SUPPLEMENT
Management of Thyroid Carcinoma in Children
and Young Adults
Louis Rapkin, MD* and Farzana D. Pashankar, MDw
Summary: Thyroid cancers represent the largest group of pediatric
carcinomas. Unlike other cancers of childhood, they have not been
prospectively studied; instead adult data has been extrapolated to
childhood and adolescent treatment. In this article we review the
treatment of both well dierentiated thyroid cancer (WDTC), as
well as medullary thyroid cancer (MTC). The approach to both
cancers relies on a low threshold of suspicion, and a willingness to
biopsy suspicious lesions. Surgery remains the primary method of
curing these patients, although radioactive iodine (RAI) may oer
some benet in WDTC for selected patients. For patients with
MTC new medications, such as Vandetanib, may oer some ad-
juvant benet following surgery. Lastly, suppression of thyroid
stimulating hormone (TSH) may be one of the most benecial
treatments for WDTC.
Key Words: papillary, follicular, medullary, thyroid, cancer, treat-
ment, guidelines
(J Pediatr Hematol Oncol 2012;34:S39S46)
T hyroid carcinomas are uncommon tumors in pediatric
patients. They comprise approximately 3% of all newly
diagnosed childhood carcinomas in the United States as
determined by the SEER database.1 The incidence of thy-
roid cancer increases rapidly between 15 and 29 years of
age, and reaches a plateau by the fth to sixth decades. In
the United States from 1975 to 2000, thyroid cancer ac-
counted for about 10% of all malignancies diagnosed in
individuals 15 to 29 years of age and was the fourth most
common cancer in this age group. Nearly 2400 individuals,
15 to 29 years of age were diagnosed with a malignant
thyroid neoplasm in the United States during the year
2000.2
Thyroid carcinomas can be classied according to the
cell of origin. Tumors derived from the thyroid follicle are
well-dierentiated thyroid carcinomas (WDTC) and in-
clude papillary thyroid carcinomas (PTC) and follicular
thyroid carcinomas (FTC). In general, PTC represents
about 80% and FTC accounts for approximately 20% of
the dierentiated thyroid carcinomas. PTCs are further
subdivided into several variants, such as the follicular var-
iant of PTC, the most frequent subtype in children. Rarer
subtypes of PTC include tall cell variant, diuse scleros-
ing type, and columnar type. Subtypes of FTCs include
Hurthle cell, clear cell, and insular carcinoma.3 Ionizing
Received for publication January 23, 2012; accepted February 1, 2012.
From the *Aac Cancer Center and Blood Disorders Service, Emory
University School of Medicine, Atlanta, GA; and wYale University
School of Medicine, New Haven, CT.
The authors declare no conict of interest.
Reprints: Louis Rapkin, MD, Childrens Healthcare of Atlanta
Egleston, Hematology/Oncology, 5455 Meridian Mark Rd. Suite
510 Atlanta, GA 30342 (e-mail: louis.rapkin@choa.org).
Copyright r 2012 by Lippincott Williams & Wilkins
J Pediatr Hematol Oncol  Volume 34, Supplement 2, May 2012
radiation remains the major risk factor for developing PTC.
Exposure to external beam radiation and internal radiation
as delivered by ingestion of radioiodine can be risk factors
for development of PTC.4,5 PTCs and FTCs are distinct
clinical entities. PTCs are often multicentric and dissem-
inate primarily through the lymphatic system, whereas
FTCs are sporadic, usually encapsulated, and metastasize
through the blood stream. They have a good prognosis with
a survival rate of >95%.6
Medullary thyroid carcinomas (MTC) are derived from
calcitonin-producing cells and account for 5% to 10% of
thyroid carcinomas. They are usually familial and are a
component of 2 genetic syndromes: Multiple Endocrine
Neoplasia (MEN)2A and MEN2B.710 The uncontrolled
cell growth seen in MTC associated with these syndromes is
due to germline mutations in the ret-oncogene (tyrosinase-
kinase receptor) on chromosome10q11.2. Over 97% of
MEN2A have ret-oncogene mutations, and 95% of patients
with MEN2B have a mutation at codon 918.1113 The bio-
logic behavior of MTC is more aggressive than PTC or FTC
and patients with MTC do not fare as well as those with
WDTC. Between 1975 and 2000, 5-year survival rates for
MTC were still good overall, ranging between 85% and
95% among patients 10 to 44 years of age.1,2
Anaplastic/undierentiated carcinomas are rare in
childhood.14
CLINICAL PRESENTATION
The peak age of onset for WDTC is between 15 and 19
years.15 The most common presenting complaint in children
is painless or tender thyroid mass with or without painless
cervical lymphadenopathy.16,17 Patients are predominantly
euthyroid, with hyperthyroidism occurring rarely.1620 Pre-
sentation of a rm, brous, or hard thyroid nodule, should
be considered as highly likely to be thyroid carcinoma.21
The most common sites of metastases of PTC beyond
the neck are the lungs; lung metastases being more frequent
in children than in adults.
Zimmerman et al22 compared 58 children and 981
adults treated for PTC at their institution. They found that
childhood PTC was more often metastatic to lymph nodes
and lungs at presentation, and more often recurrent in neck
lymph nodes postoperatively. Thompson and Hay19 re-
viewed 21 worldwide studies of thyroid carcinoma and re-
ported on nearly 1800 patients. The authors found that
regional nodal metastases were common (range, 27% to
100%; median, 60%). Local invasion was noted in 6% to
71% of cases (median, 30%) and distant metastases were
present in 6% to 28%. Tumor recurrence, both locally and
at distant sites, was more common in the pediatric group
(range, 0% to 58%; median, 30%).
Children with MTC may present with clinical features
associated with the hereditary syndromes MEN2A,
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Rapkin and Pashankar
MEN2B. Patients with MEN2A may present with pheo-
chromocytomas in 50% of cases, and hyperparathyroidism
in one third of cases; those patients without any other
manifestations of MEN2A are sometimes referred to as
familial MTC in the literature, but this is a dicult clinical
distinction to make at a young age. Patients with MEN2B
tend to have more aggressive clinical progression, often with
metastasis developing in early childhood. Patients with
MEN2B may have other associated signs and symptoms
dating back to infancy and including marfanoid habitus and
mucosal neuromas of the tongue and lips.6,2325 Twenty-ve
percent of the MTC in the United States is associated with 1
of the 3 familial syndromes listed above; however, in the
pediatric population that percentage is assumed to be much
higher, although not documented. Of those patients with
palpable disease in their thyroid, 75% will already have
cervical lymph node metastasis.26 MTC has a predilection
for mediastinal lymph nodes, liver, bone, and lung tissue.
Liver metastases are very dicult to detect with routine
imaging, even with magnetic resonance imaging (MRI).
DIAGNOSIS
In general, patients with suspected thyroid cancer, a
thyroid nodule, or persistent cervical lymphadenopathy
should undergo ultrasonography of the neck, followed by
ne needle aspiration (FNA). Ultrasonography is extremely
useful to detect enlarged cervical lymph nodes, especially in
the lateral compartment of the neck, and can help in
planning the extent of lymph node dissection. Findings on
ultrasound that are suggestive of malignancy include shape,
echogenicity, microcalcications, margin, and calcica-
tion.27 Although nodules that are largely cystic have a
lower risk of malignancy, nodules that are completely cystic
by ultrasound (US) still have up to a 3% chance of ma-
lignancy; therefore, FNA is recommended.
FNA is the most accurate test at diagnosing thyroid
carcinoma preoperatively. A recent meta-analysis in the
pediatric population supports the use of FNA in ruling out
malignant lesions.28 However, its positive predictive power
was only 53%; therefore, if any ambiguity exists after the
FNA, surgical biopsy should be strongly considered. The
eectiveness of FNA is improved when the physician doing
the biopsy has more experience; this should be a consid-
eration at each pediatric institution since the volume of
cases are signicantly less than at adult hospitals. Although
dierent rates have been obtained, up to 20% to 25% of
thyroid nodules in children may be malignant, which is a
higher rate than adults, and can aect test reliability.29,30
False-negative rates may impact the pediatric population
more than the adult population, especially if the person
performing and evaluating the FNA does not have ex-
tensive experience.
LABORATORY ASSESSMENT
There are tests that can be used in the evaluation of
thyroid nodules. These include thyroid function tests, thy-
roid-associated autoantibodies, and iodine 123 scanning.
However, these tests are rarely denitive in the diagnosis of
WDTC or MTC, although they are useful in diagnosing other
benign thyroid conditions. Hyperfunctioning nodules rarely
harbor malignancy.29
For WDTC, serum levels of thyroglobulin (Tg) are not
a valuable screening test for dierentiated thyroid cancer as
they may be elevated in various benign thyroid disorders.
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J Pediatr Hematol Oncol  Volume 34, Supplement 2, May 2012
However, Tg is a prognostic tumor marker in the follow-up
of patients after total thyroidectomy and iodine ablation
for FTC/PTC, and should be followed up.
Specic laboratory testing is important and diagnostic
for MTC, both at diagnosis and long-term follow-up. If the
calcitonin level is elevated in a patient with known MEN2
mutation, a full evaluation for detectible MTC should
be done before initial surgery.26,31 If the calcitonin is
<100 pg/mL, the average size of the primary thyroid nod-
ule, if present, is 3 mm with 98% <1 cm; it is unlikely to
have clinically apparent disease in cervical lymph
nodes. However, lymph node metastasis has been noted in
patients with calcitonin levels as low as 10 pg/mL. Distant
metastasis has been noted in patients with calcitonin levels
as low as 150 pg/mL. Ball26 reports that patients with cal-
citonin levels >3000 pg/mL and positive lymph nodes
rarely achieve a chemical remission.26 More recently Ma-
chens and colleagues reported 50% of patients with calci-
tonin between 100 and 10,000 were able to achieve
biochemical remission.32 Calcium levels should be assessed
if calcitonin level is elevated.
Carcinoembryonic antigen (CEA) also has clear asso-
ciations with MTC disease status.33 If CEA is >50 ng/mL,
patients are rarely cured with surgery. Seventy percent of
these patients were found to have cervical lymph node in-
volvement at the time of initial surgery. Higher levels cor-
related with higher rates of cervical node involvement and
distant metastasis.26
Germline mutation testing for RET mutation is
standard of care for any patient with MTC. Up to 7% of
apparently sporadic MTC will harbor a germline muta-
tion.26,34,35 These patients will then be characterized as
having a MEN syndrome based on the mutation. Testing
for pheochromocytoma should also be done in all MTC
patients before surgery.
METASTATIC EVALUATION
Assessment of distant disease is dierent for WDTC
and MTC. In WDTC, thyroid ablation, which treats
WDTC throughout the body, is also used to stage the pa-
tient. If distant sites are seen on the ablation lms, appro-
priate imaging of those areas should be performed. Up to
25% of pediatric patients have metastatic disease at the
time of presentation.36
For MTC, computed tomography (CT)/MRI of neck/
chest/abdomen may be obtained to exclude metastatic dis-
ease. Metastases are strongly associated with calcitonin
levels >5000 pg/mL, but as previously stated, may occur at
levels as low as 150 pg/mL.28 If postoperative calcitonin
levels are <150 pg/mL, then postoperative neck US may be
the only imaging required. If >150 pg/mL, imaging of the
neck chest and abdomen should be done. There are no
specic recommendations about which imaging technique,
CT, MRI or PET, should be used.
STAGING
Use of a staging scoring system is benecial for
treatment planning. The American Joint Commission on
Cancer (AJCC) and some international organizations have
agreed on a staging system on the basis of the 1997 TNM
system.37 Whereas all TNM classications are based solely
on anatomic extent, the TNM system for dierentiated
thyroid cancer incorporates age because of its strong
prognostic value (Tables 1 and 2). The TNM system for
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scoring system has been validated at the Mayo Clinic in

TABLE 1. American Joint Commission on Cancer (2010) Staging more than 2500 patients using the following multivariate
System for WDTC
formula:
Tumor Lymph Node Metastasis
3.1 (for age r39 y) or 0.08 age in years (for age
Under 45 y of age
Stage I Any T Any N M0
>40 y) + 0.3 tumor size in centimeters + 1 for
Stage II Any T Any N M1 incomplete resection + 1 for local invasion + 3 for
distant metastases
M0 indicates no distant metastasis; M1, distant metastasis. Patients with a score <6 are considered low risk,
whereas those with a score Z6 are deemed high risk.
In a report from the Mayo Clinic between the year 1940
WDTC is imperfect particularly in children, where the risk and 2000, of the 2512 patients with WDTC, 2099 patients
of recurrence is high and treatments for a T1-3N0M0 lesion (83.6%) had a score <6; 215 patients (8.6%) with a score from
may be quite dierent from that for a T4N0M0 or T1-3N1M0 6 to <7; 84 patients (3.3%) with a score from 7 to <8; and
lesion. In addition, only distant metastasis raises a patient 114 patients (4.5%) had a score Z8. The 25-year survival rate
from stage 1 to stage 2 disease in patients with WDTC was reported as 99.1% for low-risk patients and 65.4% for
under the age of 45 years.38 high-risk patients. The 40-year survival rate was 97.7% for
For WDTC, primarily PTC, several other scoring low-risk patients and 63.0% for high-risk patients.39
systems have been derived in the past 2 decades based on Staging for MTC follows the AJCC recommendations
multivariate analysis of prognostic factors. These include as listed in Table 2.
AMES (age of patient, presence of distant metastases, and
extent and size of primary cancer), AGES (patient age and MANAGEMENT RECOMMENDATIONS
tumor grade, extent, and size), EORTC (European Management of thyroid carcinoma will be divided into
Organization for Research and Treatment of Cancer) or 2 sections:
MACIS (metastatic lesions, patient age, completeness of  Management of WDTC derived from follicular epithe-
resection, invasion, and size of tumor). These systems fa- lium (PTC and FTC).
cilitate classication of patients with dierentiated thyroid  Management of MTC.
cancer into low, intermediate, or high risk of cause specic
mortality. Prognostic scoring systems are especially useful
in planning treatment for children, most of whom have MANAGEMENT OF WDTC
AJCC stage 1 disease. Thompson and Hay19 have reviewed Surgery is the primary therapy for pediatric patients
available staging systems and noted that the MACIS with WDTC. There is continuing controversy regarding the
role of prophylactic central neck dissection.
Practice guidelines on the surgical management of
TABLE 2. American Joint Commission on Cancer Staging System thyroid carcinoma in adults have been published by the
for MTC American Head and Neck Society, a joint taskforce from
the American Association of Endocrine Surgeons and the
Tumor Lymph Node Metastasis
American Association of Clinical Endocrinologists, and the
Stage I T1 N0 M0 National Cancer Center Network.38,40 For childhood thy-
Stage II T2 N0 M0 roid carcinoma, no such guidelines exist and there are no
T3 N0 M0 prospective randomized clinical trials to guide the clinician
Stage III T1 N1a M0 in the management of pediatric patients with WDTC.
T2 N1a M0
T3 N1a M0
Most surgeons currently perform total or near total
Stage IVA T4a N0 M0 thyroidectomy in pediatric patients with WDTC, rather
T4a N1a M0 than subtotal thyroidectomy based on available data that
T1 N1b M0 has shown that total/near total thyroidectomy positively
T2 N1b M0 aects disease-free survival. Jarzab et al did a retrospective
T3 N1b M0 analysis on 109 patients and found that total thyroidectomy
T4a N1b M0 resulted in a 97% disease-free survival at 10 years, whereas
Stage IVB T4b Any N M0 nonradical operation was associated with 59% and 85%
Stage IVC Any T Any N M1 risk of relapse at 5 and 10 years, respectively.41 In contrast,
M0 indicates no distant metastasis; M1, distant metastasis; N1a, meta- Newman et al, in a multi-institutional study of 327 patients,
stasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian found that the type of thyroid surgery did not aect pro-
lymph nodes); N1b, metastasis to unilateral, bilateral, or contralateral cer- gression-free survival.42 However, in that study, patients
vical (levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal
lymph nodes (level VII); NX, regional nodes cannot be assessed; N0, no
with extensive thyroid tumors, greater involvement of
regional lymph node involvement; T0, no evidence of primary tumor; T1a, cervical lymphatics, or those with distant metastases were
tumor 1 cm or less in greatest dimension, limited to thyroid; T1b, tumor treated with total or subtotal thyroidectomy, hence
>1 cm but <2 cm in greatest dimension, limited to the thyroid; T2, tumor confounding a comparative analysis of lobectomy with to-
more than 2 cm but not more than 4 cm in greatest dimension, limited to the
thyroid; T3, tumor more than 4 cm in greatest dimension, limited to the
tal/near total thyroidectomy. Another point in favor of
thyroid, or any tumor with minimal extrathyroid extension; T4a, moderately total/near total thyroidectomy is the frequent occurrence of
advanced disease evidenced by tumor of any size extending beyond the multiple foci of papillary microcarcinoma in glands of pa-
thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, tients with PTC. Dinauer et al found that patients with
esophagus, or recurrent laryngeal nerve; T4b, very advanced disease evi-
denced by tumor invading prevertebral fascia or encases carotid artery or
stage 1 PTC treated with lobectomy were more likely to
mediasteinal vessels. have recurrence than patients treated with subtotal or total
thyroidectomy.43 A practical advantage of total/near total

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Rapkin and Pashankar
thyroidectomy is that these types of resections will facilitate
radioiodine treatment and imaging. After total thyroi-
dectomy, serum Tg can be used as a tumor marker for
recurrent/residual disease.
Complications of total thyroidectomy include injury to
the recurrent laryngeal nerve and hypoparathyroidism.
Therefore, surgery must be performed by an experienced
endocrine or pediatric surgeon.
Lymph Node Dissection
Thompson and Hay summarized 21 studies on child-
hood WDTC and found 30% locally invasive tumor, as well
as 60% regional lymph node metastases.19 As a result of
these ndings, central neck dissection has been recom-
mended for children with WDTC, recognizing that central
compartment dissection is not uniformly required in a pa-
tient with PTC. Current adult guidelines state that for clin-
ically involved nodes in the central compartment, a lymph
node dissection should be performed. If the thyroid nodule is
large (T3), or extends locally beyond the thyroid (T4 tu-
mors), central compartment dissection may be used even if
the central compartment lymph nodes are not clinically in-
volved. For smaller tumors in the adult population, central
compartment dissection may be avoided.29 There is no clear
guideline for pediatric patients, as long-term survival data
are lacking. Potential harms of the central compartment
dissection should also be considered. The risk of injury to the
recurrent laryngeal nerve is increased with central compart-
ment dissection, especially if the surgeon is not experienced.
Injury to both recurrent laryngeal nerves is rare, but serious,
with most patients requiring at least temporary trache-
ostomy, and further corrective surgery at a later time.
Modied neck dissection should be performed for
clinically apparent and biopsy-proven lateral neck disease.
We do not recommend prophylactic lateral neck dissections
in children without clinically apparent disease.
Thyroid Remnant Ablation and Radioiodine
Despite total thyroidectomy, uptake of radioiodine by
residual thyroid tissue can usually be demonstrated post-
operatively. Hence, radioactive iodine ablation (RIA) of
thyroid remnant with radioiodine has been frequently rec-
ommended for pediatric thyroid cancer in the literature,
especially PTC. Many reasons are cited for this recom-
mendation, including larger primary tumors in pediatric
patients, and higher rate of cervical and metastatic disease
in pediatric patients.44 In addition, it is felt that WDTC in
pediatrics is more iodine avid, even at metastatic sites. It is
clearly acknowledged, however, there is a paucity of pro-
spective data in the pediatric population to support the
expert consensus that supports the use of RIA.
There are several purposes of the RIA treatment. The
rst is to treat residual disease, such as metastatic or un-
resectable lesions. Related to this, is the treatment of re-
sidual, microscopic disease that is assumed to be present
but is not clinically apparent, to prevent relapse. The sec-
ond purpose is to accurately stage the patient with whole
body 131I scanning, which occurs within 10 days of the
RIA. This imaging is used to detect distant sites of disease
in otherwise asymptomatic patients. The nal reason for
the RIA is the ablation of normal thyroid tissue in the neck
after surgery (generally referred to as thyroid remnant
ablation in the literature), which facilitates the use of Tg as
a tumor marker to evaluate later recurrence.
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Which patients benet from RIA is not well dened.
The trend in the medical literature is to use ablation more
frequently in children than adults due to the aggressiveness
of the disease, and due to the longer life span of children.44
Still, a recent retrospective review of 215 patients younger
than 21 treated at the Mayo clinic between 1940 and 2008
showed only 2 thyroid-related deaths in 40 years median
follow-up. This particular series had a nodal metastasis rate
of 78% and a distant metastasis rate of only 6%. Fifteen
patients died of nonthyroid malignancy later in life, and of
those diagnosed 73% received RIA.45 Although this is a
long-term single institution retrospective review, it raises
the question of how aggressively should pediatric patients
be treated. Still, there are other retrospective series in pe-
diatrics that do not show such favorable results.44 Current
adult recommendations are that primary tumors >4 cm,
those with extrathyroid invasion, those with lymph node
metastasis and those with distant metastasis should receive
131
I ablation. Those patients with primary tumors <1 cm,
and without clinical evidence of locoregional or distant
spread, may have the ablation held, recognizing that sub-
sequent Tg levels may not be useful for determining relapse
due to thyroid remnant. For those patients with primary
tumors between 2 and 4 cm, and no evidence of locore-
gional or distant spread, ablation should be used on an
individual basis.29
There is no specic recommendation for the timing of
RIA after total thyroidectomy. Thyroid-stimulating hor-
mone (TSH) will rise rapidly once thyroidectomy is per-
formed.46 Therefore, ablations can generally be done within
3 weeks of surgery, once the TSH level is >30 mcU/mL.
TSH level should be veried before ablation. Many physi-
cians delay ablation for 4 to 6 weeks from the time of
surgery with 1 to 3 weeks of hormone replacement, either as
levothyroxine (synthetic T4) or liothyronine (synthetic T3).
In addition, recombinant human TSH (Thyrogen) is now
FDA approved in adults to raise serum TSH levels after 2
injections. This is not FDA approved in children, although
its use is reported.47 There is no evidence to support that
immediate withdrawal after surgery, later withdrawal, or
recombinant TSH stimulation is superior in practice; TSH
must be >30 at the time of the ablation, regardless of the
timing. Note that if a patient has had iodine-containing
contrast or recent iodine scanning, this may saturate the
thyroid gland and prevent optimal uptake of 131I. There-
fore, at our institutions, we hold RIA therapy until 3
months after the last iodine administration.
Dosing of 131I is unclear for both the adult and pe-
diatric population. The adult literature supports doses of 30
to 100 mCi for thyroid remnant ablation, without known
metastasis. For patients with distant disease the RIA dose is
increased to 100 to 200 mCi.29 A general guideline for
dosing is as follows: microscopic metastases in the neck or
chest are treated with therapeutic doses of 131I at higher
doses (100 to 200 mCi); isolated soft-tissue metastases are
treated with 150 mCi; multiple or diuse pulmonary meta-
stases with 175 to 200 mCi; and bone metastases with
200 mCi. There are 2 papers that review pediatric dosing for
RIA.46,48 Both recommend specic dosing for surface area
or weight, respectively, and should be reviewed by any
center performing RIA.
TSH Suppression
TSH suppression is considered to be standard of care
for the adult population after surgical management and
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J Pediatr Hematol Oncol  Volume 34, Supplement 2, May 2012
RIA. Its use has been shown to reduce time to recurrence
and has improved overall survival in large adult studies.49
The evidence in pediatrics is lacking, with only 1 small
series showing benet in relapse-free survival over an 80-
year time frame.50 Nevertheless, current recommendations
are to suppress TSH in children with higher risk disease.
For those patients who presented with cervical and meta-
static disease, or who have known residual disease, we
suppress till TSH is <0.1 mU/L. For patients with low-risk
disease, we suppress to below normal limits of normal.
Adult recommendations state that suppression should be
maintained for 5 to 10 years.29 There is no standard in the
pediatric population at this time.
TSH should be checked 3 to 4 times a year in children,
due to their growth and increasing levothyroxine needs.
Long-term complications of hyperthyroidism are well
described in the adult literature and include osteoporosis,
heart failure, heart arrhythmia, and cardiac ischemia, con-
ditions which are not prevalent in children. In the pediatric
population, the short-term eects of hyperthyroidism are
well described, but long-term consequences are unknown.51
We follow echocardiograms and Dexa scans every 2 years
in these patients, and ensure that calcium and vitamin D
levels are appropriate for age.
Other Therapy
External beam radiation does not have a clear role in
the prophylactic treatment of WDTC. Its use may be ben-
ecial in patients with locally advanced disease in the neck,
or at other nonpulmonary sites of disease, as a palliative
measure.
Chemotherapy to date is not useful in WDTC, and
does not have a place in the initial therapy of WDTC.
Newer agents are being evaluated for patients with meta-
static or recurrent disease, but are beyond the scope of this
discussion.
Follow-up
After RIA, children are usually assessed every 12
months including whole-body scan, Tg level, neck ultra-
sound, and chest x-ray. After treatment with surgery and
131
I, hormone replacement therapy is needed to suppress
thyrotropin production, a compensatory mechanism for the
lost thyroid hormone. The goal of treatment is to achieve a
negative whole-body scan, negative neck ultrasonogram,
and a hormone withdrawal Tg level <5 to 10 ng/mL.19
MANAGEMENT OF MTC
MTC, as a sporadic cancer, is rare in childhood. Al-
though there is little published data in pediatrics, the
prognosis and treatment seem to be closely related to the
adult standards, which should be the standard of care.
These standards are explored in this document, and are
compatible with the American Thyroid Association rec-
ommendations published in June 2009.52
The improved understanding of MEN2 and its mo-
lecular basis, has led to the prophylactic treatment of MTC
developing into a pediatric specialty. Mostly controlled by
pediatric surgeons, prophylactic total thyroidectomy is the
standard of care.
This section will review prophylactic treatment of
MEN syndromes and the recommended timing of surgery
and the management of MTC.
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Management of Thyroid Carcinoma
Prophylactic Treatment of MTC
in MEN syndromes
In the adult population, MTC most often presents
sporadically; however, about 20% of cases are hereditary.
Cases in the pediatric population are considered inherited
until proven otherwise. It is extremely important that pa-
tients with MEN2 syndromes and their family members
receive genetic counseling and screening. MTC occurs in
about 95% of patients with MEN2A and in 100% of pa-
tients with MEN2B.53 Patients with the hereditary form
of MTC can develop metastases before 5 years of age.54
Once the disease has metastasized, it is resistant to both
chemotherapy and radiation therapy and is rarely treated
successfully.55
Sippel et al have presented risk groups for develop-
ment of MTC and recommended age for prophylactic
surgery utilizing RET mutation codon information.53 The
groups with the highest risk level for development of MTC
include patients with RET mutation codons 883 and 918.
Patients in this group should undergo prophylactic surgery
within 1 month of birth and by 6 months of age at the
latest. Patients who are recommended to have prophylactic
surgery by 5 years of age include those with RET mutations
611, 618, 620, and 634. Patients with RET mutation codons
609, 630, 768, 790, 791, 804, and 891 should be treated with
prophylactic surgery by 10 years of age. A more thorough
list of mutations and their recommended age of resection is
included in the ATA guidelines referenced above.52
Before surgery, patients should undergo calcitonin
testing and a cervical ultrasound by an experienced oper-
ator. If evidence of disease is found in the thyroid or neck,
FNA should be done to conrm whether the lesion is ma-
lignant. If MTC is established, either by imaging or ele-
vated tumor markers, then the treatment recommendations
for active disease (below) should be followed.
Patients should undergo a new baseline assessment for
calcitonin and CEA 2 to 3 months after surgery and then
have annual reassessments. Thyroid hormone replacement
therapy is also needed along with annual screening for
pheochromocytoma and hyperparathyroidism depending
on the RET mutation.53
Treatment of MTC
If a diagnosis of MTC is suspected after FNA, serum
calcitonin level and cervical ultrasound should be obtained
to help guide surgical management. If calcitonin levels are
<400 pg/mL, and metastasis to cervical lymph nodes is not
appreciated, then the surgical intent should be for cure. If
calcitonin level is >400 pg/mL, or if there is clinically ap-
parent disease on neck US, full-staging studies should be
obtained as they may alter the intent of surgery. Scans
should include CT of the neck and lung, as well as contrast-
enhanced MRI of the liver. If the work-up demonstrates
extensive amounts of disease, surgical goals may be modi-
ed on a patient by patient basis.
Curative surgical management should include total
thyroidectomy and central compartment dissection (level VI
nodes). There is no disagreement on this point.26,34,35,56 The
need for ipsilateral neck dissection is debated, as is dissection
of mediastinal nodes. A more recent review of published
data indicates ipsilateral neck dissection may not serve a
purpose if both physical exam and presurgical imaging are
negative for both lateral neck and distant metastatic disease.
Lateral neck dissection may be considered if the paratracheal
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Rapkin and Pashankar
nodes (level VI) are positive at the time of initial surgery, but
this is debated.52
When there is extensive disease seen on cervical US,
and negative metastatic work-up, then total thyroidectomy
with level VI nodal dissection, and lateral neck dissection is
warranted. Patients with demonstrable disease in the lateral
neck, or in level VII (mediastinal lymph nodes) rarely
achieve normal levels of calcitonin, referred to as a bio-
chemical remission, even with extensive surgery. In the
presence of metastatic disease, palliative surgery to relieve
tracheal compression or other symptoms should be con-
sidered rather than surgery with a curative intent.
There are some patients diagnosed with MTC whose
initial operation is a thyroidectomy only, as the disease was
not recognized before surgery. If the subsequent imaging is
negative for nodal and metastatic disease, and serum cal-
citonin levels are low, serial calcitonin levels may be used to
assess recurrence. Patients with post operative calcitonin
levels below 100 pg/mL may be followed with serial calci-
tonin levels and neck imaging; they do not necessarily re-
quire repeat surgery due to the risk of hypoparathyroidism.
The risk of hypoparathyroidism is much higher if reoper-
ation is undertaken after thyroidectomy.
After surgical control of MTC, repeat testing of cal-
citonin and CEA should be done in 3 to 6 months, with
further evaluation and imaging based on these levels. While
hormone replacement therapy should be undertaken, there
is no role for TSH suppression in MTC.
Radiation may be used in the setting of measurable
disease to control symptoms. There is no strong data to
suggest that radiation improves long-term survival when
used in high-risk patients without visible disease. Specic
retrospective reviews may show some benet.57 Radiation
may be most useful in the setting of bone or CNS meta-
stasis. There is no role for the use of RIA in MTC.
Chemotherapy is not considered eective in this
cancer. Phase II studies show a 15% to 28% response rate
with specic chemotherapies.26,34 No complete response has
ever been documented in the literature and chemotherapy
has never altered overall survival. For bony lesions, bi-
sphosphonates have been used to control symptoms.
In April of 2011 the FDA approved the rst medi-
cation for use in the treatment of metastatic or locally
advanced MTC. Vandetanib, a RET kinase inhibitor, has
been shown to lengthen progression free survival in a
double blind randomized trial.58 While overall aects on
survival have not yet been determined, Vandetanib marks
the rst time adjuvant therapy has been used successfully
in a population of patients with MTC. In addition to the
RET kinase, Vandetanib also inhibits the epidermal growth
factor receptor (EGF-R) and the vascular endothelial
growth factor receptor (VEGF-R). Currently the NIH is
evaluating the use of Vandetanib in children with MTC.
Diarrhea, rash, headache, hypertension, and nausea were
the primary side eects noted in the adult study.
Patients can be asymptomatic with a large extent of
disease for many years. For those patients with metastatic
or recurrent disease novel agents and experimental therapy
should be considered, but is beyond the scope of these
recommendations.59 Prognosis of MTC has been most
closely related to extent of disease at presentation (prog-
nostic out to 20 y after diagnosis), and if curable, extent of
rst surgery.23,24,43 There is little prospective data to guide
these numbers. Ten-year survival rates for those adult pa-
tients with disease conned to the thyroid gland is 95%.
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J Pediatr Hematol Oncol  Volume 34, Supplement 2, May 2012
Regional disease shows a 10-year survival of 75% and
metastatic disease has a 10-year survival rate of 40%. There
have been no improvements in long-term survival over the
past 30 years.
FOLLOW-UP RECOMMENDATIONS
WDTC
Life-long follow-up of patients with thyroid carcinoma
is extremely important as tumor recurrence, even years to
decades later, is not uncommon.60 After patients have
achieved a negative whole-body scan, negative neck ultra-
sonogram, and a hormone withdrawal Tg level <5 to
10 ng/mL, yearly follow-up should commence. After 2 years
with no evidence of disease, it is advised that patients un-
dergo, at a minimum, physical examination, and Tg levels
every 3 to 5 years.19
Follow-up is recommended to take place at specialized
centers with pediatricians, endocrinologists, and surgeons
experienced in the care of pediatric thyroid carcinoma.
Follow-up assessment should include physical examination,
serum TSH, neck ultrasonography, Tg level, and chest
radiograph. Increasing Tg levels should be further assessed
with whole-body scanning.19
MTC
Follow-up of calcitonin levels is the foundation of
monitoring. Four calcitonin checks over 2 to 3 years will
predict the calcitonin doubling time. If the doubling time is
<6 months, then the 5-year mortality is 75%. If the dou-
bling time is >2 years, there is little to no mortality.27
Rarely, MTC can lose the ability to secrete calcitonin.61
Calcitonin levels may also vary widely over time within the
same individual, a phenomenon that has been well de-
scribed but not explained. It is important to follow these
levels over time with the identical assay.
CEA levels also have a predictive role after surgery.
CEA doubling time (over the same 2 to 3-y period) has
similar prognostic value as the calcitonin level.26 This level
may be elevated at baseline in certain patient populations
(eg, current smokers). The rst level should be obtained 6
weeks to 4 months after surgery; persistently elevated levels
indicate residual disease.
There is no standard for imaging in these patients;
therefore choice of imaging should be determined for each
patient, based on disease location.
SCREENING/PREVENTION RECOMMENDATIONS
For WDTC, history of previous head and neck radi-
ation exposure was common in the past, but has become
quite rare. However, patients that present with a history of
radiation exposure including radiation therapy, such as
patients with Hodgkin lymphoma or previous bone marrow
transplant, are at increased risk for development of thyroid
carcinoma and should be followed up carefully. It has
been advised in the literature that these patients be assessed
with ultrasound every 6 to 12 months.32,62 The Childrens
Oncology Group has also established follow-up recom-
mendations for these patients. Please see the COG Long-
Term Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers for further in-
formation, especially the document titled Thyroid Problems
after Childhood Cancer (access at: http://www.children
soncologygroup.org/disc/LE/pdf/ThyroidProblems.pdf).
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J Pediatr Hematol Oncol  Volume 34, Supplement 2, May 2012
In addition, it is advised that all patients presenting
with new onset of hoarseness or dysphagia undergo lar-
yngoscopy. FNA biopsy is recommended for all children
presenting with persistent lymphadenopathy.19
The importance of genetic screening in regard to MTC
has been presented above.
CONCLUSIONS
Both WDTC and MTC are relatively uncommon in
childhood, although they occur more frequently than any
other tumor mentioned in the rare tumor guidelines. FNA
remains the primary method of classifying suspicious thy-
roid nodules, although if there is ambiguity in the results,
surgical biopsy should be considered. Treatment requires
surgeons who have experience in thyroidectomy and ex-
tensive neck surgeries. RIA improves outcome for high-risk
WDTC.
Even when MTC and WDTC are metastatic, patients
may survive decades before succumbing to their disease.
Therefore, these patients will require long-term follow-up
with specialists well versed in the treatment of these diseases.
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