Abstract
Background:
Recently, we reported that the thyroglobulin (Tg) doubling time (DT) was the most potent prognostic factor in patients with papillary thyroid carcinoma (PTC) who underwent total thyroidectomy. Interestingly 16.2% of the study patients had a decrease in Tg levels over time, giving negative values in Tg-DT. These patients had an excellent outcome. However, most of the patients did not receive ablation with radioactive iodine. Therefore, whether the Tg in these patients was derived from persistent disease or residual thyroid tissue could not be concluded. To resolve this question, we measured serum Tg levels in patients with medullary thyroid carcinoma (MTC) who underwent total thyroidectomy using similar surgical techniques for the treatment of PTC.
Methods:
Twenty-seven consecutive patients with MTC who underwent total thyroidectomy were selected. Of them, five patients with antibodies to Tg were excluded from the study. In the remaining 22 patients, serum Tg levels were measured before and after surgery. None of the patients received radioactive iodine ablation. They were prescribed levothyroxine as a replacement for the lost thyroid function.
Results:
Serum Tg levels were detectable preoperatively, while postoperative serum Tg levels were lower than the detectable level, 0.5 ng/mL, in all 22 patients.
Conclusions:
The results indicate that most of the patients with detectable Tg levels and negative Tg-DT values after total thyroidectomy for PTC in our previous study had persistent disease, and that their serum Tg was not from residual thyroid tissue, suggesting that up to 50% of patients with persistent PTC have a decrease in serum Tg levels in response to thyroid-stimulating hormone–suppressive therapy.
Introduction
Patients and Methods
We selected 27 consecutive patients with MTC who underwent total thyroidectomy with central compartment dissection with or without modified neck dissection between January 2007 and March 2009. None of the patients had PTC or follicular thyroid carcinoma, tumors that produce Tg. Our total thyroidectomy technique for thyroid cancer is basically extracapsular removal of the thyroid gland. Due to anatomical situations, however, subcapsular dissection may be performed only in the vicinity of the superior parathyroid glands, which we usually try to preserve. Estimated residual thyroid tissue with this procedure is <50 mg. Serum levels of TSH were measured before and 3 months after surgery as part of routine clinical studies. Frozen-stored serum samples, remaining from these studies, were subjected to measurement of Tg and Tg antibody. Five patients were positive for Tg antibody. They were excluded from the study, since the presence of Tg antibody may affect Tg measurement. There were 13 women and 9 men, ages 21–68 years (median: 49 years).
Serum Tg was measured with the Elecsys Tg Electrochemiluminescence Immunoassay (Roche Diagnostics GmbH), which has a lower limit of detection of 0.5 ng/mL. The assay method for TSH was the ARCHITECT TSH Chemiluminescent Microparticle Immunoassay (Abbott), which has a sensitivity of 0.003 mIU/L. Presence of Tg antibody was assessed with the Elecsys Anti-Tg Electrochemiluminescence Immunoassay (RSR Ltd.), and >28 IU/mL was regarded as positive for Tg antibody.
No patient underwent thyroid remnant ablation. The patients were prescribed levothyroxine as a replacement therapy after surgery.
Results
Before surgery, the median TSH level was 1.82 mIU/L (range: 0.7–2.98 mIU/L) and median Tg level was 17.8 ng/mL (range: 2.0–74.3 ng/mL). In all patients, Tg levels 3 months after total thyroidectomy decreased to <0.5 ng/mL. Serum TSH concentrations at the time of Tg measurement were within the normal range in 18 patients, mildly suppressed in 2 patients, and mildly elevated in 1 patient (range: 0.03–22 mIU/L, median: 0.271 mIU/L).
Discussion
In 2011, we reported that 16.2% of patients with PTC who underwent total thyroidectomy and who did not show Tg antibody had detectable Tg levels that decreased over time during TSH suppression therapy without radioactive iodine ablation (6). These patients had an excellent prognosis. There are two possibilities regarding the origin of Tg in these patients. The origin might be from residual thyroid tissue, or from persistent PTC disease. In the case of detectable Tg being a product of residual thyroid tissue, TSH suppression therapy will reduce Tg production from this tissue. Most articles showed that patients after total or nearly total thyroidectomy have detectable Tg levels before radioactive iodine ablation (7,8). If the actual extent of intended “total thyroidectomy” is less than total removal of the thyroid gland leaving a large amount of thyroid tissue, postoperative serum Tg level should be detectable. However, the present study showed that the postoperative serum Tg levels were less than the lowest detectable level, 0.5 ng/mL, in all patients with MTC who underwent total thyroidectomy using our surgical techniques, similar for PTC, although none of them received radioactive iodine ablation. So, this fact strongly argues against this possibility. Therefore, most of the patients with detectable Tg after total thyroidectomy in our previous study should have had persistent disease, and their serum Tg was not from residual thyroid tissue. TSH can stimulate Tg production from PTC, especially when the cancer is well differentiated (5). Thus, the patients with decreasing Tg values and negative Tg-DT in our previous article are most likely to have had metastatic PTC of a well-differentiated and indolent nature. This assumption is in accordance with the fact that they had an excellent prognosis.
In Western countries, total thyroidectomy or near-total thyroidectomy followed by radioiodine ablation of thyroid tissue (remnant ablation) is considered the standard treatment for differentiated thyroid carcinoma (5). Ablation might possibly reduce the recurrence rate by killing occult micrometastases. Mazzaferri et al. reported that cancer mortality rates were lower in patients who received thyroid ablation than in those treated with only surgery and those treated with surgery and levothyroxine therapy alone (9). Our previous study showed that 137 (32.2%) of 426 patients with PTC had detectable Tg after total thyroidectomy, indicating that a large proportion of the patients had persistent disease after surgery, although 74.9% had advanced disease (stage III, IVa, or IVc) (6). However, 69 patients, 16.2% of the whole study patients and 50.4% of the patients with persistent disease, had a decrease in Tg levels during TSH-suppressive therapy. Although this fact does not directly indicate the shrinkage or regression of persistent tumors, it suggests that up to 50% of cases of persistent PTC respond to TSH-suppressive therapy. Although short Tg-DT was strongly associated with a poor outcome, patients with long Tg-DT or negative Tg-DT values have an excellent outcome. Patients with short Tg-DT need additional treatment, such as radioactive iodine and TSH-suppressive therapy. They may be good candidates for clinical trials of new drugs. Conversely, for patients with a long Tg-DT or a Tg-DT that was negative, a watch-and-wait policy avoiding unnecessary treatment might be appropriate because these patients would be expected to have a very indolent clinical course.
Conclusions
Serum Tg was not detectable in any of the 22 patients with MTC after total thyroidectomy. This indicates that most of the patients with detectable Tg and negative Tg-DT values after total thyroidectomy for PTC in our previous study had persistent disease, suggesting that a large proportion of patients with persistent PTC have a decrease in serum Tg levels in response to TSH-suppressive therapy.
Footnotes
Disclosure Statement
None of the authors has a conflict of interest.