ORIGINAL 

Annals of Nuclear Medicine Vol. 7, No. 3, 147-152, 1993 

Thallium-201 scintigraphy in the evaluation of thyroid nodules A retrospective study of 246 cases 

Mitsuru KOIZUMI, Hideji TAGUCHI, Masabumi GoTO, Toshiharu NOMURA and Tsutomu WATARI 

Department of Radiology, Dokkyo Medical University 

There is controversy at present concerning the value of Tl-201 scintigraphy in the diagnosis of malignant thyroid nodules. The usefulness of Tl-201 scintigraphy in differentiating benign from malignant nodules was evaluated retrospectively. Tl-201 scintigraphy was performed in 101 patients with malignant thyroid nodules and in 145 with benign nodules. Early and late images were examined to compare Tl-201 uptake in nodules and normal thyroid tissue. The visual method resulted in 74 % of sensitivity and 58% of specificity for the detection of malignant nodules including incidental cancers. Excluding incidental cancers, 87 % sensi-tivity and 58 % specificity were achieved. Small cancers, including incidental cancers less than 1.5 cm in diameter and small number of viable tumor cells in a large tumor also gave negative Tl-201 scintigraphic results. Forty-two percent of the benign lesions gave false positive Tl-201 scintigraphic results. 
It is concluded that Tl-201 scintigraphy is a sensitive and useful method to use in diagnos-ing malignant thyroid nodules, but is not a specific method even with late scan, for the detection of malignant thyroid nodules. 

Key words : thallium-201 , thyroid malignancies. 

INTRODUCTION 

Nowadays, thallium-201 (Tl-201) scintigraphy is used in tumor imaging for various diseases. Tl-201 scinti-graphy of thyroid cancer is widely used in Japan. Since the application of Tl-201 scintigraphy to thyroid tumor diagnosis, several authors have reported the utility of the Tl-201 scan in diagnosing malignant thyroid tumors.1-10 Tonami et al. have reported tumor affinity with thallium in malignant thyroid tumors,1 but the specificity of thallium imaging in predicting malignant thyroid tumors has been proved to be low.2,3 Ochi et al, have shown the usefulness of late scan. With a combination of early and late thallium scintigrams, they found that in the majority of carcinoma cases there was persistent accumulation of thallium, and therefore very high sensitivity and specificity could be obtained.4 The investigators claimed that slow washout from a thyroid nodule was characteristic of thyroid cancer. However, controversy is continuing concerning the sensitivity and specificity of thallium scan for thyroid malignance.8-10 
The purpose of this investigation was to clarify the utility of thallium scintigraphy in the diagnosis of thyroid malignancies in a larger number of cases. Thallium-201 images were evaluated for sensitivity and specificity along with information on their histology. 

PATIENTS AND METHODS 

From January, 1981 through December, 1991, patients who were examined by both technetium-99m (and/or Iodine-123) and thallium-201 thyroid scinti-graphy were evaluated. One hundred and one patients with malignant lesion (62 with papillary cancer, 22 with follicular cancer, 3 with squamous cell cancer, 7 with malignant lymphoma, one with medullary thyroid cancer, and 6 with undifferentiated cancer), and 145 patients with benign lesion (65 with follic-ular adenoma, 77 with adenomatous goiter and 3 with cyst) were histologically proven. Multiple nodules had been considered to have a low preva-lence of malignancy compared with solitary nodules, but in recent studies the prevalence of malignancy in solitary nodules was 17 %, while the prevalence of malignancy in multinodular glands was 13%.10 Since the risk of malignancy in multinodular glands is not so low when compared with a solitary nodule, multinodular glands were also included in this study. There were 27 males and 74 females, aged 16-86 yr (mean age+-S.D., 56.5+-17.4 yr) in the malignant cases and fifteen males and 130 females, 19-88 yr (mean age+-S.D., 49.9+-15.8) in the benign cases. 
Following intravenous administration of 74 MBq of thallium-201 chloride, 15 min (early) and 3 hr (late) images were obtained. An Anger type gamma camera (GCA-10A, Toshiba, Japan) fitted with a low energy converging collimator setting an energy at 80 KeV with 30 % window was used. 650 K counts were collected for each image. 
The thallium scan was assessed visually following procedures reported by Ochi et al.4 For the early scans, the images were scored as follows: -, no thallium uptake or less than the uptake at non-tumor site of the thyroid, +, thallium uptake equal to non-tumor thyroid, and 2 +, increased uptake compared with non-tumor site. For late images, the following scoring was used; -, less than or equal to non-tumor thyroid activity, +, slightly higher than non-tumor thyroid activity, 2 +, markedly increased up-take as great as myocardial uptake. The images were obtained in the neck and chest field. 

RESULTS 

The results of thallium-201 scintigraphy and the findings on histological examinations are sum-marized in Table 1. When the criterion for malig-nancy was established as the uptake of Tl-201 in the late scan (2+/+, +/+, 2+/2+ and +/2+), 74% sensitivity and 58% specificity were obtained (Table 2). When malignancy was suspected, if the uptake in the late scan had increased and if no fading of activity had occurred compared with the early scan (+/+, 2+/2+, +/2+), 54% sensitivity and 77 % specificity were obtained. In trying to differentiate a malignancy from a benign lesion, the aim is to correctly diagnose all carcinoma cases. High sensitivity is therefore more important than high specificity. The former criterion for the late scan (2+/+, +/+, 2+/2+, and +/2+) was used in this evaluation. Histological diagnosis is shown in Table 1. The malignant lesions were 62 cases of papillary cancer including 12 cases of recurrent tumor, 22 cases of follicular cancer including 3 cases of recurrent tumor, 3 squamous cell cancers, seven malignant lymphomas and 6 anaplastic cancers. Follicular adenomas (65 cases), adenomatous goiters (77 cases) and operatively confirmed cysts (3 cases) were taken as the control group. 
Among malignant lesions, there were incidental tumors which were not suspected clinically, were found on the surgically resected specimen incidental-ly, and measured less than I cm in diameter. Ten cases of incidental cancer were included in the papillary cancers and were negative in both Tl-201 scintigraphy and technetium scintigraphy. And another type of cancer incidentally found at surgery was a sclerosing variant of papillary cancer. This type consisted of the diffuse scattered nests of cancer cells and proliferation of connective tissue between cancer nests. Five cases of a sclerosing variant of papillary cancer were included in the study. These cases gave negative Tl-201 results. Incidental small cancers and sclerosing variants of papillary cancers were not suspected preoperatively and were inci-dentally found when surgically treating other nodules. Excluding these cases, the sensitivity of thallium scintigraphy increased to 87% and the specificity remained at 58 %.
The sensitivity of thallium scintigraphy for malig-nancy differed according to the cell type. Sensitivity for primary papillary cancer was 58 % (29 out of 50), including incidental cancers, and was 83 % (29 out of 35) excluding clinically occult cancers. Fig. 1 shows a typical positive case of papillary thyroid cancer. Lymph node recurrences of papillary cancers werd all detected (12 cases), but sensitivity for lymph nodes metastases accompanied with the primary cancer was only 38 % (5 out of 13). Sensitivity for primary follicular cancer was 89% (17 out of 19) and all recurrent masses were also delineated (3 cases). Fig. 2 shows a scintigram of follicular thyroid cancer. All lymph node metastasis (5 cases) and hematogenous metastasis (2 cases) with primary follicular cancer was detected. Six cases of anaplastic thyroid cancer were positive in the Tl-201 scintigram. The number of thyroid malignant lymphoma patients was 7. Six patients were at stage IE and had positive Tl-201 scintigrams. One case of systemic disseminated tumor (stage IV) was Tl-201 negative. Three cases of squamous cell cancer of the thyroid were included in this study and one case had a positive scintigram, even though the degree of uptake was not so great. One case of medullary thyroid cancer had a positive Tl-201 scan. 
There were 24 cases of Tl-201 negative differen-tiated papillary and follicular cancers including inci-dential cancers. As mentioned before, there were 15 cases of incidental cancers (10 cases with small papillary cancers and 5 cases with a sclerosing variant of papillary cancer). Two nodules (one papillary and the other follicular cancer) with Tl-201 negative, were 1.5 cm in diameter. There were large tumors in 7 patients and Tl-201 was negative. These large nodules had a minimal viable tumor portion because of necrosis and/or a cystic component, or contained a minimal cancer portion in a large follicular adenoma. 
Figure 3 shows a false positive case of follicular adenoma. High intensity of Tl-201 accumulation was noted, and no or little fading of Tl-201 uptake was noted when the early and delayed scan were compared. 

DISCUSSION 

The information provided by Tl-201 scintigraphy is quite different from that provided by iodine and/or Tc-99m pertechnetate. The mechanism of iodine and Tc-99m pertechnetate uptake are known, but the mechanism of thallium accumulation in a tumor is not yet fully understood. A part of thallium uptake is mediated by Na-K-ATPase, because the thallium uptake in the thyroid gland is ouabain sensitive, where potassium is replaced by thallium.12 Since the behavior of thallium is related, but not identical, to that of potassium, the thallium accumulation is cer-tainly related to tissue cellularity to some extent. Other mechanisms of Tl-201 uptake in tumor are related to blood flow, the co-transport system, immature tumor vessels with leakage into the extra-cellular spaces and the calcium ion channel. Although the underlying mechanisms are not fully known, the delayed Tl-201 elimination from thyroid cancer was shown by a kinetic analysis.8 
Iodine-123 and Tc-99m pertechnetate scinti-graphies are the common methods used in detecting thyroid nodular lesions. However, most nodules are shown as cold nodules in iodine and/or Tc-99m scan, no specific diagnosis can be made. Tonami et al. introduced Tl-201 scintigraphy as a tool for detecting malignant lesions of the thyroid. However, the specificity of Tl-201 was proved to be low.2,3 Ochi et al. showed that a combination of early and late 
Tl-201 scintigraphy could greatly increase the relia-bility of this method. But some reports did not sup-port these results.8-10. The numbers of patients reported were not so large. The present study compared early and late scintigraphic results, and the histology of a greater number of patients showed that Tl-201 scintigraphy with the early and late scans resulted in good sensitivity for malignancy, but specificity was not so high. 
Small cancers less than 1.5 cm in diameter and sclerosing variants of papillary cancer gave negative Tl-201 results. Some large tumors with only small numbers of viable tumor cells also had a negative Tl-201 scintigram. Small nodules less than 1.5 cm in diameter and nodules with a large amount of cystic and/or necrotic components possibly give a false negative in Tl-201 scintigraphy. 
All recurrent thyroid cancers were detected with Tl-201 scintigraphy in this study. Other reports also showed the reliability of Tl-201 scintigraphy for recurrent thyroid cancers.13,14 Tl-201 scintigraphy plays a role in differentiating benign from malignant thyroid nodules, but its pitfalls have to be known. 
Since our strategy for thyroid nodules was the use of positive Tl-201 scintigraphy in practice, cases of both malignant lesions and benign lesions were included. In addition, nodules with negative Tl-201 scintigraphic results were followed up unless other methods, including the fine needle aspiration and thyroglobulin measurement, indicated malignancy. ACKNOWLEDGMENT 

The authors thank Miss Kimiko Usui for help secre-tarial work on this manuscript. 

REFERENCES 

1. Tonami N, Bunko H, Michigishi T, Kuwajima A and Hisada K : Clinical application of Tl-201 scintigraphy with cold thyroid nodules. Clin Nucl Med 2 : 75-81, 1977 
2. Tonami N, Bunko H. Michigishi T, Kuwajima A and Hisada K : Clinical application of Tl-201 scintigraphy in patients with cold thyroid nodules. Clin Nucl Med 3 : 217-221, 1978 
3. Harada T, Ito Y, Shimaoka K, et al : Clinical evalu-ation of Tl-201 chloride scan for thyroid nodules. Eur J Nucl Med 5: 12-130, 1980 
4. Ochi N, Sawa H, Fukuda T, et al : Thallium-201-chloride thyroid scintigraphy to evaluate benign and/ or malignant nodules. Cancer 50 : 236-240, 1982 
5. Makimoto K, Ohmura M, Tamada A : Combined scintiscans in the diagnosis of thyroid carcinomas. Acta Otolaryngol (Stockh) 419: 189-194, 1985 
6. Fukuchi M, Tachibana K, Kuwata K, et al : Thallium-201 imaging in thyroid carcinoma-appearance of lymphonode metastasis. J Nucl Med 19 : 19-196, 1978 
7. Senga O, Miyakawa M, Shirota H, et al : Comparison of Tl-201 chloride and Ga-67 citrate scintigraphy in the diagnosis of thyroid tumor : concise communi-cation. J Nucl Med 23 : 225-228, 1982 
8. Tennvall J, Palmer J, Biorklund A, Moller T, Rans-tam J and Akerman M : Kinetics of Tl-201 uptake in adenomas and well-differentiated carcinomas of the thyroid. A double isotope investigation with Tc-99m and Tl-201. Acta Radiologica Oncology 23 : 55-59. 1984 
9. Bleichrodt RP, Vermey A, Piers DA and Langen ZJ: Early and delayed thallium-201 imaging. Diagnosis of patients with cold thyroid nodules. Cancer 60: 2621-2623, 1987 
10. Hardoff R, Baron E and Sheinfeld M : Early and late lesion-to-non-lesion ratio of thallium-201-chloride uptake in evaluation of cold thyroid nodules. J Nucl Med 32: 1873-1876, 1991 
11. McCall A, Jarosz H, Lawrence AM and Paloyan E : The incidence of thyroid carcinoma in solitary cold nodules and in multinodular goiters. Surgery 100: 1128-1131, 1986 
12. Britten JS, Blank ME : Thallium activation of the Na+. K+_activated ATPase of rabbit kidney. Biochem Biophys Acta 159: 160-166, 1968 
13. Tonami N and Hisada K : Tl-201 scintigraphy in postoperative detection of thyroid cancer: A com-parative study with 1-131. Radiology 136: 461-464. 1980 
14. Iida Y, Hidaka A, Hatabu H, Kasagi K and Konishi J : Follow-up study of postoperative patients with thyroid cancer by thallium-201 scintigraphy and serum thyroglobulin measurement. J Nucl Med 32: 2098-2100, 1991