ORIGINAL ARTICLE 
Annals of Nuclear Medicine Vol.11, No.4, 285-290, 1997 
The value of Tc-99m tetrofosmin thyroid scintigraphy in patients with nodular goiter 
Umit KARAYALClN,* Feridun CIFTCI ,* Adil Boz,** Seher Boz*** and Binnur KARAYALCIN ** 
Departments of *Endocrinology, **Nuclear Medicine and ***Radiology, Medical School of Akdeniz University, Antalya. Turkey 
The aim of this study is to investigate the value of Tc-99m tetrofosmin (Tc-99m-TF) in conjunction with conventional Tc-99m-pertechnetate (Tc-99m-P) scintigraphy in the differentiation of malignant nodules from benign thyroid nodules. Forty-two patients [(32 females, 10 males; mean age 41+-13 years; twenty-two multinodular goiter (MNG) patients with 58 nodules and 20 solitary thyroid nodules (STN)] were included in the study. Thyroid scintigraphy with Tc-99m-P and Tc-99m-TF, thyroid ultrasonography and fine needle aspiration cytology (FNAC) were performed. After IV injection of 370-550 MBq Tc-99m-TF, images were obtained at 15 minutes and evaluated semiquantitatively by using a five point (0-4) scoring system. Four patients with a hypoactive STN, and I patient with a hypoactive MNG was found to have thyroid malignancy by histopathological examination; 2 of these patients had false negative benign FNAC results. The tetrofosmin uptake score (TUS) was 2-3-3-3 and 3 in these 5 malignant nodules. Five hyperactive (hot or warm) STN with benign FNAC had a TUS of 2-3-3-3-3. All hypoactive (cold) MNG nodules with benign FNAC (n = 21 ) had TUS<2. Our preliminary results suggest that follicular adenomas and thyroid cancers have higher tetrofosmin uptake than benign colloidal goiter nodules. Mitochondrial sequestration of tetrofosmin in benign or malignant follicular cells that proliferate more rapidly than normal follicular cells and/or hypervascularity may be responsible for this. The use of Tc-99m-TF in conjunction with Tc-99m-P thyroid scintigraphy will be helpful in the evaluation of patients with nodular goiter (NG). In patients with a STN, a hypoactive nodule with a high TUS has a higher probability of malignancy; whereas a hyperactive nodule with a high TUS is a follicular adenoma. In patients with MNG, a hypoactive nodule with a high TUS may be suggestive of malignancy despite a benign FNAC result. We think that further studies with Tc-99m-TF are required to confirm these results. 
Key words: nodular goiter, thyroid cancer, technetium-99m tetrofosmin thyroid scintigraphy 
INTRODUCTION 
IN PATIENTS with nodular goiter (NG), differentiation of malignant from benign nodules and selection of patients for operation is a common and important clinical problem. Clinical characteristics of the nodule, ultrasonography 
Received November 20, 1996, revision accepted July 23, 1997 . For reprint contact: Umit Karayalcin, M.D., Department of Endocrinology and Metabolism, Medical School of Akdeniz University, Arapsuyu, 07070, Antalya, TURKEY. E-mail : umit @ hipokrat. med, akdeniz, edu , tr 
(US), radionuclide thyroid imaging and fine needle aspiration cytology (FNAC) results are used in combination in this respect.1 Although FNAC is currently considered the 'gold standard,' false negative and false positive results may occur2; this is especially true in patients with multinodular goiter (MNG) in whom it is clinically important to identify the suspicious nodule to perform FNAC. In solitary thyroid nodule (STN) and in MNG, there are no specific ultrasonographic findings which can differentiate a benign from malignant nodule.3 With I-131 thyroid scintigraphy, the probability of malignancy in a hypoactive STN is 15-20%; this probability is 5-lO% in hypoactive MNG and 0-4% in hyperactive STN. Because I-131 is non-specific in diagnosis of malignancy, different radionuclides such as Cs-131 chloride, Ga-67 citrate, Se-75 chloride, Tl-201 chloride and technetium-99m methoxy-isobutyl-isonitrile have been tried, but specific diagnosis of a malignant nodule could not be established.1 Technetium-99m tetrofosmin which is a radionuclide used in myocardial perfusion studies, is also a non-specific tumor seeking agent, probably due to its mitochondrial uptake by rapidly proliferating malignant cells.4 In the light of these facts, we decided to investigate the possible value of Tc-99m-TF thyroid scintigraphy in the evaluation of patients with NG. 
MATERIALS AND METHODS 
Patients 
Forty-two patients (10 males, 32 females; mean age 41 d: 13 years) with NG who attended the outpatient clinic of the Department of Endocrinology and Metabolism, Medical School of Akdeniz University were included in the study. The study design was explained to the patients and informed consent was obtained from them. Thyroid ultrasonography, Tc-99m-P, Tc-99m-TF thyroid scintigraphy and FNAC were performed in all patients. Twenty-two patients had MNG with 58 nodules (34 hypoactive, 24 hyperactive). FNAC was performed from the hypoactive nodule which was the dominant nodule by physical examination (i.e. FNAC was performed from 22 hypoactive MNG nodules). Twenty patients had STN; five had a hyperactive nodule and were thyrotoxic (toxic adenoma) whereas 15 had a hypoactive nodule and were euthyroid. FNAC was performed on all hypoactive and hyperactive nodules of patients with STN. The characteristics of the patients are summarized in Table 1 . 
Methods 
Tc-99m-TF thyroid scintigraphy protocol.' After IV injection of 370-550 MBq Tc-99m-TF, images were obtained at 15 minutes and evaluated semiquantitatively by two Nuclear Medicine specialists with a 5 point scoring system [Tetrofosmin Uptake Score (TUS): 0 = no significant uptake, 1 = uptake greater than background but less than thyroid, 2 = uptake equal to thyroid, 3 = uptake greater than thyroid, 4 = prominent uptake and no visualization of extra nodular thyroid tissue]. A Toshiba GCA-602A gamma camera with a LEAP collimator was used and static images were obtained for 5 minutes with a 256 x 256 matrix. Tc-99m-P thyroid scintigraphy protocol; After IV injection of 111MBq Tc-99m-P, static images were obtained at 30 minutes from the anterior position for 400,000 counts with a pinhole collimator. The same 5 point scoring system was used for Tc-99m-P [Pertechnetate Uptake Score (PUS)]. FNAC: FNAC was performed from the solitary nodule or from the dominant nodule/or nodules of MNG patients by the same clinician. A22 gauge needle was used and a standard technique was used as described elsewhere.5 The smear of the aspirates was stained with Papanicalau and examined by the same Cytopatholog. The results were interpreted as malignant, benign, suspicion of malignancy and interpretation not possible (a second FNAC was performed on these patients). 
RESULTS 
The TUS, PUS and FNAC results for patients with STN and MNG are shown in Tables 2 and 3, respectively. Twenty patients had STN; 15 were hypoactive (PUS < 2) and 5 were hyperactive (PUS = 3 or 4). Twelve of the hypoactive nodules had a TUS of 0 (n = 1), 1 (n = 6) or 2 (n = 5). One patient with a TUS of 2 had papillary carcinoma (Fig. 1). The other 3 hypoactive nodules had a TUS of 3-3-3 (2 patients had follicular and one patient had papillary carcinoma). The TUSs of 5 hyperactive nodules were 2-3-3-3-3 and the FNAC of these nodules was benign (Fig. 2). Twenty-two patients had MNG with 58 nodules. All hypoactive MNG nodules (n = 34, PUS < 2) with benign FNAC had TUS < 3 [TUS = 0, 1 (n = 12); TUS = 2 (n = 21) (Fig. 3) and TUS = 3 (n = 1)]. One patient with a benign FNAC was operated on because of clinical suspicion of malignancy and was found to have follicular Ca. The TUS of this patient was 3 (Fig. 4). On the other hand, hyperactive MNG nodules [PUS > 2 (n = 24)] with benign FNAC had a TUS of 2 (n = 19) or 3 (n = 5). Results for the STN and MNG patients are summarized in Table 4. FNAC of STN revealed 2 malignant, 17 benign and 1 suspicious nodule. In MNG patients, there were 20 benign and 2 suspicious nodules. Ten patients were operated on (5 STN and 5 MNG) either because of malignant or suspicious FNAC or clinical judgment of a high probability of malignancy. Histopathological examination revealed that 5(50%) of these nodules were malignant (2 papillary and 3 follicular thyroid cancers). The characteristics of these 5 malignant cases are summarized in Table 5. Four were found in STN and 1 was found in MNG. All had a PUS of 0 (hypoactive) and TUS of 2-3-3-3-3. Four nodules were solid and 1 had a mixed echo pattern on US. Two patients with benign FNAC were operated on because of clinical suspicion of malignancy and were found to have papillary and follicular Ca. The TUSs of these patients were 3 and 3. 
DISCUSSION 
In the evaluation of patients with NG, there is a need for a better imaging method. This is especially true in areas of iodine deficiency for patients with MNG, since the clinician wants to perform FNAC on the nodules most highly suspected of malignancy. In addition to this, in these patients, the rate of malignancy may in fact be higher than currently expected, since many patients with benign FNAC and low probability of clinical suspicion of malignancy are not operated on. This may explain the higher rates of thyroid cancer found at autopsy than clinical thyroid cancer prevalence. T1-201 and Tc-99m methoxyisobutylisonitrile (MIBI) have been proposed as useful radionuclides in the differentiation of malignant from benign nodules by some authors,6.7 but FNAC is currently considered the gold standard in this respect.8 Tc-99m-TF, which is primarily used as a myocardial perfusion scanning agent,9-11 has also been reported to accumulate in different malignancies such as breastl2,13 and lung cancer.14-17 Recently, its value in evaluation of thyroid cancer metastasis has been shown.18,19 Although the exact mechanism of uptake in malignant tissues is not clear, it is currently thought that mitochondrial sequestration in highly proliferating malignant cells may be responsible for this.4 In patients with a hypoactive STN and benign FNAC, we found low (< 2) TUS, whereas in 4 hypoactive STN with thyroid cancer, TUS was high. This means that, high TUS in a hypoactive STN greatly increases the probability of thyroid cancer and these patients should be operated on. Conversely, low TUS in these patients decreases thyroid cancer probability, and if there is no clinical suspicion they should be followed up. It is currently accepted that hyperactive nodules with autonomous function (toxic adenomas) are, for all practical purposes, benign.20 High TUS found in 5 hyperactive benign STN suggests that, benign follicular adenomas whose cell proliferation rates are higher than normal thyroid follicular cells, also accumulate more Tc-99m-TF than normal thyroid tissue. In patients with MNG, all hypoactive benign nodules were found to have low TUS. Nevertheless, a follicular carcinoma was found in a hypoactive nodule whose FNAC was benign, but who had a TUS of 3. We suggest that, in patients with MNG and hypoactive nodules, if the TUS of the nodule is high, operation should be considered regardless of the result of FNAC. Such a protocol may increase the underestimated rate of thyroid cancer in MNG, and we have decided to start this protocol in our center to those patients who have no contraindication for thyroidectomy. In patients with MNG and hyperactive, benign nodules, high TUS may reflect high follicular cell proliferation rates of autonomous foci of goitrous tissue. These patients must be carefully evaluated for subclinical thyrotoxicosis with a TRH test. We believe that the probability of thyroid cancer is very low and they should not be operated on for this reason. In conclusion, our study suggests that a high TUS is not specific for thyroid cancer; this may also occur in thyroid adenomas and autonomous goitrous tissue. But when used appropriately as described in conjunction with conventional thyroid scintigraphy and FNAC, Tc-99m-TF thyroid scintigraphy may prove to be an important diagnostic tool in the evaluation of patients with NG, a hypoactive nodule with high TUS has a higher probability of malignancy, whereas a hyperactive STN with high TUS is a follicular adenoma. Further studies with Tc-99m-TF are required to confirm these results. 
REFERENCES 
1. Rojeski MT, Gharib H. Nodular thyroid disease evaluation and management. N Engl J Med 313: 428-434, 1985.
2. Ernest L, Mazzaferri MD. Management of a solitary thyroid nodule. N Engl JMed 328: 553-559, 1993.
3. Brander A. Viikinkoski P, Tuuhea J. Clinical versus ultrasonographic examination of the thyroid gland in common clinical practice. J Clin Ultrasound 20: 37-42, 1992.
4. Songadale JA, Younes A, Maublant J, Veyre A, Platts EA, Pickett RD. Uptake of Tc-99m tetrofosmin In isolated mitochondria: evidence for an active mechanism (Abstract). J Nucl Med 35: 46P-47P, 1994.
5. Hamming JF. Goslings BM, van Steenis GJ. The value of fine needle aspiration biopsy in patients with nodular thyroid disease divided into groups of suspicion of neoplasms on clinical grounds. Arch Intern Med 150: 113-116, 1990.
6. Kut O, Biberoglu S, Saydam S, et al. Utility of early and delayed Tl-201 scintigraphy in the evaluation of thyroid nodules. Eur J Nucl Med 22: 908, 1995.
7. Jarzab B. Puch Z, Roskosz J, et al. Tc-99m-MIBI in the assessment of locally advanced thyroid cancer. Eur J Nucl Med 22: 769, 1995.
8. Ernest L. Mazzaferi MD. Management of a solitary thyroid nodule. N Engl J Med 328: 553-559, 1993.
9. Diwakar J, Frans J. Wackers TH. Biokinetics of Techne-tium-99m-tetrofosmin: Myocardial perfusion imaging agent: Implications for a one-day imaging protocol. J Nucl Med 34: 1254-1259, 1993.
10. Smith FW. Smith T, Gemmell H. Phase I study of Tc-99m diphosphine (P53) for myocardial imaging. J Nucl Med 32: 967, 1991.
11. Higley B. Smith FW, Smith T. Technetium-99m-1,2-bis (bis(2-ethoxyethyl) phosphino) Ethane: Human biodistribution, dosimetry and safety of a new myocardial perfusion agent. J Nucl Med 34: 30-38, 1993.
12. Adalet I, Demirkol O, Muslumanoglu M. Tc-99m tetrofosmin scintigraphy in the evaluation of palpable breast masses-preliminary results. Eur J Nucl Med 22: 742, 1995.
13. Schillaci O, Scopinaro F. Danieli R. Technetium-99m-tetrofosmin scan in breast lesions-preliminary results. Eur J Nucl Med 22: 878, 1995,
14. Basoglu T, Sahin M, Coskun C. Technetium-99m-tetrofosmin uptake in malignant lung tumors. Eur J Nucl Med 22: 687-689, 1995.
15. Erdil TY, Onsel C, Sozudogru N. The value of Tc-99m tetrofosmin scintigraphy in the visualization of neoplastic lung lesions. Eur J Nucl Med 22: 774, 1995.
16. Gdznkara I, Ozpacacl T, Sahin R. Utility of tetrofosmin as a tumor detector on lung Ca. Eur J Nucl Med 22: 843, 1995.
17. Lopez A, Tabuenca MJ, Novao N. Single photon emission tomography in broncogenic carcinoma using 99m-Tc-tetrofosmin. Eur J Nucl Med 22: 843, 1995
18. Gallowitsch HJ, Kresnik E. Mikosch P. Tc-99m SESTAMIBI and Tc-99m tetrofosmin scintigraphy: alternative scintigraphic methods in follow-up of DTC? First results. Eur J Nucl Med 22: 909, 1995.
19. Klain M, Maurea S, Lastoria S, Cuocolo A. Colao A, Salvatore M . Technetium-99m-tetrofosmin imaging of differentiated mixed thyroid cancer. J Nucl Med 36: 2248-2251, 1995.
20. Howard JD. Donald AM, Michael K. Advances in the management of patients with thyroid disease. Sem Nucl Med 26: 205-220, 1995.