Clinical Impact of Detectable Antithyroglobulin Antibodies Below the Reference Limit (Borderline) in Patients with Papillary Thyroid Carcinoma with Undetectable Serum Thyroglobulin and Normal Neck Ultrasonography After Ablation: A Prospective Study

Abstract

Background:

Interference of antithyroglobulin antibodies (TgAb) with serum thyroglobulin (Tg) can occur even at detectable TgAb concentrations below the reference limit (borderline TgAb). Thus, borderline TgAb is considered as TgAb positivity in patients with thyroid cancer. This prospective study evaluated patients with papillary thyroid carcinoma with undetectable Tg and normal neck ultrasonography (US) after total thyroidectomy and ablation with ¹³¹I, and compared tumor persistence/recurrence and long-term Tg and TgAb behavior in those with borderline versus undetectable TgAb.

Methods:

A total of 576 patients were evaluated, divided into two groups: group A with undetectable TgAb (n = 420), and group B with borderline TgAb (n = 156).

Results:

Groups A and B were similar in terms of patient and tumor characteristics. The time of follow-up ranged from 24 to 120 months. During follow-up, 11 (2.6%) patients in group A and 5 (3.2%) in group B developed a recurrence (p = 0.77). In group A, recurrences occurred in 9/390 patients who continued to have undetectable TgAb and in 1/9 patients who progressed to borderline TgAb. In group B, recurrences were detected in 1/84 patients who progressed to have undetectable TgAb, in 1/45 who still had borderline TgAb, and in 3/12 who developed elevated TgAb. In the presence of Tg levels <0.2 ng/mL, recurrences were detected in 2/486 patients with undetectable TgAb, in 0/67 with borderline TgAb, and in 3/12 with elevated TgAb. The results of post-therapy whole-body scanning (RxWBS) of 216 patients with Tg ≤0.2 ng/mL and normal US at the time of ablation were also analyzed. In low-risk patients, none of the 40 patients with borderline TgAb and none of the 94 with undetectable TgAb exhibited ectopic uptake on RxWBS. In intermediate-risk patients, lymph node metastases were detected by RxWBS in 1/25 (4%) with borderline TgAb and in 2/57 (3.5%) with undetectable TgAb.

Conclusions:

The results suggest that among low- or intermediate-risk patients with undetectable Tg and normal US after thyroidectomy, those with borderline TgAb are at no greater risk of tumor persistence or recurrence than those with undetectable TgAb. When undetectable Tg levels persist, recurrence should be suspected in the case of a TgAb elevation above the reference limit.

Introduction

Measurement of serum thyroglobulin (Tg) within a few months after initial therapy is recommended for patients with papillary thyroid carcinoma (PTC). Antithyroglobulin antibodies (TgAb) should also be measured. If present, there is a well-known possibility of interference with Tg (1 –3). This interference can occur at detectable TgAb concentrations below the reference limit of the assay (borderline TgAb) (2). In fact, this limit was established to identify autoimmune thyroid disease and not to define interference with Tg. In view of the possibility of interference with Tg (2), borderline TgAb levels are currently considered as TgAb positivity in patients with PTC (2,4 –8). However, to the authors' knowledge, no study has so far evaluated the clinical outcomes of patients with borderline TgAb and whether these patients in fact differ significantly from patients with undetectable TgAb. Since borderline TgAb levels are common among patients with PTC (2), the recommendation of considering them TgAb positive may affect the management of many patients.

In most immunoassays currently used for Tg measurements, interference of TgAb underestimates Tg concentrations, and this fact is even more worrisome when it leads to an undetectable result (1 –3). In addition, neck ultrasonography (US) is routinely recommended for initial assessment after PTC therapy, regardless of the Tg and TgAb results. For these reasons, considering borderline TgAb as TgAb positive will lead to greater changes in the management of patients who exhibit undetectable basal Tg associated with normal US.

Therefore, this prospective study specifically evaluated a cohort of patients comparing tumor persistence/recurrence (clinical outcome) and the long-term behavior of Tg and TgAb in patients with undetectable versus borderline TgAb. Since second-generation assays are already widely available and used, Tg was measured in the present study with the currently most widely studied and used second-generation assay (9).

Patients and Methods

Design

This was a prospective study. The study was approved by the Research Ethics Committee of at the authors' institution.

Patients

Patients consecutively seen at the authors' institution between December 2006 and December 2014 who met the following criteria were initially selected: (i) diagnosis of PTC; (ii) submitted to total thyroidectomy followed by ablation with ¹³¹I (1.1–5.5 GBq); (iii) apparently complete tumor resection; and (iv) normal neck US, basal Tg ≤0.2 ng/mL, and TgAb below the reference limit of the assay 12–18 months after ablation. Patients with microcarcinomas restricted to the thyroid or with the noninvasive encapsulated follicular variant of PTC (E-FVPTC) (10,11) were not included. Patients with TgAb concentrations above the reference limit of the assay (elevated TgAb) were also excluded.

The patients were divided into two groups: group A with undetectable TgAb, and group B with detectable TgAb below the reference limit (borderline). Basal Tg ≤0.2 ng/mL and TgAb status (undetectable or borderline) were confirmed in all patients at an interval of approximately six weeks.

Follow-up

The patients were followed by biannual measurements of basal Tg, TgAb, clinical examination, and annual neck US. Imaging methods other than neck US (chest computed tomography [CT], fluorodeoxyglucose [FDG]-positron emission tomography [PET]/CT, and whole-body scanning [RxWBS]) were performed when basal Tg increased or TgAb became elevated. The patients were maintained on a levothyroxine (LT4) dose sufficient to obtain serum thyrotropin (TSH) of 0.3–2 mIU/L.

Assays

A chemiluminescent assay was used for the measurement of Tg (Access Thyroglobulin Assay; Beckman Coulter, Fullerton, CA). The functional sensitivity obtained at the laboratory was 0.1 ng/mL. TgAb were also measured with a chemiluminescent assay (ARCHITECT Anti-Tg; Abbott Laboratories, Abbott Park, IL), with a reference value of up to 4.11 IU/mL. The functional sensitivity obtained at the laboratory was 1.1 IU/mL. Thus, TgAb concentrations <1.1 IU/mL were classified as undetectable (group A) and between 1.1 and 4.1 IU/mL as borderline (group B).

Imaging methods

US was performed with a linear multifrequency transducer for morphological analysis (B-mode) and for power Doppler evaluation. All suspicious lesions (12,13) were submitted to US-guided fine-needle aspiration, combined with cytology and Tg measurement in the needle washout. Therapy with ¹³¹I was preceded by the administration of recombinant human TSH (rhTSH) or LT4 withdrawal for four weeks and a low-iodine diet for 10–14 days. For RxWBS, anterior and posterior whole-body images were obtained seven days after ¹³¹I therapy. CT was performed on 5 mm sequential sections. FDG-PET/CT scans were obtained after stimulation with rhTSH. All images were analyzed by radiology and nuclear medicine specialists who had extensive experience with the imaging methods in patients with thyroid cancer.

Diagnosis of a tumor in lesions apparent on the imaging methods was done by cytology or histology and/or unequivocal ectopic uptake (excluding false-positive results) on RxWBS or FDG-PET/CT.

Statistical analysis

Means were compared between groups by Student's t-test or the nonparametric Mann–Whitney U-test. Fisher's exact test or the chi-square test were used to detect differences in the proportion of cases. A p-value of <0.05 was considered significant.

Results

Characteristics of the patients

Patients in groups A and B were similar in terms of sex and age, characteristics of the primary tumor (histological subtype, vascular invasion, multicentricity, and size), extrathyroid extension, lymph node metastases, TNM stage, and risk category according to the American Thyroid Association (ATA) (14) (Table 1). The time of follow-up ranged from 24 to 120 months (median 66 months).

Table 1.

Characteristics of the Patients Studied

	Group A (n = 420)	Group B (n = 156)	p-Value
Sex			0.81
Female	335 (80%)	123 (79%)
Male	85 (20%)	33 (21%)
Age, range (median)	13–80 years (47 years)	13–77 years (46 years)	0.9
Tumor size
≤2 cm	128 (30%)	45 (29%)	0.76
2–4 cm	216 (51%)	80 (51%)	1.0
>4 cm	76 (18%)	31 (20%)	0.63
Aggressive histological subtype^a	36 (8%)	15 (9%)	0.74
Vascular invasion	26 (6%)	10 (6%)	1.0
Multicentricity	141 (33%)	51 (32%)	0.92
Extrathyroidal extension	116 (27%)	40 (25%)	0.67
Lymph node metastases (cN1)	179 (42%)	65 (41%)	0.85
TNM
T1bN0	35 (8%)	12 (7%)	0.86
T1N1	57 (13%)	20 (13%)	0.89
T2N0	84 (20%)	33 (21%)	0.81
T2N1	51 (12%)	18 (11%)	0.88
T3N0	121 (29%)	46 (29%)	0.91
T3N1	70 (16%)	27 (17%)	0.9
T4N0	1	0	1.0
T4N1	1	0	1.0
Risk category (14)
Low	182 (43%)	70 (45%)	0.77
Intermediate	236 (56%)	86 (55%)	0.85
High	2	0	1.0
Chronic lymphocytic thyroiditis on histology^b	62 (15%)	32 (20%)	0.1
Time of follow-up, range (median), months	24–120 (66)	24–120 (66)	1.0

Group A, undetectable antithyroglobulin antibody (TgAb); Group B, TgAb borderline.

Tall cell, columnar cell.

Diffuse lymphocytic infiltration present in the area of normal thyroid.

cN1, clinically apparent lymph node metastases.

Tumor recurrence

During follow-up, 11 (2.6%) patients in group A and 5 (3.2%) in group B developed recurrence (p = 0.77). Recurrences were lymph node metastases in 11 patients (7 [1.6%] in group A and 4 [2.5%] in group B; p = 0.5), pulmonary metastases in three patients (2 [0.47%] in group A and 1 [0.64%] in group B; p = 1.0), and biochemical recurrence (basal Tg >1 ng/mL without apparent disease on US, CT, and FDG-PET/CT) in two patients (2 [0.47%] in group A and none in group B; p = 1.0). Among low-risk patients according to ATA criteria (14), recurrences occurred in five patients (3 [1.6%] in group A and 2 [2.8%] in group B; p = 0.62), while recurrences were observed in 11 intermediate-risk patients (8 [3.4%] in group A and 3 [3.5%] in group B; p = 1.0). There was no case of death related to the disease.

Behavior of TgAb during follow-up

For the following results, in patients developing recurrence, the measurements up to the detection of this recurrence were considered.

Group A (n = 420)

Thirty patients had borderline TgAb on at least one occasion. Of these 30 patients, 21 spontaneously had undetectable TgAb in subsequent measurements, while the remaining nine patients continued to have borderline TgAb.

Group B (n = 156)

Ninety-nine patients had undetectable TgAb on some occasion, but these levels returned to borderline in 15 patients. TgAb became negative after 6–60 months (median 36 months). Forty-five patients continued with borderline TgAb throughout follow-up. Twelve (7.7%) patients developed persistently elevated TgAb, with stable concentrations in nine patients and progression in three patients. In group B, TgAb concentration in the initial assessment, which ranged from 1.2 to 4.1 IU/mL (median 2.8 IU/mL), was not a predictor of TgAb behavior (negative, persistently borderline, elevation) during follow-up. Patients in group B were more likely to progress to elevated TgAb (p = 0.001). In fact, TgAb elevation occurred only in patients in this group.

Relationship between TgAb behavior and recurrence

Recurrences occurred in 9/390 (2.3%) patients who had undetectable TgAb throughout follow-up, in 1/84 (1.2%) patients with initially borderline TgAb but who progressed to persistently undetectable TgAb, in 1/21 (4.7%) patients with undetectable TgAb but borderline on some occasion, in 0/15 with borderline TgAb but undetectable on some occasion, in 1/45 (2.2%) patients with borderline TgAb throughout follow-up, in 1/9 (11%) patients with initially undetectable TgAb but who progressed to persistently borderline TgAb, and in 3/12 (25%) patients who developed elevated TgAb. Only progression to elevated TgAb (observed only in patients in group B) was significantly associated with recurrence (p = 0.026).

Tg at the time of recurrence detection

At the time recurrence was detected (16 patients), 11 patients had undetectable TgAb, two had borderline TgAb, and three had elevated TgAb. Of these, 11 patients had Tg levels >0.2 ng/mL, and five had Tg levels <0.2 ng/mL (Table 2). Tg was <0.2 ng/mL in 2/11 patients with undetectable TgAb (both from group A), in 0/2 with borderline TgAb, and in 3/3 with elevated TgAb (from group B). Thus, in the presence of Tg levels <0.2 ng/mL, recurrences were detected in 2/486 (0.4%) patients with undetectable TgAb, in 0/67 with borderline TgAb, and in 3/12 (25%) with elevated TgAb. Only elevated TgAb were associated with a significantly higher risk of recurrence in the presence of an undetectable Tg (p = 0.003).

Table 2.

Association Between Antithyroglobulin Antibody Behavior and Recurrence

TgAb concentration
Initial assessment ^a	During follow-up	Last assessment ^b	Serum Tg ^c	Recurrence
Undetectable (n = 420)	Undetectable (n = 390)		<0.2 ng/mL (n = 383)	2
			>0.2 ng/mL (n = 7)^d	7
	Borderline (n = 30)	Undetectable (n = 21)	<0.2 ng/mL (n = 20)	0
			>0.2 ng/mL (n = 1)^d	1
		Borderline (n = 9)	<0.2 ng/mL (n = 8)	0
			>0.2 ng/mL (n = 1)^e	1
Borderline (n = 156)	Borderline (n = 45)		<0.2 ng/mL (n = 44)	0
			>0.2 ng/mL (n = 1)^e	1
	Undetectable (n = 99)	Undetectable (n = 84)	<0.2 ng/mL (n = 80)	0
			>0.2 ng/mL (n = 1)^d	1
		Borderline (n = 15)	<0.2 ng/mL (n = 15)	0
	Elevated (n = 9)		<0.2 ng/mL (n = 9)	3

All patients had undetectable Tg and normal neck ultrasonography.

In patients with recurrence, the results at the time of detection of this recurrence were considered.

In the last assessment in patients without recurrence or at the time of recurrence detection.

Serum Tg at the time of recurrence detection in nine patients with undetectable TgAb: 1.6, 1.8, 2.5, 3.6, 4.5, 5.6, 11, 46, and 72 ng/mL.

Serum Tg at the time of recurrence detection in two patients with borderline TgAb: 2.1 and 3.5 ng/mL.

TgAb, antithyroglobulin antibodies; Tg, thyroglobulin.

Retrospective analysis

The Tg results before ablation and RxWBS were reviewed. A total of 216 patients had Tg levels ≤0.2 ng/mL and a normal US at the time of ablation. In low-risk patients (n = 134), none of the 40 patients with borderline TgAb and none of the 94 with undetectable TgAb exhibited ectopic uptake on RxWBS. In intermediate-risk patients (n = 82), 1/25 (4%) with borderline TgAb and 2/57 (3.5%) with undetectable TgAb had metastases on RxWBS (cervical lymph nodes; p = 1.0).

Discussion

Based on the demonstration that they can interfere with Tg (2), many authors recommend that patients with PTC who have borderline TgAb be considered TgAb positive (2,4 –8). The main impact of this change is observed for low- or intermediate-risk patients who exhibit an undetectable basal Tg associated with normal neck US findings. When these patients are TgAb negative, they are categorized as having an excellent response to therapy (14). In addition, (i) there is no need for additional investigation, (ii) TSH suppression is not necessary, (iii) the estimated long-term risk of structural disease is 1–4% (14), and (iv) if Tg and TgAb continue to be negative during follow-up, repetition of imaging methods is not required (14,15). In contrast, when patients with an undetectable Tg and unremarkable US are TgAb positive, they are categorized as having an indeterminate or incomplete response to therapy (14). In these cases, (i) additional evaluations (e.g., DxWBS) is suggested by different guidelines (5,16 –20) and authors (21), (ii) some suppression of TSH (between 0.1 and 0.5 mIU/L) is recommended for most patients (14), (iii) the estimated long-term risk of structural disease is 15–20% (14), and (iv) several guidelines and reviews recommend the repetition of imaging methods during follow-up (4,5,16 –18,22). Because of all these differences, it is believed that in order to consider patients with borderline TgAb to be TgAb positive, in addition to demonstrating that interference with Tg is possible, it is necessary to know whether the evolution of these patients indeed differs significantly from those considered to be TgAb negative. To the authors' knowledge, no study has so far evaluated the clinical outcome of such patients. In a small series, Latrofa et al. (23) reported that none of the 4–12 patients (depending on the TgAb assay) with an undetectable stimulated Tg and borderline TgAb had apparent disease on US or RxWBS.

The present study was prospective and included a large number of patients who were evaluated periodically over a mean period of 5.5 years for the detection of structural disease. It is known than 3/4 of recurrences are detected within these first years of follow-up (24,25). In this study, patients were selected in whom the change in definition from TgAb negative to TgAb positive would have the greatest impact, that is, low-risk (already excluding microcarcinomas restricted to the thyroid and noninvasive E-FVPTC) or intermediate-risk patients who had an undetectable basal Tg associated with normal US findings. Furthermore, Tg was measured with the currently most widely studied and used second-generation assay (8). In addition to structural disease, the long-term behavior of Tg and TgAb was evaluated in patients with borderline TgAb. The results were also compared to those observed in similar patients with undetectable TgAb. The fact that the recurrence rate observed here was consistent with that reported for TgAb-negative patients (14) ensures that the rate is not underestimated due to selection bias.

The risk of structural disease was 3% in patients with borderline TgAb. This risk is low and is consistent with that expected for patients with an excellent response to initial therapy (14). In fact, this rate did not differ from that found in patients with undetectable TgAb. A low risk of recurrence (2%) was observed, even in patients with borderline TgAb over the period studied. In addition, Tg was detectable in patients with borderline TgAb at the time when recurrence was detected. A difference found between patients with borderline and undetectable TgAb was the higher risk of progression to elevated TgAb in the former (7.7% vs. 0%), and this finding was associated with a risk of structural disease in the presence of an undetectable Tg. However, an increase in TgAb can be detected by periodic measurements of Tg and TgAb, which are already recommended for the follow-up of all patients with PTC (14). Another finding supporting that borderline TgAb may not have a significant clinical impact was the rate of persistent disease detected by RxWBS in patients with complete tumor resection and an undetectable Tg and normal US at the time of ablation. In addition to being low (0% in low-risk patients and 4% in intermediate-risk patients), this rate did not differ from that observed in patients with undetectable TgAb.

Another observation in the present series was that some patients with initially undetectable TgAb exhibited borderline TgAb on some occasion during follow-up. Most of these patients had undetectable TgAb in subsequent measurements, and even among those with persistent borderline but not elevated TgAb, only one developed a recurrence accompanied by a Tg elevation. Thus, in patients in whom TgAb change from undetectable to borderline at some time, the recommendation is to repeat the measurement after a few months to confirm the persistence of this change. Additional investigation is probably not necessary if Tg remains undetectable and TgAb are only borderline.

One limitation of this study is that patients with borderline TgAb were not compared to patients with elevated TgAb, which would reinforce that these two groups are different. However, the demonstration that patients with borderline TgAb had the same rate of structural disease as patients with undetectable TgAb seems to be sufficient to propose that they are managed in a similar manner as the latter. Furthermore, the reported frequency of recurrence in patients with an undetectable Tg without initially apparent disease but with elevated TgAb is much higher than that found in the present study (26 –30). Interference by TgAb frequently does not result in an undetectable Tg, but in detectable yet underestimated concentrations (2). This study also did not compare patients with borderline versus undetectable TgAb with positive or elevated serum Tg. It is believed that the possibility of a significant delay in detecting residual tumor is low in these patients. More rigorous follow-up is already recommended in this situation (14). In addition, if both (Tg and TgAb) are detectable, eventual tumor progression will most likely be accompanied by an elevation of at least one of the markers, requiring investigation for recurrence. Hence, of concern were patients with excellent response to therapy (a definition that includes an undetectable Tg). An increasingly flexible follow-up has been recommended for these individuals (14,15). Furthermore, if an initially undetectable Tg is due a significant interference by TgAb, eventual tumor progression may not be accompanied by a Tg elevation, even if the TgAb remain stable. The interference of borderline TgAb with serum Tg varies according to the assay used (2). Consequently, the rates found in the present study for patients with borderline TgAb could have been different if other TgAb assays were used. However, the wish was to demonstrate that the recurrence rate is similar to that seen in patients with undetectable TgAb.

In the present study, the patients were treated with radioiodine. It is believed that the similarity in recurrence rate between patients with borderline and undetectable TgAb also occurs among those submitted to total thyroidectomy without subsequent radioiodine therapy. Only TgAb elevation was associated with a higher risk of recurrence, but the presence of thyroid remnants does not appear to increase the odds of it occurring. If this relationship existed, it would also be expected in TgAb-negative patients in the initial assessment, but no difference in the frequency of TgAb elevations during follow-up was found between patients treated or not with radioiodine (15). The possible influence of thyroid remnants may result in a lower frequency or delay of TgAb becoming negative. However, the persistence of borderline concentrations even in patients treated with radioiodine does not imply a higher risk of recurrence, which was similar to that found in TgAb-negative patients or those with a persistently undetectable TgAb. Thus, any influence of thyroid remnants on the behavior of initially borderline TgAb would not affect the recurrence rate. Finally, in the retrospective analysis of this study, after total thyroidectomy (before radioiodine) in the presence of Tg <0.2 ng/mL and normal US, the frequency of persistent disease was the same for patients with borderline and those with undetectable TgAb.

In conclusion, the results suggest that in low- or intermediate-risk patients with undetectable Tg levels measured with a second-generation assay and normal US after initial therapy, borderline TgAb do not increase the risk of structural disease when compared to undetectable TgAb. In addition, some patients with initially undetectable TgAb may develop borderline TgAb during follow-up, but spontaneous return to undetectable concentrations occurs in most of them. No additional investigation appears to be necessary if the patients continue to have undetectable Tg levels and only borderline TgAb concentrations. A minority of patients with borderline TgAb may progress to elevated TgAb, which would suggest recurrence even in the presence of an undetectable Tg.

Footnotes

Acknowledgments

This work was supported by the National Council for Scientific and Technological Development (CNPq), Brazil.

Author Disclosure Statement

The authors declare that they have no conflict of interest.

References

Rosario

, Maia

, Fagundes

, Vasconcelos

, Cardoso

, Purisch

. 2004. Antithyroglobulin antibodies in patients with differentiated thyroid carcinoma: methods of detection, interference with serum thyroglobulin measurement and clinical significance. Arq Bras Endocrinol Metabol, 48:487–492.

Spencer

, Petrovic

, Fatemi

. 2011. Current thyroglobulin autoantibody (TgAb) assays often fail to detect interfering TgAb that can result in the reporting of falsely low/undetectable serum Tg IMA values for patients with differentiated thyroid cancer. J Clin Endocrinol Metab, 96:1283–1291.

Latrofa

, Ricci

, Montanelli

, Rocchi

, Piaggi

, Sisti

, Grasso

, Basolo

, Ugolini

, Pinchera

, Vitti

. 2012. Lymphocytic thyroiditis on histology correlates with serum thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: impact on detection of serum thyroglobulin. J Clin Endocrinol Metab, 97:2380–2387.

Ringel

, Nabhan

. 2013. Approach to follow-up of the patient with differentiated thyroid cancer and positive anti-thyroglobulin antibodies. J Clin Endocrinol Metab, 98:3104–3110.

Verburg

, Luster

, Cupini

, Chiovato

, Duntas

, Elisei

, Feldt-Rasmussen

, Rimmele

, Seregni

, Smit

, Theimer

, Giovanella

. 2013. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. Thyroid, 23:1211–1225.

Giovanella

, Clark

, Chiovato

, Duntas

, Elisei

, Feldt-Rasmussen

, Leenhardt

, Luster

, Schalin-Jäntti

, Schott

, Seregni

, Rimmele

, Smit

, Verburg

. 2014. Thyroglobulin measurement using highly sensitive assays in patients with differentiated thyroid cancer: a clinical position paper. Eur J Endocrinol, 171:R33–46.

Perros

, Boelaert

, Colley

, Evans

, Gerrard Ba

, Gilbert

, Harrison

, Johnson

, Giles

, Moss

, Lewington

, Newbold

, Taylor

, Thakker

, Watkinson

, Williams

. 2014. Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf), 81:1–122.

Elisei

, Agate

, Viola

, Matrone

, Biagini

, Molinaro

. 2014. How to manage patients with differentiated thyroid cancer and a rising serum thyroglobulin level. Endocrinol Metab Clin North Am, 43:331–344.

Giovanella

, Treglia

, Sadeghi

, Trimboli

, Ceriani

, Verburg

. 2014. Unstimulated highly sensitive thyroglobulin in follow-up of differentiated thyroid cancer patients: a meta-analysis. J Clin Endocrinol Metab, 99:440–447.

10.

Rosario

, Penna

, Calsolari

. 2014. Noninvasive encapsulated follicular variant of papillary thyroid carcinoma: is lobectomy sufficient for tumours ≥1 cm?. Clin Endocrinol (Oxf), 81:630–632.

11.

Rosario

, Mourão

, Nunes

, Calsolari

. 2016. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Endocr Relat Cancer, 23:893–897.

12.

Rosario

, de Faria

, Bicalho

, Alves

, Borges

, Purisch

, Padrão

, Rezende

, Barroso

. 2005. Ultrasonographic differentiation between metastatic and benign lymph nodes in patients with papillary thyroid carcinoma. J Ultrasound Med, 24:1385–1389.

13.

Rosario

, Tavares

, Borges

, Santos

, Calsolari

. 2014. Ultrasonographic differentiation of cervical lymph nodes in patients with papillary thyroid carcinoma after thyroidectomy and radioiodine ablation: a prospective study. Endocr Pract, 20:293–298.

14.

Haugen

, Alexander

, Bible

, Doherty

, Mandel

, Nikiforov

, Pacini

, Randolph

, Sawka

, Schlumberger

, Schuff

, Sherman

, Sosa

, Steward

, Tuttle

, Wartofsky

. 2016. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid, 26:1–133.

15.

Rosario

, Mourão

, Calsolari

. 2016. Can the follow-up of patients with papillary thyroid carcinoma of low and intermediate risk and excellent response to initial therapy be simplified using second-generation thyroglobulin assays?. Clin Endocrinol (Oxf), 85:596–601.

16.

Pacini

, Schlumberger

, Dralle

, Elisei

, Smit

, Wiersinga

. 2006. European Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 154:787–803.

17.

Borson-Chazot

, Bardet

, Bournaud

, Conte-Devolx

, Corone

, D'Herbomez

, Henry

, Leenhardt

, Peix

, Schlumberger

, Wemeau

; Expert Group for French Recommendations for the Management of Differentiated Thyroid Carcinomas of Vesicular Origin, Baudin

, Berger

, Bernard

, Calzada-Nocaudie

, Caron

, Catargi

, Chabrier

, Charrie

, Franc

, Hartl

, Helal

, Kerlan

, Kraimps

, Leboulleux

, Le Clech

, Menegaux

, Orgiazzi

, Perié

, Raingeard

, Rodien

, Rohmer

, Sadoul

, Schwartz

, Tenenbaum

, Toubert

, Tramalloni

, Travagli

, Vaudrey

. 2008. Guidelines for the management of differentiated thyroid carcinomas of vesicular origin. Ann Endocrinol (Paris), 69:472–486.

18.

Pitoia

, Ward

, Wohllk

, Friguglietti

, Tomimori

, Gauna

, Camargo

, Vaisman

, Harach

, Munizaga

, Corigliano

, Pretell

, Niepomniszcze

. 2009. Recommendations of the Latin American Thyroid Society on diagnosis and management of differentiated thyroid cancer. Arq Bras Endocrinol Metabol, 53:884–887.

19.

Lepoutre-Lussey

, Deandreis

, Leboulleux

, Schlumberger

. 2014. Postoperative radioactive iodine administration for differentiated thyroid cancer patients. Curr Opin Endocrinol Diabetes Obes, 21:363–371.

20.

Pacini

, Brianzoni

, Durante

, Elisei

, Ferdeghini

, Fugazzola

, Mariotti

, Pellegriti

. 2016. Recommendations for post-surgical thyroid ablation in differentiated thyroid cancer: a 2015 position statement of the Italian Society of Endocrinology. J Endocrinol Invest, 39:341–347.

21.

Elisei

, Pinchera

. 2012. Advances in the follow-up of differentiated or medullary thyroid cancer. Nat Rev Endocrinol, 8:466–475.

22.

Rosario

, Ward

, Carvalho

, Graf

, Maciel

, Maia

, Vaisman

. 2013. Thyroid nodules and differentiated thyroid cancer: update on the Brazilian consensus. Arq Bras Endocrinol Metabol, 57:240–264.

23.

Latrofa

, Ricci

, Sisti

, Piaggi

, Nencetti

, Marinò

, Vitti

. 2016. Significance of low levels of thyroglobulin autoantibodies associated with undetectable thyroglobulin after thyroidectomy for differentiated thyroid carcinoma. Thyroid, 26:798–806.

24.

Brassard

, Borget

, Edet-Sanson

, Giraudet

, Mundler

, Toubeau

, Bonichon

, Borson-Chazot

, Leenhardt

, Schvartz

, Dejax

, Brenot-Rossi

, Toubert

, Torlontano

, Benhamou

, Schlumberger

. 2011. Long-term follow-up of patients with papillary and follicular thyroid cancer: a prospective study on 715 patients. J Clin Endocrinol Metab, 96:1352–1359.

25.

Durante

, Montesano

, Torlontano

, Attard

, Monzani

, Tumino

, Costante

, Meringolo

, Bruno

, Trulli

, Massa

, Maniglia

, D'Apollo

, Giacomelli

, Ronga

, Filetti

; PTC Study Group. 2013. Papillary thyroid cancer: time course of recurrences during postsurgery surveillance. J Clin Endocrinol Metab, 98:636–642.

26.

Chung

, Park

, Kim

, So

, Kim

, Park

, Lee

, Cho

. 2002. Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation. Clin Endocrinol (Oxf), 57:215–221.

27.

Kim

, Yoon

, Kim

, Ryu

, Gong

, Hong

, Shong

. 2008. Change of serum antithyroglobulin antibody levels is useful for prediction of clinical recurrence in thyroglobulin-negative patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab, 93:4683–4689.

28.

Hsieh

, Wang

. 2014. Sequential changes of serum antithyroglobulin antibody levels are a good predictor of disease activity in thyroglobulin-negative patients with papillary thyroid carcinoma. Thyroid, 24:488–493.

29.

Durante

, Tognini

, Montesano

, Orlandi

, Torlontano

, Puxeddu

, Attard

, Costante

, Tumino

, Meringolo

, Bruno

, Trulli

, Toteda

, Redler

, Ronga

, Filetti

, Monzani

; PTC Study Group. 2014. Clinical aggressiveness and long-term outcome in patients with papillary thyroid cancer and circulating anti-thyroglobulin autoantibodies. Thyroid, 24:1139–1145.

30.

de Meer

SGA

, Vorselaars

WMCM

, Kist

, Stokkel

MPM

, de Keizer

, Valk

, Borel Rinkes

IHM

, Vriens

. 2017. Follow-up of patients with thyroglobulin-antibodies: rising Tg-Ab trend is a risk factor for recurrence of differentiated thyroid cancer. Endocr Res, 42:302–310.