor in B was hepatocellular carcinoma. Adrenal tumors were recurrences of pheochromocytoma.

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FIGURE 3 A, B, C: SPECT images of [@Tc(V)]DMSA at the almost same level with CT. [@Tc(V)]DMSA positive tumors were metastases frommedullarythyroidcarcinoma(A, C), (K:Kidney)whereas [@“Tc(V)JDMSAnegative tumorwas found to be hepatocellularcarcinoma(B).

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FIGURE 6 Histopathology revealed well capsu lated hepatocellular carcinoma (H. E stain x 40).

right neck. Hematologic examination, liver, kidney, and lung Computed tomographic (CT) scans of abdomen revealed function tests, and serum electrolyteswere normal. But serum multiple low density areas in the liver and bilateral adrenal calcitonin level was higher than 50,000 pg/ml (normal range tumors (Fig. 1A,B,C,D). For the categorization of these tu <170 pgJml). Serum noradrenalin was 0.71 ng/ml (0.04 mars, [@mTC(V)1DMSAand [‘3I]MIBGscans were per 0.35 ng/ml), and adrenalin was 0.31 ng/ml (<0.12 ng/ml). formed. [@mTC(V)]DMSAscans showed clear accumulations Urinary noradrenalinwas 1043 ag/day (25—120)and adrena in the neck tumors (Fig. 2A), and focal accumulations were lin was 1,152 @ig/ml(2—30).Serum AFP was 4.4 ng/ml and also seen in the liver (Fig. 2B). Single photon emission corn CEA was 300 ng/ml. Hypertensive attacks were difficult to puted tomographyof the abdomen demonstrated [@mTc(V)] control by medication. DMSA accumulation in regions concordant with low density

Volume 29 a Number 6 a June 1988 1133 areasrevealedby CT(Fig. 3A,C),except one(Fig. 3B). Adrenal was seen in this case. Liver tumors, detected by CT, tumors were negative with [@mTC(V)1DMSA(Fig. 2B). [13h1] were positive with [@mTC(V)]DMSA but negative with MIBG also showed accumulations in the neck tumors (Fig. [‘31IJMIBG,indicating that liver tumors were unlikely 4A) and bilateral adrenal tumors (Fig. 4B). These findings to be metastases from pheochromocytoma. indicated that liver tumors were unlikely to be metastases Following surgical resection of bilateral pheochro from pheochromocytoma, since primary and metastatic tu mocytoma, hypertensive attacks were well controlled mors ofpheochrornocytomas are generallypositive with [‘@‘I] MIBG but negative with [@mTC(V)1DMSAscans. About the without medication. These results indicated that tumor [99mTc(y)]DMSAdefect (Fig. 3B), we interpretedthe possibil specific radiopharmaceuticals could be clinically useful ity of tumor necrosis, because the possibility of metastasis not only for the localization, but also for the categori from pheochromocytoma was low because ofthe lack of['311] zation or pathologic diagnosis of tumors. MIBG accumulation. In orderto control hypertensiveattacks, bilateral adrenal tumors were successfully resected, and his tology revealed the recurrenceof pheochromocytoma. After operation, serum and urinary catecholamine levels fell to ACKNOWLEDGMENTS normal and hypertensive attacks were well controlled without medication. Biopsy ofliver and neck tumors revealed multiple metastasesof MTC to neck lymph nodes and liver (Fig. 5), TheauthorsthankDaiichRadioisotopeLaboratories(To andprimaryhepatocellularcarcinoma(HCC)werealsofound kyo, Japan), Atsuko Ohta, Pie Ohta, and Bungo Onoue for in the liver (Fig. 6). their valuable assistance.

DISCUSSION REFERENCES This case reportdescribesE@mTC(V)]DMSAand [‘@‘I] 1. Wieland DM, Wu JL, Brown LE, Ctal. Radiolabeled MIBO scans involving a very rare case of MTC associ adrenergic neuron blocking agents: adrenal medulla ated with pheochromocytoma and HCC, and presented imaging with ‘311-iodobenzylguanidine.J. Nucl Med for two reasons. First, both [@mTc(V)]DMSAand [‘@‘I] 1980;21:349—353. MIBO were accumulated in MTC. Second, combined 2. Shapiro B, Copp JE, Sisson JC, et al. ‘311-metaiodo use of both reagents provided a good clinical informa benzylguanidine for the locating of suspected pheo chromocytoma; experience in 400 cases (441 studies). tion about the localization and categorization of tumors JNuclMed 1985; 26:576—585. in patients with advanced Sipple's syndrome. 3. Endo K, Shiomi K, Kasagi K, et al. Imaging of med Recent development of endocrinological imaging is ullary carcinoma ofthe thyroid with ‘31I-MIBG.Lan remarkable by using organ or tumor specific radiophar cet1984;ii:233. maceuticals. Localization of['31I]MIBG and [@mTc(V)] 4. Moll LV, McEwan AJ, Shapiro B, Ct al. Iodine-l3l MIBO scintigraphy of neuroendocrine tumors other DMSA in primary and metastatic MTC has been re than pheochromocytoma and neuroblastoma. J Nucl ported (3-10). On the other hand, false negative cases Med 1987; 23:979—988. with [99mTc(V)JDMSA and [‘31I]MIBGscans in the 5. Koizumi M, Endo K, Sakahara H, et al. Computed imaging of MTC are also reported (11). Miyauchi et al. tomography and ‘31I-MIBGscintigraphy in the diag have examined scintigraphic imaging and biodistribu nosis of pheochromocytoma. Ada Radio! 1986; 27:305—309. tion of[@mTc(V)]DMSA in patient with thyroid cancers 6. Ohta H, Yamamoto K, Endo K, et al. A new imaging (7). Specificaccumulationson scintigraphicimages agent for medullary carcinoma of the thyroid. J Nucl with high tumor-to-normal thyroid uptake ratio has Med 1984;25:323—325. been only seen in MTCs among thyroid malignancies. 7. Miyauchi A, Endo K, Ohta H, et al. 99m-Tc(V)- As Jeghers reported (12), tissue distribution of @mTc dimercaptosuccinic acid scintigraphy for medullary thyroid carcinoma. WorldJSurg 1986; 10:640—645. compounds is greatly affected by the technetium val 8. Endo K, Ohta H, Torizuka K, et al. Technetium ency and quality control of [@mTc(V)]DMSA will be 99m(V)-DMSA in the imaging of medullary thyroid indispensable for successful imaging of MTC. carcinoma.JNuclMed 1987;28:252—253. Recent study of [‘311]MIBGscans of MTC patients 9. Clarke SEM, Lazarus CR, Edwards 5, et al. Scintigra in Europe has indicated that scans could be useful not phy and treatment of medullary carcinoma of the thyroid with iodine-l31 metaiodobenzylguanidine. J only for detecting associated pheochromocytoma but NuclMed 1987;28:1820—1825. also in patient with familial MTC or multiple endocrine 10. Clarke SEM. Lazarus CR, Wraight P, et al. Pentava adenomatosis (13). However, it should be noted that lent [@“Tc]DMSA,[‘31IJMIBG,and [@“Tc]MDP-an uptake of both reagentsare not seen in every MTC, an evaluation ofthree imaging techniques in patients with indication of MTC cells heterogeneity or other factors medullary carcinoma ofthe thyroid. JNuclMed 1988; 29:33—38. such as tumor size and location site (8). 11. Hilditch TE, Connell JMC, Elliott AT, Ct al. Poor Most patients with pheochromocytoma are positive results with technetium-99m(V)DMSA and iodine with [‘31I]MIBGbut negative with [@mTC(V)]DMSA as 13 1MIBG in the imaging of medullary thyroid carci

1134 Ohta,Endo,Fujitaetal The Journal of Nuclear Medicine noma.JNuclMed 1986;27:1150—1153. 13. Baulieu JL, Guilloteau D, Delisle MJ, et al. Radioio 12. Jeghers D, Puttemans N, Urbain D, et al. Technetium dinated metaiodobenzylguanidine uptake in medul 99m DMSA uptake by metastatic carcinoma of the lary thyroid cancer, a French cooperative study. Can prostate.JNuelMed 1986;27:1223—1224. cer1987;60:2189—2194.

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