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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 Presentation 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 reviewed 21 worldwide studies of thyroid carcinoma and reported 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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MEN2B. Patients with MEN2A may present with pheochromocytomas 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 calcication.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 malignancy; 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 consideration 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 extensive experience.
LABORATORY ASSESSMENT
There are tests that can be used in the evaluation of
thyroid nodules. These include thyroid function tests, thyroid-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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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 patient. If distant sites are seen on the ablation lms, appropriate 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 disease. 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
r
Under 45 y of age
Stage I
Stage II
Tumor
Lymph Node
Metastasis
Any T
Any T
Any N
Any N
M0
M1
Stage IVB
Stage IVC
Tumor
Lymph Node
Metastasis
T1
T2
T3
T1
T2
T3
T4a
T4a
T1
T2
T3
T4a
T4b
Any T
N0
N0
N0
N1a
N1a
N1a
N0
N1a
N1b
N1b
N1b
N1b
Any N
Any N
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1
M0 indicates no distant metastasis; M1, distant metastasis; N1a, metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian
lymph nodes); N1b, metastasis to unilateral, bilateral, or contralateral cervical (levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal
lymph nodes (level VII); NX, regional nodes cannot be assessed; N0, no
regional lymph node involvement; T0, no evidence of primary tumor; T1a,
tumor 1 cm or less in greatest dimension, limited to thyroid; T1b, tumor
>1 cm but <2 cm in greatest dimension, limited to the thyroid; T2, tumor
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
thyroid, or any tumor with minimal extrathyroid extension; T4a, moderately
advanced disease evidenced by tumor of any size extending beyond the
thyroid capsule to invade subcutaneous soft tissues, larynx, trachea,
esophagus, or recurrent laryngeal nerve; T4b, very advanced disease evidenced by tumor invading prevertebral fascia or encases carotid artery or
mediasteinal vessels.
MANAGEMENT RECOMMENDATIONS
Management of thyroid carcinoma will be divided into
2 sections:
Management of WDTC derived from follicular epithelium (PTC and FTC).
Management of MTC.
MANAGEMENT OF WDTC
Surgery is the primary therapy for pediatric patients
with WDTC. There is continuing controversy regarding the
role of prophylactic central neck dissection.
Practice guidelines on the surgical management of
thyroid carcinoma in adults have been published by the
American Head and Neck Society, a joint taskforce from
the American Association of Endocrine Surgeons and the
American Association of Clinical Endocrinologists, and the
National Cancer Center Network.38,40 For childhood thyroid carcinoma, no such guidelines exist and there are no
prospective randomized clinical trials to guide the clinician
in the management of pediatric patients with WDTC.
Most surgeons currently perform total or near total
thyroidectomy in pediatric patients with WDTC, rather
than subtotal thyroidectomy based on available data that
has shown that total/near total thyroidectomy positively
aects disease-free survival. Jarzab et al did a retrospective
analysis on 109 patients and found that total thyroidectomy
resulted in a 97% disease-free survival at 10 years, whereas
nonradical operation was associated with 59% and 85%
risk of relapse at 5 and 10 years, respectively.41 In contrast,
Newman et al, in a multi-institutional study of 327 patients,
found that the type of thyroid surgery did not aect progression-free survival.42 However, in that study, patients
with extensive thyroid tumors, greater involvement of
cervical lymphatics, or those with distant metastases were
treated with total or subtotal thyroidectomy, hence
confounding a comparative analysis of lobectomy with total/near total thyroidectomy. Another point in favor of
total/near total thyroidectomy is the frequent occurrence of
multiple foci of papillary microcarcinoma in glands of patients with PTC. Dinauer et al found that patients with
stage 1 PTC treated with lobectomy were more likely to
have recurrence than patients treated with subtotal or total
thyroidectomy.43 A practical advantage of total/near total
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TSH Suppression
TSH suppression is considered to be standard of care
for the adult population after surgical management and
r
Other Therapy
External beam radiation does not have a clear role in
the prophylactic treatment of WDTC. Its use may be benecial 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 metastatic 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 ultrasound, 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. Although 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 recommendations published in June 2009.52
The improved understanding of MEN2 and its molecular 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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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 apparent 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 contrastenhanced MRI of the liver. If the work-up demonstrates
extensive amounts of disease, surgical goals may be modied 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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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 biochemical remission, even with extensive surgery. In the
presence of metastatic disease, palliative surgery to relieve
tracheal compression or other symptoms should be considered 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 calcitonin 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 calcitonin levels and neck imaging; they do not necessarily require repeat surgery due to the risk of hypoparathyroidism.
The risk of hypoparathyroidism is much higher if reoperation is undertaken after thyroidectomy.
After surgical control of MTC, repeat testing of calcitonin 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 metastasis. 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, bisphosphonates have been used to control symptoms.
In April of 2011 the FDA approved the rst medication 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 (prognostic 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 patients with disease conned to the thyroid gland is 95%.
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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 ultrasonogram, 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 undergo, 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 doubling 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 described 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 radiation 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 recommendations for these patients. Please see the COG LongTerm Follow-Up Guidelines for Survivors of Childhood,
Adolescent, and Young Adult Cancers for further information, 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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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 thyroid nodules, although if there is ambiguity in the results,
surgical biopsy should be considered. Treatment requires
surgeons who have experience in thyroidectomy and extensive 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.
REFERENCES
1. Bernstein L, Gurney JG. Carcinomas and other malignant
epithelial neoplasms. ICCC XI. Pediatric Monograph, NCI
SEER., 2001.
2. Waguespack S, Wells S, Ross J, et al. Thyroid Cancer, SEER
AYA Monograph.
3. Halac I, Zimmerman D. Thyroid nodules and cancers in
children. Endocrinol Metab Clin North Am. 2005;34:725744. x.
4. Rachmiel M, Charron M, Gupta A, et al. Evidence-based
review of treatment and follow up of pediatric patients with
differentiated thyroid carcinoma. J Pediatr Endocrinol Metab.
2006;19:13771393.
5. Cotterill SJ, Pearce MS, Parker L. Thyroid cancer in children
and young adults in the North of England. Is increasing
incidence related to the Chernobyl accident? Eur J Cancer.
2001;37:10201026.
6. Hung W, Sarlis NJ. Current controversies in the management
of pediatric patients with well-differentiated nonmedullary
thyroid cancer: a review. Thyroid. 2002;12:683702.
7. Skinner MA, DeBenedetti MK, Moley JF, et al. Medullary
thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg. 1996;31:177181;
discussion 181182.
8. Brauckhoff M, Gimm O, Weiss CL, et al. Multiple endocrine
neoplasia 2B syndrome due to codon 918 mutation: clinical
manifestation and course in early and late onset disease. World
J Surg. 2004;28:13051311.
9. Skinner MA. Management of hereditary thyroid cancer in
children. Surg Oncol. 2003;12:101104.
10. Feinmesser R, Lubin E, Segal K, et al. Carcinoma of the
thyroid in childrena review. J Pediatr Endocrinol Metab.
1997;10:561568.
11. Anso GE, Domene HM, Garcia R, et al. Very early detection
of RET proto-oncogene mutation is crucial for preventive
thyroidectomy in multiple endocrine neoplasia type 2 children:
presence of C-cell malignant disease in asymptomatic carriers.
Cancer. 2002;94:323330.
12. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin
Oncol. 2001;13:4451.
13. Fitze G. Management of patients with hereditary medullary
thyroid carcinoma. Eur J Pediatr Surg. 2004;14:375383.
14. Hill CS, Ibanez ML, Samaan NA, et al. Medullary (solid)
carcinoma of the thyroid gland: an analysis of the M.D.
Anderson Hospital experience with patients with the tumor, its
special features, and its histogenesis. Medicine. 1973;52:141171.
r
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50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.