Prepubertal Children with Papillary Thyroid Carcinoma Present with More Invasive Disease Than Adolescents and Young Adults

Abstract

Introduction:

Pediatric papillary thyroid carcinomas (PTCs) are more invasive than adult PTCs. No large, contemporary cohort study has been conducted to determine whether younger children are at higher risk for advanced disease at presentation compared to adolescents. We aimed to describe pediatric PTC and contextualize its characteristics with a young adult comparison cohort.

Methods:

The National Cancer Database was interrogated for pediatric and young adult PTCs diagnosed between 2004 and 2017. Clinical variables were compared between prepubertal (≤10 years old), adolescent (11–18 years old), and young adult (19–39 years old) groups. Multivariable logistic regression modeling for independent predictors of metastases was conducted. A subanalysis of microcarcinomas (size ≤10 mm) was performed.

Results:

A total of 4860 pediatric (prepubertal n = 274, adolescents n = 4586) and 101,159 young adult patients were included. Prepubertal patients presented with more extensive burden of disease, including significantly larger primary tumors, higher prevalence of nodal and distant metastases, and increased frequency of features such as lymphovascular invasion, and extrathyroidal extension (ETE). Prepubertal age was an independent predictor of positive regional nodes (adjusted odds ratio [AOR] = 1.36 [95% confidence interval {CI} 1.01–1.84], p = 0.04) and distant metastatic disease (AOR = 3.12 [CI 1.96–4.96], p < 0.001). However, there was no difference in survival between groups (p = 0.32). Prepubertal age independently predicted lymph node metastases for microcarcinomas (AOR = 2.19 [CI 1.10–4.36], p = 0.03). Prepubertal (n = 41) versus adolescent (n = 937) patient age was associated with gross ETE (p = 0.004), even with primary tumors ≤1 cm in size.

Conclusions:

Patients aged <11 years old present with more advanced disease than adolescents, with a higher likelihood of nodal and distant metastatic disease at time of diagnosis, although survival is high. Prepubertal children undergo more extensive treatment, likely reflective of more invasive disease at the outset, even in the setting of a subcentimeter primary tumor.

Introduction

Pediatric differentiated thyroid carcinoma (DTC) is rare, although its incidence has increased over time, with 6.4 cases per 1,000,000 diagnosed between 1997 and 2008 and 11.0 cases per 1,000,000 diagnosed between 2009 and 2018.¹ While pediatric DTC only accounts for 1% of pediatric cancer cases in prepubertal children, the disease comprises 7% of adolescent cancer cases for patients aged 15–19 years old.² More than 90% of pediatric DTCs are papillary thyroid carcinomas (PTCs), as follicular carcinoma is uncommon in children.^3
–5 Survival is high, with a cause-specific mortality of only 1% at 30 years.⁶ Children are ultimately less likely to die of the disease than adults, even in the presence of distant metastases, and 30-year recurrence rates are comparable.⁶

PTC has been reported to present more extensively in children compared to adults. Historically, studies have demonstrated that up to 57% of pediatric PTCs are multifocal and 30% are bilateral.^7

–11 Children have traditionally presented with more distant and locally advanced disease as well, with pulmonary metastases diagnosed in up to 25% of cases.^{3,7,8,11

–14} One of the only large analyses conducted for pediatric PTC studied 740 Belarusian children, 92% of whom were exposed to radiation as a consequence of the Chernobyl nuclear disaster, and found that younger age was associated with recurrent nodal disease and pulmonary metastases.¹⁵ Much of the historic data were obtained in the context of a significant proportion of these patients having undergone ionizing radiation to the head and neck before diagnosis.¹⁶ Now only 3% of patients present with a history of ionizing radiation.¹⁷

The American Thyroid Association (ATA) published its first set of guidelines for pediatric DTC in 2015.¹⁸ Based on the data characterizing pediatric PTC as more invasive, total thyroidectomy was recommended as the initial surgical approach for almost all pediatric PTC patients, with a prophylactic central neck dissection to be considered at the time of surgery.¹⁸ At the time the guidelines were written, the ATA stated that it was unclear whether younger patients are at higher risk.¹⁸ More recent studies have further described contemporary pediatric PTC and have attempted to investigate whether outcomes differ for younger children compared to adolescents. These analyses have found that closer to 35% of pediatric patients present with multifocal disease,^19,20 although estimated rates of distant metastases at presentation still range from 5% to 19%.^{6,20

–25}

The literature also suggests that for pediatric PTC, younger age at presentation is associated with recurrence,^26,27 distant metastases,^{6,21,22,27,28} extrathyroidal extension (ETE),^27,28 lymphovascular invasion (LVI),⁵ and regional lymph node positivity.^27
–29 One recent study demonstrated that prepubertal compared to pubertal patients had a greater extent of DTC as evaluated by the ATA risk classification; however, there were only 54 patients in total, 9 of whom were prepubertal.³⁰ Pediatric PTC remains a rare disease, and these analyses are based on retrospective, single-institution reviews of small cohorts of patients, which may undermine their conclusiveness and generalizability. Although additional studies have been published in the intervening years since the guidelines were written, as reviewed here, large-scale analysis of prepubertal PTC patients is needed to help guide management and support or refute the existing data.

We aimed to validate the existing literature with respect to the presentation of pediatric PTC using a large, diverse, generalizable patient cohort, as well as compare disease severity at time of diagnosis to that of young adults with PTC. In addition, we strove to determine whether prepubertal children present with more extensive disease than adolescents. The goal of this study was to further our understanding of the relationship between age and progressive PTC to improve management of pediatric patients. We used the National Cancer Database (NCDB), a comprehensive clinical oncology database sponsored by the American College of Surgeons and the American Cancer Society, to address our aims.³¹

Materials and Methods

Study population and definitions

The NCDB was queried for all pediatric (≤18 years old) and young adult (19–39 years old) patients diagnosed with PTC between 2004 and 2017 using the primary site code of C73.9, and papillary histology codes as defined by the International Classification of Diseases for Oncology, third revision. Patients with benign disease (134), nonpapillary histology (10,050), and who were diagnosed at the reporting facility but treated elsewhere (2577) were excluded (Supplementary Fig. S1). Pediatric patients were classified as prepubertal (≤10 years old) or adolescent (11–18 years old). The NCDB extracts patient variables, including patient demographics, cancer staging and treatment, and overall survival from >70% of newly diagnosed cancer cases in the United States from 1500 Commission on Cancer-accredited facilities.³¹

The NCDB faithfully captures pediatric patients, with a coverage rate of 68% of all pediatric (<19 years old) and 79% of all adolescent and young adult (15–39 years old) cancer diagnoses in the United States.³² LVI was reported for patients diagnosed between 2010 and 2017, while ETE was coded for patients diagnosed from 2004 to 2015. Noncoded data were excluded for those variables as detailed in Tables 2 and 3. Missing data were otherwise detailed. The thyroid is not considered a paired organ in the NCDB; as such, bilaterality is not a coded variable.

A prophylactic lymphadenectomy was defined as one performed in the setting of a clinical N0 nodal stage, while a therapeutic lymphadenectomy was defined as one in which the patient was diagnosed as clinically stage N1. “Neck dissection, NOS” describes a patient who underwent a lymphadenectomy but for whom clinical nodal stage was not coded or unknown. The clinical stages for the NCDB registry are coded by the physician or registry staff based on the medical record and the AJCC Cancer Staging Manual edition in use during the year in which the case was diagnosed. The Weill Cornell Medicine Institutional Review Board designated this analysis as exempt, given the use of publicly available deidentified data.

Statistical analysis

Demographic, tumor, and treatment variables were first compared between prepubertal and adolescent patients, and then between all three groups (prepubertal, adolescent, and young adult; denoted as “all” preceding the p-value) using Pearson's chi-squared test for categorical variables and the Kruskal–Wallis test or Wilcoxon's rank-sum for continuous nonparametric data, as appropriate. Multivariable logistic regression modeling for independent predictors of positive regional lymph node and distant metastases in pediatric patients (≤18 years old) was performed. Sex, race, ethnicity, tumor size, LVI, ETE, and multifocality were found to predict metastases to lymph nodes and distant organs at an alpha level of 0.01 on univariate analysis and were included in the multivariable models. Adjusted odds ratios (AORs) are reported. Kaplan–Meier analysis for overall survival for all three groups was executed.

Finally, a subanalysis of tumor and treatment characteristics for microcarcinomas (tumor size ≤10 mm) was conducted. Multivariable regression modeling for independent predictors of regional lymph node metastases in the pediatric (≤18 years old) cohort was performed for the microcarcinoma subgroup. Sex, ethnicity, LVI, ETE, and multifocality predicted regional lymph node disease on univariate analysis at an alpha level of 0.01 and were included in the multivariable model for the microcarcinoma cohort. A multivariable model for distant metastatic disease in the microcarcinoma cohort could not be constructed as sample sizes were insufficient. All statistical tests were performed using Stata software, version 16.1 (Stata Corp., College Station, TX). Significance was evaluated at the 0.05 alpha level and hypothesis tests were two-sided.

Results

This analysis included 4860 pediatric (prepubertal n = 274, adolescent n = 4586) and 101,159 young adult patients for a total sample size of 106,019. Clinicodemographics differed significantly between pediatric and young adult cohorts (Table 1). The median ages for each group were as follows: prepubertal 9 years old (interquartile range [IQR] 7–10), adolescent 16 years old (IQR 15–18), and young adult 32 years old (28–36) (all p < 0.001).

Table 1.

Clinicodemographics Summary of Pediatric and Young Adult Cohorts

	Prepubertal (n = 274)	Adolescent (n = 4586)	p ^a	Young adult (n = 101,159)	p ^b
Median age, years	9 (7–10)	16 (15–18)	<0.001	32 (28–36)	<0.001
Sex, female	177 (64.6)	3760 (82.0)	<0.001	83,546 (82.6)	<0.001
Hispanic ethnicity	58 (21.2)	680 (14.8)	0.01	11,706 (11.6)	<0.001
Race			0.49		<0.001
White	238 (86.9)	3896 (85.0)		83,755 (82.8)
Black	13 (4.7)	207 (4.5)		6283 (6.2)
Asian	9 (3.3)	250 (5.4)		6819 (6.7)
Unknown/other	14 (5.1)	233 (5.1)		4302 (4.3)
Rural/urban county of treatment^c			0.18		<0.001
Rural	1 (0.4)	70 (1.6)		1090 (1.1)
Metro	221 (84.3)	3780 (85.5)		87,073 (88.8)
Urban	40 (15.3)	569 (12.9)		9846 (10.1)
Distance to treatment facility >11.2 mi^d	195 (71.2)	2950 (64.3)	0.02	54,828 (54.2)	<0.001

Data are presented as n (%) or median (IQR). Bolded numbers represent statistically significant p-values.

Prepubertal age group versus adolescent age group.

Prepubertal age group compared to adolescent group and to young adult group.

Area-based measure of rurality and urban influence, using the typology published by the USDA Economic Research Service.

Median distance traveled for treatment for overall cohort was 11.2 mi.

IQR, interquartile range; USDA, United States Department of Agriculture.

Female sex comprised 82.0% (n = 3760) of the adolescent group and 82.6% (n = 83,546) of the young adult group, which differed from the only 64.6% (n = 177) of female patients in the prepubertal group (all p < 0.001). A higher proportion of prepubertal patients were Hispanic (n = 58, 21.2%) compared to the adolescent (n = 680, 14.8%) and young adult (n = 11,706; 11.6%) groups (all p < 0.001). Prepubertal patients were least likely to undergo treatment in a rural county (all p < 0.001) and had to travel further to obtain care (all p < 0.001).

Prepubertal patients present with more extensive disease than either adolescent patients or young adult patients (Table 2). Children younger than the age of 11 years presented with larger primary tumors, with 22.6% (n = 62) of prepubertal patients presenting with tumors >4 cm in size. Only 13.5% (n = 620) of adolescent children and 8.3% (n = 8363) of young adults presented with such large tumors (all p < 0.001). In addition, prepubertal compared to adolescent patients more frequently presented with LVI (n = 74, 57.8% vs. n = 898, 36.1%, p < 0.001), and gross ETE (n = 108, 47.4% vs. n = 933, 24.9%, p < 0.001). There was no difference in the frequency of multifocal tumors between prepubertal and adolescent children (n = 102, 37.2% vs. n = 1628; 35.5%, p = 0.56).

Table 2.

Tumor Pathologic and Treatment Characteristics by Patient Age at Presentation

	Prepubertal (n = 274)	Adolescent (n = 4586)	p ^a	Young adult (n = 101,159)	p ^b
Primary tumor characteristics
Tumor size, cm			<0.001		<0.001
0–1	41 (15.0)	937 (20.4)		33,950 (33.5)
>1–2	62 (22.6)	1337 (29.2)		30,968 (30.6)
>2–4	81 (29.6)	1472 (32.1)		24,566 (24.3)
>4	62 (22.6)	620 (13.5)		8363 (8.3)
Unknown	28 (10.2)	220 (4.8)		3308 (3.3)
Multifocality	102 (37.2)	1628 (35.5)	0.56	39,274 (38.8)	<0.001
LVI^c (n = 59,186)	74 (57.8)	898 (36.1)	<0.001	9725 (17.2)	<0.001
Gross ETE^d (n = 87,065)	108 (47.4)	933 (24.9)	<0.001	13,401 (16.1)	<0.001
Positive margins	76 (27.7)	708 (15.4)	<0.001	10,522 (10.4)	<0.001
Nodal and metastatic disease characteristics
Positive regional lymph nodes	184 (67.2)	2399 (52.3)	<0.001	32,503 (32.1)	<0.001
Median no. nodes examined	14 (2–42)	4 (1–17)	<0.001	1 (0–7)	<0.001
Median no. positive nodes	8 (1–18)	2 (0–9)	<0.001	1 (0–4)	<0.001
Distant metastases	31 (11.3)	101 (2.2)	<0.001	520 (0.5)	<0.001
Surgical treatment
Surgical therapy			0.001		<0.001
None or unknown	5 (1.8)	69 (1.5)		1411 (1.4)
Nodulectomy	9 (3.3)	44 (1.0)		1013 (1.0)
Hemithyroidectomy	11 (4.0)	329 (7.2)		10,704 (10.6)
Total thyroidectomy	249 (90.9)	4144 (90.3)		88,031 (87.0)
Lymphadenectomy	225 (82.1)	3446 (75.1)	0.009	62,326 (61.6)	<0.001
Prophylactic	51 (18.6)	1377 (30.0)	<0.001	31,789 (51.0)	<0.001
Therapeutic	85 (31.0)	901 (19.6)		11,329 (18.2)
Neck dissection, NOS	89 (32.5)	1168 (25.5)		19,208 (30.8)
Adjuvant treatment
RAI therapy	172 (62.8)	2719 (59.3)	0.25	50,702 (50.1)	<0.001
Chemotherapy	2 (0.7)	4 (0.1)	0.003	123 (0.1)	0.01

Data are presented as n (%), or median (IQR). Bolded numbers represent statistically significant p-values.

Prepubertal age group versus adolescent age group.

Prepubertal age group compared to adolescent group and to young adult group.

LVI reported for patients diagnosed 2010–2017.

ETE reported for patients diagnosed 2004–2015.

ETE, extrathyroidal extension; LVI, lymphovascular invasion; NOS, not otherwise specified; RAI, radioactive iodine therapy.

Young adult patients, on the contrary, presented with multifocal tumors more frequently than either pediatric group (n = 39,274; 38.8%, all p < 0.001). Prepubertal patients were much more frequently diagnosed with regional lymph node (n = 184, 67.2% vs. n = 2399; 52.3%, p < 0.001), and distant metastatic (n = 31, 11.3% vs. n = 101, 2.2%, p < 0.001) disease compared to adolescent patients. Conversely, in comparison, 32.1% (n = 32,503) of young adult patients presented with positive regional lymph nodes and 0.5% (n = 520) presented with distant metastases. When a lymphadenectomy was performed, the median number of lymph nodes examined for prepubertal patients was 14 (IQR 2–42) compared to adolescent patients, who had a median of 4 (IQR 1–17) examined (p < 0.001).

Prepubertal children had a higher median number of positive metastases to regional lymph nodes on examination than adolescent patients (8 [IQR 1–18] vs. 2 [IQR 0–9], p < 0.001). The yield of positive lymph nodes was 87% for prepubertal, 78% for adolescent, and 64% for young adult patients. Prepubertal age compared to adolescent age was an independent predictor of both regional lymph node (AOR = 1.36 [95% confidence interval {CI} 1.01–1.84], p = 0.04) and distant metastatic (AOR = 3.12 [CI 1.96–4.96], p < 0.001) disease on multivariable regression modeling (Fig. 1).

FIG. 1.

Multivariable logistic regression analysis of independent predictors for regional lymph node metastases (a) and distant metastases (b) in the pediatric cohort (n = 4860). ORs and 95% CIs are indicated. Filled-in circles represent statistically significant values. CI, confidence interval; OR, odds ratio.

Pediatric patients underwent more extensive thyroid cancer treatment (Table 2). The majority of pediatric patients underwent total thyroidectomy, in line with current management guidelines, although 7.2% (n = 329) of adolescent patients were managed with hemithyroidectomy, compared to 4.0% (n = 11) of prepubertal children (p = 0.001). A high proportion of young children and adolescents underwent adjuvant radioactive iodine therapy (n = 172, 62.8% vs. n = 2719, 59.3%, p = 0.25). Prepubertal patients less frequently underwent prophylactic lymphadenectomies than adolescent patients (n = 51, 18.6% vs. n = 1377, 30.0%), but more often required therapeutic lymphadenectomies (n = 85, 31.0% vs. n = 901, 19.6%, p < 0.001). Fewer young adult patients required therapeutic lymphadenectomies (n = 11,329, 18.2%, all p < 0.001).

Approximately 63% of patients who underwent a prophylactic lymphadenectomy had lymph node metastases on final pathology, regardless of age at presentation. Nevertheless, overall survival did not differ based on patient age and was high (Fig. 2). Median follow-up was 68.8 months (5.7 years). Five-year survival data were reported for 151 prepubertal, 2454 adolescent, and 53,420 young adult patients. Five-year survival was 99.1% for prepubertal patients, 99.2% for adolescent patients, and 99.1% for young adult patients (all p = 0.32). Median survival-time was not reached for any group.

FIG. 2.

Overall survival in pediatric and young adult papillary thyroid carcinoma patients stratified by age at presentation and represented by Kaplan–Meier curves. y-Axis begins at 75% survival to facilitate discernment. x-Axis denotes survival in months (dashed line at 5 years).

Prepubertal age was associated with more advanced disease even when the cohort was restricted to patients who presented with small primary tumors (≤10 mm) (Table 3). This included 41 prepubertal patients, 937 adolescent patients, and 33,950 young adult patients. Prepubertal compared to adolescent patients still had a higher frequency of gross ETE (n = 6, 20.7% vs. n = 53, 6.7%, p = 0.004), positive regional lymph nodes (n = 21, 51.2% vs. n = 253, 27.0%, p = 0.001), and distant metastases (n = 1, 2.4% vs. n = 3, 0.3%, p = 0.04), although sample size was limited for the latter comparison.

Table 3.

Subgroup Analysis of Tumor and Treatment Characteristics for Patients Diagnosed with Microcarcinomas (≤10 mm) Stratified by Age at Presentation

	Prepubertal (n = 41)	Adolescent (n = 937)	p ^a	Young adult (n = 33,950)	p ^b
Primary tumor characteristics
Multifocality	10 (24.4)	265 (28.3)	0.59	11,702 (34.5)	<0.001
LVI^c (n = 20,119)	5 (23.8)	63 (11.7)	0.10	1276 (6.5)	<0.001
Gross ETE^d (n = 29,399)	6 (20.7)	53 (6.7)	0.004	1895 (6.6)	0.01
Positive margins	3 (7.3)	50 (5.3)	0.58	1772 (5.2)	0.82
Nodal and metastatic disease characteristics
Positive regional lymph nodes	21 (51.2)	253 (27.0)	0.001	6250 (18.4)	<0.001
Median no. nodes examined	7 (1–22)	2 (0–6)	<0.001	1 (0–3)	<0.001
Median no. positive nodes	1 (0–8.5)	0 (0–2)	0.002	0 (0–1)	<0.001
Distant metastases	1 (2.4)	3 (0.3)	0.04	77 (0.2)	0.01
Surgical treatment
Surgical therapy			0.007		<0.001
None or unknown	0	3 (0.3)		217 (0.7)
Nodulectomy	4 (9.8)	17 (1.8)		485 (1.4)
Hemithyroidectomy	4 (9.8)	129 (13.8)		5846 (17.2)
Total thyroidectomy	33 (80.5)	788 (84.1)		27,402 (80.7)
Lymphadenectomy	33 (80.5)	620 (66.2)	0.06	18,447 (54.3)	<0.001
Prophylactic	9 (22.0)	334 (35.6)	0.01	10,516 (57.0)	0.004
Therapeutic	8 (19.5)	85 (9.1)		2188 (11.9)
Neck dissection, NOS	16 (39.0)	201 (21.5)		5743 (31.1)
Adjuvant treatment
RAI therapy	17 (41.5)	294 (31.4)	0.18	9753 (28.7)	0.04
Chemotherapy	0	2 (0.2)	0.77	27 (0.1)	0.37

Data are presented as n (%) or median (IQR). Bolded numbers represent statistically significant p-values.

Prepubertal age group versus adolescent age group.

Prepubertal age group compared to adolescent group and to young adult group.

LVI reported for patients diagnosed 2010–2017.

ETE reported for patients diagnosed 2004–2015.

Prepubertal age at presentation was associated with higher regional lymph node metastatic burden as well, with a higher median number of positive lymph nodes on examination compared to adolescent patients (1 [IQR 0–8.5] vs. 0 [IQR 0–2], p = 0.002). Young adult patients had the highest frequency of multifocal microcarcinomas (n = 11,702, 34.5%) compared to prepubertal (n = 10, 24.4%) and adolescent patients (n = 265, 28.3%) (all p < 0.001). On multivariable regression modeling of the pediatric microcarcinoma cohort, prepubertal age compared to adolescent age remained an independent predictor of regional lymph node metastases (AOR = 2.19 [CI 1.10–4.36], p = 0.03) (Fig. 3).

FIG. 3.

Multivariable logistic regression analysis of independent predictors for regional lymph node metastases in the pediatric microcarcinoma cohort (n = 978). ORs and 95% CIs are indicated. Filled-in circles represent statistically significant values.

Discussion

This analysis of pediatric PTCs is a cohort study that captures ∼70% of all pediatric thyroid cancer diagnoses in the United States and characterizes the association between patient age with respect to onset of puberty and presenting stage of disease. It is the largest study of pediatric PTC since the Belarusian analysis, which found that younger age at diagnosis in patients with a history of ionizing radiation was associated with recurrent nodal disease and pulmonary metastasis.¹⁵ We report a spectrum of disease severity for pediatric PTC, wherein prepubertal children present with the most extensive disease and young adults present most favorably, with adolescents assuming an intermediate profile.

Specifically, prepubertal children are most likely to have lymph node disease, ETE, LVI, and distant metastases at the time of diagnosis, even in the setting of a small primary tumor (≤10 mm). Adolescent children, in turn, present with these disease characteristics more frequently than young adults. On multivariable regression modeling, controlling for potentially confounding factors, prepubertal age compared to adolescent age was found to be an independent predictor of nodal and distant metastatic disease.

Some small, institutional retrospective analyses have reported similar conclusions that younger children generally present with more invasive disease than adolescents, with specific emphasis on higher propensity for distant metastatic disease.^{5,21,26

–30} With respect to the influence of extent of disease on patient outcomes, one study found that age as a continuous variable was not related to disease-free survival (DFS) or distant metastasis-free survival (DMFS); yet, children <15 years old had distinct clinical manifestations such as lymph node metastases and ETE, which did predict both DFS and DMFS.³³ The authors concluded that a cutoff age of 14 would be more appropriate for diagnosis of “pediatric” PTC³³ essentially supporting the notion of two distinctive phenotypes currently represented in the <18 years of age cohort.

The more invasive phenotype of PTC observed in prepubertal children compared to adolescents and young adults, especially with regard to its propensity to metastasize distantly, implies differing tumor biology. Molecular studies have shown that point mutations in BRAF and RAS, which are very commonly detected in adult PTCs, are significantly more rare in pediatric tumor specimens.^34
–36 Gene rearrangements involving receptor tyrosine kinases such as RET, NTRK1, NTRK3, and ALK, on the contrary, are highly prevalent in pediatric PTCs, and are associated with more aggressive clinical disease than fusion gene-negative PTCs.^34

–38 One study aimed to explore the molecular mechanisms underlying distant metastatic disease in PTC and found that these same gene fusions (RET, ALK, or NTRK1) are independently associated with metastases on multivariate analysis.³⁹

Another study of 106 pediatric Korean patients by Lee et al demonstrated that fusion oncogenes were specifically more prevalent in PTC patients aged <10 years old.⁴⁰ Our data demonstrate that the female sex preponderance observed in adult PTC patients holds for the adolescent population (82%), but only 65% of prepubertal patients diagnosed with PTC are female (p < 0.001). Future studies should continue to investigate this genomic landscape to ultimately facilitate a precision approach to treatment.

Current management guidelines for pediatric PTC recommend total thyroidectomy for almost all patients, in part, because children are considered to have a higher likelihood of multifocal and bilateral disease than adults.^7,41 We found that young adult PTCs were just as frequently multifocal, even for patients with primary microcarcinomas. Literature suggests that of those patients with multifocal disease, 69% will have bilateral nodules.²⁰ Another review found that 38.4% of pediatric patients younger than the age of 17 years presented with bilateral disease.⁴² As such, they concluded that total thyroidectomy should still be the standard of care for most pediatric PTC patients.⁴² Neither of these studies included an adult comparison cohort for contextualization.

Although the frequency of multifocal disease is high based on our data, it is similar to that of young adult patients, who are often safely managed with lobectomy in the appropriate clinical context. Indeed, a few recently published retrospective studies have suggested that lobectomy might be safely considered for some early-stage pediatric PTCs.^43,44 However, given that patients aged <11 years old generally present with the more advanced disease phenotype, even in the setting of T1 tumors, they are likely to continue to require more aggressive management and surveillance.

There are limitations to this study. As a retrospective analysis of the NCDB, it is reliant on accurate coding of patient and treatment variables for reliable analysis.³¹ As discussed, bilaterality is not a coded variable. Tumor size was used as a proxy for the clinical T stage of each patient, as this variable was not reliably coded for cases diagnosed before 2008. Moreover, the NCDB does not collect data on DFS or cancer recurrence. Relatedly, median follow-up time for survival was only 6 years, which does not approach median survival time. In addition, facility type data are not collected for pediatric patients, which preclude stratification of treatment with respect to cancer center type.

Significantly, there is no information collected by the NCDB regarding tumor mutational profiles. Multivariable regression modeling for independent predictors of distant metastatic disease was unable to be performed for the microcarcinoma cohort secondary to small sample size. Finally, there is no strict age cutoff for the onset of puberty, and there are developmental differences in the timing of maturation between female and male patients.

Conclusions

Pediatric PTC patients present with more extensive disease than adult PTC patients, but age <11 years old is an independent predictor for high regional disease burden and distant metastases at the time of presentation, even for those with small primary tumors. Pediatric PTCs are no more frequently multifocal than those diagnosed in young adults. Additional research is needed to determine whether adolescent patients may be safely managed less conservatively than younger children with PTCs and to further elucidate the specific molecular derangements that underlie this divergence in presentation.

Footnotes

Authors' Contributions

J.W.T.: Conceptualization, data curation, methodology, formal analysis, writing-original draft, and writing-review and editing. C.E.E. and J.A.G.: Data curation and writing-review and editing. T.B.: Methodology, formal analysis, and writing-review and editing. R.Z.: Supervision and writing-review and editing. T.J.F.: Conceptualization, methodology, supervision, and writing-review and editing. B.M.F.: Conceptualization, methodology, formal analysis, supervision, and writing-review and editing.

Author Disclosure Statement

All authors have no related conflicts of interests to declare and have approved the final article for submission.

Funding Information

There are no external funding sources to report.

References

National Cancer Institute. Browse the SEER Cancer Statistics Review 1975–2018. n.d. Available from: https://seer.cancer.gov/csr/1975_2018/browse_csr.php?sectionSEL=2&pageSEL=sect_02_table.02 [Last accessed: April 17, 2021].

Dinauer

, Breuer

, Rivkees

. Differentiated thyroid cancer in children: Diagnosis and management. Curr Opin Oncol, 2008; 20(1):59–65; doi: 10.1097/CCO.0b013e3282f30220

Handkiewicz-Junak

, Wloch

, Roskosz

, et al. Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer. J Nucl Med, 2007; 48(6):879–888; doi: 10.2967/jnumed.106.035535

Dermody

, Walls

, Harley

. Pediatric thyroid cancer: An update from the SEER database 2007–2012. Int J Pediatr Otorhinolaryngol, 2016; 89:121–126; doi: 10.1016/j.ijporl.2016.08.005

Motazedian

, Shafiei

, Vatankhah

, et al. Differentiated thyroid carcinoma: Comparison of histopathologic characteristics, clinical course, and outcome between young children and adolescents. Med Oncol, 2013; 30(2):506; doi: 10.1007/s12032-013-0506-y

Hay

, Johnson

, Kaggal

, et al. Papillary thyroid carcinoma (PTC) in children and adults: Comparison of initial presentation and long-term postoperative outcome in 4432 patients consecutively treated at the Mayo Clinic During Eight Decades (1936–2015). World J Surg, 2018; 42(2):329–342; doi: 10.1007/s00268-017-4279-x

Grigsby

, Gal-or

, Michalski

, et al. Childhood and adolescent thyroid carcinoma. Cancer, 2002; 95(4):724–729; doi: 10.1002/cncr.10725

Welch Dinauer

, Tuttle

, Robie

, et al. Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults. Clin Endocrinol (Oxf), 1998; 49(5):619–628; doi: 10.1046/j.1365-2265.1998.00584.x

Borson-Chazot

, Causeret

, Lifante

J-C

, et al. Predictive factors for recurrence from a series of 74 children and adolescents with differentiated thyroid cancer. World J Surg, 2004; 28(11):1088–1092; doi: 10.1007/s00268-004-7630-y

10.

Wada

, Sugino

, Mimura

, et al. Treatment strategy of papillary thyroid carcinoma in children and adolescents: Clinical significance of the initial nodal manifestation. Ann Surg Oncol, 2009; 16(12):3442–3449; doi: 10.1245/s10434-009-0673-4

11.

La Quaglia

, Black

, Holcomb

, et al. Differentiated thyroid cancer: Clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A Report from the Surgical Discipline Committee of the Children's Cancer Group. J Pediatr Surg, 2000; 35(6):955–959; discussion 960; doi: 10.1053/jpsu.2000.6935

12.

Chow

S-M

, Law

SCK

, Mendenhall

, et al. Differentiated thyroid carcinoma in childhood and adolescence-clinical course and role of radioiodine. Pediatr Blood Cancer, 2004; 42(2):176–183; doi: 10.1002/pbc.10410

13.

Zimmerman

, Hay

, Gough

, et al. Papillary thyroid carcinoma in children and adults: Long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery, 1988; 104(6):1157–1166.

14.

Vassilopoulou-Sellin

, Klein

, Smith

, et al. Pulmonary metastases in children and young adults with differentiated thyroid cancer. Cancer, 1993; 71(4):1348–1352; doi: 10.1002/1097-0142(19930215)71:4<1348::aid-cncr2820710429>3.0.co;2-3

15.

Demidchik

, Demidchik

, Reiners

, et al. Comprehensive clinical assessment of 740 cases of surgically treated thyroid cancer in children of Belarus. Ann Surg, 2006; 243(4):525–532; doi: 10.1097/01.sla.0000205977.74806.0b

16.

Fowler

, Pokorny

, Harberg

. Thyroid nodules in children: Current profile of a changing disease. South Med J, 1989; 82(12):1472–1478; doi: 10.1097/00007611-198912000-00005

17.

Martucci

, Crocoli

, De Pasquale

, et al. Thyroid cancer in children: A multicenter international study highlighting clinical features and surgical outcomes of primary and secondary tumors. Front Pediatr, 2022; 10:914942; doi: 10.3389/fped.2022.914942

18.

Francis

, Waguespack

, Bauer

, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid, 2015; 25(7):716–759; doi: 10.1089/thy.2014.0460

19.

Chen

, Huang

, Ji

, et al. Multifocal papillary thyroid cancer in children and adolescents: 12-year experience in a single center. Gland Surg, 2019; 8(5):507–515; doi: 10.21037/gs.2019.09.03

20.

Rubinstein

, Herrick-Reynolds

, Dinauer

, et al. Recurrence and complications in pediatric and adolescent papillary thyroid cancer in a high-volume practice. J Surg Res, 2020; 249:58–66; doi: 10.1016/j.jss.2019.12.002

21.

O'Gorman

, Hamilton

, Rachmiel

, et al. Thyroid cancer in childhood: A retrospective review of childhood course. Thyroid, 2010; 20(4):375–380; doi: 10.1089/thy.2009.0386

22.

Liu

, Hu

, Huang

, et al. Factors associated with distant metastasis in pediatric thyroid cancer: Evaluation of the SEER database. Endocr Connect, 2019; 8(2):78–85; doi: 10.1530/EC-18-0441

23.

Sugino

, Nagahama

, Kitagawa

, et al. Distant metastasis in pediatric and adolescent differentiated thyroid cancer: Clinical outcomes and risk factor analyses. J Clin Endocrinol Metab, 2020; 105(11):dgaa545; doi: 10.1210/clinem/dgaa545

24.

Alzahrani

, Alswailem

, Moria

, et al. Lung metastasis in pediatric thyroid cancer: Radiological pattern, molecular genetics, response to therapy, and outcome. J Clin Endocrinol Metab, 2019; 104(1):103–110; doi: 10.1210/jc.2018-01690

25.

Chesover

, Vali

, Hemmati

, et al. Lung metastasis in children with differentiated thyroid cancer: Factors associated with diagnosis and outcomes of therapy. Thyroid, 2021; 31(1):50–60; doi: 10.1089/thy.2020.0002

26.

Hampson

, Stephens

, Wasserman

. Young age is associated with increased rates of residual and recurrent paediatric differentiated thyroid carcinoma. Clin Endocrinol (Oxf), 2018; 89(2):212–218; doi: 10.1111/cen.13720

27.

Liu

, Wang

, Li

, et al. Clinical heterogeneity of differentiated thyroid cancer between children less than 10 years of age and those older than 10 years: A retrospective study of 70 cases. Eur Thyroid J, 2021; 10(5):364–371; doi: 10.1159/000516830

28.

Lazar

, Lebenthal

, Steinmetz

, et al. Differentiated thyroid carcinoma in pediatric patients: Comparison of presentation and course between pre-pubertal children and adolescents. J Pediatr, 2009; 154(5):708–714; doi: 10.1016/j.jpeds.2008.11.059

29.

Ngo

, Ngo

, Van Le

Pediatric thyroid cancer: Risk factors for central lymph node metastasis in patients with CN0 papillary carcinoma. Int J Pediatr Otorhinolaryngol, 2020; 133:110000; doi: 10.1016/j.ijporl.2020.110000

30.

Lazar

, Lebenthal

, Segal

, et al. Pediatric thyroid cancer: Postoperative classifications and response to initial therapy as prognostic factors. J Clin Endocrinol Metab, 2016; 101(5):1970–1979; doi: 10.1210/jc.2015-3960

31.

Commissionon Cancer. National Cancer Database. n.d. Available from: https://www.facs.org/quality-programs/cancer/ncdb [Last accessed: January 30, 2020].

32.

Mallin

, Browner

, Palis

, et al. Incident Cases Captured in the National Cancer Database Compared with Those in U.S. Population Based Central Cancer Registries in 2012–2014. Ann Surg Oncol, 2019; 26(6):1604–1612; doi: 10.1245/s10434-019-07213-1

33.

Sugino

, Nagahama

, Kitagawa

, et al. Cutoff age between pediatric and adult thyroid differentiated cancer: Is 18 years old appropriate?. Thyroid, 2022; 32(2):145–152; doi: 10.1089/thy.2021.0255

34.

Alzahrani

, Alswailem

, et al. Genetic alterations in pediatric thyroid cancer using a comprehensive childhood cancer gene panel. J Clin Endocrinol Metab, 2020; 105(10):dgaa389; doi: 10.1210/clinem/dgaa389

35.

Penko

, Livezey

, Fenton

, et al. BRAF mutations are uncommon in papillary thyroid cancer of young patients. Thyroid, 2005; 15(4):320–325; doi: 10.1089/thy.2005.15.320

36.

Alzahrani

, Murugan

, Qasem

, et al. Single point mutations in pediatric differentiated thyroid cancer. Thyroid, 2017; 27(2):189–196; doi: 10.1089/thy.2016.0339

37.

Pekova

, Sykorova

, Dvorakova

, et al. RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid, 2020; 30(12):1771–1780; doi: 10.1089/thy.2019.0802

38.

Stosic

, Fuligni

, Anderson

, et al. Diverse oncogenic fusions and distinct gene expression patterns define the genomic landscape of pediatric papillary thyroid carcinoma. Cancer Res, 2021; 81(22):5625–5637; doi: 10.1158/0008-5472.CAN-21-0761

39.

Lan

, Bao

, Ge

, et al. Genomic landscape of metastatic papillary thyroid carcinoma and novel biomarkers for predicting distant metastasis. Cancer Sci, 2020; 111(6):2163–2173; doi: 10.1111/cas.14389

40.

Lee

, Lee

, Im

S-W

, et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest, 2021; 131(18); doi: 10.1172/JCI144847

41.

Kaliszewski

, Diakowska

, Wojtczak

, et al. The occurrence of and predictive factors for multifocality and bilaterality in patients with papillary thyroid microcarcinoma. Medicine (Baltimore), 2019; 98(19):e15609; doi: 10.1097/MD.0000000000015609

42.

Baumgarten

, Jenks

, Isaza

, et al. Bilateral papillary thyroid cancer in children: Risk factors and frequency of postoperative diagnosis. J Pediatr Surg, 2020; 55(6):1117–1122; doi: 10.1016/j.jpedsurg.2020.02.040

43.

Memeh

, Ruhle

, Alsafran

, et al. Total thyroidectomy vs thyroid lobectomy for localized papillary thyroid cancer in children: A propensity-matched survival analysis. J Am Coll Surg, 2021; 233(1):39–49; doi: 10.1016/j.jamcollsurg.2021.03.025

44.

Sudoko

, Jenks

, Bauer

, et al. Thyroid lobectomy for T1 papillary thyroid carcinoma in pediatric patients. JAMA Otolaryngol Head Neck Surg, 2021; 147(11):943–950; doi: 10.1001/jamaoto.2021.2359