Advances in Pediatrics 64 (2017) 171–190

ADVANCES IN PEDIATRICS

Pediatric Thyroid Cancer

Christine M. Chan, MDa, Jonathan Young, MDb,
Jeremy Prager, MDb, Sharon Travers, MDa,*
a
Section of Endocrinology, Department of Pediatrics, Children’s Hospital Colorado, University of
Colorado Denver, 13123 East 16th Avenue, Aurora, CO 80045, USA; bDepartment of Pediatric
Otolaryngology, Children’s Hospital Colorado, University of Colorado Denver, 13123 East 16th
Avenue, Aurora, CO 80045, USA

Keywords
 Medullary thyroid cancer  Differentiated thyroid cancer  Pediatric thyroid cancer
Key points
 Evidence supports that the incidence of differentiated thyroid cancers (DTCs) is
increasing in the pediatric population.
 Despite the more aggressive tendency of DTCs in children, prognosis is excellent
but early diagnosis could decrease the extent of intervention required and overall
recurrence rates.
 Medullary thyroid cancer (MTC) is rare in children and usually hereditary.
 Treatment centers around removal of the thyroid gland prior to development of
MTC.
 Care of children with thyroid cancer should include a team of experienced pe-
diatric surgeons and subspecialists.

INTRODUCTION
Thyroid cancer remains a rare malignancy in the pediatric population,
comprising 0.7% of all childhood cancers [1], and the overall incidence of thy-
roid cancer is increasing. The increasing incidence of thyroid cancer is largely
driven by the increase in papillary thyroid cancer (PTC) and has been in part
attributed to increased detection of small tumors. Studies have shown, how-
ever, an increased incidence across all tumor sizes, suggesting that surveillance,
more sensitive diagnostic procedures, and earlier detection are not the sole ex-
planations [2,3]. Historically, evaluation and management of thyroid nodules
and thyroid cancer in the pediatric population has largely been based on adult

*Corresponding author. E-mail address: Sharon.travers@childrenscolorado.org

http://dx.doi.org/10.1016/j.yapd.2017.03.007
0065-3101/17/ª 2017 Elsevier Inc. All rights reserved.
172 CHAN, YOUNG, PRAGER, ET AL

guidelines. Given the differences in presentation, pathophysiology, and long-

term outcomes, however, the American Thyroid Association (ATA) has
recently published guidelines specifically for management of thyroid nodules
and DTC in the pediatric population [4].

BACKGROUND AND EPIDEMIOLOGY

Per the Surveillance, Epidemiology, and End Results program (a National Can-
cer Institute registry of cancer incidence and survival in the United States),
1.8% of thyroid malignancies diagnosed in the United States are in
patients under 20 years of age [5]. There is a female preponderance, with a
peak incidence in adolescents ages 15 years to 19 years [5]. In this age group,
thyroid cancer is the second most common cancer among girls. Nearly all pe-
diatric thyroid cancers are DTCs, with a majority (>90%) PTC. DTC cells
resemble normal thyroid cells in behavior and appearance, and differentiated
tumors tend to grow more slowly and be less aggressive than undifferentiated
or poorly differentiated tumors. Follicular thyroid cancer (FTC), also a DTC,
is less common (<10%) and medullary and undifferentiated thyroid cancers are
rare in the pediatric population. The histologic criteria for DTCs are the same
for children and adults.
PTCs are well-differentiated thyroid cancers arising from thyroid follicular
cells. They are characteristically unencapsulated tumors with often ill-defined
margins. In children, PTC is frequently multifocal and locoregional metastases
are present in the majority of patients at the time of diagnosis. Children with
PTC are also more likely than adults to have pulmonary metastases (up to
25%) compared with adults [6]. The diagnosis of PTC is based on a constellation
of cytologic and nuclear features, including presence of psammoma bodies (calci-
fied structures thought to arise from tumor cell necrosis), enlarged nuclei, nuclear
overlapping, nuclear clearing, and nuclear grooves. Within the category of PTC,
there are histologic variants, including classic, follicular, and diffuse sclerosing,
the lattermost of which is more aggressive. There has been more recent discus-
sion in the literature regarding the noninvasive encapsulated follicular variant of
PTC and its reclassification as a neoplasm rather than a malignancy [7].
FTC is also a DTC, although it occurs much less often in the pediatric pop-
ulation than PTC and has a different clinical behavior. Histologic variants of
FTC include oncocytic (Hürthle cell) and clear cell variants. In general, pediat-
ric FTC is less aggressive than PTC, presenting with less advanced disease,
fewer distant metastases, and a lower rate of recurrence. FTC in children is
generally a unifocal tumor that does not have the tendency to spread to
regional lymph nodes like PTC. Although FTC can be prone to hematogenous
metastases, more often than not, FTC in children is minimally invasive and has
a low risk for recurrence and metastases.
Genetic alterations are known to play a role in the pathogenesis of thyroid
cancer. The MAPK and PI3K/AKT signaling pathways play an important
role in the regulation of cell proliferation, differentiation and survival
(Fig. 1). Alterations in the BRAF and RAS genes as well as RET/PTC and
PEDIATRIC THYROID CANCER 173

Fig. 1. The MAPK and PI3K/AKT signaling pathways regulate cell differentiation, prolifera-
tion, and survival. Activation of these pathways secondary to alterations in certain genes
and proteins plays an important role in thyroid cancer pathogenesis. (From Nikiforov YE, Ni-
kiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol
2011;7(10):571; with permission.)

PAX8/PPARc rearrangements result in protein changes that cause activation of

these pathways. Mutations in BRAF are the most common molecular abnor-
mality in adult PTC, followed by mutations in RAS and RET/PTC rearrange-
ments [8]. In contrast, BRAF mutations are less common in children with PTC
and RET/PTC rearrangements are more common [9,10]. These molecular dif-
ferences have potential implications on response to iodine-131 (I-131) therapy
as well as disease aggressiveness and mortality. Mutations in RAS and the
PAX8/PPARc rearrangements are more common in adult FTC [8], but the mo-
lecular characteristics of pediatric FTC are largely unstudied.

RISK FACTORS
There are several risk factors for the development of thyroid nodules and thy-
roid cancer. These include radiation exposure, thyroid disease (eg, autoimmune
174 CHAN, YOUNG, PRAGER, ET AL

thyroid disorders), and genetic syndromes. An extreme example of radiation

exposure is highlighted in the Chernobyl nuclear accident in 1986, after which
childhood thyroid cancers began to appear [11]. More common in the clinical
setting are childhood cancer survivors who received radiation therapy as part
of their treatment of cancers, such as brain tumors, leukemias, and lymphomas.
In this population, peak incidence of thyroid nodules occurs approximately
15 years after exposure [12]. The risk is greater in children who received radia-
tion at a younger age. There are also several genetic syndromes associated with
an increased risk of thyroid neoplasias. Patients with APC-associated polyposis
have mutations in the APC gene, which encodes the APC protein, an important
tumor suppressor. These patients typically develop numerous colorectal ade-
nomas, which progress to carcinomas over time if untreated. PTC is a well-
known albeit infrequent extracolonic manifestation of APC-associated polyposis
[13]. Patients with Carney complex characteristically have abnormalities in skin
pigmentation, cardiac myxomas, endocrine tumors (most commonly adrenocor-
tical disease), and schwannomas. Thyroid abnormalities in Carney complex
include development of multiple thyroid nodules, follicular adenomas, and
DTC. DICER1 syndrome results from a germline mutation of DICER1 resulting
in a tumor susceptibility syndrome with increased risk for pleuropulmonary blas-
toma, ovarian sex cord–stromal tumors, cystic nephromas, and thyroid neopla-
sias (multinodular goiter, adenomas, or DTC). PTEN hamartoma tumor
syndromes are characterized by germline mutations in PTEN and hamartoma-
tous tumors, and patients are at increased risk for breast, thyroid, and endome-
trial cancers. Thyroid abnormalities include multinodular goiter, follicular
adenomas, and DTC with an over-representation of FTC [14,15]. Werner syn-
drome is characterized by premature aging and cancer predisposition with symp-
toms beginning in young adulthood. The most common cancers are soft tissue
sarcomas, osteosarcomas, melanomas, and DTC.

PRESENTATION AND DIAGNOSIS

In children, DTC most often presents as a painless thyroid nodule or mass.
The thyroid nodule may be first noted by the patient or parent or incidentally
at a well-child visit. Sometimes, the thyroid nodule is not palpable and it is
discovered incidentally on imaging done for another purpose. This is most
common with thyroid nodules that are smaller and deeper within the thyroid
gland. Some children with DTC present with cervical lymphadenopathy alone,
which is not surprising given that up to 80% of children with PTC have
regional lymph node involvement at the time of their diagnosis [16–20]. A
large, hard nodule, especially one that is adherent to adjacent tissues, has a
high likelihood of harboring cancer. After it has been determined that a child
has a thyroid nodule or mass, the next step is to obtain blood work for mea-
surement of thyroid function with thyrotropin (TSH), thyroxine (T4), and
triiodothyronine (T3) levels. Although thyroid cancer typically does not affect
thyroid function, there may be an increased risk of thyroid nodule formation
and cancer developing in a gland affected by autoimmune lymphocytic
PEDIATRIC THYROID CANCER 175

infiltration [21]. Consequently, children with thyroid nodules may have coex-
isting thyroid autoimmunity and hypothyroidism. There are some thyroid
nodules that have autonomous function and produce excess amount of thyroid
hormones leading to subclinical or overt hyperthyroidism. Laboratory findings
of hyperthyroidism include a suppressed thyrotropin with normal or elevated
T4/T3 levels. Unless there is a family history of MTC, it is not recommended
to routinely measure calcitonin levels in a child who presents with a thyroid
nodule because the prevalence of sporadic MTC is very low [4].
Imaging and fine-needle aspiration
For hyperfunctioning nodules, evaluation should proceed with nuclear medicine
imaging, such as an iodine-123 (I-123) thyroid scan. In the absence of hyperthy-
roidism, nuclear medicine thyroid scans are not recommended and ultrasound of
the thyroid gland (Fig. 2) is indicated and should be performed preferably in a
center that has experience and expertise in thyroid and cervical lymph node im-
aging. Depending on the ultrasound characteristics of the nodule and the under-
lying clinical context of the patient, a decision is made as to whether a fine-needle
aspiration (FNA) biopsy of the nodule is warranted. Benign nodules are more
likely to have smooth margins, translucent halos, and homogenous isoechogenic-
ity or hyperechogenicity (see Fig. 2B). Nodules that have these benign features
may be followed over time with repeat ultrasound and biopsied at a later date
if there is increased growth of the nodule and/or development of suspicious

Fig. 2. (A) Normal thyroid ultrasound. (B) Ultrasound of low-suspicion (hyperechoic, regular
margins) thyroid nodule. (C, D) Ultrasounds of high-suspicion (hypoechoic, irregular margins,
and microcalcifications present) thyroid nodule.
176 CHAN, YOUNG, PRAGER, ET AL

features. Nodule characteristics that are concerning for malignancy and generally
lead to biopsy include hypoechogenicity, irregular margins, increased blood flow,
and/or microcalcifications (see Fig. 2C, D) [22–24]. In adults, the size of the
nodule is also a criterion for biopsy, as the 2015 ATA adult guidelines indicate
that FNA is generally not warranted for nodules less than 1 cm in size, unless a
patient is considered high risk [25]. Assigning a specific nodule size for a growing
child whose thyroid gland is also changing in size may not, however, be appro-
priate. Consequently, the 2015 ATA management guidelines for children with
thyroid nodules and DTC state that nodule characteristics rather than a specific
size cutoff should be the primary determinant for biopsy consideration. An ultra-
sound that does not show a discrete nodule but rather a diffusely enlarged thyroid
gland with microcalcifications should also be biopsied because this may represent
a diffusely infiltrative PTC (Fig. 3). As part of the thyroid ultrasound, the neck
should also be evaluated to identify abnormal cervical lymph nodes that may
be biopsied at the same time as the thyroid nodule [26]. The risk of malignancy
is low in hyperfunctioning thyroid nodules so FNA is generally not recommen-
ded with the assumption that surgery will remove the nodule [4,27].
Once it has been determined that FNA biopsy of a thyroid nodule is indi-
cated, the procedure should be done using ultrasound guidance and with
age-appropriate anesthesia. The overall incidence of malignancy in a solitary
thyroid nodule in children is estimated to be approximately 22% to 26%, which
is higher than the incidence in adults of 5% to 14% [28]. Cytopathology find-
ings on FNA are reported using the Bethesda System for Reporting Thyroid
Cytopathology and 6 possible categories exist: (1) nondiagnostic or unsatisfac-
tory (specimen with limited cellularity), (2) benign, (3) atypia of undetermined
significance or follicular lesion of undetermined significance (AUS/FLUS), (4)
follicular/Hürthle cell neoplasm or suspicious for follicular/Hürthle cell
neoplasm, (5) suspicious for malignancy, and (6) malignant [29]. Those chil-
dren with benign FNA results should be followed serially with thyroid ultra-
sound, and repeat FNA is indicated if there is growth of the nodule and/or
development of suspicious characteristics. In children, 28% of AUS/FLUS

Fig. 3. Ultrasound demonstrating diffuse, scattered microcalcifications characteristic of an

infiltrative PTC, such as the diffuse sclerosing variant.
PEDIATRIC THYROID CANCER 177

lesions and 58% of suspicious for follicular/Hürthle cell neoplasm are deter-
mined to be malignant based on surgical pathologies [30]. Given these percent-
ages, it is recommended that children with these 2 FNA results undergo
surgery consisting of thyroid lobectomy and isthmusectomy [4]. Surgery can
also be considered in cases of a large benign nodule (>4 cm) for cosmetic rea-
sons and also because false-negative results are more often seen with large le-
sions. Although FNA biopsies are an effective way to guide the necessity of
surgery, there are some limitations of the procedure, such as obtaining non-
diagnostic samples due to inadequate aspirates and variability in cytopathologic
interpretations. The estimated sensitivity and specificity of FNA biopsies to
differentiate malignant from benign lesions are 94% and 81%, respectively [28].
PTC is the most common thyroid malignancy diagnosis found on FNA bi-
opsy. As stated previously, PTC is 1 of 2 DTCs, the other being FTC. When
compared with adults with the same tumor type, children with PTC tend to
have larger primary tumors and more widespread cancer, with regional neck
lymph node metastases occurring in 60% to 80% of children at diagnosis.
The next most common site of metastases is the lung, occurring in 10% to
25% of children, followed by bone metastases, which occur rarely and in less
than 5% [16–20]. The chance of having pulmonary metastases is inversely
related to patient age and increases with the size of the tumor, extrathyroidal
extent, and the burden of cervical lymph node disease [19]. Baseline chest
radiograph may not be helpful because they can be normal in as many as
42% of patients who are later determined to have pulmonary metastases by nu-
clear medicine imaging [31].
After a diagnosis of thyroid cancer has been made, surgical consultation for
thyroidectomy is the next course of action. Studies have shown that the initial
surgical approach has the greatest impact for the risk of later recurrence, and
children with DTC overall have better outcomes when their surgery is per-
formed by experienced thyroid surgeons [16,19,32]. Thus, the ATA pediatric
guidelines recommend that children with DTC only be operated on by such
surgeons and in a hospital with the full spectrum of pediatric specialty care,
including endocrinology, radiology (especially ultrasound), nuclear medicine,
anesthesia, and intensive care [4].

PRESURGERY EVALUATION
Prior to surgery, it is critical to evaluate for the presence and location of neck
lymph node disease by ultrasound and FNA, if this was not done at the time of
the initial thyroid nodule evaluation. Ultrasound findings suggestive of cervical
lymph node metastasis include increased size of the lymph node, rounded
shape, loss of central hilum, cystic appearance, peripheral vascularity on
Doppler, and microcalcifications [33]. If any of these characteristics are present,
FNA of the lymph node(s) should be obtained to confirm the presence of cer-
vical metastasis, because this influences the extent of surgery.
Preoperative evaluation should also include evaluation of vocal cord
function because the recurrent laryngeal nerve is located within the
178 CHAN, YOUNG, PRAGER, ET AL

tracheoesophageal groove just posterior to the thyroid gland, and it is at risk of

involvement when there is extrathyroidal extension of the tumor. CT or MRI
of the neck is recommended if there is concern for invasion into the aerodiges-
tive tract, which may manifest as changes in phonation with vocal cord paral-
ysis, dyspnea, dysphagia, hematemesis, or hemoptysis. Although CT imaging
has a much shorter image acquisition time and thus obviates sedation in very
young children in comparison with MRI, the iodine component of the contrast
load may delay the postoperative evaluation and treatment with radioactive
iodine. Therefore, preoperative imaging should be discussed with the team
of specialists who are providing care because it may affect the timing of addi-
tional treatment.

SURGERY
The current recommendation for PTC in a pediatric patient is for a total thy-
roidectomy. Even in patients who appear to have unilateral disease on preop-
erative evaluation, studies have demonstrated that there is an increased
incidence of multifocal disease [34,35]. A total thyroidectomy removes the tu-
mor burden and permits the use of radioactive iodine for postoperative imaging
and treatment. It has also been shown that total thyroidectomy reduces the risk
of recurrence. At 40-year follow-up in 1 study, patients who were treated with a
unilateral lobectomy had a 35% local recurrence rate compared with 6% in pa-
tients treated with bilateral lobar resection [16].
Thyroidectomy is customarily performed by direct access through a horizon-
tal incision in the neck. The thyroid gland is composed of a left lobe and right
lobe joined by a central isthmus. The gland is approached 1 lobe at a time and
its blood supply is cut off systematically, while preserving the parathyroid
glands and superior laryngeal and recurrent laryngeal nerves. Once both lobes
are freed, the gland’s attachment to the trachea is divided and the gland is
removed.

Surgical treatment of cervical lymph nodes

The nodal compartments of the neck have been anatomically and surgically
defined as the lateral and central neck levels. The lateral neck contains levels
I–V and the central neck comprises level VI (Fig. 4). The 2015 pediatric
ATA guidelines recommend removal of the lymph nodes in level VI (central
neck dissection [CND]) in patients with preoperative or intraoperative evidence
of gross extrathyroidal invasion, central lymphadenopathy, or lateral cervical
metastases [4]. Additionally, tumors that are larger than 4 cm in size also
have a higher risk of lymph node metastasis and, therefore, a CND is sug-
gested. There are also cases of lymph node metastases seen with tumors less
than 1 cm in size as well as a series reporting 36% metastasis with tumors
less than or equal to 4 cm in size [19,36]. Therefore, in a patient with a small
tumor and no evidence of extrathyroidal extension or lymph node metastases,
a prophylactic CND may be considered although this is not without
controversy.
PEDIATRIC THYROID CANCER 179

Fig. 4. Anatomy of the zones of the neck. (From Som PM, Curtin HD, Mancuso AA. An
imaging-based classification for the cervical nodes designed as an adjunct to recent clinically
based nodal classifications. Arch Otolaryngol Head Neck Surg 1999;125(4):388-96; with
permission.)

Lateral neck dissection (LND) is indicated if there is presence of metastatic

disease on preoperative imaging and biopsy. It is imperative to have FNA
confirmation prior to proceeding with surgical excision. Therapeutic LND re-
moves disease burden and potentially increases the efficacy of I-131 treatment.
Routine prophylactic LND is not recommended by the ATA guidelines [4].
Berry picking, which refers to the removal of suspicious nodes from the
neck without a formal neck dissection, should not be done because it is an
incomplete oncological approach and may make revision surgery both neces-
sary and more difficult.

Risks of surgery
Total thyroidectomy is associated with several well-known risks, including
bleeding, hypoparathyroidism, and injury to the recurrent laryngeal nerve.
These risks can manifest in the immediate postoperative period with develop-
ment of a compressive hematoma, hypoparathyroidism with hypocalcemia, dif-
ficulty breathing, voice changes such as hoarseness and pitch problems, and
dysphagia. Meticulous surgical technique as well as appropriate postoperative
care can prevent the development of a compressive hematoma requiring re-
exploration of the surgical bed. In addition, excellent surgical technique also
lends to preservation and minimal perturbation of the parathyroid glands.
Parathyroid hormone and serum calcium levels are checked intraoperatively
180 CHAN, YOUNG, PRAGER, ET AL

and postoperatively to help with management of hypocalcemia. The risk for

developing temporary hypocalcemia after total thyroidectomy may be as
high as 52%, but the risk of permanent hypoparathyroidism is likely very
low (<2%) in high-volume tertiary endocrine practices [37–40]. The risk of per-
manent hypoparathyroidism increases, however, in patients with widespread
disease requiring more extensive surgery and in 1 report may exceed 12%
[19]. Lastly, intraoperative laryngeal nerve monitoring is often used to supple-
ment the precision taken in dissecting the gland away from the recurrent laryn-
geal nerve. Average rates of injury to the recurrent laryngeal nerve resulting in
significant palsies ranges from 2% to 6% [41,42].
Lymphadenectomy within the central and lateral neck compartments presents
several additional risks for patients. These risks include injury to additional
nerves, including the spinal accessory nerve and hypoglossal nerve, as well as
injury to the lymphatic system. Injury to the spinal accessory nerve can result
in weakness of the shoulder. Injury to the hypoglossal nerve can result in weak-
ness of tongue movement affecting speech and deglutition. The average rates of
injuries to these nerves ranges from less than 1% to 6% [16,19]. The lymphatic
system is at risk when operating inferiorly in the neck around the level of the clav-
icle. As the lymphatic tissue is removed from the supraclavicular region, the
thoracic duct or other lymphatic channels may be encountered. These are iso-
lated and divided with surgical clips or suture ligation to minimize the risk of
chyle leak. In addition, cervical lymphadenectomy of the central and lateral
neck elevates the risk of hypocalcemia and hypoparathyroidism due to the revas-
cularization and/or removal of parathyroid glands.

POSTSURGICAL EVALUATION AND TREATMENT

After surgery, children are sent home on thyroid hormone replacement (levo-
thyroxine) to recuperate and then 6 weeks to 8 weeks later, they return for
their postoperative evaluation typically performed by a thyroid team/endocri-
nologist. The primary purpose of this evaluation is to determine whether
further surgery is necessary and whether I-131 therapy is indicated. To aid
with this decision, children who received total thyroidectomies and appropriate
lymph node dissections are stratified into 1 of 3 risk levels (low, intermediate,
and high) for the likelihood of persistent cervical disease and/or distant metas-
tases [4]. This stratification is based on the surgery and pathology results with
extensive cervical lymph node involvement and extrathyroid invasion confer-
ring higher risk levels.

Thyroglobulin measurements and iodine-123 scan

Thyroglobulin (Tg) and thyrotropin levels are also measured at this first
follow-up visit. Tg is a glycoprotein that is synthesized and secreted from the
thyroid gland as part of normal thyroid hormone synthesis. It is also produced
and secreted from DTC cells; thus, in the absence of any normal thyroid tissue
(ie, after total thyroidectomy), Tg levels can be used as a marker of residual
and/or recurrent thyroid disease [43,44]. Tg increases with thyrotropin
PEDIATRIC THYROID CANCER 181

stimulation, so it is important to interpret a Tg level in the context of the cor-

responding thyrotropin level. A suppressed Tg level is one measured when the
thyrotropin is low (ie, with patient on levothyroxine) and is generally 5 times to
10 times lower magnitude compared with a stimulated, Tg which is measured
when the thyrotropin is elevated (ie, when a patient comes off levothyroxine
treatment). After surgery and prior to I-131 treatment, a suppressed Tg level
of less than 0.5 ng/mL indicates minimal risk of residual disease whereas higher
levels, especially values greater than 2 ng/mL, indicate probable residual dis-
ease [43]. Unfortunately, there are some limitations in the utility of Tg mea-
surements. The most common is the presence of Tg antibodies, which
occurs in approximately 25% of patients with DTC [45]. Tg antibodies inter-
fere with most Tg assays resulting in falsely low values [46]. Thus, Tg anti-
bodies are always measured simultaneously with the measurement of Tg
levels and interpretation of results made accordingly.
If on review of the surgery and pathology report it is found that a child’s tu-
mor was confined to the thyroid gland and there was no disease or just inci-
dental microscopic disease in a small number of central neck lymph nodes,
then this child is stratified into the low-risk group for recurrence [4]. If this child
also has a low suppressed Tg level, I-131 therapy is not necessarily indicated
and surveillance can be recommended going forward [4]. For children in the
intermediate-risk and high-risk groups (based on extent of neck lymph node
disease), an I-123 whole-body diagnostic scan and stimulated Tg level are rec-
ommended for further stratification and the determination and dosing of I-131
treatment. A thyrotropin-stimulated Tg provides a more sensitive marker for
residual disease than a suppressed Tg. In preparation for the I-123 scan, levo-
thyroxine therapy is stopped approximately 3 weeks to 4 weeks prior to the
scan to achieve a thyrotropin level above 30 mIU/L, which facilitates the up-
take of I-123. In adults, recombinant human thyrotropin can be administered
in lieu of levothyroxine withdrawal. The procedure for administering recombi-
nant human thyrotropin involves 2 intramuscular injections spaced 24 hours
apart followed by the I-123 dosing on day 3. The major advantage of using re-
combinant human thyrotropin is to avoid hypothyroid symptoms that result
when discontinuing levothyroxine. Data using recombinant human thyro-
tropin in children are few but preliminary studies indicate that its use may
be safe and effective [47]. A low-iodine diet is also prescribed for 10 days to
14 days prior to the scan because this may also enhance radioiodine uptake.
This diet can be challenging for children to adhere to and includes avoidance
of iodized and sea salt, sea food, dairy products, egg yolks, most chocolate, and
commercial bakery products that contain iodine/iodate dough conditioners or
high-iodine ingredients.

Iodine-131 treatment
The diagnostic I-123 scan and stimulated Tg level show the anatomic location
(Fig. 5A) and estimation of residual thyroid cancer, respectively, and these re-
sults are used to determine whether I-131 treatment should be given and, if so,
182 CHAN, YOUNG, PRAGER, ET AL

Fig. 5. (A) I-123 scan showing physiologic distribution of the tracer in the salivary glands and
bowel (yellow arrow). There is residual uptake in both sides of the thyroid operative bed (blue
arrows). There is additional uptake superior to the expected region of the left lobe, which may
represent cervical lymph nodes (red arrow). (B) Post–I-131 treatment scan showing increased
uptake in both sides of the thyroid operative bed (blue arrows). There is again additional up-
take superior to the expected region of the left lobe, which suggests local regional lymph node
metastatic disease (red arrow). There is low-level diffuse uptake within the lungs that was not
present on pretherapy I-123 and suggests pulmonary metastasis (orange arrow).

at what dose. Whereas I-131 in the past was considered standard adjunctive
treatment to surgery in children with DTC, there is now some concern
regarding long-term adverse consequences [48,49]. Therefore, it is essential
to balance the risks and benefits of this intervention. Because there is currently
no strong evidence that I-131 improves disease-free survival in adults with
small stage 1 disease, the ATA guidelines for children recommend selective
treatment with I-131, considering each case individually [4]. The desired out-
comes of I-131 are to eliminate iodine-avid residual disease and decrease the
risk of thyroid cancer recurrence. I-131 also destroys any residual normal thy-
roid tissue that is left after surgery. This provides a clean slate and improves
the sensitivity of using Tg levels and future I-123 scans as markers of recurrent
thyroid cancer [43,44]. There is overall consensus that I-131 therapy is benefi-
cial and thus indicated in children who have lymph node or local regional dis-
ease that is not amenable to surgery and in those who have distant metastases
that are known or presumed to be iodine avid [4,50]. Studies have shown that
I-131 therapy may be effective in children with pulmonary metastases and
often results in complete remission [51]. Many experts also recommend that
postsurgical I-131 be given to children whose initial presentation was advanced
with large tumors and/or in whom there was extensive neck lymph node dis-
ease evident from surgery and pathology findings [50]. After the decision has
been made to proceed with I-131 therapy, the patient undergoes the same
PEDIATRIC THYROID CANCER 183

preparation as described for the I-123 scan: levothyroxine withdrawal and low-
iodine diet. The patient’s family is interviewed by the nuclear medicine staff to
determine whether the patient should be admitted for isolation after the I-131
dose (usually 24–48 hours) or if outpatient therapy is appropriate. Although
nausea and vomiting can occur after administration of I-I31, the treatment is
usually well tolerated by children; 5 to 7 days after the I-131 dose is given, a
whole-body diagnostic scan is performed, which shows the anatomic locations
of iodine uptake, thus providing further information regarding a patient’s
extent of disease (Fig. 5B).

Thyrotropin suppression
After surgery and I-131 therapy (if administered), patients are treated with lev-
othyroxine for both replacement purposes and to decrease risk of recurrent
thyroid cancer [17]. Because thyrotropin can stimulate the growth of DTC
cells, the goal of levothyroxine treatment is to keep thyrotropin levels low to
prevent this stimulation. The degree of thyrotropin suppression that is recom-
mended directly correlates to the stratified risk level for recurrence [4]. For
example, in those children stratified to the low-risk group for recurrent disease,
it is recommended to keep their thyrotropin levels in the low to normal range
of 0.5 mIU/L to 1.0 mIU/L. Children who are in the intermediate-risk and
high-risk groups for recurrence should maintain their thyrotropin levels
initially between 0.1 mIU/L and 0.5 mIU/L and less than 0.1 mIU/L, respec-
tively [4]. Children on suppressive levothyroxine therapy should be monitored
for the development of hyperthyroid symptoms, such as linear growth acceler-
ation, bone age advancement, decreased school performance, tachycardia, and
elevated blood pressure.

SURVEILLANCE
In all children treated for thyroid cancer, long-term surveillance is necessary for
detecting residual or recurrent disease because relapses have been shown to
occur 20 years to 30 years from the time of initial diagnosis [52]. Recurrence
rates in children vary between 15% and 40%, and factors that have an impact
on this rate include age at diagnosis (with younger patients having higher recur-
rence rates), extent of initial surgery, I-131 therapy, degree of thyrotropin sup-
pression, and initial response to therapy [16–19,53]. Because the most likely
location for PTC recurrence is in the neck, regular ultrasound imaging with
careful attention to lymph node morphology and size is an important part of
follow-up. Interpretation of the ultrasound is done in conjunction with mea-
surement of Tg levels, which serve as a sensitive marker for detecting residual
or recurrent thyroid disease. For children who receive I-131 therapy, an I-123
diagnostic whole-body scan is typically repeated 1 year to 2 years after their
initial treatment to assess clinical response and for restaging purposes [4]. Other
imaging, such as CT, may be done depending on the clinical scenario (Fig. 6).
It is not unusual for children with DTC to require repeat surgeries and/or I-131
therapies depending on their disease course. Rarely, children with DTC
184 CHAN, YOUNG, PRAGER, ET AL

develop progressive disease that is not amenable to surgery or further I-131

doses (if non–iodine-avid disease). In these few children, systemic therapy
with chemotherapy can be considered. There are a few positive clinical expe-
riences using tyrosine kinase inhibitors, such as sorafenib, an agent that is
Food and Drug Administration approved for advanced iodine-refractory
DTC in adults [54].

Fig. 6. Chest CT of patient (with diffuse lung uptake on I-123 scan) showing pulmonary nod-
ules consistent with lung metastases.

FOLLICULAR THYROID CANCER

The initial evaluation and treatment of FTC in children is the same as for
PTC. The FNA of a nodule that is later diagnosed to be FTC by surgical pa-
thology is generally an indeterminate lesion. As described previously, children
with indeterminate lesions should undergo thyroid lobectomy and isthmusec-
tomy. Ultimately, a diagnosis of FTC requires differentiation between follic-
ular adenoma and carcinoma by identification of capsular and/or vascular
invasion. Based on the extent of invasion, FTC is classified as either minimally
or widely invasive. Minimally invasive FTCs are those tumors that have
microscopic capsular invasion alone and/or limited vascular invasion. Widely
invasive FTC is rare in children and shows widespread infiltration into blood
vessels and/or adjacent thyroid tissue. Widely invasive FTC is more common
in adults and has a greater risk of morbidity with a greater likelihood of me-
tastases and recurrence. If final pathology reveals a minimally invasive FTC,
completion thyroidectomy may not be indicated. If a tumor is greater than
or equal to 4 cm and/or there are more than 3 vascular invasions identified,
completion thyroidectomy with or without I-131 therapy is recommended.
The follow-up of FTC is similar to that of PTC in that serial Tg and measure-
ments and ultrasounds are performed.
PEDIATRIC THYROID CANCER 185

OUTCOMES OF DIFFERENTIATED THYROID CANCER AND

RISKS OF SECONDARY TUMORS
Children with DTC (especially PTC) are more likely to present with advanced
disease, but their overall survival rate is excellent—approximately 98% at
40 years [16,19]. This is believed attributable to more favorable biologic
behavior of their thyroid cancer as well as high iodine avidity of tumor cells.
Even children who have pulmonary metastases generally do well after I-131
therapy; they are either in remission or are living with stable metastatic disease
[31,51]. Long-term surveillance is lifelong and the treatment of DTC, specif-
ically I-131, may be associated with long-term adverse consequences, including
chronic sialadenitis, xerostomia, dental caries, ocular dryness, and transient
gonadal dysfunction in postpubescent boys and girls [48]. Reproductive out-
comes do not seem affected because there is no increase in infertility, miscar-
riage, or birth defects post–I-131 therapy [48]. A decline in leukocytes and
platelet counts commonly occurs in the first month after I-131 exposure with
recovery to normal counts by 3 months. Long-term bone marrow suppression
is atypical. There is accumulating evidence, however, that the risk for devel-
oping second primary malignancies is increased after I-131 treatment. From
data collected by the national cancer registries, there is an estimated 42%
excess relative risk of developing a second primary malignancy in those pa-
tients who received I-131 as part of their treatment and no increased risk in
those who did not receive I-131. The absolute risk is low, however, with
only 1 of 227 patients developing a secondary cancer over a decade
(0.44%). The cancer types were mostly salivary cancer, leukemias, and renal
cancer. In general, the risks of these side effects seem positively correlated
with the dose of cumulative I-131 exposure, but no threshold dose has clearly
been identified [48,49].

MEDULLARY THYROID CANCER

MTC is rare in the pediatric population, accounting for 5% of all thyroid can-
cers [5]. Unlike DTC, MTC arises from the parafollicular C cells of the thy-
roid. These cells are of neural crest origin embryologically and do not
produce thyroid hormone. They produce calcitonin and are not responsive
to thyrotropin. There are 2 subtypes of MTC, sporadic and familial. Most
cases of sporadic MTC occur in adulthood. Hereditary MTC accounts for
most MTC in children and adolescents, often as part of the multiple endocrine
neoplasia (MEN) 2 syndromes. MEN2A includes MTC, pheochromocytoma,
and hyperparathyroidism. MEN2B includes MTC, pheochromocytoma, and
mucosal neuromas.
Calcitonin levels are elevated in patients with MTC. Calcitonin levels in in-
fants, however, can be higher and a value considered highly suggestive of
MTC in an adult must be interpreted taking into account the age of the child
[55]. Because MTC cells are not responsive to radioiodine, ideally MTC should
be treated with thyroidectomy prior to metastasizing. After thyroidectomy, pa-
tients with MTC do not require therapy to suppress thyrotropin but should
186 CHAN, YOUNG, PRAGER, ET AL

receive thyroid hormone replacement to maintain normal serum thyrotropin

levels. For patients with metastatic MTC who are unable be treated surgically,
there are other potential therapies, including external beam radiation or systemic
drug therapy. The ATA has published guidelines focusing on the management
of patients with sporadic and hereditary MTC, but these guidelines are not spe-
cific to the pediatric population [56]. Patients diagnosed with MTC should un-
dergo genetic testing for RET gene mutations. RET is a protooncogene located
on chromosome 10q11.2. RET encodes a receptor tyrosine kinase and plays
an important role in regulation of cell proliferation, growth, differentiation,
migration, and survival [57]. Nearly all patients with MEN2A, MEN2B, and fa-
milial MTC have germline mutations in RET. Activating RET mutations are
associated with the various forms of MTC and inactivating mutations can be
seen in patients with Hirschsprung disease.
Because sporadic MTC is rare in the pediatric population, most children
who are at risk for developing MTC are identified during evaluation for pos-
itive family history of MTC and/or MEN. Genetics consultation and evalua-
tion should be completed for these children to determine RET mutation
status. In children with hereditary MTC, there is a natural progression from
C-cell hyperplasia (CCH) to MTC, to metastases, to locoregional lymph nodes,
and to distant metastases. The timing over which this progression occurs de-
pends greatly on the specific RET mutation. Although prophylactic thyroidec-
tomy implies removal prior to development of MTC, many patients have
CCH or even small foci of MTC already present. Recommendations for the
timing of thyroidectomy depend on the RET mutation and are detailed in
the recently revised ATA guidelines for management of MTC [56] and summa-
rized in (Table 1). The highest risk (ATA-HST) category for development of
MTC includes patients with MEN2B and RET codon M918 T mutation.
The high-risk (ATA-H) category includes patients with RET codon C634
and A883 F mutations. The moderate-risk (ATA-MOD) category includes pa-
tients with RET codon mutations other than the previously mentioned
M918 T, C634, and A883 F. Children with highest-risk M918 T mutation
should undergo thyroidectomy as early as possible within the first few months
to a year of life. Children with ATA-H mutations should undergo thyroidec-
tomy at or prior to age 5 years. Children with moderate-risk mutations should
undergo thyroidectomy when the serum calcitonin levels become elevated or
may elect to proceed sooner in discussion with their care team if parents are
concerned about the potentially lengthy evaluation period. For post-
thyroidectomy surveillance, patients should have physical examination, neck
ultrasound, and serum calcitonin/carcinoembryonic antigen levels every
6 months for 1 year and then annually thereafter. Per the ATA guidelines,
for ATA-HST and ATA-H categories, screening for pheochromocytoma
should begin at age 11 years. For the ATA-MOD category, pheochromocy-
toma screening should begin at age 16 years. For patients with MEN2A,
screening for hyperparathyroidism should occur at the same time as pheochro-
mocytoma screening.
PEDIATRIC THYROID CANCER 187

Table 1
Management of children with RET germline mutation identified on genetic screening
American Thyroid Association
medullary thyroid cancer risk
RET mutation category Timing of thyroidectomy
All MEN2B and M918T ATA-HST <1 y of age
C634 and A883F ATA-H 5 y of age
All others ATA-MOD When calcitonin levels become
elevated or earlier per family
preference if appropriate

SUMMARY
In summary, evidence supports that the incidence of DTCs is increasing in the
pediatric population. Therefore, on all well-child physical examinations, a care-
ful neck examination should be performed. Despite the more aggressive ten-
dency of DTCs in children, prognosis is excellent but early diagnosis could
decrease the extent of intervention required and overall recurrence rates.
MTC is rare in children and usually hereditary. Treatment centers around
removal of the thyroid gland prior to development of MTC. Care of children
with thyroid cancer should include a team of experienced pediatric surgeons
and subspecialists.
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