Thyroid Cancer Guidelines
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The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:
All the guidelines advocate ultrasound evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions. [1, 5, 6]
Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows [1, 5, 6] :
AACE/AME/ETA and NCCN suggest a serum calcitonin assay as an optional test, [5, 6] but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. [1] All three guidelines recommend radionuclide imaging in patients with a low TSH level. [1, 5, 6]
Differentiated thyroid cancers arise from thyroid follicular epithelial cells and constitute 90% of all thyroid cancers. The subtypes and approximate frequencies of differentiated thyroid cancers are as follows:
ATA guidelines state that FNAB provides the most economical and accurate methodology for diagnosing differentiated thyroid cancers. Due to potential false negatives or sampling error, it is recommended that FNAB procedures be performed under ultrasound (US) guidance. US guidance is particularly important for nodules located posteriorly and for those that are difficult to palpate. Additionally, certain features found on US examination are predictive for malignancy and may guide FNAB decision-making. [1]
Papillary thyroid cancer is characterized by the following US features:
Follicular thyroid cancer is characterized by the following US features:
Benign US features are as follows:
In 2017, an ATA task force recommended that encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion be reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), given its excellent prognosis. This was a weak recommendation based on moderate-quality evidence. [7]
Malignancy risk
Cytological analysis of FNAB specimens is used to estimate malignancy risk. The most appropriate cytological classification of malignancy risk is the Bethesda system for thyroid cytopathology, which comprises the following categories [8] :
For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended. [1]
If FNAB cytology is indeterminate, the use of molecular markers such as BRAF, RAS, RET/PTC, Pax8-PPARɣ, or galectin-3 may be considered to guide management. [1]
An iodine-123 (123I) thyroid scan may be considered if the cytology report documents a follicular neoplasm, especially if serum thyroid-stimulating hormone (TSH) is in the low-normal range [1] . No radionuclide scan is needed for a reading of “suspicious for papillary carcinoma” or “Hürthle cell neoplasm”, as either lobectomy or total thyroidectomy is recommended depending on the nodule size and risk factors. [1]
The NCCN recommends that FNAB should be the primary test for differentiated thyroid cancer. If FNAB reveals papillary carcinoma, follicular neoplasm, follicular lesion of undetermined significance, or Hürthle cell neoplasm, the following diagnostic recommendations should be undertaken (these are uniform for all differentiated thyroid carcinomas) [5] :
Patients with medullary thyroid carcinoma (MTC) can be identified by pathologic diagnosis or by prospective genetic screening. According to the revised ATA guidelines, an FNAB result suspicious for MTC should prompt the following:
According to 2009 ATA guidelines, a calcitonin level >100 pg/mL should be considered suspicious of MTC [2] . Although calcitonin is a valuable tumor marker in patients with MTC, the 2015 Revised ATA guidelines note that clinical judgment should be exercised in the interpretation of calcitonin test results. Serum levels can be falsely high or low in a variety of clinical diseases, can be elevated in children under 3 years of age, and can be higher in males than females. [4]
The NCCN recommends the following diagnostic procedures when FNAB results indicate MTC [5] :
The familial medullary thyroid carcinoma (MTC) syndromes consist of multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC. They are inherited in an autosomal dominant fashion. Children inheriting any of these syndromes have a 100% risk of developing MTC.
MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone.
MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops around 10 years of age, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.
Genetic testing is now the mainstay in the diagnosis of the familial MTC syndromes. Germline RET proto-oncogene mutations (on chromosome arm 10q) discovered in these syndromes include the following [2] :
Guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals that have a documented RET mutation and are at risk for aggressive medullary thyroid carcinoma. [2]
The original ATA guidelines [2] stratified risk level of RET carriers into four categories, A through D, based upon the increasing aggressiveness of the particular mutation. Due to some confusion and lack of uniformity with other staging guidelines, the revised ATA guidelines [4] transition category D to “highest risk” (HST), transition category C to “high risk” (H), and combine categories B and A into “moderate risk”. The risk stratification, screening schedules, and prophylactic thyroidectomy schedules are described in the table below.
Table. Revised ATA MTC Risk Levels and Pediatric Recommendations (Open Table in a new window)
Risk Level
RET codon Mutation
Possible Diagnoses
Prophylactic Thyroidectomy
Recommendations
Follow-up
Highest Risk (HST)
M918T+All MEN2B
MEN2B
Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.
Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr
High Risk (H)
C634, A883F
MEN2A
At or before age 5 yr, to be determined on the basis of serum Ctn
Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.
Moderate Risk (MOD)
All other mutations
MEN2A
When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.
Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr
CEA=carcinoembryonic antigen; Ctn=calcitonin; MEN=multiple endocrine neoplasia; US=ultrasound
The staging for thyroid cancer follows the TNM system, developed by the American Joint Committee on Cancer (AJCC). [9] See Thyroid Cancer Staging.
The treatment of choice for differentiated thyroid cancers is surgery, whenever possible, followed by radioiodine (131I) in selected patients and thyrotropin suppression in most patients, according to the National Comprehensive Cancer Network (NCCN) guidelines. [5]
NCCN guidelines recommend total thyroidectomy for patients who meet any of the following criteria [5] :
The NCCN considers either total thyroidectomy or lobectomy to be acceptable for patients who meet all of the following criteria [5] :
If a lobectomy is performed, completion of the thyroidectomy is recommended for any of the following [5] :
ATA guidelines recommend near-total or total thyroidectomy for all patients with thyroid cancer >1 cm, unless there are contraindications to this surgery. Lobectomy may be considered for small (<1 cm), low-risk, thyroidal papillary carcinomas in the absence of prior radiation or clinically involved cervical nodal metastases. [1]
Both the NCCN and ATA recommend that therapeutic neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. The ATA, but not the NCCN, advises that prophylactic central-compartment neck dissection (level VI) may be considered in patients with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4). [1, 5]
The ATA does not have comprehensive guidelines for the treatment of follicular thyroid cancer (FTC) and Hürthle cell carcinoma as separate entities from papillary thyroid cancer; however, there are several individual recommendations that apply decision-making principles to these conditions. [1]
The ATA recommends that if cytology readings report a follicular neoplasm, an 123I thyroid scan may be considered, especially if serum thyroid-stimulating hormone (TSH) is in a low-normal range. If a concordant autonomously functioning nodule is not seen, lobectomy or total thyroidectomy should be considered.
If the cytology report indicates “Hürthle cell neoplasm” or “suspicious for papillary carcinoma”, the ATA recommends a lobectomy or thyroidectomy, depending on nodule size and other risk factors.
For patients with an isolated indeterminate (“follicular neoplasm” or “Hürthle cell neoplasm”) solitary nodule who prefer a more limited approach, the ATA recommends an initial lobectomy.
The ATA recommends a total thyroidectomy for patients with indeterminate nodules in any of the following situations:
The ATA recommends that patients with indeterminate nodules who have bilateral nodular disease or who wish to avoid future surgery should undergo total or near-total thyroidectomy. [1]
The NCCN guidelines recommend lobectomy plus isthmusectomy as the initial surgery for patients with follicular neoplasms and Hürthle cell carcinomas, with prompt completion of thyroidectomy if invasive cancer is found on the final histologic section. Therapeutic neck dissection of involved compartments is recommended for clinically apparent/biopsy-proven disease.
The NCCN recommends total thyroidectomy as the initial procedure only if invasive cancer or metastatic disease is apparent at the time or surgery, or if the patient wishes to avoid a second, completion thyroidectomy should the pathologic review reveal cancer. [5]
NCCN guidelines recommend radioiodine (131I) therapy if any of the following are present [5] :
Radioiodine therapy is not recommended if all of the following are present [5] :
Radioiodine therapy is selectively recommended if any of the following are present when the combination of clinical factors predicts a significant risk of recurrence: [5]
The ATA recommends radioiodine therapy for all patients if any of the following are present: [1]
Radioiodine therapy is not recommended for patients with unifocal cancer <1 cm without other higher- risk features; or for patients with multifocal cancer when all foci are <1 cm in the absence of other higher-risk features. [1]
Radioiodine therapy is also recommended for selected patients with 1-4 cm thyroid cancers confined to the thyroid who have documented lymph node metastases or other higher risk features, when the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer. [1]
The ATA and NCCN guidelines recommend treatment with levothyroxine to suppress thyroid-stimulating hormone (TSH) levels. Degree of suppression is based on risk, as follows [1, 5] :
The National Comprehensive Cancer Network (NCCN) guidelines recommend total thyroidectomy and bilateral central neck dissection (level VI) for all patients with medullary thyroid carcinoma (MTC) whose tumor is ≥1 cm or who have bilateral thyroid disease, as well as the following [5] :
External beam radiation therapy (EBRT) is an option for treatment of incomplete tumor resection when further surgical resection is no longer possible. EBRT can also be considered for adjuvant treatment for extrathyroidal extension (T4a or T4b) with positive margins
Other therapy considerations are as follows:
Suppression of thyroid-stimulating hormone (TSH) is not appropriate; TSH is kept in the normal range by adjusting levothyroxine dose.
No curative treatment currently exists for anaplastic thyroid cancer (ATC). The majority of patients present with unresectable or metastatic disease. National Comprehensive Cancer Network (NCCN) guidelines recommend attempting total thyroidectomy in patients with resectable disease. [5]
The American Thyroid Association (ATA) ATC guidelines recommend total lobectomy or total or near-total thyroidectomy with a therapeutic lymph node dissection for patients with intrathyroidal ATC. In patients with extrathyroidal invasion, an en bloc resection should be considered if grossly negative margins (R1 resection) can be achieved. [3] Both the NCCN and ATA guidelines recommend adjuvant radiation therapy, chemotherapy, or both. [3, 5]
National Comprehensive Cancer Network (NCCN) recommendations for treatment of recurrent or metastatic thyroid disease include external beam radiation therapy (EBRT). [5] Systemic therapy can be considered for tumors with all the following characteristics:
Oral kinase inhibitors (eg, vandetanib) are associated with longer progression-free survival but are not curative; side effects that may have a significant effect on quality of life should be considered. Kinase inhibitor therapy may not be appropriate for a symptomatic patients with indolent disease progression
Thyroid cancer in the pediatric population is relatively rare, accounting for 1.5-3% of all carcinomas in the United States and Europe. Features of pediatric thyroid cancers are as follows:
Children tend to have a recurrence rate of around 40%, which is higher than the adult population; however, long-term survival rate is higher. Pediatric patients tend to have a 5-year survival rate of 99.3% and a 10-year survival rate of 98.5% [10] .
American Thyroid Association (ATA) guidelines on management of thyroid disease during pregnancy and the postpartum include the following recommendations on thyroid nodules and cancer in these patients [7] :
Recommendations for subsequent pregnancy in women with thyroid cancer include the following:
[Guideline] Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan. 26 (1):1-133. [Medline]. [Full Text].
American Thyroid Association Guidelines Task Force, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun. 19 (6):565-612. [Medline]. [Full Text].
[Guideline] Smallridge RC, Ain KB, Asa SL, Bible KC, Brierley JD, Burman KD, et al. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012 Nov. 22 (11):1104-39. [Medline]. [Full Text].
[Guideline] Wells SA Jr, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised american thyroid association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun. 25 (6):567-610. [Medline]. [Full Text].
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. Version 2.2017 — May 17, 2017; Accessed: December 26, 2017.
[Guideline] Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedüs L, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010. 33 (5 Suppl):51-6. [Medline]. [Full Text].
[Guideline] Haugen BR, Sawka AM, Alexander EK, Bible KC, Caturegli P, Doherty GM, et al. American Thyroid Association Guidelines on the Management of Thyroid Nodules and Differentiated Thyroid Cancer Task Force Review and Recommendation on the Proposed Renaming of Encapsulated Follicular Variant Papillary Thyroid Carcinoma Without Invasion to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features. Thyroid. 2017 Apr. 27 (4):481-483. [Medline].
Cibas ES, Ali SZ. The Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2009 Nov. 19 (11):1159-65. [Medline].
Thyroid. Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC Cancer Staging Manual. 7th Ed. New York, NY: Springer-Verlag; 2010. 87-96.
Vaisman F, Corbo R, Vaisman M. Thyroid carcinoma in children and adolescents-systematic review of the literature. J Thyroid Res. 2011. 2011:845362. [Medline]. [Full Text].
Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see commetns]. Cancer. 1998 Dec 15. 83 (12):2638-48. [Medline].
Chindris AM, Casler JD, Bernet VJ, Rivera M, Thomas C, Kachergus JM, et al. Clinical and molecular features of Hürthle cell carcinoma of the thyroid. J Clin Endocrinol Metab. 2015 Jan. 100 (1):55-62. [Medline].
[Guideline] Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar. 27 (3):315-389. [Medline]. [Full Text].
Risk Level
RET codon Mutation
Possible Diagnoses
Prophylactic Thyroidectomy
Recommendations
Follow-up
Highest Risk (HST)
M918T+All MEN2B
MEN2B
Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.
Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr
High Risk (H)
C634, A883F
MEN2A
At or before age 5 yr, to be determined on the basis of serum Ctn
Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.
Moderate Risk (MOD)
All other mutations
MEN2A
When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.
Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr
Kemp M Anderson Medical University of South Carolina College of Medicine
Kemp M Anderson is a member of the following medical societies: Association of American Medical Colleges, American Medical Association
Disclosure: Nothing to disclose.
Eric J Lentsch, MD Assistant Professor of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Mariclaire Cloutier Freelance editor, Medscape Drugs & Diseases
Disclosure: Nothing to disclose.
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