Low postoperative nonstimulated thyroglobulin as a criterion to spare radioiodine ablation

in Endocrine-Related Cancer
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  • 1 Postgraduation Program, Endocrinology Service, Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil

This study evaluated the recurrence rate in patients with papillary thyroid carcinoma (PTC) who had low nonstimulated thyroglobulin (Tg), measured with a second-generation assay, after total thyroidectomy and who were not submitted to ablation with 131I. The objective was to define whether low postoperative nonstimulated Tg can be used as a criterion to spare patients with PTC from therapy with 131I. This was a prospective study including 222 patients with PTC (except for microcarcinoma restricted to the thyroid and tumor with extensive extrathyroid invasion (pT4), aggressive histology, extensive lymph node (LN) involvement, or known residual disease). After thyroidectomy, all patients had nonstimulated Tg<0.3 ng/ml, negative antithyroglobulin antibodies (TgAb) and neck ultrasonography (US) showing no anomalies. Because of this finding, the patients were not submitted to ablation with 131I. The time of follow-up ranged from 15 to 102 months (median 62 months). Of the 222 patients, 217 (97.7%) continued to have nonstimulated Tg <0.3 ng/ml and negative US. Tg was undetectable in the last assessment in 185 of these patients and detectable in 32. Five patients (2.2%) exhibited an increase in Tg, and LN metastases were detected in 4 (structural recurrence). One patient progressed to an increase in Tg, but disease was not detected by the imaging methods (biochemical recurrence). The results obtained here suggest that patients with PTC who have low nonstimulated Tg (measured with a second-generation assay and in the absence of TgAb) and negative neck US after thyroidectomy do not require ablation with 131I.

Abstract

This study evaluated the recurrence rate in patients with papillary thyroid carcinoma (PTC) who had low nonstimulated thyroglobulin (Tg), measured with a second-generation assay, after total thyroidectomy and who were not submitted to ablation with 131I. The objective was to define whether low postoperative nonstimulated Tg can be used as a criterion to spare patients with PTC from therapy with 131I. This was a prospective study including 222 patients with PTC (except for microcarcinoma restricted to the thyroid and tumor with extensive extrathyroid invasion (pT4), aggressive histology, extensive lymph node (LN) involvement, or known residual disease). After thyroidectomy, all patients had nonstimulated Tg<0.3 ng/ml, negative antithyroglobulin antibodies (TgAb) and neck ultrasonography (US) showing no anomalies. Because of this finding, the patients were not submitted to ablation with 131I. The time of follow-up ranged from 15 to 102 months (median 62 months). Of the 222 patients, 217 (97.7%) continued to have nonstimulated Tg <0.3 ng/ml and negative US. Tg was undetectable in the last assessment in 185 of these patients and detectable in 32. Five patients (2.2%) exhibited an increase in Tg, and LN metastases were detected in 4 (structural recurrence). One patient progressed to an increase in Tg, but disease was not detected by the imaging methods (biochemical recurrence). The results obtained here suggest that patients with PTC who have low nonstimulated Tg (measured with a second-generation assay and in the absence of TgAb) and negative neck US after thyroidectomy do not require ablation with 131I.

Introduction

In patients with papillary thyroid carcinoma (PTC) submitted to total thyroidectomy with complete tumor resection, ablation of thyroid remnant with 131I is not required in patients with microcarcinoma restricted to the thyroid with nonaggressive histology (Cooper et al. 2009, Rosario et al. 2013, Lepoutre-Lussey et al. 2014, Perros et al. 2014). In contrast, adjuvant therapy with 131I has been recommended when the histological data (tumor size, extrathyroid invasion, histologic subtype, vascular invasion, lymph node (LN) involvement) suggest a higher risk of recurrence (Cooper et al. 2009, Rosario et al. 2013, Lepoutre-Lussey et al. 2014, Perros et al. 2014). The need for radioiodine is controversial in the remaining patients. In these individuals, when postoperative-stimulated thyroglobulin (Tg) is low (in the absence of anti-Tg antibodies (TgAb)), post-therapy whole-body scanning (RxWBS) rarely detects persistent disease (Nascimento et al. 2011, Rosario et al. 2011, Furtado et al. 2015) and the risk of recurrence is very low (about 1% in 5 years), even without the administration of radioiodine (Vaisman et al. 2010, Rosario et al. 2012, Orlov et al. 2015). In fact, many authors recommend low postoperative-stimulated Tg as a criterion to spare these patients from therapy with 131I (Vaisman et al. 2010, Nascimento et al. 2011, Rosario et al. 2011, 2012, 2013, Schlumberger et al. 2011, Orlov et al. 2015).

Only two studies correlated postoperative nonstimulated Tg, measured with a second-generation assay, with the RxWBS results and both demonstrated the absence of metastases on this imaging method in patients with low Tg (Giovanella et al. 2008, Rosario et al. 2015a). Little information is available about the rate of recurrence in patients with low nonstimulated Tg after thyroidectomy who were not submitted to radioiodine therapy because of this finding. In previous studies involving patients not submitted to ablation of thyroid remnant who had low postoperative nonstimulated Tg, most patients had microcarcinoma restricted to the thyroid and nonaggressive histology (Durante et al. 2012, Ibrahimpasic et al. 2012, Nascimento et al. 2013, Angell et al. 2014); thus, there was already no indication for radioiodine. Taking together all of these series, the number of patients with non-T1aN0-NxM0 stage tumors was only about 100 (Durante et al. 2012, Ibrahimpasic et al. 2012, Nascimento et al. 2013, Angell et al. 2014). Furthermore, all of these series were retrospective studies. In two of them, neck ultrasonography (US) for the exclusion of small LN metastases was not performed in all patients (Nascimento et al. 2013, Angell et al. 2014).

This prospective study evaluated the recurrence rate in patients with PTC who had low nonstimulated Tg, measured with a second-generation assay, and negative neck US after total thyroidectomy and who were not submitted to ablation with 131I because of this finding.

Materials and methods

The study was approved by the Research Ethics Committee of our institution.

Design

This was a prospective study. The selection criteria and follow-up protocol of the patients were predefined and rigorously followed.

Patients

Patients consecutively seen at our institution from 2006 to 2014, who met the following criteria, were first selected: diagnosis of PTC, submitted to total thyroidectomy with apparently complete tumor resection, and no signs of persistent disease after surgery. The patients were not submitted to elective central compartment LN dissection. Patients with a tumor ≤1 cm (uni- or multifocal) restricted to the gland (T1aNxM0) and nonaggressive histology (Rosario et al. 2004a, 2007) and patients with the noninvasive encapsulated follicular variant of papillary carcinoma (E-FVPTC; Rosario et al. 2014a), who clearly would not benefit from ablation with 131I, were excluded. Patients with one of the following characteristics were also excluded because of a higher risk of recurrence: extensive extrathyroid invasion (pT4); aggressive histological subtype (e.g., tall-cell, columnar-cell, diffuse follicular variant) or vascular invasion; LN metastases detected by preoperative US or during intraoperative inspection by the surgeon (clinical N1 (cN1)) if >3 positive L, or LN >1.5 cm, or LN exhibiting macroscopic extranodal tumor invasion; or combination of a tumor >4 cm, minimal extrathyroid invasion, and LN metastases (cN1).

Therapy with levothyroxine (L-T4) was initiated immediately after surgery, adjusting the dose to maintain thyrotropin (TSH) <2 mIU/l. Serum Tg and TgAb were measured during L-T4 use 3–6 months after thyroidectomy. Neck US was performed on the same occasion. The 391 patients selected were evaluated; 44 patients (11.2%) with positive TgAb, 119 patients (30.4%) with Tg>0.3 ng/ml, and 6 patients (1.5%) with positive neck US were excluded. Finally, 222 patients (56.7%) had Tg<0.3 ng/ml with TSH <2 mIU/l, negative TgAb, and US showing no anomalies, and because of this finding, they were not submitted to ablation with 131I.

Follow-up

The patients were maintained on 0.3–2 mIU/l TSH and were followed up by clinical examination, measurement of Tg and TgAb at intervals of 6–12 months, and annual neck US. An increase in Tg was defined as two consecutive measurements of Tg≥0.3 ng/ml (interval 3–6 months) or one measurement ≥1 ng/ml, with TSH <2 mUI/l. Imaging methods other than US (chest and mediastinal computed tomography (CT), fluorodeoxyglucose-positron emission tomography (FDG-PET)/CT, RxWBS with 131I) were performed when nonstimulated Tg converted to levels ≥1 ng/ml. The time of follow-up ranged from 15 to 102 months (median 62 months).

Imaging methods

US was performed with a linear multifrequency transducer for morphological analysis (B-mode) and for power Doppler evaluation. All suspected lesions apparent on the scans (Rosario et al. 2005, 2014b) were evaluated by US-guided fine-needle aspiration biopsy. RxWBS was obtained 7 days after 131I administration (3.7 GBq) with L-T4 withdrawal for 4 weeks. Chest and mediastinal CT with contrast was performed on 5 mm sequential sections. FDG-PET/CT was carried out after stimulation with recombinant human TSH.

Assays

Chemiluminescent assays were used for the measurement of Tg (Access Thyroglobulin Assay, Beckman Coulter, Fullerton, CA) and TgAb (Immulite 2000, Diagnostic Products Corporation, Los Angeles, CA, USA) (reference value of up to 40 IU/ml) or ARCHITET Anti-Tg, Abbott Laboratories, IL, USA (reference value of up to 4.11 IU/ml). Patients with TgAb were excluded (Rosario et al. 2004b). The functional sensitivity obtained with the second-generation Tg assay at our laboratory was 0.1 ng/ml (Rosario et al. 2015b). We used this cut off to define undetectable serum Tg (i.e., ≤0.1 ng/ml).

Statistical analysis

Fisher's exact test and the χ2 test were used for statistical analysis. A P-value <0.05 was considered significant.

Results

Characteristics of the patients

The characteristics and risk classification of the patients are shown in Tables 1 and 2 respectively.

Table 1

Characteristics of the patients studied

Number of patients studied222
Gender
 Female181 (81.5%)
 Male41 (18.5%)
Age (years)
 18–78 (median: 49)
Tumor size
 Range0.6–5 cm
 ≤1 cma34 (15.3%)
 >1 cm and ≤2 cm88 (39.6%)
 >2 cm and ≤4 cm85 (38.3%)
 >4 cm15 (6.7%)
Minimal extrathyroid invasion (pT3)68 (30.6%)
Multicentricity of the tumor70 (31.5%)
TNM classification
 T1bNxM060 (27%)
 T2NxM049 (22%)
 T3NxM083 (37.4%)
 T1N1M018 (8.1%)
 T2N1M012 (5.4%)

All with extrathyroid invasion (pT3) or clinically apparent lymph node metastases (cN1).

Table 2

Risk classification of the patients studied

Risk classificationRiskNRecurrenceP-value
American Thyroid Association (Cooper et al. 2009)Low1242a (1.6%)0.65
British Thyroid Association (Perros et al. 2014)Intermediate983 (3%)
European Thyroid Association (Lepoutre-Lussey et al. 2014)Low1091 (1%)0.37
High1134a (3.5%)
All patients2225a (2.2%)

Only one patient exhibited biochemical recurrence (Tg elevation without apparent disease on the imaging methods).

Follow-up

Among the 222 patients, 217 (97.7%) continued to have nonstimulated Tg <0.3 ng/ml, negative TgAb, and neck US without anomalies. Serum Tg was undetectable in the last assessment in 185 of 217 patients (85.2%) and detectable in 32 patients (14.7%) (range 0.12–0.28 ng/ml; median 0.2 ng/ml).

Five of the 222 patients (2.2%) exhibited an increase in nonstimulated Tg, and LN metastases were detected in four (by neck US in three patients and by FDG-PET/CT in one patient (structural recurrence)). After surgery, two patients were free of disease (undetectable nonstimulated Tg, negative TgAb, US without anomalies), and two patients continued to have detectable nonstimulated Tg but <1 ng/ml and no apparent tumor detected by the imaging methods. One patient progressed to an increase in serum Tg, but no tumor was detected by US or CT (biochemical recurrence). After receiving 3.7 GBq 131I and RxWBS showing uptake only in the thyroid bed, serum Tg had already declined by more than 70%. The characteristics of the five patients with recurrence are shown in Table 3.

Table 3

Characteristics of the patients with recurrence

SexFFFMF
Age (years)3850583248
TNM classificationT3NxM0T3NxM0T2NxM0T2N1M0T3NxM0
Postoperative nonstimulated Tg (ng/ml)UNDUND0.250.180.21
Interval between surgery and recurrence (months)6048483036
Tg at time of recurrent disease (ng/ml)0.562.41.65.62
Site of recurrenceCervical LNCervical LNCervical LNCervical LNUnknown
Positive imaging methodUSUSUSFDG-PETNone

F, female; M, male; UND, undetectable.

Recurrence (LN metastases) was observed in two (1.3%) of the 153 patients with undetectable initial Tg. Among the 69 patients with detectable initial Tg (range 0.15–0.29 ng/ml; median 0.22 ng/ml), recurrences were diagnosed in 3 (4.3%) (LN metastases in two and biochemical recurrence in the other).

The frequency of tumor recurrence according to the initial risk classification is shown in Table 2.

Discussion

First, we highlight some characteristics of the present study. This was a prospective study including a large number of patients. To our knowledge, this is so far the first prospective study that evaluated tumor recurrence in patients with low postoperative nonstimulated Tg, who were not treated with 131I because of this result. In contrast to previous studies in which most of the patients had microcarcinoma restricted to the thyroid (Durante et al. 2012, Ibrahimpasic et al. 2012, Nascimento et al. 2013, Angell et al. 2014), these patients and those with noninvasive E-FVPTC (Rosario et al. 2014a) were excluded from the present study because there is consensus that ablation of thyroid remnant is not necessary in these cases. More than half the patients were older than 45 years and 2 of 3 had a multicentric tumor >1 and ≤4 cm (T1b-2Nx), tumor >4 cm or with extrathyroid invasion (T3Nx), or clinically apparent LN metastases (T1-2cN1). Additionally, the patients were not submitted to elective LN dissection of the central compartment, and it is possible that 1 of 3 cN0 patients had clinically not apparent metastases (pN1) and that up to 40% of these patients had five or more affected LN (Scherl et al. 2014). Finally, the median follow-up time was 5 years, and it is known that 3 of 4 recurrences occur in these first years (Brassard et al. 2011, Durante et al. 2013). The rate of recurrence was the same (3 of 112 (2.6%)) when only patients with a follow-up time >5 years were analyzed.

Even when measured with a second-generation assay, undetectable or low nonstimulated Tg can be achieved in many patients submitted to total thyroidectomy (Giovanella et al. 2008, Durante et al. 2012, Nascimento et al. 2013, Angell et al. 2014, Rosario et al. 2015a, 2015b). In these patients, two studies have shown that RxWBS did not reveal persistent disease in any case after the administration of 131I (1.1–3.7 GBq; Giovanella et al. 2008, Rosario et al. 2015a). A third study (Robenshtok et al. 2013) showed uptake outside the thyroid bed in 12% of patients with undetectable postoperative nonstimulated Tg, but the Tg assay was not a second-generation assay, and 14 of 17 patients exhibited findings indicating a high risk of persistent disease (4 with important LN involvement (>10 LN or LN >3 cm), 9 with an aggressive histological subtype associated with vascular and/or extrathyroid invasion, and 1 with classical PTC >1 cm associated with vascular invasion and LN metastases). Furthermore, postoperative US was not performed in that study. We believe that the combination of neck US increases the sensitivity in detecting persistent LN metastases after thyroidectomy, as occurs after therapy with 131I (Iervasi et al. 2007, Rosario & Purisch 2008, Castagna et al. 2011a, Chindris et al. 2012).

The fact that RxWBS was negative for metastases in these patients suggests that therapy with 131I does not provide any benefit (Nascimento et al. 2011, Rosario et al. 2011). However, to define whether low postoperative nonstimulated Tg, measured with a second-generation assay, can indeed be used as a criterion to exclude therapy with 131I, it was necessary to evaluate the risk of recurrence in the absence of this treatment, which was the objective of our study. The rate of tumor recurrence was only 2% in the present series. Serum Tg was undetectable in the last assessment in 85% of patients without recurrence and Tg continued to be <0.3 ng/ml in the remaining patients. Additionally, neck US remained negative in all of these patients. These results make unlikely the long-term occurrence of a relevant number of additional recurrences (Brassard et al. 2011). The rate of recurrence was low (∼3%) even in patients classified as intermediate (Cooper et al. 2009, Perros et al. 2014) or high risk (Lepoutre-Lussey et al. 2014). This finding suggests that the importance of histological data as predictors of recurrence risk is minimized after complete tumor resection and when low Tg is achieved. This idea is supported by the low risk of recurrence in patients initially classified as intermediate risk but with an excellent response to thyroidectomy followed by radioiodine (Tuttle et al. 2010, Castagna et al. 2011b, Rosario et al. 2015c).

Elective dissection of the cervical LNs was not performed in the present study. Indeed, there is no consensus about the need for this procedure. We believe that, for the selection of patients who can be spared from ablation with 131I based on postoperative Tg, the absence of LN metastases can be demonstrated by US and perioperative examination (cN0) and does not require confirmation by elective dissection of the central neck compartment (Rosario et al. 2011, 2012). Supporting this view, in previous studies in which 131I therapy was not performed because of the finding of low postoperative stimulated Tg, the patients were also not submitted to elective dissection of the LN and yet the rate of recurrence was very low (no LN dissection or 131I therapy) (Vaisman et al. 2010, Rosario et al. 2012, Orlov et al. 2015).

The results obtained here suggest that patients with PTC (except for tumor with extensive extrathyroid invasion (pT4), aggressive histology, extensive LN involvement, or known residual disease) who have low nonstimulated Tg, measured with a second-generation assay and in the absence of TgAb, and negative neck US after thyroidectomy do not require ablation with 131I.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

Study design: G F Mourão, P W Rosario. Study conduct: G F Mourão. Data management: G F Mourão, P W Rosario. Data analysis: G F Mourão, P W Rosario. Data interpretation: G F Mourão, P W Rosario. Manuscript writing: all authors. Manuscript review and approval: all authors.

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  • Schlumberger M, Borget I, Nascimento C, Brassard M & Leboulleux S 2011 Treatment and follow-up of low-risk patients with thyroid cancer. Nature Reviews. Endocrinology 7 625628. (doi:10.1038/nrendo.2011.133).

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  • Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, Brokhin M, Omry G, Fagin JA & Shaha A 2010 Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 20 13411349. (doi:10.1089/thy.2010.0178).

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  • Vaisman A, Orlov S, Yip J, Hu C, Lim T, Dowar M, Freeman JL & Walfish PG 2010 Application of post-surgical stimulated thyroglobulin for radioiodine remnant ablation selection in low-risk papillary thyroid carcinoma. Head & Neck 32 689698. (doi:10.1002/hed.21371).

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  • Angell TE, Spencer CA, Rubino BD, Nicoloff JT & LoPresti JS 2014 In search of an unstimulated thyroglobulin baseline value in low-risk papillary thyroid carcinoma patients not receiving radioactive iodine ablation. Thyroid 24 11271133. (doi:10.1089/thy.2013.0691).

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  • Brassard M, Borget I, Edet-Sanson A, Giraudet AL, Mundler O, Toubeau M, Bonichon F, Borson-Chazot F, Leenhardt L & Schvartz C et al. 2011 Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients. Journal of Clinical Endocrinology and Metabolism 96 13521359. (doi:10.1210/jc.2010-2708).

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  • Castagna MG, Tala Jury HP, Cipri C, Belardini V, Fioravanti C, Pasqui L, Sestini F, Theodoropoulou A & Pacini F 2011a The use of ultrasensitive thyroglobulin assays reduces but not abolishes the need for TSH stimulation in patients with differentiated thyroid carcinoma. Journal of Endocrinological Investigation 34 219223. (doi:10.3275/7571).

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  • Castagna MG, Maino F, Cipri C, Belardini V, Theodoropoulou A, Cevenini G & Pacini F 2011b Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients. European Journal of Endocrinology 165 441446. (doi:10.1530/EJE-11-0466).

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  • Chindris AM, Diehl NN, Crook JE, Fatourechi V & Smallridge RC 2012 Undetectable sensitive serum thyroglobulin (< 0.1 ng/ml) in 163 patients with follicular cell-derived thyroid cancer: results of rhTSH stimulation and neck ultrasonography and long-term biochemical and clinical follow-up. Journal of Clinical Endocrinology and Metabolism 97 27142723. (doi:10.1210/jc.2011-3017).

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  • Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F & Schlumberger M et al. 2009 Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19 11671214. (doi:10.1089/thy.2009.0110).

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  • Durante C, Montesano T, Attard M, Torlontano M, Monzani F, Costante G, Meringolo D, Ferdeghini M, Tumino S & Lamartina L et al. 2012 Long-term surveillance of papillary thyroid cancer patients who do not undergo postoperative radioiodine remnant ablation: is there a role for serum thyroglobulin measurement? Journal of Clinical Endocrinology and Metabolism 97 27482753. (doi:10.1210/jc.2012-1123).

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  • Durante C, Montesano T, Torlontano M, Attard M, Monzani F, Tumino S, Costante G, Meringolo D, Bruno R & Trulli F et al. 2013 Papillary thyroid cancer: time course of recurrences during postsurgery surveillance. Journal of Clinical Endocrinology and Metabolism 98 636642. (doi:10.1210/jc.2012-3401).

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  • Furtado MS, Rosario PW & Calsolari MR 2015 Persistent and recurrent disease in patients with papillary thyroid carcinoma with clinically apparent (cN1), but not extensive, lymph node involvement and without other factors for poor prognosis. Archives of Endocrinology and Metabolism 59 285291. (doi:10.1590/2359-3997000000081).

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  • Giovanella L, Ceriani L, Suriano S, Ghelfo A & Maffioli M 2008 Thyroglobulin measurement before rhTSH-aided 131I ablation in detecting metastases from differentiated thyroid carcinoma. Clinical Endocrinology 69 659663. (doi:10.1111/j.1365-2265.2008.03244.x).

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  • Ibrahimpasic T, Nixon IJ, Palmer FL, Whitcher MM, Tuttle RM, Shaha A, Patel SG, Shah JP & Ganly I 2012 Undetectable thyroglobulin after total thyroidectomy in patients with low- and intermediate-risk papillary thyroid cancer – is there a need for radioactive iodine therapy? Surgery 152 10961105. (doi:10.1016/j.surg.2012.08.034).

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  • Iervasi A, Iervasi G, Ferdeghini M, Solimeo C, Bottoni A, Rossi L, Colato C & Zucchelli GC 2007 Clinical relevance of highly sensitive Tg assay in monitoring patients treated for differentiated thyroid cancer. Clinical Endocrinology 67 434441. (doi:10.1111/j.1365-2265.2007.02907.x).

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  • Lepoutre-Lussey C, Deandreis D, Leboulleux S & Schlumberger M 2014 Postoperative radioactive iodine administration for differentiated thyroid cancer patients. Current Opinion in Endocrinology, Diabetes and Obesity 21 363371. (doi:10.1097/MED.0000000000000100).

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  • Nascimento C, Borget I, Al Ghuzlan A, Deandreis D, Chami L, Travagli JP, Hartl D, Lumbroso J, Chougnet C & Lacroix L et al. 2011 Persistent disease and recurrence in differentiated thyroid cancer patients with undetectable postoperative stimulated thyroglobulin level. Endocrine-Related Cancer 18 R29R40. (doi:10.1677/ERC-10-0292).

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  • Nascimento C, Borget I, Troalen F, Al Ghuzlan A, Deandreis D, Hartl D, Lumbroso J, Chougnet CN, Baudin E & Schlumberger M et al. 2013 Ultrasensitive serum thyroglobulin measurement is useful for the follow-up of patients treated with total thyroidectomy without radioactive iodine ablation. European Journal of Endocrinology 169 689693. (doi:10.1530/EJE-13-0386).

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  • Orlov S, Salari F, Kashat L, Freeman JL, Vescan A, Witterick IJ & Walfish PG 2015 Post-operative stimulated thyroglobulin and neck ultrasound as personalized criteria for risk stratification and radioactive iodine selection in low- and intermediate-risk papillary thyroid cancer. Endocrine 50 130137. (doi:10.1007/s12020-015-0575-0).

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  • Perros P, Boelaert K, Colley S, Evans C, Evans RM, Gerrard Ba G, Gilbert J, Harrison B, Johnson SJ & Giles TE et al. 2014 Guidelines for the management of thyroid cancer. Clinical Endocrinology 81 (Suppl 1) 1122. (doi:10.1111/cen.12515).

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  • Robenshtok E, Grewal RK, Fish S, Sabra M & Tuttle RM 2013 A low postoperative nonstimulated serum thyroglobulin level does not exclude the presence of radioactive iodine avid metastatic foci in intermediate-risk differentiated thyroid cancer patients. Thyroid 23 436442. (doi:10.1089/thy.2012.0352).

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  • Rosario PW & Purisch S 2008 Does a highly sensitive thyroglobulin (Tg) assay change the clinical management of low-risk patients with thyroid cancer with Tg on T4 < 1 ng/ml determined by traditional assays? Clinical Endocrinology 68 338342. (doi:10.1111/j.1365-2265.2007.03043.X).

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  • Rosario PW, Fagundes TA & Purisch S 2004a Treatment of papillary microcarcinoma of the thyroid. Arquivos Brasileiros de Endocrinologia e Metabologia 48 855860. (doi:10.1590/S0004-27302004000600012).

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  • Rosario PW, Maia FF, Fagundes TA, Vasconcelos FP, Cardoso LD & Purisch S 2004b Antithyroglobulin antibodies in patients with differentiated thyroid carcinoma: methods of detection, interference with serum thyroglobulin measurement and clinical significance. Arquivos Brasileiros de Endocrinologia e Metabologia 48 487492. (doi:10.1590/S0004-27302004000400008).

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  • Rosario PW, de Faria S, Bicalho L, Alves MF, Borges MA, Purisch S, Padrão EL, Rezende LL & Barroso AL 2005 Ultrasonographic differentiation between metastatic and benign lymph nodes in patients with papillary thyroid carcinoma. Journal of Ultrasound in Medicine 24 13851389.

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  • Rosario PW, Borges MA, Valadão MM, Vasconcelos FP, Rezende LL, Padrão EL, Barroso AL & Purisch S 2007 Is adjuvant therapy useful in patients with papillary carcinoma smaller than 2 cm? Thyroid 17 12251228. (doi:10.1089/thy.2006.0254).

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  • Rosario PW, Xavier AC & Calsolari MR 2011 Value of postoperative thyroglobulin and ultrasonography for the indication of ablation and 131I activity in patients with thyroid cancer and low risk of recurrence. Thyroid 21 4953. (doi:10.1089/thy.2010.0145).

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  • Rosario PW, Mineiro Filho AF, Prates BS, Silva LC & Calsolari MR 2012 Postoperative stimulated thyroglobulin of less than 1 ng/ml as a criterion to spare low-risk patients with papillary thyroid cancer from radioactive iodine ablation. Thyroid 22 11401143. (doi:10.1089/thy.2012.0190).

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  • Rosario PW, Ward LS, Carvalho GA, Graf H, Maciel RM, Maciel LM, Maia AL & Vaisman M 2013 Thyroid nodules and differentiated thyroid cancer: update on the Brazilian consensus. Arquivos Brasileiros de Endocrinologia e Metabologia 57 240264. (doi:10.1590/S0004-27302013000400002).

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  • Rosario PW, Penna GC & Calsolari MR 2014a Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: is lobectomy sufficient for tumours ≥1 cm? Clinical Endocrinology 81 630632. (doi:10.1111/cen.12387).

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  • Rosario PW, Tavares WC, Borges MA, Santos JB & Calsolari MR 2014b Ultrasonographic differentiation of cervical lymph nodes in patients with papillary thyroid carcinoma after thyroidectomy and radioiodine ablation: a prospective study. Endocrine Practice 20 293298. (doi:10.4158/EP13307.OR).

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  • Rosario PW, Mourão GF, Siman TL & Calsolari MR A low postoperative nonstimulated serum thyroglobulin level excludes the presence of persistent disease in low-risk papillary thyroid cancer patients: implication for radioiodine indication Clinical Endocrinology 2015a [in press] doi:10.1111/cen12668).

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  • Rosario PW, Mourão GF, Siman TL & Calsolari MR 2015b Serum thyroglobulin measured with a second-generation assay in patients undergoing total thyroidectomy without radioiodine remnant ablation: A prospective study. Thyroid 25 769775. (doi:10.1089/thy.2014.0496).

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  • Rosario PW, Furtado MS, Mourão GF & Calsolari MR 2015c Patients with papillary thyroid carcinoma at intermediate risk of recurrence according to American Thyroid Association criteria can be reclassified as low risk when the postoperative thyroglobulin is low. Thyroid 25 12431248. (doi:10.1089/thy.2015.0294).

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  • Scherl S, Mehra S, Clain J, Dos Reis LL, Persky M, Turk A, Wenig B, Husaini H & Urken ML 2014 The effect of surgeon experience on the detection of metastatic lymph nodes in the central compartment and the pathologic features of clinically unapparent metastatic lymph nodes: what are we missing when we don't perform a prophylactic dissection of central compartment lymph nodes in papillary thyroid cancer? Thyroid 24 12821288. (doi:10.1089/thy.2013.0600).

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  • Schlumberger M, Borget I, Nascimento C, Brassard M & Leboulleux S 2011 Treatment and follow-up of low-risk patients with thyroid cancer. Nature Reviews. Endocrinology 7 625628. (doi:10.1038/nrendo.2011.133).

    • Search Google Scholar
    • Export Citation
  • Tuttle RM, Tala H, Shah J, Leboeuf R, Ghossein R, Gonen M, Brokhin M, Omry G, Fagin JA & Shaha A 2010 Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 20 13411349. (doi:10.1089/thy.2010.0178).

    • Search Google Scholar
    • Export Citation
  • Vaisman A, Orlov S, Yip J, Hu C, Lim T, Dowar M, Freeman JL & Walfish PG 2010 Application of post-surgical stimulated thyroglobulin for radioiodine remnant ablation selection in low-risk papillary thyroid carcinoma. Head & Neck 32 689698. (doi:10.1002/hed.21371).

    • Search Google Scholar
    • Export Citation