Dynamic Risk Stratification in the Follow-Up of Children and Adolescents with Differentiated Thyroid Cancer

Abstract

Background:

Risk stratification for persistent disease is an important step in pediatric differentiated thyroid cancer (DTC) management. The dynamic risk stratification (DRS) is a well validated system for adults, but not yet for children and adolescents. This study evaluated the DRS as well as other prognostic factors in pediatric DTC.

Methods:

Patients aged ≤18 years from four DTC tertiary teaching hospitals in Southern Brazil were included. Clinical characteristics were systematically retrieved, and all patients were classified according to the risk-stratification system of the 2015 American Thyroid Association pediatric DTC guidelines (ATA risk) and according to DRS (excellent, indeterminate, biochemical, or structural incomplete responses). Disease status was evaluated after initial therapy and at last follow-up visit.

Results:

Sixty-six patients aged 14.5 ± 3.0 years were studied of whom 54 (81.8%) were girls and 62 (93.9%) had papillary thyroid carcinomas. Tumor size was 2.3 cm (P25–75 1.6–3.5); 41 (63.1%) had cervical and 18 (27.7%) distant metastasis at diagnosis. All patients underwent total thyroidectomy, and 63 (95.5%) received radioiodine. Patients were classified according to DRS after initial therapy (n = 63) as follows: 21 (33%) excellent, 13 (21%) indeterminate, 6 (9%) biochemical, and 23 (37%) structural incomplete responses. Notably, after six years (P25–75 2.7–10.0), most patients remained in the same category. Interestingly, the cutoff analysis of stimulated postoperative thyroglobulin (sPOTg) through receiver operating characteristic curve showed that the value of 37.8 ng/mL showed 81% sensitivity and 100% specificity to predict an excellent response. Prognostic factors associated with persistent disease in the univariate analysis were TNM, ATA risk, DRS, and sPOTg.

Conclusion:

DRS after initial therapy and sPOTg are strong predictors of disease outcome and might be helpful for defining follow-up strategies in pediatric DTC.

Introduction

Differentiated thyroid cancer (DTC), which includes papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most common endocrine tumor during childhood (1 –3). PTC is the most common form of thyroid cancer in both children and adults and represents >90% of all DTC diagnoses. Notably, DTC incidence in children and adolescents is increasing at a rate of 1.1% per year (4 –9). In Brazil, thyroid cancer currently accounts for 2% of all pediatric cancers (10).

DTC has distinct presentations in pediatric patients compared to adults (3,11 –14). Although children and adolescents more often present with extensive and aggressive disease and display a higher frequency of persistence/recurrence, their prognosis is excellent, with a low mortality rate, even for those presenting with advanced disease at diagnosis (3,11 –15).

Currently, one of the most important steps in the management of adult patients with DTC is risk stratification for persistent/recurrent disease (16,17). However, there is no single postoperative staging system that has been validated for children and adolescents with DTC, and the utility of extrapolating adult risk and staging systems into the pediatric setting is limited by the observed clinical disparity between the two age groups (18,19). The American Joint Committee on Cancer (AJCC) TNM classification system is widely used for describing the extent of disease and prognosis in the adult population (20). However, as it was developed to predict mortality and not persistence/recurrence, the TNM classification system remains limited in terms of determining prognosis in children and adolescents (18). The most recent 2015 American Thyroid Association (ATA) guidelines for children with DTC suggest using the TNM system to categorize patients into three risk groups, which also provide guidance for postoperative management: low, intermediate, and high (18). However, its utility is limited, since it only takes into account the histopathological data but does not consider response to therapy.

A novel risk-stratification system was recently described, which stratifies response to therapy following initial treatment and during follow-up. This approach has been termed “dynamic risk stratification” (DRS) (21 –25). Nevertheless, while the response to therapy assessment has been validated for adult patients with DTC, it has only been evaluated in a few cohorts of children and adolescents (26,27). Of interest, it was recently demonstrated that stimulated postoperative thyroglobulin (sPOTg) after initial treatment seems to have a promising role as a tool for identifying children and adolescents with DTC at high risk of persistent disease (19).

The primary objective of the present study was to evaluate the DRS as a prognostic tool to stratify risk for persistent and/or recurrent disease in a contemporary DTC cohort of children and adolescents attending four DTC referral centers in southern Brazil. The secondary objective was to evaluate the role of sPOTg as a prognostic factor in this population.

Methods

Patients and study design

Sixty-six children and adolescents with histological diagnosis of DTC before the age of 18 years were included in this retrospective study. This number corresponds to all consecutive pediatric patients who were followed at four referral centers for DTC treatment in southern Brazil from 2000 to 2016: Hospital de Clínicas de Porto Alegre (n = 31), Hospital Nossa Senhora da Conceição (n = 24), Santa Casa de Porto Alegre (n = 9), and Hospital São Lucas da Pontifícia Universidade Católica do Rio Grande do Sul (n = 2).

Treatment protocol and follow-up

The DTC treatment protocol used in these institutions consists of performing total thyroidectomy, administering or not administering an ablative or therapeutic dose of radioactive iodine (RAI) as indicated, and levothyroxine suppression therapy (18,19,28,29). Decisions regarding cervical lymph node dissection were made at the discretion of the surgical team at the center where the patients underwent surgery. Of the 66 patients, 44 have been operated in the four institutions included in this study. However, 22 patients were referred to these institutions after the surgical procedure. The surgical notes and the referral report were reviewed, and data about the lymph node status were registered. Follow-up duration was defined as the time between the thyroidectomy and the last medical visit to the clinic. During the first evaluation, the following data were recorded for each patient: patient demographics, tumor characteristics (date of diagnosis, histological features, extrathyroidal extension, and lymph node involvement), and treatment (surgery, RAI, and other interventions).

The follow-up protocol called for an initial assessment at three to six months post surgery, which included a physical examination of the neck, measurements of serum thyroglobulin (Tg) levels under thyrotropin (TSH) suppression (Tg-T4), and measurement of antithyroglobulin antibodies (TgAb). In a second evaluation, 6–12 months after the initial treatment, serum Tg was measured under conditions of a stimulated TSH (sTg) with endogenous hypothyroidism (TSH >30 mIU/L). Neck ultrasound (US) was also performed during the first year of follow-up. Patients classified as disease free (see below) were scheduled for annual visits that included a physical examination of the neck and measurements of Tg-T4 and TgAb. Patients with persistent disease were scheduled for medical visits twice a year and evaluated for additional therapy as needed. Additional imaging studies (e.g., neck US, diagnostic ¹³¹I whole-body scan [WBS], and computed tomography [CT]) were performed as indicated when clinical or laboratory findings raised suspicion of persistent or recurrent disease.

Risk stratification and outcomes

To evaluate the initial risk for this pediatric population, all patients were classified according the eighth AJCC TNM staging system (I or II) (20). N0 status was determined by clinical examination of the neck or pre- and postoperative neck US imaging or macroscopic examination during surgery and pathological examination of patients with lymph node resection. Additionally, they were stratified according to the 2015 ATA pediatric guidelines (18) into three thyroid cancer risk levels: low, intermediate, and high.

Disease status was defined based on clinical examination, Tg-T4 and sTg levels, neck US, post-RAI WBS (when available), and additional imaging exams when indicated. Patients were classified into four categories: excellent response, indeterminate response, biochemical incomplete response, or structural incomplete response.

In patients submitted to RAI, an excellent response was defined as negative imaging and Tg-T4 < 0.2 ng/mL or sTg <1.0 ng/mL (21). A biochemical incomplete response was defined as negative imaging and Tg-T4 > 1.0 ng/mL or sTg >10.0 ng/mL or rising TgAb levels. A structural incomplete response was defined as structural or functional evidence of disease with any Tg or TgAb level. An indeterminate response was defined as nonspecific findings on imaging studies or Tg-T4 between 0.2 and 1.0 ng/mL or sTg between 1.0 and 10.0 ng/mL or TgAb stable or declining.

In patients not submitted to RAI, an excellent response was defined as negative imaging and Tg-T4 < 0.2 ng/mL or sTg <2.0 ng/mL (21). A biochemical incomplete response was defined as negative imaging and Tg-T4 > 5.0 ng/mL or sTg >10.0 ng/mL or increasing Tg levels over time or rising TgAb levels. Structural incomplete response was defined as structural or functional evidence of disease with any Tg or TgAb level. An indeterminate response was defined as nonspecific findings on imaging studies or Tg-T4 between 0.2 and 5.0 ng/mL or sTg between 2.0 and 10.0 ng/mL or TgAb stable or declining.

Recurrence was defined as new biochemical or structural evidence of disease detected in a patient who had previously been determined to be disease free.

DRS

The response to treatment, based on the criteria described above, was evaluated after initial treatment, which includes surgery and RAI, and at the last follow-up visit. The patients were classified into the four categories of DRS: excellent response, indeterminate response, biochemical incomplete response, or structural incomplete response.

sPOTg

sPOTg was measured before administration of RAI in those patients who received this treatment and in the first year after thyroidectomy in those patients who did not receive RAI. In both groups, sPOTg measurements were made under stimulated conditions following four weeks of thyroid hormone withdrawal (endogenous hypothyroidism), and sPOTg was considered appropriate if TSH was >30 mIU/L. Serum levels of TgAb were evaluated in the same blood sample from which sPOTg was measured, and patients with positive results were excluded from this analysis (n = 5).

Statistical analysis

Clinical and laboratory data are reported as the mean ± standard deviation or median and percentiles 25 and 75 (P25–75) for continuous variables and absolute numbers and percentages for categorical variables. Comparative analyses were performed using an unpaired Student's t-test, Mann–Whitney U-test, Fisher's test, or chi-square test as appropriate.

Clinical variables, such as sex, age at diagnosis, tumor size, histological subtype, multicentricity, lymph node and distant metastasis, sPOTg, ATA risk, and DRS after initial treatment, were evaluated as potential prognostic factors for DTC persistent disease by univariate analysis. sPOTg was also assessed using the area under the receiver operating characteristic (ROC) curve with sPOTg as a continuous prognostic variable and disease status at follow-up as the outcome variable.

All tests were two-tailed, and all analyses were performed using IBM SPSS Statistics for Windows v20.0 (IBM Corp., Armonk, NY). A two-tailed p-value of <0.05 was considered statistically significant.

Results

Clinical characteristics

Sixty-six children and adolescents with DTC (81.8% girls) with a mean age at diagnosis of 14.5 ± 3.0 years were included in this study. Of these, 62 (93.9%) had PTC and four (6.1%) had FTC. The median tumor size was 2.3 cm (P25–75 1.6–3.5). Cervical metastasis was identified in 41 (63.1%) patients (N1a = 11; N1b = 30) and distant metastasis in 18 (27.7%). The clinical and oncological characteristics of the studied patients are described in Table 1.

Table 1.

Characteristics of 66 Children and Adolescents with Differentiated Thyroid Carcinoma

Age at diagnosis (years)	14.5 ± 3.0
Female sex, n (%)	54 (81.8)
Histology, n (%)
Papillary	62 (93.9)
Follicular	4 (6.1)
Tumor size (cm)	2.3 (1.6–3.5)
Lymph node metastasis (N1), n (%)	41 (63.1)
Distant metastasis, n (%)	18 (27.7)
TNM AJCC stage n (%)
I	47 (72.3)
II	18 (27.7)
RAI therapy, n (%)	63 (95.5)
RAI activity (mCi)	100 (100–150)
Follow-up (years)	6.0 (2.7–10.0)

Data are expressed as the mean ± standard deviation (SD), median (percentiles 25–75), or frequencies.

AJCC, American Joint Committee on Cancer; RAI, radioactive iodine.

All patients underwent total thyroidectomy; 12 had been submitted only to central neck dissection and 33 to central and lateral neck dissection. Of the 66 patients, information about the surgical lymph node status was available for 45 subjects. Using the TNM classification, it was possible to classify those patients as follows: 4 with N0, 11 with N1a, and 30 with N1b. Of the 30 patients classified as N1b, 19 presented with unilateral disease, 8 with bilateral disease, and 3 with extensive invasive burden disease.

In terms of RAI therapy, 63 (95.5%) patients received RAI being 42 therapeutic (mean 124.2 ± 38.5 mCi) and 21 ablative (mean 89.7 ± 37.0 mCi). In relation to the three patients who did not receive any RAI, all were classified as T1N0M0, and hence were in the ATA low-risk category. Post-therapy WBS were performed in 60 patients; 3 (5%) patients had no uptake, 39 (65.0%) patients only had cervical uptake, and 18 (30.0%) patients were found to have distant metastases that were localized in the lungs in all of them.

DRS

Data concerning the disease status after initial therapy were available for 63 patients: 21 (33%) had an excellent response, 13 (21%) an indeterminate response, 6 (9%) a biochemical persistent disease, and 23 (37%) a structural incomplete response (Fig. 1).

FIG. 1.

Follow-up outcomes, according to the dynamic risk stratification (DRS). DTC, differentiated thyroid cancer.

After a median follow-up of 6.0 (2.7–10.0) years, 19 (90%) of the patients with an excellent response in the first evaluation remained disease free, two (10%) were reclassified as having an indeterminate response, and none had persistent disease (biochemical or structural).

Those patients with an indeterminate response after initial therapy showed similar results: the majority (n = 8; 62%) remained in the indeterminate response category, four (31%) were reclassified as having an excellent response, and only one (7%) developed structural disease (cervical lymph node metastasis).

Among the six patients with biochemical disease after the initial therapy, one (17%) displayed an excellent response at follow-up, one (17%) was considered to have indeterminate response, and the majority (66%) remained in the biochemical disease group (Fig. 1). Notably, only one of the patients not initially classified as having structural persistent disease developed a metastasis (a cervical lymph node metastasis in a patient with indeterminate response after initial treatment).

All patients with structural persistent disease were evaluated for additional therapy (i.e., surgical interventions and/or RAI) at the discretion of the attending physician. Among the patients (n = 23) diagnosed with structural persistent disease after the initial treatment, only three (13%) reached an excellent response status after additional treatment (two patients underwent surgical intervention for cervical persistent disease, and one patient had a pulmonary metastasis that resolved after a cumulative dose of 350 mCi of RAI). Most of the patients classified as having structural persistent disease after initial therapy continued to have structural disease (n = 14; 61%), and six (26%) exhibited an indeterminate response (Fig. 1). No deaths were recorded.

Additional treatment

Among the patients with an excellent response after initial treatment (n = 21), only one was submitted to a new neck exploration (negative for metastasis), and none received additional RAI. Among the 13 patients with indeterminate response after initial treatment, three were submitted to revisional cervical surgery (all three positive for lymph node metastasis), and one received a second RAI treatment. Related to patients with a biochemical incomplete response (n = 6) after initial therapy, two were submitted to revisional surgery for cervical lymph node metastasis, and three received additional RAI. Among the 23 patients with structural persistent disease after initial treatment, 12 underwent revisional neck exploration (11 positive and 1 negative for lymph node metastasis), and 16 received at least one more RAI treatment.

ATA pediatric risk classification versus DRS after initial therapy

Next, the ATA pediatric risk classification and DRS were compared after initial therapy. It was observed that both systems had a good correlation, with 59% of low, 31% of intermediate, and 5% of high-risk patients showing excellent response to therapy (Table 2). On the other hand, only 8% of low-risk patients, 19% of intermediate-risk patients, and 81% of high-risk patients had a structural incomplete response to therapy.

Table 2.

ATA Pediatric Risk Stratification and Dynamic Risk Stratification Based on Response to Initial Treatment in Pediatric Thyroid Cancer

	ATA risk stratification			sPOTg (ng/mL)
Response to initial treatment	Low (n = 24)	Intermediate (n = 16)	High (n = 22)	<37.8	>37.8
Excellent response (n = 20)	14 (59%)	5 (31%)	1 (5%)	14 (100%)	0 (0%)
Indeterminate response (n = 13)	6 (25%)	5 (31%)	2 (9%)	5 (71%)	2 (29%)
Biochemical incomplete response (n = 6)	2 (8%)	3 (19%)	1 (5%)	1 (25%)	3 (75%)
Structural incomplete response (n = 23)	2 (8%)	3 (19%)	18 (81%)	1 (8%)	12 (92%)

ATA, American Thyroid Association; sPOTg, stimulated postoperative thyroglobulin.

DRS after initial treatment and excellent response

Next, the proportion of patients in the ATA pediatric risk classification and DRS systems who achieved an excellent response at the last follow-up was analyzed. As expected, differences were observed in these rates according to the ATA pediatric risk stratification. Patients achieved an excellent response in 79% for low-risk, 31% for intermediate-risk, and 9% for high-risk patients (p = 0.007). This difference was also observed in DRS categories after response to initial treatment. Excellent response rates were 90% for excellent response, 30% for indeterminate response, 16% for biochemical persistent disease, and 13% for structural persistent disease (p = 0.01).

Role of sPOTg as a predictor of disease status

Data on sPOTg and disease status at follow-up were available for 43/66 (65%) patients included in this study, and five were excluded because of the presence of positive TgAb. The median value of sPOTg was 18.9 ng/mL (P25–75 9.0–221). The time interval between surgery and sPOTg was a median of 2.0 months (P25–75 1.0–4.0). To evaluate the performance of sPOTg in predicting persistent disease (biochemical or structural), a ROC curve was used (Fig. 2), which resulted in an area under the curve of 0.92 [confidence interval 0.83–1.00]. A sPOTg level of 37.8 ng/mL was determined as the optimal cutoff point to predict persistent disease, with a sensitivity of 81% and specificity of 100%. Of interest, all patients with an excellent response (n = 20) had a sPOTg <37.8 ng/mL, and 92% of patients with structural persistent disease had a sPOTg above the cutoff level (Table 2).

FIG. 2.

Receiver operating characteristic curve of sPOTg for excellent response. sPOTg, stimulated postoperative thyroglobulin.

Prognostic factors and univariate and multivariate analysis

To investigate factors associated with persistent disease at follow-up, patients were grouped into disease-free or persistent disease categories. Univariate analysis indicated that tumor size, lymph node and distant metastasis, ATA pediatric risk, DRS after initial treatment, and sPOTg were all associated with persistent disease (Table 3). The variables sex, age at diagnosis, histological subtype, and multicentricity were not associated with persistent disease. An additional analysis using a multivariate model that included all variables with p-values of <0.05 in the univariate analysis and disease status as the dependent variable showed that only DRS after initial therapy was an independent prognostic factor for persistent disease (Table 4). Unfortunately, the statistical model did not support the sPOTg variable.

Table 3.

Univariate Analysis of Predictors of Persistent Disease Status

	Disease status		Univariate analysis
	Disease free	Persistent disease	p
Male sex	2/27 (7.4)	9/36 (25.0)	0.058
Age at diagnosis (years)	14.5 ± 2.7	14.3 ± 3.3	0.839
Tumor size (cm)	2.0 (1.2–2.6)	2.7 (1.8–4.0)	0.019
Lymph node metastasis	8/26 (30.7)	32/36 (88.8)	<0.001
Distant metastasis	1/26 (3.8)	17/36 (47.2)	<0.001
sPOTg (ng/mL)	8.8 (3.1–14.6)	167.0 (11.9–508.9)	<0.001
Follicular cancer	3/27 (11.1)	1/36 (2.7)	0.177
Multicentricity	6/20 (30.0)	15/29 (51.7)	0.128
ATA pediatric risk			<0.001
Low	19/26 (73.1)	5/36 (13.9)
Intermediate	5/26 (19.2)	11/36 (30.5)
High	2/26 (7.7)	20/36 (55.6)
DRS after initial treatment			<0.001
Excellent	19/27 (70.4)	2/36 (5.5)
Indeterminate	4/27 (14.8)	9/36 (25.0)
Biochemical persistent	1/27 (3.7)	5/36 (13.9)
Structural persistent	3/27 (11.1)	20/36 (55.6)

Data are expressed as the mean ± SD, median (percentiles 25–75), or frequencies.

DRS, dynamic risk stratification.

Table 4.

Multivariate Analysis of Predictors of Persistent Disease Status

	OR [CI]	p
Tumor size (cm)	1.5 [0.8–3.0]	0.17
Lymph node metastasis	16.8 [0.6–523.9]	0.08
Distant metastasis	1.7 [0.01–136.0]	0.79
ATA pediatric risk
Low	1.0	0.73
Intermediate	1.0 [0.4–27.3]	0.17
High	2.0 [0.03–164.1]
DRS after initial treatment
Excellent	1.0	0.006
Indeterminate	35.2 [3.7–762.5]	0.027
Biochemical persistent	54.9 [2.5–3933.1]	0.05
Structural persistent	13.9 [1.1–313.7]

Discussion

Risk-stratification systems for recurrence/persistence of disease are critical for providing the best care available for DTC patients, but these tools are not yet well validated for the pediatric population. This study shows that both DRS and sPOTg are powerful prognostic tools to predict disease status at follow-up in children and adolescents with DTC.

Identifying patients at greater risk of adverse outcomes is as important step in the management of DTC patients. Since DTC is known to be usually an indolent neoplasia, the “over follow-up effect” with unnecessary surveillance, diagnostic tests, and medical appointments is a concern (17). This issue may have even more impact in the pediatric population, since these patients are expected to have lifelong follow-up. Another important aspect regarding children and adolescents with DTC is the paucity of data and studies in this population. DTC in pediatric patients has a distinct presentation and prognosis. Thus, extrapolating results from studies of adult population might lead to equivocal conclusions.

The DRS was validated in a seminal study by Tuttle et al. in 2010 (21). Several studies have further corroborated the DRS as an important instrument for risk stratification in adult patients with DTC (22 –25). A central aspect of this system is to consider the dynamic response of the patient to initial therapy and follow-up treatment. The DRS, based on information from imaging studies and serum Tg levels, provides a better prediction of the risk of recurrent/persistent disease and allows the individualization of a patient's management and follow-up.

Despite all these observations that qualify DRS as one of the major tools in the follow-up of patients with DTC, it has been poorly studied in children. Accordingly, there is no recommendation for its use in the ATA management guidelines for children with thyroid cancer (18). In fact, to the best of the authors' knowledge, only two studies have evaluated the DRS in the pediatric DTC population. In the first study, Lazar et al. (26) evaluated the DRS system in a cohort of 54 patients with median age at diagnosis of 13.9 years and a median of 8.8 years of follow-up. The authors observed that those patients classified as having a complete response after initial treatment displayed a good prognosis: 82.9% of the patients remained in the excellent response status on long-term follow-up. On the other hand, all the patients with an incomplete response remained with persistent disease. Of interest, the proportion of variance associated with the DRS was greater than that explained by the ATA risk-stratification system (0.79 vs. 0.25), suggesting that the DRS is a more precise predictor for disease outcome. The second study evaluated a cohort of 77 pediatric DTC patients and also demonstrated that the DRS was useful to predict disease outcomes at long-term follow-up: the risk of recurrent/persistent disease was significantly higher in the indeterminate group (hazard ratio [HR] = 10.2; p = 0.045) and in the structural incomplete group (HR = 98.7; p = 0.005) compared to the group with an excellent response (27).

The present study shows that in a cohort of 66 pediatric patients with DTC, the DRS after initial therapy is an excellent tool for predicting disease status. Notably, the DRS status category after initial therapy remained unchanged for most patients during a median follow-up of six years. These findings are especially important for the group of patients with an excellent response after initial treatment, since 90% (21/23) of them remained disease-free during long-term follow-up.

Another important finding of this study is the demonstration of the usefulness of sPOTg as a prognostic factor for DTC in the pediatric population. Tg is a specific and sensitive marker for the presence of follicular thyroid cells, and serum Tg measurement is a cornerstone tool in the follow-up of DTC patients and is considered the most sensitive method to detect persistent or recurrent disease. Moreover, sPOTg has been suggested as a prognostic factor in adult patients with DTC by many studies (30 –35). Recently, the usefulness of sPOTg as a prognostic factor was demonstrated in a small DTC pediatric population followed at the authors' institution (19). Here, including patients from four referral centers, a similar sPOTg cutoff level to predict disease status (37.8 ng/mL) was observed. Of note, this value is much higher than that found in the adult population with DTC, indicating different cutoff values for these two populations. According to a recent metanalysis (30), the best cutoff of sPOTg for predicting persistent disease in adult DTC patients is 10.0 ng/mL. These observations might help to guide the follow-up of young patients with DTC, differentiating those who require a less intensive treatment from those who are candidates for more aggressive treatment and follow-up.

This study has some strengths: first, the relatively large number of patients of this rather uncommon disease in children; and second, its multicenter design, which strengths the external validity of the results. However, it should be noted that although six years is a reasonable length of follow-up to assess clinical outcomes, observations for longer periods should be studied to reach more definitive conclusions. Another possible limitation is that there was no standardization of surgical treatment to address lymph node disease. On the other hand, the data reflect real-life clinical practice, enhancing the external validity of the findings. However, this possible limitation may be partially mitigated by the fact that the surgery reports of all patients were reviewed and that they underwent a clinical examination of the neck and postoperative neck US, which allowed the presence of suspicious lymph nodes to be identified.

In conclusion, adequate risk stratification in DTC is crucial to avoid, on one hand, the overtreatment of low-risk patients and, on the other hand, the under-treatment of high-risk patients. This study demonstrates that the DRS after initial therapy and sPOTg are reliable prognostic factors in children and adolescents with DTC. Performing sPOTg and the DRS are acceptable, widely available, practical, timely, low-cost, and high-value strategies that should be used consistently in the management of pediatric DTC patients.

Footnotes

Acknowledgments

This work has been made possible by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Fundo de Incentivo a Pesquisa (FIPE), and Programa de Apoio a Núcleos de Excelência (PRONEX)/Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul (FAPERGS).

Author Disclosure Statement

The authors have nothing to declare.

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