Abstract
Background:
Stimulated thyroglobulin (Tg) ≤1 ng/mL after thyroidectomy (after L-thyroxine [L-T4] withdrawal or administration of recombinant human thyrotropin [rhTSH]) has been proposed as a criterion to spare patients with papillary thyroid cancer (PTC), who are at low risk of recurrence, from ablation with iodine-131 (131I). The objective of this prospective study was to evaluate the recurrence rate using this approach.
Methods:
This prospective study included 136 patients with PTC who underwent total thyroidectomy with apparently complete tumor resection and who presented no signs of persistent disease after surgery. The patients were classified as low risk of recurrence (nonaggressive histology, T1b—3 N0 M0). All patients had stimulated Tg ≤1 ng/mL, negative anti-Tg antibodies (TgAb), and neck ultrasound (US) showing no anomalies ∼16 weeks after thyroidectomy, and none of them were submitted to ablation with 131I. The time of follow-up ranged from 12 to 72 months (median: 44 months).
Results:
Among the patients studied, 134 (98.5%) continued to have serum Tg concentrations of <1 ng/mL during therapy with L-T4 (Tg/T4) and had negative TgAb and neck US. Lymph node metastases were detected by neck US in one patient. An increase of TgAb was observed in another patient, but she has not developed apparent disease to date. There was only one case of recurrence even among the 60 patients with tumors >4 cm or minimal extrathyroid invasion (T3 N0 M0).
Conclusions:
Low-risk patients with PTC who have stimulated Tg ≤1 ng/mL after thyroidectomy do not require ablation with 131I.
Introduction
First, DxWBS is no longer recommended for the follow-up of low-risk patients (1,2,5). Second, it is known that a high proportion of patients achieve stimulated Tg ≤1–2 ng/mL with total thyroidectomy only (6 –11) and the specificity of this tumor marker is not compromised by remnant thyroid tissue in these cases. Third, RxWBS rarely detects metastases in low-risk patients with postoperative stimulated Tg ≤1 ng/mL and negative neck ultrasound (US) (6 –8). In fact, we previously showed that stimulated Tg ≤1 ng/mL can be obtained in 50% of low-risk patients after total thyroidectomy, and that this finding is an excellent predictor of the absence of metastases upon RxWBS (7). Stimulated Tg ≤1 ng/mL measured after thyroidectomy has been proposed as a criterion to spare low-risk patients from ablation (7,8,11).
The objective of this prospective study was to evaluate the recurrence rate in low-risk patients who had stimulated Tg ≤1 ng/mL and negative neck US after total thyroidectomy and who did not undergo ablation with 131I.
Methods
Design
This was a prospective study.
Patients
Patients consecutively seen at our institution who met the following criteria were first selected: (i) diagnosis of PTC, (ii) history of total thyroidectomy with apparently complete tumor resection, (iii) no signs of persistent disease after surgery, and (iv) being classified as having a low risk of recurrence. Patients having one of the following characteristics were excluded because of a higher risk of recurrence: (i) a tumor of >4 cm and extrathyroidal invasion (both), (ii) extensive extrathyroid invasion, irrespective of tumor size, (iii) aggressive histological subtype (e.g., tall-cell, columnar-cell, diffuse follicular variant) or vascular invasion, (iv) lymph node metastases detected by preoperative US or being suspected during surgery. The patients were not submitted to elective central compartment lymph node dissection. Patients with microcarcinoma restricted to the gland (T1a N0 M0), who clearly would not benefit from ablation with 131I (1 –3), were also excluded.
The 269 patients initially selected were evaluated ∼16 weeks after thyroidectomy by the measurement of stimulated Tg (after levothyroxine [L-T4] withdrawal or administration of recombinant human TSH [rhTSH]), anti-Tg antibodies (TgAb), and neck US. Thirty patients with stimulated Tg ≤1 ng/mL, but with TgAb, and 103 patients with stimulated Tg >1 ng/mL were excluded from the study. The 136 patients with stimulated Tg ≤1 ng/mL, negative TgAb, and US showing no anomalies, who did not undergo ablation with 131I, constituted the final sample.
The study was approved by the Research Ethics Committee of our institution.
Follow-up
After stimulated Tg ≤1 ng/mL was obtained, which ruled out the need for ablation, the first control assessment was performed ∼3 months later when all patients had Tg/T4 <1 ng/mL and negative TgAb as expected. Thereafter, the patients were maintained on 0.3–2 mIU/L TSH [L-T4 dose: 1.5–2.6 μg/(kg·day)] and were followed up by clinical examination, measurement of Tg during L-T4 therapy (Tg/T4) and TgAb at intervals of 6–12 months, and annual neck US. Imaging methods other than US (first, chest and mediastinum computed tomography [CT] and 18F-fluorodeoxyglucose positron-emission tomography [FDG-PET]/CT; if negative, RxWBS were performed in the case of an increase in Tg/T4 (≥1 ng/mL) or TgAb (>40 IU/mL). The time of follow-up ranged from 12 to 72 months (median: 44 months).
Imaging methods
Neck US was performed with a linear multifrequency 10-MHz transducer. All suspected lesions apparent on the scans (12) were evaluated by US-guided fine-needle aspiration biopsy.
Assays
Chemiluminescent assays were used for the measurement of Tg (Access Tg Assay; Beckman Coulter, Fullerton, CA; functional sensitivity of 0.1 ng/mL), TgAb (Immulite 2000; Diagnostic Products Corp., Los Angeles, CA; detection limit of 20 IU/mL and reference value of up to 40 IU/mL), and TSH (Immulite 2000; reference values of 0.4–4 mIU/L). Patients with TgAb were excluded.
Results
Characteristics of the patients
The characteristics of the patients are shown in Table 1. Seventy-six patients had tumors >1 and ≤4 cm restricted to the thyroid (T1b–2 N0 M0), whereas 60 patients had tumors >4 cm or minimal extrathyroid invasion (T3 N0 M0).
Follow-up
Among the patients studied, 134 continued to have Tg/T4 <1 ng/mL, negative TgAb and negative US. Tg/T4 was undetectable (≤0.1 ng/mL) in the last assessment in 121 of these patients and detectable in 13, all of them with levels of <0.5 ng/mL (range: 0.12–0.48 ng/mL). When compared to the measurement obtained about 3 months after Tg stimulation which ruled out the need for ablation, Tg/T4 concentrations were stable in the last assessment in six patients and had a reduction of ≥0.2 ng/mL in the other seven. None of the patients had an increase of Tg/T4. These patients were not submitted to a second Tg stimulation or imaging methods other than US.
Lymph node metastases were detected by neck US in one patient (patient 1 in Table 2). This patient underwent surgery. Six months after treatment, the patient had normal neck US and chest CT and stimulated Tg was <2 ng/mL in the absence of TgAb. On the basis of these findings, the patient did not receive 131I and continues to be without apparent disease 14 months after surgery. An increase of TgAb (from <20 to 78 IU/mL) with undetectable Tg/T4 was observed in another patient (patient 2 in Table 2), but she has not developed apparent disease to date (US, CT, FDG-PET, and RxWBS). The characteristics of these two patients are shown in Table 2.
None of the 76 patients with tumors ≤4 cm and restricted to the thyroid (T1b–2 N0 M0) had apparent disease. Only one case of recurrence (1.6%) was detected even among the 60 patients with tumors >4 cm or minimal extrathyroid invasion (T3 N0 M0).
Discussion
It is known that stimulated Tg levels ≤1 ng/mL occur in a high proportion of patients after total thyroidectomy, and ablation with 131I is not always necessary to have this outcome (6 –11). Second, in patients with PTC, apparently complete tumor resection and low risk of persistent/recurrent disease (T1–3 N0, nonaggressive histology), the finding of postoperative stimulated Tg levels ≤1 ng/mL combined with negative neck US, is predictive of the absence of metastases upon RxWBS (7,8). Finally, in this situation, the occurrence of recurrence over the years after ablation with 131I is exceptional (8 –10). It now remains to be determined whether the same evolution would be observed if these patients had not been treated with 131I, since in the previous studies all subjects had been submitted to 131I ablation.
In the present situation, that is, low-risk patients with postoperative stimulated Tg ≤1 ng/mL in the absence of TgAb and negative neck US, the administration of 131I is unlikely to influence patient evolution. A therapeutic effect on apparent metastases does not occur, considering that RxWBS is negative in these cases (7,8). The destruction of small thyroid remnants also does not seem to be relevant. This is demonstrated by the fact that the presence of discrete uptake in the thyroid bed, which also indicates remnant thyroid tissue, does not influence the risk of recurrence in patients with stimulated Tg ≤1 ng/mL and normal neck US after ablation with 131I (13). However, studies in which patients are not treated with 131I are necessary to confirm this and to exclude other eventual benefits of ablation, such as a therapeutic effect on micrometastases that are not apparent on RxWBS.
To our knowledge, there is only one study reporting the evolution of patients who were not submitted to ablation, since they had low postoperative Tg (11). In that study, 58 low-risk patients (nonaggressive PTC subtype, almost all T1–2 N0 M0) with stimulated Tg ≤1 ng/mL did not receive 131I and none of them had recurrence after a mean follow-up period of 3.3 years (11). In the present investigation which included a larger number of patients (n=136), the apparent recurrence rate was also very low (∼1%) after a mean follow-up period of 3.7 years. Although recurrence may occur later, it is known that two-thirds of recurrences are observed during these first years of follow-up (14). Approximately 10% of the present patients had detectable Tg/T4 (>0.1 ng/mL) in the last assessment, but we believe that recurrence is unlikely in these cases. First, Tg levels were low (<0.5 ng/mL) in all of these patients. Second, it is known that patients with detectable Tg/T4, but with stimulated Tg <1.4 ng/mL (15) or < 2 ng/mL (16), rarely relapse, and stimulated Tg was ≤1 ng/mL in all patients (inclusion criterion). Third, Tg concentrations were stable or decreasing, a fact that also predicts the absence of long-term disease (17). In addition, neck US continued to be negative in all of these patients.
Interestingly, the fact that patients with postoperative stimulated Tg ≤1 ng/mL were submitted to ablation did not guarantee the absence of recurrence in previous studies (8 –10). We also observed this fact when reviewing data from 108 patients seen at our institution, who were similar to the present patients and submitted to the same follow-up protocol, but who underwent ablation with 131I (7). One case of neck recurrence was also detected in this group (unpublished data).
In the previous series, even patients classified as T3 N0 M0, with postoperative stimulated Tg ≤1 ng/mL, did not show ectopic uptake on RxWBS (7,8) and rarely relapsed after ablation (8,9). In agreement with these findings, the recurrence rate was low (≤2%) in the 60 patients of this series who had tumors >4 cm or minimal extrathyroid invasion (T3 N0 M0). These data suggest that, once postoperative stimulated Tg ≤1 ng/mL is achieved, these patients classified as high risk of recurrence by some authors (1) may not require 131I. This hypothesis agrees with the recent demonstration that the long-term risk of recurrence is low even in patients initially not considered to be at low risk, once stimulated Tg ≤1 ng/mL is achieved and imaging methods are negative (18). In other words, the importance of the initial histological data seems to be minimized when Tg after initial therapy is considered (18).
Although undetectable Tg/T4 measured by highly sensitive assays is a predictor of low-stimulated Tg, at present, the criterion proposed (7,8,11) and evaluated in this study to spare low-risk patients from ablation would be stimulated Tg. Tg/T4 would be reserved for very low-risk patients [microcarcinomas restricted to the thyroid (1)] to rule out the need for adjuvant therapy.
Finally, prophylactic dissection of the cervical lymph nodes was not performed in the present investigation or in the study of Vaisman et al. (11). We believe that, for the selection of patients who can be spared from ablation with 131I based on postoperative stimulated Tg ≤1 ng/mL, the absence of lymph node metastases can be demonstrated by US and perioperative examination (7) and does not require confirmation by prophylactic dissection of the central neck compartment as suggested by other authors (8).
The results obtained here suggest that low-risk patients with PTC who have stimulated Tg ≤1 ng/mL in the absence of TgAb and combined with negative neck US after thyroidectomy do not initially require ablation with 131I as long as Tg/T4 remains <1 ng/mL and TgAb and US continue to be negative. These patients would be followed up by periodic measurement of Tg/T4 and TgAb and neck US, maintaining on 0.5–2 mIU/L TSH. Studies involving a larger number of patients and a longer follow-up are needed to confirm this proposal.
Footnotes
Disclosure Statement
The authors declare that no competing financial interests exist.