FDG PET in thyroid cancer: thyroxine or not?

FDG PET in Thyroid Cancer: Thyroxine or Not? For decades, highly specific functional imaging in thyroid cancer was associated with several disadvantages of hypothyroidism. To achieve an optimal radioiodine uptake in remnant tissue and in malignant thyroid cells, it was necessary to withdraw thyroid hormone medication to increase thyroidstimulating hormone (TSH) secretion to values .30 mIU/L, if possible (1). This kind of functional imaging uses the Na1/I2 symporter in cells originating from the thyroid gland to detect cancer cells scintigraphically. The Na1/I2 symporter gene expression in thyroid cancer cells depends on several characteristics of the malignant cells, particularly on the degree of differentiation of the thyroid carcinoma. In most carcinomas, the Na1/I2 symporter gene expression is decreased (2), and a correlation of tumor stage and degree of decrease has been observed (3). An increased expression in papillary thyroid carcinomas has also been described (4). In cases of poorly differentiated carcinoma and in Hürthle cell carcinoma, radioiodine scintigraphy is frequently negative in individuals with recurrence or metastatic disease. Patients with radioiodine-negative tumor tissue have a significantly poorer prognosis because of the higher malignancy potential of the tumor cells and the lack of radioiodine therapy options. Initial reports on the use of 13-cis-retinoic acid to induce radioiodine uptake in thyroid cancer gave encouraging results (5–7), but it is still too early to recommend this treatment for routine use. In addition to radioiodine, several malignancy-specific and organ-nonspecific radiopharmaceuticals can be used for functional imaging in thyroid cancer. Thallium chloride was used initially (8) and subsequently was replaced by 99mTc-labeled myocardial tracers (9,10). PET imaging with FDG is now accepted as the method of choice with the highest sensitivity and is currently used, if available, in clinical routine. For all clinicians who plan and perform PET scanning, the question arises: Should the thyroid hormones be withdrawn before FDG PET to increase the chance of detecting tumor sites with this technique? Various parameters with possible influence on FDG uptake in thyroid cancer cells and also in other organs must be considered. The organ-specific influence of TSH on thyroid cells through the TSH receptor comes first to the mind of physicians who are experienced with thyroid cancer. In normal thyroid cells, the TSH adenylate cyclase system is most important for the control of growth and function. The receptor belongs to the family of G protein–coupled receptors. It is preferentially coupled to the a subunit of the stimulatory guanyl-nucleotide–binding protein Gsa (11). The metabolic demand can be expected to increase during hypothyroidism. In contrast to benign adenomas, which show a high intensity in immunohistochemical detection of the TSH receptor, Tanaka et al. (12) and Lazar et al. (3) have observed a weak intensity in most thyroid carcinomas. Thyroid carcinomas with Gsa mutations do not concentrate iodine (13). The TSH-receptor expression was correlated with the prognosis (12). But in most malignant cells, other mechanisms of growth control must also be considered. Ohta et al. (14) observed a growth inhibition of some human thyroid carcinoma cells by the activation of adenylate cyclase through the b-adrenergic receptor. In addition to glucose consumption, the expression of several glucose transporter genes and hexokinase activity must be considered as parameters that influence FDG uptake. In a small group of cases, Lazar et al. (3) found an increased expression of GLUT-1 to be associated with a loss of radioiodine uptake in metastases. Their observation agrees with the fact that most tumors take up either FDG or radioiodine (15–18). Matthaei et al. (19) observed in isolated rat adipocytes an increased activity of glucose transporters (primarily GLUT-4) but a decreased total number of transporters in hypothyroidism. Börner et al. (20) found an increased FDG uptake in toxic adenomas. Whether this phenomenon is caused by direct alteration of the TSH receptor, which is associated with an increased iodine uptake, or secondarily by a suppression of TSH release remains to be determined. Which of these mechanisms has more influence on FDG uptake also must be examined. In general, the degree of differentiation affects the TSH dependency because very poorly differentiated thyroid carcinoma cells are less dependent on TSH (because of a loss of intact TSH receptors). The thyroglobulin response to TSH is significantly greater (.10-fold) in thyroid remnant and well-differentiated thyroid tumors than in poorly differentiated tumors (,3-fold) (21). In addition to TSH, the influence of thyroid hormones on several mechanisms that have a role in FDG distribution must be considered. The metabolic activity is decreased in several organs during hypothyroidism because of decreased organ functions. In most cases, this can be expected to hold true for tumor cells. Therefore, the tumor-tobackground ratio can be changed in both directions because FDG uptake in the tumor and in the background can be altered. An increased FDG uptake in a pituitary adenoma after therapy of hypothyroidism has been observed in spite of a size reduction of the tumor (22). Received Feb. 23, 2000; revision accepted Apr. 4, 2000. For correspondence or reprints contact: Frank Grünwald, MD, Department of Nuclear Medicine, University of Frankfurt, Theodor-Stern-Kai 7, Frankfurt/Main 60590, Germany.