For WDTC, primarily PTC, several other scoring systems have been derived in the past 2 decades based on multivariate analysis of prognostic factors. These include AMES (age of patient, presence of distant metastases, and extent and size of primary cancer), AGES (patient age and tumor grade, extent, and size), EORTC (European Organization for Research and Treatment of Cancer) or MACIS (metastatic lesions, patient age, completeness of resection, invasion, and size of tumor). These systems facilitate classification of patients with differentiated thyroid cancer into low, intermediate, or high risk of cause specific mortality. Prognostic scoring systems are especially useful in planning treatment for children, most of whom have AJCC stage 1 disease. Thompson and Hay19 have reviewed available staging systems and noted that the MACIS scoring system has been validated at the Mayo Clinic in more than 2500 patients using the following multivariate formula:
3.1 (for age ≤39 y) or 0.08×age in years (for age >40 y)+0.3×tumor size in centimeters+1 for incomplete resection+1 for local invasion+3 for distant metastases
Patients with a score <6 are considered low risk, whereas those with a score ≥6 are deemed high risk.
In a report from the Mayo Clinic between the year 1940 and 2000, of the 2512 patients with WDTC, 2099 patients (83.6%) had a score <6; 215 patients (8.6%) with a score from 6 to <7; 84 patients (3.3%) with a score from 7 to <8; and 114 patients (4.5%) had a score ≥8. The 25-year survival rate was reported as 99.1% for low-risk patients and 65.4% for high-risk patients. The 40-year survival rate was 97.7% for low-risk patients and 63.0% for high-risk patients.39
Staging for MTC follows the AJCC recommendations as listed in Table 2.
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 affects 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 affect 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 thyroidectomy is that these types of resections will facilitate radioiodine treatment and imaging. After total thyroidectomy, 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 childhood WDTC and found 30% locally invasive tumor, as well as 60% regional lymph node metastases.19 As a result of these findings, central neck dissection has been recommended for children with WDTC, recognizing that central compartment dissection is not uniformly required in a patient with PTC. Current adult guidelines state that for clinically 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 tumors), central compartment dissection may be used even if the central compartment lymph nodes are not clinically involved. 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 compartment 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 tracheostomy, and further corrective surgery at a later time.
Modified 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 postoperatively. Hence, radioactive iodine ablation (RIA) of thyroid remnant with radioiodine has been frequently recommended for pediatric thyroid cancer in the literature, especially PTC. Many reasons are cited for this recommendation, 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 prospective 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 first is to treat residual disease, such as metastatic or unresectable lesions. Related to this, is the treatment of residual, microscopic disease that is assumed to be present but is not clinically apparent, to prevent relapse. The second 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 final 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.
Which patients benefit from RIA is not well defined. 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 pediatrics 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 131I ablation. Those patients with primary tumors <1 cm, and without clinical evidence of locoregional or distant spread, may have the ablation held, recognizing that subsequent 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 locoregional or distant spread, ablation should be used on an individual basis.29
There is no specific recommendation for the timing of RIA after total thyroidectomy. Thyroid-stimulating hormone (TSH) will rise rapidly once thyroidectomy is performed.46 Therefore, ablations can generally be done within 3 weeks of surgery, once the TSH level is >30 mcU/mL. TSH level should be verified before ablation. Many physicians 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. Therefore, 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 pediatric 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 diffuse pulmonary metastases 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 specific dosing for surface area or weight, respectively, and should be reviewed by any center performing RIA.
TSH suppression is considered to be standard of care for the adult population after surgical management and 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 benefit 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 metastatic 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, conditions which are not prevalent in children. In the pediatric population, the short-term effects 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.
External beam radiation does not have a clear role in the prophylactic treatment of WDTC. Its use may be beneficial 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.
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 131I, 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.
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 patients 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 patients 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 development 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 operator. If evidence of disease is found in the thyroid or neck, FNA should be done to confirm whether the lesion is malignant. If MTC is established, either by imaging or elevated 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 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 contrast-enhanced MRI of the liver. If the work-up demonstrates extensive amounts of disease, surgical goals may be modified 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 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. Specific retrospective reviews may show some benefit.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 effective in this cancer. Phase II studies show a 15% to 28% response rate with specific 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 first 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 affects on survival have not yet been determined, Vandetanib marks the first 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 effects 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 first surgery.23,24,43 There is little prospective data to guide these numbers. Ten-year survival rates for those adult patients with disease confined to the thyroid gland is 95%. 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.
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
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 first 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.
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 Children’s Oncology Group has also established follow-up recommendations for these patients. Please see the COG Long-Term 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.childrensoncologygroup.org/disc/LE/pdf/ThyroidProblems.pdf).
In addition, it is advised that all patients presenting with new onset of hoarseness or dysphagia undergo laryngoscopy. 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.
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.
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;34:725–744 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;19:1377–1393
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;37:1020–1026
6. Hung W, Sarlis NJ. Current controversies in the management of pediatric patients with well-differentiated nonmedullary thyroid cancer: a review. Thyroid. 2002;12:683–702
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;31:177–181 discussion 181–182
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;28:1305–1311
9. Skinner MA. Management of hereditary thyroid cancer in children. Surg Oncol. 2003;12:101–104
10. Feinmesser R, Lubin E, Segal K, et al. Carcinoma of the thyroid in children—a review. J Pediatr Endocrinol Metab. 1997;10:561–568
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;94:323–330
12. Alsanea O, Clark OH. Familial thyroid cancer. Curr Opin Oncol. 2001;13:44–51
13. Fitze G. Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg. 2004;14:375–383
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;52:141–171
15. Harac HR, Williams ED. Childhood thyroid cancer in England and Wales. Br J Cancer. 1995;72:777–783
16. Arici C, Erdogan O, Altunbas H, et al. Differentiated thyroid carcinoma in children and adolescents. Clinical characteristics, treatment and outcome of 15 patients. Horm Res. 2002;57:153–156
17. Grigsby PW, Gal-or A, Michalski JM, et al. Childhood and adolescent thyroid carcinoma. Cancer. 2002;95:724–729
18. Shapiro NL, Bhattacharyya N. Population-based outcomes for pediatric thyroid carcinoma. Laryngoscope. 2005;115:337–340
19. Thompson GB, Hay ID. Current strategies for surgical management and adjuvant treatment of childhood papillary thyroid carcinoma. World J Surg. 2004;28:1187–1198
20. Harness JK, Sahar DE, et al.Clark O, Duh Q-Y, Kebebew E Childhood thyroid carcinoma. Textbook of Endocrine Surgery. 20052nd ed Philadelphia, PA Elsevier Saunders Company:93–101
21. Niedziela M. Pathogenesis, diagnosis and management of thyroid nodules in children. Endocr Relat Cancer. 2006;13:427–453
22. Zimmerman D, Hay ID, Gough IR, et al. Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery. 1988;104:1157–1166
23. O’Riordain DS, O’Brien T, Crotty TB, et al. Multiple endocrine neoplasia type 2B: more than an endocrine disorder. Surgery. 1995;118:936–942
24. Norton JA, Froome LC, Farrell RE, et al. Multiple endocrine neoplasia type IIb: the most aggressive form of medullary thyroid carcinoma. Surg Clin North Am. 1979;59:109–118
25. Samaan NA, Draznin MB, Halpin RE, et al. Multiple endocrine syndrome type IIb in early childhood. Cancer. 1991;68:1832–1834
26. Ball DW. Medullary thyroid cancer: monitoring and therapy. Endocrinol Metab Clin North Am. 2007;36:23–37
27. Moon WJ, Jung SL, Lee JH, et al. Benign and malignant thyroid nodules: US differentiation—multicenter retrospective study. Radiology. 2008;247:762–770
28. Stevens C, Lee JKP, Sadatsafavi M, et al. Pediatric thyroid fine needle aspiration cytology: a meta-analysis. J Pediatr Surg. 2009;44:2184–2191
29. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167–1214
30. Jameson JL, Weetman APFauci AS, Braunwald E, Kasper DL. Disorders of the thyroid gland. Harrison’s Online. 20087th ed McGraw-Hill Co. Inc.
31. Weber T, Schilling T, Buchler MW. Thyroid carcinoma. Curr Opin Oncol. 2006;18:30–35
32. . The Canadian Pediatric Thyroid Nodule Study: an evaluation of current management practices. J Ped Surg. 2008;43:826–830
33. Machens A, Dralle H. Biomarker-based risk stratification for previously untreated medullary thyroid cancer. Clin Endo Metab. 2010;95:2655–2663
34. Jiménez C, Hu MI, Gagel RF. Management of medullary thyroid carcinoma. Endocrinol Metab Clin North Am. 2008;37:481–496
35. Brandi ML, Gagel RF, Angeli A, et al. Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab. 2001;86:5658–5671
36. La Quaglia MP, Black T, Holcomb GW III, et al. Differentiated thyroid cancer: clinical characteristics, treatment, and outcome in patients under 21 years of age who present with distant metastases. A report from the Surgical Discipline Committee of the Children’s Cancer Group. J Pediatr Surg. 2000;35:955–959 discussion 960
37. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Handbook. 20107th ed NY Springer Verlag
38. Cobin RH, Gharib H, Bergman DA, et al. AACE/AAES medical/surgical guidelines for clinical practice: management of thyroid carcinoma. Endocr Pract. 2001;7:203–220
39. Hay ID, McConahey WM, Goellner JR. Managing patients with papillary thyroid carcinoma: insights gained from the Mayo Clinic’s experience of treating 2,512 consecutive patients during 1940 through 2000. Trans Am Clin Clim Assoc. 2002;113:241–260
40. Thyroid carcinoma. NCCN practice guidelines. v.1., 2005
41. Jarzab B, Handkiewicz Junak D, Wloch J, et al. Multivariate analysis of prognostic factors for differentiated thyroid carcinoma in children. Eur J Nucl Med. 2000;27:833–841
42. Newman KD, Black T, Heller G, et al. Differentiated thyroid cancer: determinants of disease progression in patients <21 years of age at diagnosis: a report from the Surgical Discipline Committee of the Children’s Cancer Group. Ann Surg. 1998;227:533–541
43. Dinauer CA, Tuttle RM, Robie DK, et al. Clinical features associated with metastasis and recurrence of differentiated thyroid cancer in children, adolescents and young adults. Clin Endocrinol. 1997;49:619–628
44. Jarzab B, Handkiewicz-Junak D, Wloch J. Juvenile differentiated thyroid carcinoma and the role of radioiodine in its treatment: a qualitative review. Endocr Relat Cancer. 2005;12:773–803
45. Hay ID, Gonzolez-Losada T, Reinalda MS, et al. Long-term outcome in 215 children and adolescents with papillary thyroid cancer treated during 1940 through 2008. World J Surg. 2010;34:1192–1202
46. Serhal DI, Nasrallah MP, Arafah BM. Rapid rise in serum thyrotropin concentrations after thyroidectomy of withdrawal of suppressive thyroxine therapy in preparation for radioactive iodine administration to patients with differentiated thyroid cancer. J Clin Endocrinol Metab. 2004;89:3285–3289
47. Luster M, Handkiewicz-Junak D, Grossi A, et al. Recombinant tyrotropin use in children and adolescents with differentiated thyroid cancer. J Clin Endocrinol Metab. 2009;94:3948–3953
48. Franzius C, Dietlein M, Biermann M, et al. Procedure guideline for radioiodine therapy and 131 iodine whole-body scintigraphy in paediatric patients with differentiated thyroid cancer. Nuklearmedizin. 2007;46:224–231
49. Hovens GC, Stokkel MP, Kievit J, et al. Associations of serum thyrotropin concentrations with recurrence and death in differentiated thyroid cancer. J Clin Endocrinol Metab. 2007;92:2610–2615
50. Landau D, Vini L, A’Hern R, et al. Thyroid cancer in children: the Royal Marsden Hospital experience. Europ J Cancer. 2000;36:214–220
51. Segni M, Gorman CA. The aftermath of childhood hyperthyroidism. J Pediatr Endocrinol Metab. 2001;14(suppl 5):1277–1282
52. Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19:565–612
53. Sippel RS, Kunnimalaiyaan M, Chen H. Current management of medullary thyroid cancer. Oncologist. 2008;13:539–547
54. Moore SW, Zaahl MG. Multiple endocrine neoplasia syndromes, children, Hirschsprung’s disease and RET. Pediatr Surg Int. 2008;24:521–530
55. Puñales MKC, Possatti da Rocha A, Meotti C, et al. Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid. 2008;18:1261–1268
56. Pelizzo MR, Boschin IM, Bernante P, et al. Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol. 2007;33:493–497
57. Hyer SL, Vini L, A’Hern R, et al. Medullary thyroid cancer: multivariate analysis of prognostic factors influencing survival. Eur J Surg Oncol. 2000;26:686–690
58. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double blind phase III trial. J Clin Oncol. 2012;30:134–141
59. Sherman SI. Early clinical studies of novel therapies for thyroid cancers. Endocrinol Metab Clin North Am. 2008;37:511–524
60. Luster M, Lassmann M, Freudenberg LS, et al. Thyroid cancer in childhood: management strategy, including dosimetry and long-term results. Hormones. 2007;6:269–278
61. Franc S, Niccoli-Sire P, Cohen R, et al. Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf). 2001;55:403–409
62. Brignardello E, Corrias A, Isolato G, et al. Ultrasound screening for thyroid carcinoma in childhood cancer survivors: a case series. J Clin Endocrin Metab. 2008;93:4840–4843
Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
papillary; follicular; medullary; thyroid; cancer; treatment; guidelines