Clinical Significance of Diffusely Increased ¹⁸F-FDG Uptake in the Thyroid Gland

MATERIALS AND METHODS

The study was approved by the Mayo Clinic Institutional Review Board. All patients with diffuse high ¹⁸F-FDG uptake in the thyroid gland from November 2004 through June 2006 were studied. Patients with focal thyroid uptake and those having a history of thyroid cancer were excluded.

Patients were prospectively enrolled at the time each PET examination was done during the enrollment period. Patients who had more than one examination during the study period were counted only once. Distinctly increased ¹⁸F-FDG uptake in the thyroid, resulting in visualization of both thyroid lobes on the 3-dimensional maximum-intensity-projection images, was used as the sole criterion for inclusion. Only the first PET examination demonstrating this finding was studied for each patient. The intensity level was set manually, with liver being set at a light-gray level. Thyroid uptake was always then confirmed on axial PET/CT fused images. Inclusion was decided by a consensus of 2 experienced PET/CT readers.

Uptake in the thyroid was measured in a semiquantitative manner as maximum standardized uptake value (SUV_max) corrected for body weight. The SUV is the decay-corrected ratio between the measured uptake in a region of interest and the expected uptake if ¹⁸F-FDG were distributed evenly throughout the body. A circular region of interest with a fixed diameter of 1.5 cm was placed over the region of highest intensity in each lobe of the thyroid, and uptake was automatically quantified as SUV_max. The higher of the 2 values between the thyroid lobes was used in the statistics.

Patients included in the study were followed for any subsequent clinical or laboratory evaluation of thyroid status. Clinical information was also reviewed retrospectively to determine whether there had been a previous diagnosis of thyroid disease; ultrasound studies of the thyroid or neck; measurements of serum thyroid-stimulating hormone (TSH), thyroid hormones, antithyroglobulin, anti-TPO, or anti-TSH-receptor antibody levels; or use of thyroid hormone medication. This review was done through a detailed study of the medical records.

A control group of patients with no thyroid uptake was also studied. This group was included to determine the proportion of patients already carrying the diagnosis of (nonmalignant) thyroid disease when there was no thyroid uptake. The control group consisted of the same number of patients as those found to have diffuse thyroid uptake. The 2 groups were matched for age and sex. Similarly, the charts of these patients were studied for evidence of any prior benign thyroid disease.

Finally, from those patients with diffuse thyroid uptake and no prior history of thyroid disease, we selected only those having serum TSH measured within 8 wk after the PET study. The relationship between the levels of serum TSH and the SUV_max of their thyroid was studied using bivariate analysis. Similarly, correlation analysis was performed between SUV_max of the thyroid and available TPO antibody levels measured within 6 wk of the PET study.

RESULTS

Between November 2004 and June 2006, 4,732 patients without thyroid cancer underwent ¹⁸F FDG PET of the body. One hundred thirty-eight (2.9%) were found to have diffusely increased ¹⁸F-FDG uptake in the thyroid. Ninety-one were female and 47 male, and their mean age was 58.8 y.

Four of these patients were denied access to their data for research purposes, and 1 patient received no care other than the PET scan at our institution. Therefore, 133 patients with available data were included in the study. In most patients, the indication for the PET study was oncology imaging. The finding of diffusely increased thyroid uptake was reported on the PET scan interpretation as “suggestive of thyroiditis.”

Findings are demonstrated in Figure 3. Sixty-three patients (47.4%) carried the clinical diagnosis of hypothyroidism or autoimmune thyroiditis before undergoing the PET scan, and 56 of those patients were already receiving replacement therapy with thyroxine. Importantly, in 26 of 56 patients already receiving thyroxine replacement therapy at the time of the PET examination, the finding of diffuse increased ¹⁸F-FDG uptake prompted repeated determination of TSH levels; in 7 of those, TSH was found to be above 5 mIU/L. Two of the patients having prior thyroid disease had a history of Graves' disease. One was hyperthyroid on propylthiouracil therapy, and the other euthyroid at the time the PET study was performed. The SUVs in those patients were low, at 3.1 and 3, respectively.

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FIGURE 3. 

Thyroid-related findings in 133 patients with diffuse thyroid ¹⁸F-FDG uptake.

In 4 patients with a prior history of thyroid disease, ultrasound with fine-needle aspiration biopsy performed after the PET scan revealed cytologic features consistent with chronic thyroiditis. All 4 patients were already receiving thyroxine replacement therapy at the time of the PET study. The SUVs_max were 6.5, 8.4, 11.2, and 16.8. Ultrasound and fine-needle aspiration biopsy results from those patients are shown in Table 1.

Thirty-eight (28.6%) of the 133 study patients did not have any further work-up for thyroid disease, usually because of the terminal nature of their primary disease.

Thirty-two (24.1%) of the 133 study patients were examined for thyroid disease after PET. Nineteen patients (14.3%) were found to have either subclinical or overt hypothyroidism or autoimmune thyroiditis. In this group, 14 had elevated TSH values (TSH > 5 mIU/L), 6 of whom had overt hypothyroidism (serum free thyroxine < 0.8 ng/dL). Eleven patients had elevated serum TPO antibody levels (>40 IU/mL), and 9 had ultrasound findings suggestive of chronic autoimmune thyroiditis (Table 2). On the basis of these results, thyroxine replacement therapy was instituted in 12 of 19 patients. Finally, in 13 patients (9.8%), either TSH was normal (11 patients) or ultrasound of the thyroid was negative (2 patients); thyroid autoantibodies were not measured in these patients.

Overall, of the 70 patients with no prior history of thyroid disease, 29 had serum TSH measured and 12 had serum TPO antibodies determined. We found that 14 (48.3%) of the 29 had elevated serum TSH levels (above 5 mIU/L) and 11 (91.7%) of 12 were positive for elevated TPO antibodies.

In the control group of 133 patients without thyroid uptake, only 13 (9.8%) had a prior history of hypothyroidism; 11 of those were receiving thyroxine replacement therapy. This percentage is significantly lower than the corresponding percentage (47.4%) in the group having diffuse increased thyroid uptake (P < 0.0001). Interestingly, no patient in the control group carried a definite diagnosis of chronic autoimmune thyroiditis before undergoing PET, whereas 1 had a prior diagnosis of Graves' disease treated with radioactive iodine.

Twenty-one of the patients with diffuse thyroid uptake and no prior history of thyroid disease had serum TSH levels determined within 8 wk after the PET study. For those 21 patients, serum TSH values correlated with the SUV_max of the thyroid. The mean SUV_max for this group was 8.01 (range, 3.8–14.3), and the mean serum TSH value was 24.83 mIU/L (range, 0.2–159 mIU/L). No significant correlation (P = 0.089) was found between TSH levels and ¹⁸F-FDG uptake in the thyroid (Fig. 4).

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FIGURE 4. 

Plot of serum TSH vs. SUV_max in 21 patients with no prior history of thyroid disease. P value was found to be 0.089.

Serum TPO antibody levels within 6 wk after PET/CT were available in 19 patients. Similarly, serum TPO antibody levels correlated with ¹⁸F-FDG uptake in the thyroid. The mean SUV_max was 7.69 (range, 4.3–13.4), and the mean serum TPO antibody level was 1,855 IU/mL (range, 20–7,520 IU/mL). No significant correlation was found between the levels of TPO antibodies and SUV_max (P = 0.675).

DISCUSSION

The expanding use of PET in clinical practice underlines the need to clarify the clinical significance of and further evaluate incidental findings. To our knowledge, there have been no previous studies regarding diffusely increased ¹⁸F-FDG uptake in patients already receiving replacement thyroxine therapy or other therapy for nonmalignant thyroid disease. In addition, the literature does not address whether the level of ¹⁸F-FDG uptake in the thyroid might itself have clinical significance.

Other studies relative to ours include one by Yasuda et al. (13) in which diffuse ¹⁸F-FDG uptake was found in the thyroid in 36 (3.3%) of 1,102 healthy subjects who underwent PET as part of a cancer screening program in Japan. Kim et al. (8) found, in a retrospective study, diffuse thyroid uptake in 45 (1.1%) of 4,136 patients undergoing PET for non–thyroid-related malignancies. Kang et al. (7) reported this finding in only 8 (0.6%) of 1,330 subjects (999 cancer patients and 331 healthy subjects. Are et al. (14), in a recent study, reviewed the PET examinations of 8,800 patients for thyroid incidentaloma (diffuse or focal ¹⁸F-FDG uptake), looking for evidence of malignancies. They reported that 162 patients (1.8%) were found to have diffuse thyroid uptake, and only 2 of them (1.2%) were found to have malignancy.

In the present study, we found 2.9% of the patients to have diffusely increased ¹⁸F-FDG uptake. This percentage is similar to the 3.3% found by Yasuda et al. (in a healthy population, though) and more than the percentages (0.6%–1.8%) found in the rest of the studies (7,8,14). The assumed exclusion in those studies of patients with any prior history of benign thyroid disease may account for that difference.

Yasuda et al. (13) reported that 7 (19.4%) of 36 had hypothyroidism and 27 (75.0%) of 36 had positive TPO antibodies. Kim et al. (8) found 10 (22.2%) of 45 to have hypothyroidism and 6 (100.0%) of 6 with positive TPO or thyroglobulin antibodies. Similarly, we found 14 (48.3%) of 29 patients to have elevated serum TSH levels and 11 (91.7%) of 12 to have positive TPO antibodies.

Thyroid ultrasonography, fine-needle aspiration biopsies, and thyroid autoantibody studies done on patients with diffuse uptake were all suggestive of chronic lymphocytic (Hashimoto's) thyroiditis. The fact that we did not find any significant correlation between the levels of ¹⁸F-FDG uptake in the thyroid and TSH levels in the serum suggests that even mild or low ¹⁸F-FDG uptake in the thyroid gland should not be ignored. Although not reflecting thyroid status, such uptake may be associated with overt or subclinical hypothyroidism requiring thyroid hormone therapy, dose adjustment, or further evaluation.

In the present study, we also found that even patients receiving replacement therapy for primary hypothyroidism can demonstrate diffusely increased ¹⁸F-FDG uptake in their thyroid gland. This finding appears to be quite common, representing 47.4% of our 133 study patients with the incidental finding of diffusely increased ¹⁸F-FDG uptake.

Yasuda et al. (13) suggested that lymphocytic infiltration of the thyroid may account for increased ¹⁸F-FDG uptake. Autoimmune thyroiditis is characterized by lymphocytic infiltration of the thyroid (15,16). Lymphocytes within the thyroid gland are reportedly the source of TPO antibodies (17,18). It has been suggested that the titer of TPO antibodies reflects the degree of lymphocytic infiltration in the thyroid (19,20). In the present study, no correlation was found between the TPO antibody titers and SUV_max. Therefore, we believe that lymphocytic infiltration, per se, is not solely responsible for the increased accumulation of ¹⁸F-FDG seen in the thyroid of these patients with lymphocytic thyroiditis. Rather, these changes may reflect some other related intrathyroidal process, such as the active formation of fibrosis.

A potential limitation of the current study was its use of the SUV_max of a visually selected region of the thyroid. Placing the region on the transaxial slice of visually greatest activity conforms to common clinical practice. We assumed that because the activity in the thyroid glands was diffusely increased visually, a single measurement should have reflected a reasonable sample and therefore the activity of the underlying disease.

Questions may also arise regarding the reliability of uptake measurements using SUV_max instead of the mean SUV. SUV_max was used with the intention of avoiding error introduced by region-of-interest size and of enhancing reproducibility. Nevertheless, we correlated the 2 values (SUV_max and the mean SUV) in a sample of 21 patients from our study. Using a circular region of interest with a fixed diameter of 1 cm placed over the most intense region of ¹⁸F-FDG uptake, we calculated both SUV_max and the mean SUV and correlated them using bivariate analysis. We found a strong statistical correlation (P < 0.0001) between the 2 values. Therefore, we assumed that uptake measurements done with either SUV_max or the mean SUV would have yielded similar results.

CONCLUSION

The results of the present study suggest that the incidental finding of diffusely increased ¹⁸F-FDG uptake in the thyroid gland is associated with chronic lymphocytic (Hashimoto's) thyroiditis, with or without the presence of hypothyroidism. These findings seem to be unaffected by thyroid status or treatment with thyroid hormone. The level of ¹⁸F-FDG uptake was neither suggestive of the degree of the hypothyroidism nor correlative with the levels of TPO antibodies in the serum. This finding is significant and should always be reported as likely abnormal. Some of these patients may require follow-up, the instigation of thyroid hormone therapy, or adjustment of their thyroid hormone dose. Longer follow-up studies would be needed to determine whether increased ¹⁸F-FDG uptake in euthyroid patients might predict future development of hypothyroidism.