In recent years, the management of thyroid cancers has become far more nuanced. With specifically tailored treatments becoming commonplace, it is important to consider each patient individually. Additionally, it is important to note that while a number of different groups have put forth guidelines for the management of thyroid surveillance and cancer therapy,[1, 2, 3, 4, 5, 6, 7] there some controversy among guidelines regarding certain scenarios, which has raised concerns about the effects on patient outcomes.[8] For the sake of clarity, this article will largely refer to guidelines from the following organizations, and the following classification systems:
Evaluation of any thyroid complaint begins with a thorough history and a physical examination that includes inspection for adjacent cervical lymphadenopathy. Important historical factors are as follows:
When a nodule is discovered, either incidentally on imaging or on physical exam, patients should undergo the following:
The AACE/AME guideline has an algorithm that comprises data from clinical assessment, imaging, cytology, and molecular markers and incorporates both TI-RADS[14] and the Bethesda classification[13] to help guide clinical decisions regarding nodule evaluation and work-up.[15] Ultrasound (US) features are used to categorize risk of malignancy and classify nodules as low risk (US1), intermediate risk (US2), or high risk (US3).[15]
US1 criteria include the absence of any intermediate-risk or high-risk features and the presence of one or more of the following features:
US2 criteria include the absence of any high-risk features and the presence of one or more of the following features:
US3 criteria include the presence of one or more of the following:
The AACE/AME guidelines use clinical criteria to guide consideration of fine needle aspiration (FNA). Features that argue against performing FNA are termed Clinical 1; those that favor FNA are termed Clinical 2.[15]
Presence of one or more of the following argues against performing FNA:
Presence of one or more of the following favors performing FNA:
The AACE/AME guidelines provide recommendations for follow-up of nodules, based on size and US risk classification. For nodules smaller than 5 mm, recommendations are as follows:
For nodules 5-10 mm, recommendations are as follows:
For nodules > 10-20 mm, recommendations are as follows:
For nodules > 20-40 mm, recommendations are as follows:
For nodules > 40 mm, FNA is recommended.
FNA results are best evaluated based on the Bethesda classification.[13] Classifications, follow-up, and malignancy risk are as follows:
Of note, NIFTP was formerly referred to as encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion.[16]
NCCN guidelines provide treatment recommendations based on the Bethesda classification, as follows[2] :
When molecular testing is performed on lesions, as per the NCCN guidelines (ie, high-suspicion Bethesda III or low-suspicion BethesdA IV), those lesions that lack informative molecular diagnostics or are suggestive of malignancy should be considered for lobectomy or thyroidectomy. If testing shows Bethesda V or VI, subtype-specific treatment is recommended. If molecular diagnostics are suggestive of malignancy, considerations include lobectomy or total thyroidectomy for definitive diagnosis and treatment, or nodule surveillance.[2]
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 fine needle aspiration biopsy (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, especially 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.
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:
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[13] :
For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended. 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 TSH is in the low-normal range. 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, further diagnostic procedures should be selected accordingly, as shown below.[2]
Papillary carcinoma ≥ 1 cm:
Papillary carcinoma < 1 cm:
Follicular neoplasm (Bethesda IV) and Hürthle cell (Bethesda IV):
Medullary thyroid carcinoma:
If a RET proto-oncogene is identified, conduct genetic testing to determine whether the patient has multiple endocrine neoplasia type 2B (MEN2B) or MEN2A/familial medullary thyroid carcinoma (FMTC).[2]
For both MEN2B and MEN2A, further workup is as follows:
In addition, patients with MEN2A should have serum calcium and parathyroid hormone (PTH) measured.
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. In MEN 2B, MTC usually develops around 10 years of age and has a high propensity for rapid growth and metastasis. In MEN 2A, MTC can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.
Guidelines from the American Thyroid Association (ATA)[9] and NCCN[2] recommend prophylactic thyroidectomy for individuals that have a documented RET mutation and are at risk for aggressive MTC. Risk varies with the underlying RET mutation.
The original ATA guidelines, from 2009,[17] 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, published in 2015,[9] 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. American Thyroid Association Medullary Thyroid Cancer Risk Levels and Treatment Recommendations (Open Table in a new window)
Risk Level |
RET codon Mutation |
Possible Diagnosis |
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 on 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, 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 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 NCCN guidelines.[2] When suppression therapy is used, NCCN and ATA guidelines recommend basing the degree of suppression on the risk of recurrence, as follows[1, 9] :
The NCCN recommends that in patients who remain disease free for several years, TSH levels can probably be maintained within the reference range (0.5–2 mU/L).[2]
NCCN guidelines recommend total thyroidectomy plus therapeutic neck dissection of any involved compartments for patients with PTC if any of the following are present[2] :
If none of those risk factors are present, total thyroidectomy versus lobectomy plus isthmusectomy can be considered.
NCCN recommendations for postoperative management include the following[2]
If RAI imaging shows no uptake, the NCCN recommends monitoring disease versus external beam or intensity-modulated radiation therapy (EBRT/IMRT). EBRT/IMRT can be considered upfront for patients with viscerally invasive disease or rapid progression. If RAI uptake is present, RAI treatment is preferred, followed by post-treatment 131I whole body imaging.
In patients with recurrent disease and widely metastatic disease, the tumor should be evaluated for actionable mutations such as ALK, NTRK, RET gene fusions, DNA mismatch repair (dMMR), micro-satellite instability (MSI), and tumor mutational burden (TMB). If found, they can be addressed with targeted therapies.[2]
NCCN guidelines recommend total thyroidectomy for follicular thyroid cancer and Hürthle cell carcinoma that is invasive or metastatic, or if that is the patient's preference. Neck dissection is recommended for involved compartments. Otherwise, lobectomy/isthmusectomy can be performed; however, if pathology reports widely invasive cancer or encapsulated angioinvasive disease involving ≥4 vessels, completion thyroidectomy is indicated.[2]
Consideration should be given to levothyroxine treatment to maintain normal or low TSH and to measuring TG and anti-TG antibodies 6-12 weeks postoperatively. In patients with gross residual disease, TSH suppression therapy should be delayed until completion of RAI work-up and treatment if indicated.
For gross residual disease, patients can undergo measurement of TSH, TG, and anti-TG antibodies at 6-12 weeks or undergo 123I or 131I total body imaging with TSH stimulation. The latter is preferred for viscerally invasive or rapidly progressing disease.
If RAI imaging shows no uptake, the NCCN recommends monitoring disease versus EBRT/IMRT. Radiation therapy can be considered upfront for patients with viscerally invasive or rapid progression. If RAI uptake is present, RAI treatment is preferred, followed by post-treatment 131I whole body imaging.
In patients with recurrent disease and widely metastatic disease, the tumor should be evaluated for actionable mutations such as ALK, NTRK, RET gene fusions, DNA mismatch repair (dMMR), micro-satellite instability (MSI), and tumor mutational burden (TMB). If found, they can be addressed with targeted therapies.[2]
For medullary thyroid carcinoma (MTC) without a RET mutation, NCCN treatment recommendations vary by tumor size.[2] For MTC < 1 cm, the NCCN recommends total thyroidectomy, with consideration of level IV neck dissection. For MTC ≥ 1 cm, recommended treatment is as follows:
Patients should have postoperative levothyroxine to normalize TSH
For treatment of MTC related to MEN2B, NCCN recommendations are as follows:
For treatment of MTC related to MEN2A, NCCN recommendations are as follows:
Prior to thyroid surgery, pheochromocytoma removal by laparoscopic adrenalectomy is recommended, along with preoperative treatment with alpha-adrenergic blockade (phenoxybenzamine) or alpha-methyltyrosine to avoid a hypertensive crisis during surgery.
As with many other aggressive cancers, the treatment approach for anaplastic thyroid cancer (ATC) has benefited from a better understanding of specific tumor characteristics and the development of targeted chemotherapeutics. Given the aggressive nature and relatively poor outcomes with this cancer, guidelines recommend a prompt evaluation of tumor and a multidisciplinary discussion with surgeons, oncologists, palliative care specialists, and the patient. In particular, the potential for rapid airway and vascular compromise make early evaluation critical.
For staging, patient should undergo fluorodeoxyglucose (FDG) PET/CT or dedicated body CT or MRI. Patients with stage IVA or IVB disease who wish to pursue surgery can undergo complete resection (R0 or R1) with early adjuvant therapy to follow. Importantly, surgical planning must take into account the need to limit wounds that might lead to complications that would prevent early chemotherapy and radiation therapy.[18] Following surgery for stage IVA/IVB disease, patients should undergo definitive-intention radiation therapy with chemotherapy (taxane monotherapy or a taxane in combination with a platinum agent or anthracycline).[12]
Patients with stage IVB ATC, even if resectable, and stage IVC ATC who desire aggressive care should undergo genetic testing for actionable mutations, including BRAF V600E, ALK, NTRK, RET fusions, which may guide selection of targeted therapy with tyrosine kinase inhibitors. In some cases of stage IVB ATC, such targeted therapy can allow surgery for previously unresectable disease.[12] Stage IVC ATC that tests negative for those mutations can also be evaluated for high programmed death ligand 1 (PD-L1) expression, as these patients may be candidates for checkpoint inhibitor therapy.
Patients with stage IVC ATC can also opt for early palliative chemotherapy and/or radiation, as they will not be candidates for surgical resection. Close communication with patients and their family is important in these cases, as many individual factors may enter into the choice between palliative therapies or more aggressive care.[12]
NCCN recommendations for treatment of recurrent or metastatic thyroid disease include external beam radiation therapy (EBRT), with consideration of systemic therapy for tumors that have all the following characteristics[2] :
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 symptomatic patients with indolent disease.[2]
For recurrent disease and widely metastatic disease, the tumor should be evaluated for actionable mutations such as ALK, NTRK, RET gene fusions, DNA mismatch repair (dMMR), micro-satellite instability (MSI), and tumor mutational burden (TMB). This may guide use of targeted therapy.[2]
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[19] :
Recommendations for subsequent pregnancy in women with thyroid cancer include the following:
Overview
Which organizations have issued guidelines on the diagnosis and management of thyroid cancer?
What are the guidelines on the initial evaluation of thyroid nodules?
What are differentiated thyroid cancers?
What are ATA guidelines on the diagnosis of differentiated thyroid cancers?
How is the malignancy risk of differentiated thyroid cancers determined?
What are the NCCN guidelines on the diagnosis of differentiated thyroid cancers?
What are the ATA guidelines on the diagnosis of medullary thyroid carcinoma (MTC)?
What are the NCCN guidelines on the diagnosis of medullary thyroid carcinoma (MTC)?
What are the guidelines on diagnosis and management of familial MTC syndromes?
What are the treatment guidelines for differentiated thyroid cancers?
What are the NCCN and ATA treatment guidelines for papillary thyroid cancer (PTC)?
What are the ATA treatment guidelines for follicular thyroid cancer and Hürthle cell carcinoma?
What are the NCCN treatment guidelines for follicular thyroid cancer and Hürthle cell carcinoma?
What are the NCCN guidelines on radioiodine therapy in the treatment of thyroid cancer?
What are the ATA guidelines on radioiodine therapy in the treatment of thyroid cancer?
What are the NCCN and ATA guidelines on levothyroxine in the treatment of thyroid cancer?
What are the NCCN guidelines on the primary treatment of medullary thyroid carcinoma (MTC)?
What are the guidelines on the treatment of anaplastic thyroid cancer?
What are the NCCN guidelines on the treatment of metastatic thyroid cancer?
What are the ATA treatment guidelines for thyroid cancer during pregnancy?
What are the treatment guidelines for pediatric thyroid cancer?