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The Impact of Thyroid Stunning on Radioactive Iodine Ablation Compared to Other Risk Factors
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Thyroid stunning has been reported as the temporary impairment of thyroid tissue after a 111-MBq or greater diagnostic 131I dose that decreases the final absorbed dose in ablative therapy. Concerns regarding the reality of stunning have arisen in part due to a flawed study design in prior reports. To assess whether a stunning effect has any impact on therapeutic outcomes, we compared initial treatment ablation rates in patients who received 111- to 185-MBq 131I diagnostic scans (n = 37) before ablative doses of 3700-7400 MBq with ablation rates in patients who did not receive any 131I before the initial treatment dose (n = 63). Ablation rates were 64.9% for scanned patients and 66.7% for nonscanned patients, a nonsignificant difference. Nonscanned patients with metastatic lesions (n = 23) were ablated at a higher rate (78.3%) than scanned patients (n = 9) (66.7%), but the difference was not significant (P = 0.50). It is possible that the reported stunning phenomenon, specifically its impact in temporarily impairing tissue, has been overemphasized.
The existence of thyroid stunning (i.e., inhibited thyroidal iodide uptake after administration of diagnostic amounts of (131)I) is controversial and is currently a subject of debate. To our knowledge, the stunning phenomenon has not been investigated previously in vitro.
Growth-arrested porcine thyroid cells that formed a tight and polarized monolayer in a bicameral chamber were irradiated with 3-80 Gy (131)I present in the surrounding culture medium for 48 h. The iodide transport capacity after irradiation was evaluated 3 d later by measuring the transepithelial (basal to apical) flux of trace amounts of (125)I.
The basal-to-apical (125)I transport decreased with increasing absorbed dose acquired from (131)I; a nearly 50% reduction was observed already at 3 Gy. Stable iodide at the same molarity as (131)I (10(-8) mol/L) had no effect on the (125)I transport. Cell number and epithelial integrity were not affected by irradiation.
Stunning of iodide transport is detected after (131)I irradiation of cultured thyroid cells. The degree of inhibition of transport is dependent on the absorbed dose.
Currently, little is known about the prognostic significance of achieving successful ablation with the first dosage of I-131 in patients with differentiated thyroid cancer. This study aimed to assess the following: (i) whether successful or unsuccessful ablation at post-ablation follow-up has prognostic consequences; (ii) possible factors predicting success of ablation in a patient.
In order to do this, we retrospectively studied 180 patients with a median follow-up of 55 months. Ablation was considered to be successful if 1 year after the initial dosage of I-131 patients fulfilled all of the following criteria: not dead from thyroid cancer, no additional therapy needed for any kind for thyroid cancer within the first year, undetectable thyroglobulin (Tg) levels under TSH stimulation, and negative I-131 scintigraphy. Tg levels at the time of ablation (P < 0.001), lymph node metastasis (P = 0.04) and distant metastasis (P < 0.001) have a significant influence on the success of ablation. P values were calculated by Mann-Whitney U test and Chi-square test, respectively.
Patients with successful ablation had a better prognosis than those with unsuccessful ablation: disease-free survival was 87% versus 49% after 10 years; additionally, thyroid-cancer related survival was 93% versus 78%.
We conclude that the extent of the remaining normal or neoplastic thyroid tissue influences the outcome of ablation, and that successful ablation leads to a better prognosis. It seems that it is very important to achieve complete ablation as soon as possible in order to ensure the best possible prognosis for a patient.
Thyroid stunning refers to reduced uptake of (131)I in the thyroid tissue (or tumor) during radioiodine ((131)I) therapy compared with the uptake measured after the previous administration of (131)I for diagnostic purposes. The phenomenon is clinically important, as it can potentially lead to the undertreatment of thyroid cancer or to unnecessarily high absorbed doses in critical organs. Previous clinical and experimental studies indicated that thyroid stunning is absorbed dose dependent. The aim of this study was to investigate the effects of (131)I irradiation on (125)I(-) transport and cell proliferation at low absorbed doses in vitro.
Primary cultured porcine thyroid cells were grown to form a confluent monolayer of epithelial cells on a filter in a bicameral culture system. The cells were continuously irradiated with (131)I in the culture medium for 48 h to obtain 0.0015-1.5 Gy. At 3 d after irradiation was stopped, the transepithelial iodide transport capacity was evaluated by measuring (125)I(-) transport from the basal chamber compartment to the apical chamber compartment. The effect of (131)I irradiation on DNA synthesis was estimated by pulse labeling with (3)H-thymidine of both subconfluent and confluent cells irradiated with up to 9 Gy. Total DNA content was measured to quantify cell numbers.
A statistically significant reduction in (125)I(-) transport was seen at absorbed doses of >or=0.15 Gy, with a 50% reduction at 1.5 Gy, compared with the results observed for nonirradiated control cells. (3)H-Thymidine incorporation was already statistically significantly reduced at absorbed doses of 0.01-0.1 Gy, but 0.15-0.3 Gy did not affect DNA synthesis. However, absorbed doses of >or=1 Gy again resulted in reduced DNA synthesis. A 50% reduction was obtained at 4 Gy. Total DNA measurements revealed a statistically significant reduction in cell numbers at 8 Gy.
The lowest absorbed dose from (131)I that reduced iodide transport was 0.15 Gy. Because stunning was found at low absorbed doses, it might occur for (131)I treatment not only of thyroid cancer but also of thyrotoxicosis. On the basis of differences in dose responses, radiation-induced thyroid stunning and cell cycle arrest may be independent phenomena.
The aim of the study was to compare the success rate of an uptake-related ablation protocol in which the dose depends on an I-131 24-h neck uptake measurement and a fixed-dose ablation protocol in which the dose depends on tumour stage.
All differentiated thyroid carcinoma patients with M0 disease who had undergone (near-) total thyroidectomy followed by I-131 ablation were included. In the uptake-related ablation protocol, 1100 (uptake >10%), 1850 (uptake 5-10%) and 2800 MBq (uptake <5%) were used. In the fixed-dosage ablation strategy, 3700 (T1-3, N0 stage) and 5550 MBq (N1 and/or T4 stage) were applied. We used I-131 uptake on whole-body scintigraphy and thyroglobulin-off values to evaluate the ablation 6-12 months after treatment.
In the uptake-related ablation protocol, 60 out of 139 (43%) patients were successfully treated versus 111 out of 199 for the fixed-dose ablation protocol (56%) (P=0.022). The differences were not statistically significant for patients with T4 (P=0.581) and/or N1 (P=0.08) disease or for patients with T4N1 tumour stage (P=0.937).
The fixed-dose I-131 ablation protocol is more effective in ablation of the thyroid remnant in differentiated thyroid carcinoma patients than an uptake-related ablation protocol. This difference is not observed in patients with a N1 and/or T4 tumour stage.
To assess the impact of histopathology of non-neoplastic thyroid tissue on ablation outcome in patients with papillary thyroid cancer (PTC).
The study included 124 patients referred for I-131 ablation therapy after total thyroidectomy for unifocal nonmetastatic PTC. All patients received 100 mCi of I-131 ablation dose. Follow-up whole body scan (WBS) and estimation of serum thyroglobulin level were carried out 6-9 months after ablation therapy and results were divided into complete or incomplete ablation.
Incomplete ablation was found in 66.6% (12 of 18), 64% (16 of 25), 39.1% (nine of 23), 30% (six of 20), 33% (six of 18), and 20% (four of 20) in patients with PTC in a background of Hashimoto's thyroiditis, lymphocytic thyroiditis, colloid nodular goiter, nodular hyperplasia, multinodular goiter, and normal thyroid tissue, respectively. Patients with Hashimoto's thyroiditis and lymphocytic thyroiditis had statistically significant higher failure rate to achieve complete ablation compared with other groups. This significant difference was lacking between different nonautoimmune histopathologies and normal thyroid tissue. For patients with thyroid disorders of autoimmune origin (Hashimoto's thyroiditis and lymphocytic thyroiditis), incomplete ablation was found in 65.1% (28 of 43) versus 34.4% (21 of 61) for all other nonautoimmune histopathologies collectively; the difference was statistically significant.
Histopathology of non-neoplastic thyroid tissue has a significant impact on ablation outcome in patients with PTC. Patients with a histopathology of non-neoplastic thyroid tissue of autoimmune origin have a significantly lower incidence of successful complete ablation after a single I-131 ablative dose (100 mCi) compared with those with nonautoimmune histopathology or with normal thyroid tissue.
Most patients with differentiated thyroid cancer are treated with radioiodine (131-I) after thyroidectomy. The characteristics predictive of successful remnant ablation with low activities of 131-I are ill defined and could help stratify patients into those who should receive higher activities.
In a case series of 193 consecutive patients with papillary thyroid cancer who underwent total thyroidectomy and received 30 mCi (1110 MBq) of 131-I, we assessed the percentage of successful radioremnant ablation as defined by a composite of scintigraphic and biochemical endpoints. Clinical, histological, scintigraphic, and biochemical covariables were analyzed to identify associations with treatment failure.
Successful radioremnant ablation with low-activity 131-I was obtained in 78% of the entire cohort of patients. The presence of limited microscopic extrathyroidal extension, nodal micrometastases, or an elevated stimulated ablation was associated with failure to ablate the remnant. While accounting for other factors in a multivariable analysis, patients with an ablation thyroglobulin of at least 6 μg/l were at a more than five times greater risk (P<0.001) to fail 30 mCi 131-I remnant ablation.
The majority of patients with papillary thyroid carcinoma experienced successful ablation. However, elevated-stimulated ablation thyroglobulin levels were strongly predictive of ablation failure, suggesting that this biochemical marker correlates with a more aggressive tumor profile and identifies those patients who might benefit from additional therapy.
A patient with papillary carcinoma of the thyroid was scanned with 10 mCi of I-131 postoperatively before thyroablation therapy. Two weeks later, the patient was given 100 mCi of I-131. The posttherapy scan showed very little uptake in the thyroid remnant, suggesting that the thyroid was stunned before therapy. This case was compared with another in which the patient was scanned with I-123 followed by I-131 therapy. There was excellent uptake of the therapy dose. Pretherapy scanning with a high dose of I-131 may suppress the thyroid tissue and inadvertently prevent maximum uptake of a subsequently administered therapy dose of I-131.
The aim of this study was to investigate the influence of the diagnostic administration of 74 MBq 131I on subsequent uptake of therapeutic radioiodine in thyroid cancer patients. Retention measurements were performed using a whole-body counter in 24 patients 6 weeks after total thyroidectomy. Profile scans were performed 2, 24, 48 and 72 h after the administration of the diagnostic dose and 72 h after the administration of the ablation-therapeutic dose (4.4 GBq). The mean ( +/- S.D.) effective half-life of the diagnostic dose in thyroid remnants was 40.3 +/- 23.0 h. The uptake in the thyroid remnants of the subsequent ablation dose 72 h after administration was 30.4 +/- 19.8% of that predicted from the diagnostic study. The greater reduction in uptake was associated with the longer half-life of iodine and higher uptake in the thyroid remnants at 24 h, with a longer interval between surgery and administration of the diagnostic dose and a shorter period between administration of the diagnostic and ablation doses. Our results show that a diagnostic dose of 74 MBq 131I markedly reduces thyroid uptake of an ablation dose of 131I. This should be taken into account during radiation dose planning whenever a quantitative dosimetric study is to be performed.
To understand stunning effects of a diagnostic dose of iodine-131 (I-131).
Four hundred and sixty-eight patients (101 males, 367 females, ages: 6-75 years with well differentiated thyroid cancer, following total or nearly total thyroidectomy, were studied. One hundred and eleven MBq (3 mCi) diagnostic (Dx) doses of I-131 whole body scan (WBS) were obtained after withholding thyroxine after 6 weeks and triiodothyronine for 2 weeks. One week to one month later, 3.7-7.4 GBq (100-200 mCi) I-131 was given to them, then a therapeutic (Tx) dose of I-131 WBS was performed. The serum thyroid simulating hormone level was usually above muIU/ml.
Of the 468 patients, 344 (73.5%) had scintigraphic patterns of apparently decrease uptake in 240 thyroid remnants and 104 metastatic lesions on the Tx dose of I-131 WBS compared to Dx dose of I-131 WBS. Stunning phenomenon occurred in 50 cases, including 42 thyroid remnants and 18 metastatic lesions.
Dx dose of I-131 may influence the uptake of a subsequently administered Tx dose of I-131.
Twenty-six patients who had undergone recent surgery for differentiated thyroid cancer were investigated using iodine-131 iodide (120 MBq). Uptake in the thyroid bed was measured at 3 days using a dual-head gamma camera. An ablation activity of 131I iodide (4,000 MBq) was administered 3-38 (median 14) days later and uptake in the thyroid bed measured once or twice, 1-3 days post therapy. For measurements post therapy, the gamma camera was operated in the high-count rate mode with appropriate correction factors to compensate for any count loss. A further 16 patients were given iodine-123 iodide (200 MBq) as the diagnostic agent and uptake was measured at 24 h. The ablation activity was administered 5-47 (median 19) days later and uptake again measured at 24 h. In some cases, a further measurement of uptake was made within the period 1-3 days post therapy. Reduced uptake of the therapeutic administration ( P<0.001) was observed in all 26 patients given diagnostic 131I, with a median value of 32.8% (range 6%-93%) of the uptake in the diagnostic study. In the patients given diagnostic 123I, reduced uptake of the ablative radioiodine was observed in 15 of the 16 patients ( P<0.001), and overall the median value was 58.8% (range 17%-130%) of the diagnostic uptake. In one case the uptake post therapy was increased. The stunning observed in the group given 123I was significantly less ( P<0.001) than in the group given 131I. In the patients given diagnostic 131I, stunning appeared to increase in severity the longer the time interval between the diagnostic and therapeutic radionuclides, for intervals up to 25 days. Thereafter, there seemed to be some recovery of uptake capability. Overall there was no evidence of a large rapid loss of radionuclide from the thyroid bed 1-3 days post therapy. The stunning observed using 123I could not be explained by errors in the estimation of relative uptake due to different tissue absorption of the 131I and 123I photons, nor by the radiation dose delivered by the 123I. However, the ablative 131I itself may cause stunning because the cumulated activity, over the first few hours of uptake, is not insignificant when compared with all the cumulated activity from a diagnostic administration of 131I. The resultant radiation dose to the thyroid remnant, as the therapeutic radioiodine is being taken up, may be sufficient to inhibit the uptake process, thus leading to a reduction in maximum uptake when compared with that of a diagnostic activity of radioiodine.
Radioiodine ablation of thyroid tissue after subtotal thyroidectomy has been shown to decrease recurrence in certain subsets of patients with well-differentiated thyroid cancer. In a substantial percentage of cases (20-30%), initial ablation of the thyroid remnant fails, necessitating a second treatment. The factors associated with ablation failure are not fully understood. In particular, it is not certain whether the use of doses higher than 3.70 GBq would result in any additional benefit, or whether there is a 'stunning' effect of the diagnostic dose of 131I on the subsequent ablation rate. A retrospective analysis was performed of all patients (n=389) with well-differentiated thyroid cancer treated at our institution between 1992 and 2001. Remnant ablation success was determined by a whole-body radioiodine scan. The following factors, thought to be associated with thyroid remnant ablation, were studied by logistic regression analysis: age, gender, tumour histology, stage, pre-therapy neck uptake of 131I, diagnostic dose, ablation dose, time between diagnostic and therapeutic dose (T1), time between therapeutic administration and the first follow-up whole-body scan (T2) and the thyroid-stimulating hormone (TSH) level measured at the time of therapy. Follow-up whole-body scans were available in 214 patients. We found no association with age, gender, histology, TSH level, neck uptake, diagnostic dose and successful ablation. The therapeutic dose was the only variable found to be associated with success (odds ratio, 1.96 per 1.85 GBq increment; 95% confidence interval, 1.11-3.46). Our results confirm the presence of a significant percentage of ablation failures (24.4%) despite the use of high ablative doses (3.70-7.40 GBq). Higher therapeutic doses are associated with higher rates of successful ablation, even when administered to patients with more advanced stages. Using our protocol, higher diagnostic doses were not associated with higher rates of ablation failure.
Debates regarding thyroid stunning-a phenomenon whereby a diagnostic dose of radioiodine decreases uptake of a subsequent therapeutic dose by remnant thyroid tissue or by functioning metastases-have been fueled by inconsistent research findings. Quantitative studies evaluating radioiodine uptake and qualitative studies using visual observations both compare thyroid function on the diagnostic scan (DxSCAN) versus the posttreatment whole-body scan (RxWBS). The variability of findings may be the result of a lack of consensus in clinical nuclear medicine regarding many parameters of radioiodine usage including the need to obtain a pretreatment diagnostic scan, appropriate therapeutic dose, time between therapy dose administration and DxSCAN, and how successful ablation is measured. In the studies considered in this review, those that used (123)I rather than (131)I for DxSCAN, allowed less time to elapse between diagnostic and therapy dose, and more time between therapy dose and RxWBS (at least 1 week), did not observe stunning. However, groups that recognized stunning did not demonstrate any difference in outcomes (determined by successful first-time ablation). Whether stunning is a temporary phenomenon whereby stunned tissue eventually rejuvenates, or whether observed stunning actually constitutes "partial ablation," is yet to be delineated.
Remnant ablation can be achieved by either administering an empiric fixed dose or using dosimetry-guided techniques. Because of the technical and logistic difficulties, most centers have adapted the fixed-dose or standard-dose technique for remnant ablation using (131)I. In the late 1970s, low-dose (131)I remnant ablation was introduced, and subsequently many centers confirmed the effectiveness of such therapy. However, the optimal dose (administered activity) of (131)I for remnant ablation is not yet settled. In a randomized clinical trial to find out the smallest possible effective dose for remnant ablation in cases of differentiated thyroid carcinoma, between July 1995 and January 2002, 565 patients were randomized into eight groups according to (131)I administered activity, starting at 15 mCi and increasing activity in increments of 5 mCi until 50 mCi. In the postrandomization phase, 56 patients were excluded from the study for various reasons, and final analysis was done with 509 patients. The mean age of the patients was 37.5 +/- 12.7 yr with a female to male ratio of 2.6. The surgical procedure was total/near-total thyroidectomy in 72% and subtotal or hemithyroidectomy in the rest. Histology was papillary thyroid carcinoma in 80.6% of patients and follicular thyroid carcinoma in the rest. With one dose of (131)I, remnant ablation was achieved in 59.6, 63.6, 81.4, 83.6, 79.4, 78.3, 84.4, and 81.8% of patients in the 15- to 50-mCi groups, respectively (overall ablation rate, 77.6%). The successful ablation rate was statistically different in patients receiving less than 25 mCi of (131)I compared with those receiving at least 25 mCi [63 of 102 (61.8%) vs. 332 of 407 (81.6%); P = 0.006]. However, there was no significant intergroup difference in outcome among patients receiving 25-50 mCi of (131)I. Patients with small tumor size (</=5 cm), adequate surgery (total/near-total thyroidectomy), and radioiodine neck uptake of less than or equal to 10% had odds ratios of 2.4 [confidence interval (CI), 1.3-3.98], 2.6 (CI, 1.6-4.2), and 2.2 (CI, 1.4-3.5), respectively, for successful remnant ablation. Patients receiving at least 25 mCi of (131)I had a three times better chance of getting remnant ablation than patients receiving lesser activity of (131)I. Any activity of (131)I between 25 and 50 mCi appears to be adequate for remnant ablation.
Recent publications described many discrepant findings about thyroid "stunning" after the administration of (131)I diagnostic activities to patients with differentiated thyroid carcinoma. Stunning may play a major role in reducing the therapeutic efficacy of high (131)I activities given for ablation therapy.
Participation in a multicenter study to investigate differences in iodine biokinetics in the hypothyroid state and after the application of recombinant human thyroid-stimulating hormone enabled us to study quantitative changes in thyroid iodine biokinetics after the administration of 74 MBq of (131)I twice within 6 wk and an ablation activity of 3-4 GBq 7-12 d after the second diagnostic administration of (131)I in 6 patients.
The uptake and half-life of the first 74 MBq of (131)I were significantly reduced to a mean of 44% and a mean of 51%, respectively, after the second diagnostic administration and further reduced to a mean of 40% and a mean of 30%, respectively, during ablation therapy. The residence times were reduced to 25% in the second dosimetric assessment and to 10% during therapy compared with the value in the first assessment. For one patient, an estimated absorbed dose as high as 38 Gy was found in the first diagnostic study. The mean dose for all patients after the first assessment was 15 Gy; after each further assessment, the dose was reduced according to the decrease in residence time.
This study shows a severe impact of 74 MBq of (131)I on the biokinetics of thyroid remnants during subsequent radioiodine therapy.
In an attempt to obviate the necessity for hospitalisation, the ablative dose of 131I in the treatment of thyroid cancer is divided into two or three fractions at weekly intervals in some hospitals with no special bed for 131I treatment. Thyroid stunning has been observed in patients receiving a 131I dose between 74 and 370 MBq (2-10 mCi). However, the influence of 131I uptake after administration of a higher dose, such as 1,110-1,850 MBq of 131I, has never been reported. In this study, we evaluated the degree of reduction in 131I uptake after patients received 1,480 MBq of 131I and evaluated the clinical value of fractionated ablative doses of 131I.
Thirty-five patients with functional thyroid cancer received a total of 4,440 MBq (120 mCi) of 131I which was divided into three fractions administered at weekly intervals. In all patients two 131I whole-body scans were performed. The first scan was performed directly prior to the second dose of 131I (7 days after the first administration of 131I), and the second scan was performed 7 days after the second administration of 131I and directly prior to the third administration. Regions of interest including the neck and lungs were drawn to calculate the uptake of 131I in the thyroid remnant and possible cervical lymph node and lung metastases.
The mean uptake of 131I was 2.73% 7 days after the first administration, and decreased significantly to 0.26% 7 days after the second administration. The mean decrease was as high as 80.7%. The decrease in 131I uptake was significant in all patients except the two with lung metastases. In the two patients with lung metastases, no definite evidence of decreased uptake was noted; the uptake of 131I in the lung metastases even increased on the second 131I image in one of these patients. After administration of 1,480 MBq of 131I, the decreased uptake was significant in all neck lesions but not in lung metastases.
The use of fractionated ablative doses of 131I is not to be recommended in patients without lung metastases. However, the influence of fractionated ablative doses of 131I in patients with lung metastases is worthy of further study.
The aim of this study was to determine the efficacy of low (1110 MBq (30 mCi)) and high (3700 MBq (100 mCi)) 131I doses on the ablation of post-surgical remnants in patients with thyroid cancer based on the measurement of post-operative cervical uptake.
The study was conducted on 155 patients without metastases after thyroidectomy who received a 1110 or 3700 MBq ablative dose and who were assessed by pre-therapy cervical uptake. The patients were divided into six groups according to the uptake result and the dose received. Successful therapy was defined as a negative scan 6 months to 1 year after ablation.
Ablative therapy was successful in 90% of patients with uptake <2% who received the 1110 MBq dose (n=30) and in 92.5% of patients who received the 3700 MBq dose (n=40), P=0.95. In the group with uptakes ranging from 2% to 5%, successful therapy was observed in 65% of patients receiving 1110 MBq (n=20) and in 86.6% of patients receiving 3700 MBq (n=30), P=0.14. In patients with uptake >5%, a 46.6% success rate was obtained for the 1110 MBq dose (n=15), while efficacy was 70% in patients receiving 3700 MBq (n=20), P=0.16.
This study demonstrated the efficacy of low doses in patients with lower remnants after surgery (uptake <2%), the inverse correlation between uptake and ablation efficacy with low and high doses, and the usefulness of the measurement of cervical uptake for the definition of the ablative 131I dose.
To determine, based on published literature and expert clinical experience, current indications for the post-surgical administration of a large radioiodine activity in patients with differentiated thyroid cancer.
A literature review was performed and was then analyzed and discussed by a panel of experts from 13 European countries.
There is general agreement that patients with unifocal microcarcinomas = 1 cm in diameter and no node or distant metastases have a <2% recurrence rate after surgery alone, and that post-surgical radioiodine confers recurrence and cause-specific survival benefits in patients, strongly suspected of having persistent disease or known to have tumor in the neck or distant sites. In other patients, there is limited evidence that after complete thyroidectomy and adequate lymph node dissection performed by an expert surgeon, post-surgical radioiodine provides clear benefit. When there is any uncertainty about the completeness of surgery, evidence suggests that radioiodine can reduce recurrences and possibly mortality.
This survey confirms that post-surgical radioiodine should be used selectively. The modality is definitely indicated in patients with distant metastases, incomplete tumor resection, or complete tumor resection but high risk of recurrence and mortality. Probable indications include patients with tumors >1 cm and with suboptimal surgery (less than total thyroidectomy or no lymph node dissection), with age <16 years, or with unfavorable histology.
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