Version May 2024
INTRODUCTION — Surgery is the primary mode of therapy for patients with differentiated thyroid cancer, followed by radioiodine therapy (when indicated) and thyroid hormone suppression therapy. After initial surgery, patients with thyroid cancer are typically managed by endocrinologists specializing in the treatment of thyroid cancer.
This topic will provide a broad overview of the therapeutic options for patients with differentiated thyroid cancer. The specific therapies for differentiated thyroid cancer are reviewed in detail separately.
●(See "Differentiated thyroid cancer: Surgical treatment".)
●(See "Differentiated thyroid cancer: Radioiodine treatment".)
●(See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy".)
●(See "Differentiated thyroid cancer: External beam radiotherapy".)
●(See "Overview of thyroid disease and pregnancy", section on 'Thyroid cancer'.)
CLASSIFICATION — Thyroid follicular epithelial-derived cancers are divided into three categories:
●Papillary cancer – 85 percent
●Follicular cancer – 12 percent
●Anaplastic (undifferentiated) cancer – <3 percent
Papillary and follicular cancers are considered differentiated cancers, and patients with these tumors are often treated similarly, despite numerous biologic differences. Most anaplastic (undifferentiated) cancers appear to arise from differentiated cancers. The treatment of anaplastic thyroid cancer is reviewed separately. (See "Anaplastic thyroid cancer".)
Other malignant diseases of the thyroid include medullary thyroid cancer (MTC) (which can be familial, either as part of the multiple endocrine neoplasia type 2 [MEN2] syndrome or isolated familial MTC) and primary thyroid lymphoma. Cancers that metastasize to the thyroid include breast, colon, renal cancer, and melanoma. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)
GUIDELINES — The American Thyroid Association (ATA) published evidence-based guidelines in 2015 for the staging and management of differentiated thyroid cancer [1]. In addition, guidelines have been published by the National Comprehensive Cancer Network (NCCN) [2] and a European consensus group [3]. Our approach below is largely consistent with the ATA and NCCN guidelines [1,2].
SURGICAL MANAGEMENT — Surgery is the primary mode of therapy for patients with differentiated thyroid cancer. Preoperative ultrasound is important for planning the surgical procedure. In the absence of prospective trials, conclusions regarding the optimal surgical approach are based upon retrospective analyses and expert consensus opinions [1,3-7].
After initial surgery, patients with thyroid cancer are typically managed by endocrinologists specializing in the treatment of thyroid cancer.
Preoperative imaging — All patients should have a preoperative ultrasound evaluation of the central and lateral neck lymph nodes in order to plan the surgical procedure. Additional imaging beyond routine preoperative neck ultrasound should be obtained in patients presenting with locally advanced disease. The role of preoperative imaging in determining the surgical approach is reviewed separately. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Importance of preoperative imaging'.)
Choice of surgical procedure — Surgery is the primary mode of therapy for patients with differentiated thyroid cancer. Surgery should be performed by an experienced thyroid surgeon to minimize the risk of hypoparathyroidism and recurrent laryngeal nerve (RLN) injury. In one study, complications were lower when surgery was performed by surgeons performing at least 25 thyroidectomies per year [8].
The operative approach depends upon the extent of the disease (eg, primary tumor size and the presence of extrathyroidal extension or lymph node metastases), the patient's age, and the presence of comorbid conditions. The choice of procedure is discussed briefly below and in more detail elsewhere. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Choice of procedure'.)
●Tumor <1 cm without extrathyroidal extension and no lymph nodes – When surgery is planned for unilateral intrathyroidal differentiated thyroid cancer <1 cm, a thyroid lobectomy is preferred unless there are clear indications to remove the contralateral lobe (eg, clinically evident thyroid cancer in the contralateral lobe, previous history of head and neck radiation, strong family history of thyroid cancer, or imaging abnormalities that will make follow-up difficult).
●Tumor 1 to 4 cm without extrathyroidal extension and no lymph nodes – For intrathyroidal tumors between 1 and 4 cm, the initial surgical procedure can either be a total thyroidectomy or thyroid lobectomy. Total thyroidectomy would be chosen either based on patient preference, the presence of ultrasonographic abnormalities in the contralateral lobe (nodules, thyroiditis in the contralateral lobe, or nonspecific lymphadenopathy that will make follow-up difficult), or on a decision by the treatment team that radioiodine therapy may be beneficial either as adjuvant therapy or to facilitate follow-up.
●Tumor ≥4 cm, extrathyroidal extension, or metastases – Total thyroidectomy is recommended if the primary tumor is 4 cm in diameter or greater, there is extrathyroidal extension of tumor, or there are metastases to lymph nodes or distant sites.
●Any tumor size and history of childhood head and neck radiation – Total thyroidectomy should also be performed in all patients with thyroid cancer who have a history of exposure to ionizing radiation of the head and neck, given the high rate of tumor recurrence with lesser operations in these patients [9]. (See "Radiation-induced thyroid disease".)
●Multifocal papillary microcarcinoma (fewer than five foci) – Unilateral lobectomy and isthmusectomy is an appropriate procedure for patients whose pathology reports subsequently show multifocal papillary microcarcinomas with fewer than five foci.
●Multifocal papillary microcarcinoma (more than five foci) – When multifocal papillary cancer is appreciated preoperatively, particularly when a large number of microcarcinoma are suspected (eg, greater than five foci, especially if the foci are in the 8 to 9 mm size range), we are more likely to perform a total thyroidectomy.
For patients whose initial procedure was a lobectomy and in whom pathology shows multifocal papillary microcarcinomas with more than five foci, especially if the foci are in the 8 to 9 mm range, we typically refer patients for completion thyroidectomy.
The approach to lymph node dissection is reviewed separately. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Approach to lymph node dissection' and "Neck dissection for differentiated thyroid cancer".)
Postoperative complications — The management of potential metabolic (eg, hypoparathyroidism) and anatomic (eg, laryngeal nerve damage) postsurgical complications is reviewed separately. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Complications'.)
Postoperative thyroid hormone
●Lobectomy – For low- and intermediate-risk patients whose initial surgery was a lobectomy, we do not begin thyroid hormone (T4) immediately postoperatively (unless the patient has Hashimoto's thyroiditis and the preoperative thyroid-stimulating hormone [TSH] was high normal) [10]. Instead, we measure serum TSH six weeks after surgery and determine the need for T4 based upon the TSH and evaluation of postoperative disease status. Following lobectomy, a TSH between 0.5 and 2 mIU/mL is considered acceptable.
●Total thyroidectomy – After total thyroidectomy, all patients require postoperative thyroid hormone therapy (T4 [levothyroxine]) to replace normal hormone production and/or to suppress regrowth of tumor. The initial dose and type of thyroid hormone (T4 or T3 [liothyronine]) depend upon the likelihood of needing radioiodine scanning/ablation and the method of preparation for radioiodine scanning. These decisions are based upon the estimated risk of persistent/recurrent disease. In the immediate postoperative period, complete clinicopathologic findings may be unavailable to fully estimate these risks, and the clinician may need to modify dosing four to six weeks postoperatively. (See 'Initial risk stratification' below.)
T4 (usually 1.6 to 2 mcg/kg per day) can be started immediately postoperatively in the following patients:
•American Thyroid Association (ATA) low- and intermediate-risk patients (table 1) who are unlikely to need radioiodine scanning or ablation. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)
•Selected ATA intermediate- and high-risk patients (table 1) in whom radioiodine scanning and ablation will be done using recombinant human TSH (rhTSH [thyrotropin alfa]). (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Choice of method for increasing TSH'.)
The higher doses are used in selected intermediate- and high-risk patients, modified by age and other comorbid conditions. TSH is measured four to six weeks postoperatively, and the dose is adjusted as needed to achieve goal TSH. The initial TSH goal is based upon the risk of recurrence as determined by clinicopathologic findings and postoperative thyroglobulin (Tg). (See 'Thyroid hormone suppression' below.)
The long-term TSH goals depend upon structural and biochemical response to initial therapy, which is determined by ongoing assessment and risk stratification. (See 'Dynamic risk stratification' below.)
•For patients in whom radioiodine scanning and ablation will be done using thyroid hormone withdrawal (typically ATA high-risk patients), short-term thyroid hormone replacement can be initiated postoperatively with T3, 25 mcg two to three times daily. After two to three weeks, T3 is discontinued and imaging is performed once the patient's serum TSH concentration is above 25 to 30 mU/L.
Another alternative is simply to withhold any thyroid hormone therapy until the patient's serum TSH concentration is above 30 mU/L. These options are reviewed in detail separately. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Choice of method for increasing TSH'.)
INITIAL RISK STRATIFICATION — After surgery, the presence or absence of persistent disease and risk for recurrent disease should be assessed in order to determine the need for additional treatment, in particular radioiodine therapy.
Postoperative evaluation — We typically obtain a serum TSH and a nonstimulated serum thyroglobulin (Tg) approximately four to six weeks after thyroidectomy or lobectomy in order to better define the postoperative disease status.
While we agree with the American Thyroid Association (ATA) guidelines that the optimal cutoff value for either a stimulated or nonstimulated postoperative Tg four to six weeks after surgery is not clearly established [1], we expect nonstimulated Tg values of:
●<5 ng/mL after a total thyroidectomy
●<30 ng/mL after thyroid lobectomy
Serum Tg values above these cutoffs should prompt reevaluation of the completeness of the initial surgery (usually with neck ultrasonography) and consideration of the possibility of persistent metastatic disease.
Diagnostic (pre-radioiodine treatment) whole-body scans for localization of persistent disease before remnant ablation, adjuvant radioiodine therapy, or radioiodine treatment of metastatic thyroid cancer are performed less often. They can be performed when the extent of residual disease cannot be determined from surgery and neck ultrasonography and when the presence of residual disease may alter the decision to treat with radioiodine or the administered activity [1]. However, because almost all patients have thyroid remnants, our approach is to omit the pre-radioiodine treatment diagnostic scan, administer empiric therapeutic doses of iodine-131 (131-I) therapy (based upon surgical and ultrasonography findings), and obtain only a post-radioiodine treatment scan for localization of uptake. (See 'Radioiodine therapy' below and "Differentiated thyroid cancer: Radioiodine treatment", section on 'Pretreatment scanning'.)
Risk classification — The clinicopathologic features of each case are important for providing prognostic information. Since the tumor, node, metastases (TNM) staging system is designed to stratify risk based upon disease-specific mortality and may not accurately predict the risk of recurrence/persistent disease in thyroid cancer, we use TNM staging (table 2) to estimate mortality and the ATA risk stratification system to estimate the risk of recurrence (table 1).
Staging is reviewed briefly below and in more detail separately. (See "Differentiated thyroid cancer: Clinicopathologic staging".)
●TNM staging system – Formal disease staging is based upon applying the individual TNM descriptors in the American Joint Commission on Cancer (AJCC) staging scheme (table 2). (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'TNM system'.)
●ATA risk stratification system – We use the ATA initial risk stratification system to estimate the risk of persistent/recurrent disease. This system is designed to stratify patients as having either low (papillary thyroid cancer confined to thyroid), intermediate (regional metastases, worrisome histologies, extrathyroidal extension, or vascular invasion), or high (gross extrathyroidal extension, distant metastases, or postoperative serum Tg suggestive of distant metastases) risk of recurrence, primarily based upon clinicopathologic findings (table 1) [1]. The risk of recurrence, however, follows a continuum across the three discrete risk categories (low, intermediate, and high). Additional prognostic variables (eg, extent of lymph node involvement, degree of vascular invasion in follicular thyroid cancer) were included in a modified version of the risk stratification system, although the additional variables have not been rigorously evaluated. This topic is reviewed in more detail elsewhere. (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'ATA risk stratification'.)
Serum-specific molecular profiles (eg, BRAF, TERT) may be used to predict risk of extrathyroidal extension, lymph node metastases, and even distant metastases. While these observations need further validation, it is likely that the specific molecular profile of the primary tumor may have significant prognostic value that could be incorporated into the stratification systems. (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Molecular characteristics'.)
While initial risk stratification can be used to guide initial therapeutic and diagnostic follow-up strategy decisions, it is important to recognize that initial risk estimates may need to change as new data are accumulated during follow-up. (See 'Dynamic risk stratification' below.)
SUBSEQUENT MANAGEMENT BASED ON RISK CLASSIFICATION — Postoperative management includes treatment with thyroid hormone suppressive therapy (most patients) and radioiodine (high-risk and selected intermediate-risk patients). Postoperative management depends upon the risk of recurrence/persistent disease (table 1). (See 'Risk classification' above.)
Thyroid hormone suppression — After initial thyroidectomy, whether or not radioiodine therapy is administered, thyroid hormone (T4 [levothyroxine]) therapy is required in most patients to prevent hypothyroidism and to minimize potential TSH stimulation of tumor growth.
Our approach for initial thyroid hormone suppression is based upon risk of disease recurrence (table 1):
●American Thyroid Association (ATA) low risk – For patients with low-risk disease treated with thyroidectomy who have detectable serum thyroglobulin (Tg) levels (with or without remnant ablation), the serum TSH initially can be maintained between 0.1 and 0.5 mU/L. For similar patients who have undetectable serum Tg levels (with or without remnant ablation) or who were treated with lobectomy, TSH can be maintained in the mid to lower half of the reference range (0.5 to 2.0 mU/L). In the latter setting, thyroid hormone treatment may be unnecessary if a patient can maintain their TSH in this range.
●ATA intermediate risk – For patients with intermediate-risk disease, the serum TSH initially can be maintained between 0.1 and 0.5 mU/L.
●ATA high risk – For patients with high-risk disease, the serum TSH initially should be less than 0.1 mU/L.
TSH goals for long-term follow-up are based on response to therapy assessments further modified by comorbid conditions that increase the potential risks of prolonged TSH suppression (such as menopause, tachycardia, osteopenia, older age, osteoporosis, or atrial fibrillation) (figure 1) [1]. The dose also may be decreased to allow the TSH to rise into the normal range in intermediate-risk patients who demonstrate an excellent response to therapy. (See 'Monitoring response to therapy' below.)
The hypothesis that reduction of serum TSH concentrations to below the normal range decreases morbidity and mortality in all patients with differentiated thyroid cancer has not been proven, but some retrospective studies suggested improved relapse-free survival when serum TSH concentrations were undetectable during follow-up [11,12]. In reports from the National Thyroid Cancer Treatment Cooperative Study (NTCTCS, a multicenter prospective tumor registry), greater TSH suppression was associated with improved progression-free survival in high-risk papillary cancer patients [13,14], whereas milder degrees of TSH suppression were still associated with excellent outcomes in patients with intermediate-risk features (table 3) [14]. In a follow-up report from the NTCTCS, a moderate degree of TSH suppression (TSH in the low normal to just below normal reference range) was associated with improved overall and disease-free survival in all stages, even in those with distant metastatic disease [15]. There was no additional survival benefit with aggressive TSH suppression (TSH undetectable to subnormal).
In a randomized trial of suppressive versus replacement therapy in 433 Japanese patients with papillary thyroid cancer [16], with achieved mean TSH levels of 0.07 and 3.19 mU/L, respectively, disease-free five-year survival, recurrence rates, and sites of recurrence were not significantly different between the two groups. However, these data might not be generalizable, since the majority of the participants had lobectomies and prophylactic central neck dissections and some had prophylactic lateral neck dissections, forms of surgery generally not done in most Western countries.
These findings, combined with the risks of overly aggressive T4 therapy, including the potential for acceleration of bone loss [17-19], atrial fibrillation [20], and cardiac dysfunction [21-23], emphasize the importance of tailoring the T4 dose to the extent of the disease and the likelihood of recurrence [24]. These decisions can be based in part upon staging by the tumor, node, metastases (TNM) system (table 2) in conjunction with the proposed ATA risk of recurrence system (table 1) [1]. (See 'Risk classification' above and "Differentiated thyroid cancer: Clinicopathologic staging".)
Radioiodine therapy — Radioiodine is administered after thyroidectomy in patients with differentiated thyroid cancer to ablate residual normal thyroid tissue (remnant ablation), provide adjuvant therapy of subclinical micrometastatic disease, and/or provide treatment of clinically apparent residual or metastatic thyroid cancer. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Goals'.)
The decision to treat with radioiodine depends upon the risk of recurrence/persistent disease (table 1). (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)
We routinely administer radioiodine after total thyroidectomy in high-risk patients and in selected intermediate-risk patients, depending upon specific tumor characteristics (eg, clinically significant lymph node metastases outside of the thyroid bed, or other higher-risk features).
●ATA low-risk disease – In the absence of a proven benefit on either disease-free survival or recurrence, we do not routinely administer radioiodine for remnant ablation to patients with low-risk disease, especially patients with unifocal tumors <1 cm without other high-risk features or multifocal cancer when all foci are <1 cm in the absence of other high-risk features, even in the presence of small-volume regional lymph node metastases (less than five lymph nodes measuring less than 2 mm).
●ATA intermediate-risk disease – We suggest postoperative radioiodine ablation to selected intermediate-risk patients, including those with clinically significant lymph node metastases outside of the thyroid bed; vascular invasion; or more aggressive histologic subtypes such as tall cell, columnar cell, insular, or poorly differentiated histologies.
●ATA high-risk disease – We recommend postoperative radioiodine ablation to patients with high-risk disease, including patients with distant metastases, macroscopic tumor invasion, and/or incomplete tumor resection with gross residual disease.
The data to support these recommendations, patient preparation, dosing, monitoring, and complications of radioiodine treatment are reviewed in detail separately. (See "Differentiated thyroid cancer: Radioiodine treatment".)
Role of adjuvant external beam radiation therapy — External beam radiotherapy (EBRT) can be used as adjuvant therapy after macroscopically complete surgical excision to prevent recurrence, particularly for older patients with gross extrathyroid extension at the time of surgery or selected younger patients with extensive disease and poor histologic features (eg, insular or poorly differentiated histology) whose disease is resected but in whom there is a high likelihood of residual microscopic disease. This topic is reviewed in detail separately. (See "Differentiated thyroid cancer: External beam radiotherapy".)
MONITORING RESPONSE TO THERAPY — Monitoring strategies are based upon the patient's American Thyroid Association (ATA) risk of recurrence (table 1) and the reassessment of response to therapy at each follow-up visit. This strategy is in keeping with the ATA guidelines for the management of patients with thyroid nodules and differentiated thyroid cancer [1].
Dynamic risk stratification — While initial staging systems can be used to guide initial therapeutic and diagnostic follow-up strategy decisions, it is important to recognize that initial risk estimates may need to change as new data are accumulated during follow-up [25]. In our practice, we restratify patients on each follow-up visit using a reclassification system that emphasizes the response to therapy for each individual patient. The response to therapy is assessed primarily with ultrasonography and measurements of serum thyroglobulin (Tg). (See 'Initial monitoring during year 1' below.)
As originally conceived, these clinical outcomes described the best response to initial therapy during the first two years of follow-up [25,26], but are now being used to describe the clinical status at any point during follow-up. (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Dynamic risk stratification'.)
At each follow-up visit, patients are classified as having one of the following clinical outcomes (table 4) [26,27]:
●Excellent response – No clinical, biochemical, or structural evidence of disease.
●Biochemical incomplete response – Abnormal Tg or rising Tg antibody values in the absence of localizable disease.
●Structural incomplete response – Persistent or newly identified locoregional or distant metastases.
●Indeterminate response – Nonspecific biochemical or structural findings that cannot be confidently classified as either benign or malignant. This includes patients with stable or declining antithyroglobulin (anti-Tg) antibody levels without definitive structural evidence of disease.
The precise definition of type of response is dependent on the extent of initial therapy (table 4).
Reclassification at each follow-up visit allows clinician to tailor ongoing management recommendations to the current clinical status (rather than the initial risk stratification estimates) (table 5 and table 6). (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Dynamic risk stratification'.)
Initial monitoring during year 1 — For the detection of possible persistent/recurrent disease during the first year after thyroidectomy or lobectomy, we monitor [1,2,28]:
●Neck ultrasound
●TSH
●Serum Tg levels on thyroid hormone suppression
Serum Tg on thyroid hormone suppression is generally measured every three to six months for the first year, with ultrasound at 6- to 12-month intervals depending on initial risk assessment (table 5). (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Thyroid cancer follow-up'.)
Additional imaging (cross-sectional or function imaging [eg, magnetic resonance imaging (MRI), computed tomography (CT), fludeoxyglucose-positron emission tomography (FDG-PET)]) is usually reserved only for (table 5) (see 'Imaging' below):
●ATA high-risk patients (table 1) who typically have either a biochemical or structural incomplete response to therapy
●ATA low/intermediate-risk patients who demonstrate a structural or biochemical incomplete response to therapy during the first year of follow-up
These patients require further evaluation to identify residual disease, with consideration for additional therapies. In general, gross residual disease (structural incomplete response) in cervical lymph nodes identified by physical examination or ultrasound should be confirmed by fine-needle aspiration (FNA) and surgical resection considered. (See 'Management of persistent or recurrent disease' below.)
Diagnostic whole-body radioiodine scanning may still have a role in the follow up of higher-risk patients. (See 'Diagnostic whole-body scan' below.)
Serum thyroglobulin measurements — Serum Tg levels are used to monitor patients with differentiated thyroid cancer for persistent or recurrent disease after initial therapy (lobectomy, thyroidectomy with or without radioiodine ablation) (table 5). (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Monitoring response to therapy'.)
In the first year after treatment of differentiated thyroid cancer, we measure thyroid hormone-suppressed serum Tg and Tg antibodies every three to six months. Serial Tg measurements should be performed using the same assay. Use of an assay with a functional sensitivity of 0.05 to 0.1 ng/mL is preferable. Anti-Tg antibodies, present initially in approximately 25 percent of patients with thyroid cancer, interfere with all assays for Tg. As a result, we measure anti-Tg antibodies, using the same assay over time, with each measurement of serum Tg. Tg assays are reviewed in detail elsewhere. (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Thyroglobulin assay'.)
Serum Tg can be measured while taking suppressive doses of thyroid hormone (TSH suppressed) or with TSH stimulation (after thyroid hormone withdrawal or after administration of recombinant human TSH [rhTSH (thyrotropin alfa)]). Stimulated Tg measurements are generally not necessary in ATA low-risk patients who do not receive radioiodine to ablate thyroid remnants, or in ATA intermediate/high-risk patients who have a detectable Tg on suppression (ie, evidence of biochemical incomplete response to therapy). Stimulated Tg values are useful in ATA intermediate- and high-risk patients with an undetectable suppressed Tg to document an excellent response to therapy or, conversely, to identify the presence of persistent/recurrent disease [29].
In the newer, more sensitive Tg assays (functional sensitivity <0.05 ng/mL), serum Tg concentrations (measured while receiving T4 [levothyroxine] suppression therapy) correlate with rhTSH-stimulated Tg concentrations and, therefore, may decrease the need for rhTSH-stimulated measurements [30-34].
The interpretation of the serum Tg level depends upon the initial therapy (table 4).
Thyroidectomy with 131-I ablation — For patients who had a total thyroidectomy and radioiodine remnant ablation, an excellent response is a nonstimulated Tg <0.2 ng/mL (or TSH-stimulated Tg <1 ng/mL) (table 4).
Thyroidectomy without 131-I ablation — For patients who have had total or near-total thyroidectomy without radioiodine ablation, an excellent response is a nonstimulated Tg <0.2 ng/mL (or TSH-stimulated Tg <2 ng/mL). The interpretation of serum Tg levels may be difficult in this subset of patients as it depends upon the size of the thyroid remnant [35]. Many patients do have undetectable basal Tg levels (<0.2 ng/mL), and basal serum Tg (along with anti-Tg antibodies) should be measured in such patients as rising values over time are suspicious for growing thyroid tissue or cancer (table 4). (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Predictor of clinical outcomes'.)
Lobectomy — Periodic measurement of serum Tg should also be performed in patients who were treated with lobectomy. Although specific criteria for distinguishing normal residual thyroid tissue from persistent or recurrent thyroid cancer have not been defined, most patients with an excellent response should have a serum Tg level <30 ng/mL (table 4) [36,37]. Previously, a rising Tg value over time was considered to be a reliable marker of recurrent disease. However, subsequent studies have demonstrated that changes in serum Tg over time are not reliable indicators of recurrent disease and that rising Tg levels are more likely to be related to residual thyroid tissue/nodules than to a true structural disease recurrence [38-40].
Thyroglobulin antibodies — In patients with anti-Tg antibodies, serum Tg concentrations alone cannot be used as a marker to detect persistent or recurrent disease after thyroidectomy and ablation of residual normal thyroid tissue. Nevertheless, we measure serum Tg and anti-Tg antibodies as we do in patients without anti-Tg antibodies because disease recurrence can be heralded by a rise in Tg antibodies with or without a corresponding rise in serum Tg, and conversely, a significant fall in these titers suggests future recurrence is unlikely [41]. (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Surrogate tumor marker'.)
In high-risk patients with persistent positive anti-Tg antibodies, imaging in addition to neck ultrasound (including neck and chest CT and/or PET-CT) may be warranted to detect structural disease.
Imaging — Neck ultrasound is performed at 6- to 12-month intervals depending on risk assessment (table 5). Ultrasonography has been particularly useful at identifying malignant cervical lymph nodes, the most common site of recurrent papillary thyroid cancer. Ultrasonographic lymph node characteristics most consistent with malignancy are a cystic appearance, microcalcifications, loss of the normal fatty hilum, and peripheral vascularization (image 1) [42]. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Thyroid cancer'.)
If there is biochemical or ultrasound evidence of recurrence, other tests that may be indicated to identify the sites of disease include a diagnostic whole-body scan (radioiodine imaging on a low-iodine diet with TSH stimulation), CT or MRI, skeletal radiographs, or skeletal radionuclide imaging [43]. In patients with evidence of distant metastases, FDG-PET scanning may provide useful prognostic information [44]. This was illustrated in a study of 125 patients with well-differentiated thyroid cancer who underwent FDG-PET scanning; uptake of FDG in a large volume of tissue correlated with poor survival, predicting outcome better than uptake of radioiodine.
In most studies, T4 therapy was not withdrawn before FDG-PET scanning was done, but in one small study, more lesions were identified after therapy was withdrawn [45]. The use of rhTSH before FDG-PET scan significantly increases the number of lesions detected, but treatment changes due to true positive lesions are uncommon (6 percent in one study of 63 patients) [46].
FDG-PET may complement iodine-131 (131-I) scanning [47]. In a study of 239 patients with metastases and high Tg, the sensitivity of FDG-PET was 49 percent, the sensitivity of 131-I was 50 percent, and the combined sensitivity was 90 percent. FDG-PET was more likely to be positive in 131-I negative patients [48].
Diagnostic whole-body scan — Diagnostic whole-body radioiodine scanning may have a role in the follow-up of patients with high or intermediate risk (with higher-risk features) of persistent disease (table 1). However, we are in agreement with the ATA guidelines that routine follow-up diagnostic whole-body scanning one year after radioiodine ablation is not required in low- and intermediate-risk (with lower-risk features) patients (table 5) [1].
Two studies [49,50], but not a third [51], suggested that whole-body scanning is unnecessary if rhTSH-stimulated serum Tg concentrations are less than 2 ng/mL. Another study reported that a combination of rhTSH-stimulated Tg and neck ultrasound has a better predictive value than either rhTSH-stimulated Tg alone or in combination with radioiodine scanning [52].
When diagnostic radioiodine scanning is performed, we suggest using rhTSH stimulation for radioactive iodine scanning when the likelihood of requiring additional radioactive iodine therapy is low. If the patient is very likely to need additional radioiodine therapy (high-risk patients), thyroid hormone withdrawal is the preferred approach. This topic is reviewed in more detail separately. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Choice of method for increasing TSH' and "Differentiated thyroid cancer: Radioiodine treatment", section on 'Pretreatment scanning'.)
Ongoing monitoring after year 1 — Ongoing follow-up (neck ultrasound, serum Tg) is guided by assessment of the individual patient's response to therapy during the first one to two years of follow-up (table 6). Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, but recurrences may occur many years or even decades later, particularly in patients with papillary cancer [53]. Nonetheless, continued routine use of surveillance neck ultrasound in ATA low- to intermediate-risk patients with no biochemical or clinical evidence of disease is more likely to identify false-positive findings than true structural disease recurrence [54,55].
A serum TSH is measured annually and six to eight weeks after any dose adjustments of T4. Although the serum TSH should be maintained <0.1 mU/L in patients with a structurally incomplete response (table 4), patients with a better response to therapy can have their TSH goal raised [1]. As examples:
●For patients who initially presented with high-risk disease but who have an excellent or indeterminate clinical response to therapy, a TSH goal of 0.1 to 0.5 mU/L for up to five years is acceptable, after which time the degree of suppression can be further relaxed (with continued surveillance for recurrence).
●For patients who initially presented with low-risk disease and who have an excellent clinical response to therapy, a TSH goal of 0.5 to 2 mU/L is acceptable.
●For patients with a biochemically incomplete response, the serum TSH should be maintained between 0.1 and 0.5 mU/L.
MANAGEMENT OF PERSISTENT OR RECURRENT DISEASE — Recurrent tumor in the neck may be detected by clinical examination or rising serum thyroglobulin (Tg) concentrations, but ultrasonography is the most sensitive technique for localization (image 1) [35,56]. (See 'Imaging' above and "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Thyroid cancer follow-up'.)
Highly sensitive detection tools (such neck ultrasonography, computer tomography [CT] scans, magnetic resonance imaging [MRI], and highly sensitive serum thyroglobulin assays) can identify very small volume persistent or recurrent disease that may not demand immediate intervention. Thus, we differentiate "detectable findings" from "actionable findings" [57]. The key factors that differentiate detectable from actionable findings include:
●Tumor size (volume)
●Tumor location
●Tumor growth rate (biochemical or structural doubling time)
●Symptoms
●Patient preference
Minimal disease — Although many patients will still have abnormal serum Tg levels after surgery, indicating a persistence of detectable disease, surgery is not always indicated.
Surgical resection is typically reserved for patients with clinically significant, low-volume metastatic disease, eg, central neck lymph nodes at least >0.8 cm in diameter or, possibly, larger nodes in the lateral compartments (>1.5 to 2 cm), especially if they are increasing in size (more than 3 to 5 mm in any dimension) or are significantly fludeoxyglucose-positron emission tomography (FDG-PET) positive (standardized uptake value [SUV] 5 to 10). However, we recognize that aggressive surgical resection of small-volume disease in the central or lateral neck does not have a proven benefit in terms of improving overall survival. Therefore, it is important to ensure that the risk of persistent low-level disease outweighs the risk of surgical resection in patients with potentially stable low-volume disease.
Surgery is usually followed by a reevaluation of the clinical status, which always includes serum Tg determinations, may include radioiodine scanning, and, if there is persistent radioiodine uptake, radioiodine therapy. However, if the patient had a recombinant human thyroid-stimulating hormone (rhTSH [thyrotropin alfa])-stimulated radioiodine scan before such surgery and if gross recurrent disease failed to concentrate radioiodine before surgery, there is likely no role for postoperative imaging and radioiodine therapy. Recurrent disease that is FDG avid (positive on FDG-PET scanning) is unlikely to respond to even high-dose radioiodine therapy [58]. (See 'High serum thyroglobulin and negative radioiodine scan' below.)
Extensive disease — Recurrence within the thyroid bed may be associated with soft-tissue, laryngeal, tracheal, or esophageal invasion, which may require more extensive resection; imaging studies with contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) may be valuable to detect such locally extensive disease. (See 'Imaging' above and "Differentiated thyroid cancer: Surgical treatment", section on 'Surgery for invasive disease'.)
Patients who develop distant metastases during long-term follow-up are treated like those with metastases found at the time of initial treatment; however, radioiodine therapy may be less effective in these patients [59]. (See 'Subsequent management based on risk classification' above.)
Other options for treating recurrent/metastatic disease include the following [60-63]:
●Radioiodine, if scans demonstrate uptake.
●Systemic chemotherapy (eg, kinase inhibitors).
●External radiotherapy.
●Percutaneous ethanol injection of cervical nodal metastases.
●Radiofrequency ablation of cervical, osseous, and pulmonary metastases – This is an alternative for patients who are poor surgical candidates and whose metastases do not concentrate radioiodine, but expertise in this treatment modality is not widely available.
●Palliative embolization of bone metastases – Palliative embolization may reduce symptoms or be used prior to surgery.
Surgery may be considered for patients with single distant metastases, including patients with a single bone metastasis [64], brain metastases [65], or limited pulmonary metastases [66]. The five-year survival for 31 patients with papillary cancer after thoracic metastasectomy was 64 percent [66], and radical surgical extirpation of isolated bone metastases is associated with improved survival [67].
Pamidronate may reduce bone pain from skeletal metastases and improve quality of life, and in one study, resulted in partial radiologic improvement in 2 of 10 patients [68]. Zoledronic acid can also be used, although its greater potency may increase risk of hypocalcemia and osteonecrosis of the jaw (ONJ) (although this remains a rare complication) [69,70]. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw'.)
Denosumab (a receptor activator of nuclear factor kappa-B [RANK] ligand inhibitor) is also available for the prevention of skeletal related events (pathologic fracture, need for surgery or external beam irradiation to a bone metastasis, or spinal cord compression) in patients with bone metastases from solid tumors. Thus, denosumab is an alternative to bisphosphonate therapy in the management of thyroid cancer patients with bone metastases [71]. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Denosumab'.)
Systemic chemotherapy or palliative external radiotherapy may be considered for patients with either local or distant recurrence or when radioiodine fails to control local growth and spread of disease. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy" and "Differentiated thyroid cancer: External beam radiotherapy".)
High serum thyroglobulin and negative radioiodine scan — It is not uncommon to identify patients who have abnormal serum Tg values after total thyroidectomy and radioiodine ablation with no evidence of radioiodine avidity on diagnostic and, often, post-therapy radioiodine scans [72,73]. These false-negative scans may reflect inadequate TSH stimulation, iodine contamination, the presence of tumor deposits too small to be detected by a scintillation camera, or loss of iodine uptake through tumor dedifferentiation.
The management of such patients is controversial, and there are insufficient data to determine optimal therapy [74].
Our approach to patients with radioiodine-negative, serum Tg-positive disease is as follows:
●Measurement of 24-hour urinary iodine excretion to exclude exogenous iodine excess causing a false-negative scan.
●Neck ultrasound and neck and chest CT (without iodinated contrast).
●In high-risk patients or those in whom the basal or stimulated Tg is ≥10 ng/mL, additional imaging studies should be performed to include whole-body FDG-PET scan (preferably combined with CT imaging).
In various studies, ultrasonography [75,76], CT [75], MRI [77], or scintigraphy with 111-indium-penetreotide, 99m-technetium-sestamibi, or 99m-technetium-tetrafosmin [78-80] detected foci of cancer in from 25 to 50 percent of patients with negative diagnostic radioiodine scans. Distant metastases can also be identified by chest and bone radiographs [81]. In addition, FDG-PET may be useful. In a review of PET imaging in scan-negative patients that summarized 12 studies, sensitivity ranged from 60 to 95 percent and specificity from 25 to 90 percent [82]. Metastatic lesions with high avidity for glucose in PET imaging, measured by elevated standard uptake values, are associated with resistance to radioiodine therapy and worse prognosis [58,83].
●We agree with the American Thyroid Association (ATA) guidelines that radioiodine is usually not necessary in patients with nonstimulated Tg values <5 ng/mL (or stimulated Tg values less than 10 ng/mL) in the absence of structurally evident disease. However, we will consider empiric radioiodine administration (100 to 200 mCi) in patients with radiographically detectable micrometastatic pulmonary metastases that do not concentrate FDG on PET imaging or with progressively rising Tg levels. (See "Differentiated thyroid cancer: Radioiodine treatment".)
●External radiotherapy for patients with critically placed bone metastases. (See "Differentiated thyroid cancer: External beam radiotherapy".)
●Patients with progressive macrometastatic disease unresponsive to radioiodine should be considered for systemic therapy or an appropriate clinical trial.
Studies show 42 to 75 percent of patients with high serum Tg and negative diagnostic radioiodine scans had demonstrable uptake, most often in the neck and mediastinum, after administration of a high dose (therapeutic dose) of radioiodine (eg, 150 mCi [5550 MBq]) [75,84,85]. Distant metastases were more often identified in patients with higher serum Tg concentrations (>200 ng/mL) [84]. In a study of 27 patients with negative diagnostic scans and positive post-treatment scans, 56 percent had progressive disease that did not respond to radioiodine, while 44 percent had stable disease that did not regress after radioiodine [86].
In some [72,84,85,87], but not all [88], studies, radioiodine administration resulted in reductions in serum Tg concentrations in patients with high serum Tg and negative diagnostic radioiodine scans, but there is no evidence that the treatment affects prognosis. Furthermore, when there is no structural evidence of disease, observation with T4 (levothyroxine) suppression is often associated with a slow decline in Tg levels over many years. These observations question whether empiric radioiodine therapy for scan-negative, Tg-positive patients has any significant clinical benefit beyond improved disease localization [50,74,89,90].
PROGNOSIS — Most patients with papillary cancer do not die of their disease. However, a number of factors have been identified that are associated with a higher risk for tumor recurrence and cancer-related mortality. The most important prognostic factors are age at diagnosis, size of the primary tumor, and the presence of soft tissue invasion or distant metastases (table 2). (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Prognostic features'.)
When compared with papillary thyroid cancer, follicular cancer typically occurs in older patients. In addition, it is more commonly associated with an aggressive clinical course, distant metastases, and higher mortality than papillary thyroid cancer. Women may have a better prognosis than men. (See "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)", section on 'Prognostic features'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Thyroid cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Surgical management – The primary therapy for differentiated (papillary and follicular) thyroid cancer is surgery.
•Preoperative imaging – All patients should have a preoperative ultrasound evaluation of the central and lateral neck lymph nodes in order to plan the surgical procedure. Additional imaging beyond routine preoperative neck ultrasound should be obtained in patients presenting with locally advanced disease. (See 'Preoperative imaging' above and "Differentiated thyroid cancer: Surgical treatment", section on 'Importance of preoperative imaging'.)
•Choice of surgical procedure – Surgical options include total/near-total thyroidectomy and unilateral lobectomy with isthmusectomy. The operative approach depends upon the extent of the disease (eg, primary tumor size and the presence of extrathyroidal extension or lymph node metastases), the patient's age, and the presence of comorbid conditions. Subtotal thyroidectomy is an inadequate procedure for patients with thyroid cancer. (See 'Choice of surgical procedure' above and "Differentiated thyroid cancer: Surgical treatment", section on 'Choice of procedure'.)
•Postoperative thyroid hormone replacement – After total thyroidectomy, all patients require postoperative thyroid hormone therapy (T4 [levothyroxine]) to replace normal hormone production and/or to suppress regrowth of tumor. Thyroid-stimulating hormone (TSH) is measured four to six weeks postoperatively, and the initial dose is adjusted as needed to achieve goal TSH. For selected low- and intermediate-risk patients whose initial surgery was a lobectomy, we measure serum TSH six weeks after surgery and determine the need for T4 based upon the TSH and evaluation of postoperative disease status. (See 'Postoperative thyroid hormone' above.)
●Initial risk stratification – In order to determine the need for additional treatment (in particular, radioiodine therapy) after surgery, we use the American Thyroid Association (ATA) initial risk stratification system to estimate the risk of persistent/recurrent disease. This system is designed to stratify patients as having either low (papillary thyroid cancer confined to thyroid), intermediate (regional metastases, worrisome histologies, extrathyroidal extension, or vascular invasion), or high (gross extrathyroidal extension, distant metastases, or postoperative serum thyroglobulin [Tg] suggestive of distant metastases) risk of recurrence primarily based upon clinicopathologic findings (table 1). (See 'Postoperative evaluation' above.)
●Management based on risk stratification – Subsequent management includes treatment with thyroid hormone-suppressive therapy (most patients) and radioiodine (high-risk and selected intermediate-risk patients). (See 'Thyroid hormone suppression' above and 'Radioiodine therapy' above and "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)
●Thyroid hormone suppression – The initial degree of TSH suppression is individualized based upon the extent of the disease and the likelihood of recurrence (table 1). TSH goals for long-term follow-up are based on response to therapy assessments further modified by comorbid conditions that increase the potential risks of prolonged TSH suppression (such as menopause, tachycardia, osteopenia, older age, osteoporosis, or atrial fibrillation) (figure 1). (See 'Thyroid hormone suppression' above.)
•High-risk disease – For most patients with high-risk disease, we recommend an initial serum TSH goal of <0.1 mU/L (Grade 1B).
•Intermediate- or low-risk disease – For patients with intermediate-risk disease, or low-risk disease treated with thyroidectomy who have detectable serum Tg levels, we suggest an initial serum TSH goal between 0.1 and 0.5 mU/L (Grade 2C).
For other low-risk patients who have undetectable serum Tg levels (with or without remnant ablation) or who were treated with lobectomy, TSH can be maintained in the mid to lower half of the reference range (0.5 to 2.0 mU/L).
●Monitoring – Ongoing monitoring strategies are based upon the patient's ATA risk of recurrence (table 1) and the reassessment of response to therapy at each follow-up visit (table 4). (See 'Dynamic risk stratification' above.)
For the detection of possible persistent/recurrent disease during the first year after thyroidectomy or lobectomy, we monitor neck ultrasound, TSH, and serum Tg levels on thyroid hormone suppression. The timing, frequency, and type of additional testing used to detect recurrent disease is based on both ATA initial risk stratification and ongoing response to therapy evaluations (table 5 and table 6). (See 'Initial monitoring during year 1' above and 'Ongoing monitoring after year 1' above.)
●Persistent or recurrent disease – Options for treating recurrent/metastatic disease include surgery, radioiodine (if scans demonstrate uptake), chemotherapy, and external radiotherapy. (See 'Management of persistent or recurrent disease' above and "Differentiated thyroid cancer: External beam radiotherapy" and "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy".)
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