Version July 2025
INTRODUCTION —
When therapy is indicated, 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 experienced in the treatment of thyroid cancer.
This topic will provide a broad overview of the classification of malignant thyroid neoplasms and 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 —
Follicular cell-derived neoplasms are classified based on histologic architecture, cytologic features, molecular profile patterns, and potential for aggressive behavior (table 1) [1-3]. Thyroid follicular epithelial-derived malignant neoplasms include:
●Well-differentiated cancers
•Papillary cancer
•Follicular cancer
•Invasive encapsulated follicular subtype of papillary thyroid cancer
•Oncocytic (Hürthle cell) cancer
Patients with these tumors are often treated similarly, despite numerous biologic differences. Each of these four well-differentiated cancer categories can be further classified into specific subtypes (formerly known as "variants") (figure 1). While the papillary thyroid carcinoma category has multiple well-defined subtypes, the other three well-differentiated thyroid carcinoma phenotypes share the subtype definitions of minimally invasive, encapsulated angioinvasive, or widely invasive. (See "Papillary thyroid cancer: Clinical features and prognosis", section on 'Papillary thyroid cancer subtypes' and "Follicular thyroid cancer (including oncocytic carcinoma of the thyroid)", section on 'Clinical features'.)
●High-grade follicular cell-derived non-anaplastic cancer – High-grade follicular cell-derived non-anaplastic thyroid carcinoma defines a group of thyroid cancers with a prognosis that is intermediate between well-differentiated thyroid cancers and anaplastic thyroid cancer. This category consists of two distinct tumor types (figure 1):
•Differentiated high-grade thyroid carcinomas that retain a well-differentiated cytologic/architectural phenotype (eg, papillary, follicular, or oncocytic carcinoma histologic features) but have increased mitotic counts and/or tumor necrosis (picture 1).
•Poorly differentiated thyroid carcinomas, which is based on the Turin proposal [4] and include invasive tumors that have lost their architectural and cytologic differentiation but do not demonstrate features of anaplastic thyroid carcinoma.
To be classified as either differentiated high-grade thyroid carcinoma or poorly differentiated thyroid carcinoma, the tumors also must demonstrate invasive properties such as capsular invasion, vascular invasion, extrathyroidal extension, or invasion into surrounding thyroid parenchyma.
●Anaplastic (undifferentiated) cancer – Most anaplastic cancers appear to arise from differentiated cancers and are more aggressive. (See "Anaplastic thyroid cancer".)
Each of the major histologic phenotypes demonstrates a predominant molecular phenotype (RAS-like versus BRAF-like) [5]. For example, the papillary thyroid cancer group and the differentiated high-grade thyroid carcinoma group signals primarily as BRAF-like tumors [6-8]. Conversely, the follicular thyroid cancer, invasive encapsulated follicular subtype of papillary thyroid cancer, and the poorly differentiated thyroid carcinoma groups signal primarily as RAS-like tumors. The oncocytic carcinomas of the thyroid have a unique molecular phenotype consisting of widespread chromosomal losses and mitochondrial deoxyribonucleic acid (DNA) mutations.
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, neither of which arise from thyroid follicular cells. Cancers that metastasize to the thyroid include breast, colon, kidney cancer, and melanoma. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging".)
SURGICAL MANAGEMENT —
Surgery is the primary mode of therapy for patients with differentiated thyroid cancer. After initial surgery, patients with thyroid cancer are typically managed by endocrinologists experienced 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 [9].
The operative approach (total thyroidectomy versus thyroid lobectomy) 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 preferences, and the presence of comorbid conditions. The choice of procedure is discussed in detail elsewhere. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Choice of procedure'.)
The approach to lymph node dissection is also 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
Thyroid lobectomy and isthmusectomy — For low- and intermediate-risk patients whose initial surgery was a lobectomy with isthmusectomy, we do not begin levothyroxine immediately postoperatively (unless the patient has Hashimoto's thyroiditis and the preoperative thyroid-stimulating hormone [TSH] was elevated or high normal) [10]. Instead, we measure serum TSH six weeks after surgery and determine the need for levothyroxine based upon the TSH and evaluation of postoperative disease status (algorithm 1). Following lobectomy, a TSH between 0.5 and 3 mU/L is considered acceptable.
Total thyroidectomy — After total thyroidectomy, all patients require postoperative thyroid hormone therapy to replace normal hormone production and to suppress regrowth of tumor. The initial dose and type of thyroid hormone (levothyroxine or liothyronine) depend upon the likelihood of needing radioiodine scanning/ablation and the method of preparation for radioiodine scanning (algorithm 1). These decisions are based upon the estimated risk of persistent/recurrent disease. (See 'Initial risk stratification' below.)
●Radioiodine scanning and ablation unlikely or decision uncertain – In American Thyroid Association (ATA) low- and intermediate-risk patients (table 2) who are unlikely to need radioiodine scanning or ablation, levothyroxine (usually 1.6 to 2 mcg/kg per day) can be started immediately postoperatively. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)
Typically, patients at low risk are treated with 1.6 mcg/kg and those at intermediate risk are treated with 2 mcg/kg. If the complete clinicopathologic findings to fully estimate risk of persistent/recurrent disease are unavailable in the immediate postoperative period, the clinician may need to initiate levothyroxine (1.6 mcg/kg per day) and modify the strategy once the findings are available. Older patients (>65 years) and those with comorbidities may be treated with a slightly lower initial dose (eg, 1.3 mcg/kg per day) with dose modifications as needed. (See 'Initial risk stratification' below.)
●Radioiodine scanning and ablation likely
•Recombinant human TSH (rhTSH) – Selected ATA intermediate- and high-risk patients (table 2) in whom radioiodine scanning and ablation will be pursued using rhTSH (thyrotropin alfa) can initiate levothyroxine (1.6 to 2 mcg/kg per day) immediately postoperatively (algorithm 1). Some experts also routinely use rhTSH for radioiodine scanning and therapy in patients with gross residual disease or distant metastasis. These patients can also initiate levothyroxine immediately. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Choice of method for increasing TSH'.)
The 2 mcg/kg dose is used in selected intermediate- and high-risk patients, modified by age and other comorbid conditions.
•Thyroid hormone withdrawal – For patients in whom radioiodine scanning and ablation will be done using thyroid hormone withdrawal, short-term thyroid hormone replacement can be initiated postoperatively with T3, 25 mcg two times daily (algorithm 1). 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'.)
After the scanning is completed, levothyroxine is administered (1.6 to 2 mcg/kg daily). A lower initial dose (eg, 1.3 mcg/kg daily) may be used in older adults and those with comorbidities.
●Adjustment of levothyroxine – TSH is measured four to six weeks after initiation of levothyroxine. 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.)
INITIAL RISK STRATIFICATION —
After surgery, the presence or absence of persistent disease and risk for recurrent disease should be assessed to determine the need for additional treatment, in particular radioiodine therapy. 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.)
Postoperative evaluation
●Thyroglobulin/thyroglobulin antibody – We typically obtain nonstimulated serum thyroglobulin (Tg) and Tg antibody levels approximately four to six weeks after thyroidectomy (table 3) or lobectomy 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 [11], 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 scans – 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 now than in the past.
They can be obtained 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 [11]. 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 4) to estimate mortality risk and the ATA risk stratification system to estimate the risk of recurrence (table 2).
●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 4). (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 stratifies patients primarily based upon clinicopathologic findings (table 2) [11]. The risk of recurrence, however, follows a continuum across the three discrete risk categories (low, intermediate, and high):
•Low risk – Papillary thyroid cancer confined to thyroid.
•Intermediate risk – Regional metastases, worrisome histologies, extrathyroidal extension, or vascular invasion.
•High risk – Gross extrathyroidal extension, distant metastases, or postoperative serum Tg suggestive of distant metastases) risk of recurrence.
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. (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'ATA risk stratification'.)
Tumor-specific molecular profiles (eg, mutations in 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. (See "Differentiated thyroid cancer: Clinicopathologic staging", section on 'Molecular characteristics'.)
MANAGEMENT BASED ON INITIAL RISK STRATIFICATION —
Postoperative management depends upon the risk of persistent/recurrent disease (table 2). Most patients receive thyroid hormone suppressive therapy whereas radioiodine is reserved for high-risk and selected intermediate-risk patients. (See 'Risk classification' above.)
Thyroid hormone suppression — After initial thyroidectomy, levothyroxine is required to prevent hypothyroidism and, in most patients, to minimize potential TSH stimulation of tumor growth. (See 'Postoperative thyroid hormone' above.)
Our approach to thyroid hormone suppression is based upon the extent of disease and risk of disease recurrence (based on ATA risk stratification system) (table 2 and table 3). Thyroid hormone suppression therapy should be monitored with serum TSH, measured annually and six to eight weeks after any levothyroxine dose adjustments.
Initial TSH goals
●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 initial TSH goal is 0.1 and 0.5 mU/L.
For ATA low-risk patients who have undetectable serum Tg levels (with or without remnant ablation), TSH can be maintained in the mid to lower half of the reference range (0.5 to 3.0 mU/L).
For patients treated with lobectomy, thyroid hormone treatment may be unnecessary if a patient can maintain their TSH in the goal range (lower limit of normal to 3 mU/L).
●ATA intermediate risk – For patients with intermediate-risk disease, the initial serum TSH goal is 0.1 and 0.5 mU/L.
●ATA high risk – For patients with high-risk disease, the serum TSH initially should be <0.1 mU/L.
Adjustment of TSH goals based on response to therapy — Thyroid-stimulating hormone (TSH) goals for long-term follow-up are based on response to therapy assessments (table 5), 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 2) [11]. During the first one to two years of follow-up, 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. For patients who initially presented with high-risk disease but who have an excellent 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). (See 'Excellent 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 [12,13]. Some retrospective studies suggested improved relapse-free survival when serum TSH concentrations were undetectable during follow-up [14,15]. 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 [16,17], whereas milder degrees of TSH suppression were still associated with excellent outcomes in patients with intermediate-risk features (table 6) [17]. 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 [18]. 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 [19], 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 levothyroxine therapy, including the potential for acceleration of bone loss [20-22], atrial fibrillation [23], cardiac dysfunction [24-27], and cognitive decline [28] emphasize the importance of tailoring the levothyroxine dose to the extent of the disease and the likelihood of recurrence [29]. These decisions can be based in part upon staging by the tumor, node, metastases (TNM) system (table 4) in conjunction with the proposed ATA risk of recurrence system (table 2) [11]. (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 2). Radioiodine is typically reserved for high-risk patients and selected intermediate-risk patients. This topic is reviewed in detail separately. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)
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 2 and table 3) and the reassessment of response to therapy at each follow-up visit (table 5 and table 7). This strategy is in keeping with the ATA guidelines for the management of patients with thyroid nodules and differentiated thyroid cancer [11].
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 [30]. 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 'Tests to monitor' below.)
As originally conceived, these clinical outcomes described the best response to initial therapy during the first two years of follow-up [30,31], 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 5) [31,32]:
●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 5).
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 3 and table 7). (See 'Ongoing management based on dynamic risk stratification' below.)
Tests to monitor — For the detection of possible persistent/recurrent disease after thyroidectomy or lobectomy, we monitor (table 3 and table 7) [11,33,34]:
●Serum Tg and Tg antibody levels
●Neck ultrasound
Other imaging is warranted in selected patients. (See 'Other imaging' below.)
Most recurrences of differentiated thyroid cancer occur within the first five years after initial treatment, but recurrences occasionally occur many years or even decades later, particularly in patients with papillary cancer [35].
Serum thyroglobulin measurements
Monitoring strategy
●Frequency of Tg measurement and assay – In the first year after treatment of differentiated thyroid cancer (lobectomy, thyroidectomy with or without radioiodine ablation), we measure serum Tg every three to six months (table 3). Subsequently, the frequency of monitoring depends on response to therapy (table 7).
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. (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Monitoring response to therapy'.)
For patients taking suppressive doses of thyroid hormone, we measure the Tg while taking thyroid hormone (TSH-suppressed Tg).
●Concurrent Tg antibody measurement – We measure anti-Tg antibodies, using the same assay over time, with each measurement of serum Tg. Anti-Tg antibodies are present initially in approximately 25 percent of patients with thyroid cancer who have concomitant autoimmune thyroiditis. Anti-Tg antibodies interfere with all assays for Tg. Tg assays are reviewed in detail elsewhere. (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Thyroglobulin assay'.)
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 may 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 [36]. (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Surrogate tumor marker'.)
●Role of stimulated Tg measurement – Serum Tg can also be measured 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 Tg >0.9 ng/mL on suppression (table 7).
•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 [37].
In the newer, more sensitive Tg assays (functional sensitivity <0.1 ng/mL), serum Tg concentrations (measured while receiving levothyroxine suppression therapy) correlate with rhTSH-stimulated Tg concentrations and, therefore, may obviate the need for rhTSH-stimulated measurements [38-42].
Interpretation of results — The interpretation of the serum Tg level depends upon the initial therapy and presence of Tg antibodies (table 5). For patients who have had thyroidectomy without iodine-131 (131-I) ablation or lobectomy, the interpretation of serum Tg levels may be difficult.
●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 5).
●Thyroidectomy without 131-I ablation – Interpretation of Tg depends upon the size of the thyroid remnant [43]. Many patients do have undetectable basal Tg levels (<0.2 ng/mL), and rising values over time are suspicious for growing thyroid tissue or cancer (table 5). (See "Differentiated thyroid cancer: Role of serum thyroglobulin", section on 'Predictor of clinical outcomes'.)
●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, and many patients have Tg levels that are in the 2 to 10 range (table 5) [44,45]. 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 [46-48].
Imaging
Neck ultrasound — In the first year after treatment of differentiated thyroid cancer (lobectomy, thyroidectomy with or without radioiodine ablation), we obtain a neck ultrasound, typically at 6- to 12-month intervals depending on risk assessment (table 3). Subsequently, the frequency of ultrasound imaging depends on response to therapy (table 7).
Recurrent tumor in the neck may be detected by clinical examination or rising serum Tg concentrations, but ultrasonography is the most sensitive technique for localization [43,49]. 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) [50]. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Thyroid cancer'.)
Other imaging — Additional imaging is usually reserved only for (table 3 and table 7) [11,34]:
●ATA high-risk patients (table 2) who typically have either a biochemical or structural incomplete response to therapy.
●ATA low/intermediate-risk patients who demonstrate a biochemical or structural incomplete response to therapy during the first year of follow-up.
Cross-sectional or functional imaging may include magnetic resonance imaging (MRI), computed tomography (CT), or fludeoxyglucose-positron emission tomography (FDG-PET):
●MRI, CT – Contrast-enhanced CT or MRI is valuable to detect locally extensive disease in patients with biochemical or structural incomplete response.
●FDG-PET scan – 18 FDG-PET scanning is usually reserved for selected patients with a biochemical incomplete response (eg, Tg >10 ng/mL) or structural incomplete response (eg, no evidence of radioiodine-avid disease) (table 7). In patients with evidence of distant metastases, FDG-PET scanning may also provide useful prognostic information [51]. 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, levothyroxine therapy was not withdrawn before FDG-PET scanning was done, but in one small study, more lesions were identified after therapy was withdrawn [52]. 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) [53].
FDG-PET may complement iodine-131 (131-I) scanning [54]. 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 [55].
●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 2). 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 3) [11].
Two studies [56,57], but not a third [58], 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 [59].
When diagnostic radioiodine scanning is performed, we typically use rhTSH stimulation for radioiodine scanning. Thyroid hormone withdrawal is an alternative 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 MANAGEMENT BASED ON DYNAMIC RISK STRATIFICATION —
Ongoing management is guided by assessment of the individual patient's response to therapy during the first one to two years of follow-up [11,34].
Excellent response to therapy — For patients with an excellent response to therapy (table 5) and no evidence of recurrence, monitoring should decrease in intensity and frequency (table 7). Continued routine use of surveillance neck ultrasound after five years in ATA low- to intermediate-risk patients with an excellent response to therapy (ie, no biochemical or clinical evidence of disease) is more likely to identify false-positive findings than true structural disease recurrence [60,61].
For patients who initially presented with low- or intermediate-risk disease and who have an excellent clinical response to therapy, a TSH goal of 0.5 to 3 mU/L is acceptable as the risk of recurrence is low (1 to 4 percent) [62]. For patients who initially presented with high-risk disease but who have an excellent 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). TSH goals are modified based on concurrent medical conditions that increase the risk of TSH suppression. (See 'Thyroid hormone suppression' above.)
Biochemical incomplete response — A biochemical incomplete response or recurrence is defined as the absence of localizable disease on imaging studies and an abnormal Tg (in the absence of Tg antibodies) or rising Tg antibodies. The threshold for an abnormal Tg depends on the initial therapy (table 5). (See 'Dynamic risk stratification' above.)
Approximately 20 percent of patients with a biochemical incomplete response will develop structural disease, whereas 30 to 60 percent will have normalization of Tg indicative of an excellent response [62,63]. Disease specific mortality is <1 percent.
For patients with a biochemically incomplete response, the serum TSH should be maintained between 0.1 and 0.5 mU/L. We use the serum Tg levels to help inform imaging frequency.
Nonstimulated Tg <10 ng/mL and stable or declining Tg or Tg antibodies — Continue ultrasound monitoring (table 7) and TSH suppression therapy.
Nonstimulated Tg ≥10 ng/ml, rising Tg, or rising Tg antibodies — Obtain additional imaging (RAI imaging, MRI/CT neck and chest, FDG-PET) to identify structural disease and assess radioiodine avidity. (See 'Other imaging' above.)
●Structural disease not identified – If structural disease is not identified, continue monitoring (table 7) and TSH suppression therapy.
Negative radioiodine 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. In the absence of radioiodine-avid disease on imaging, we seldom recommend empiric radioiodine therapy.
●Structural disease identified – If possible structural disease is eventually identified, biopsy is warranted to confirm diagnosis. Treatment is based on several factors (eg, size, location, rate of growth, radioiodine avidity). (See 'Structural incomplete response or recurrence' below.)
Structural incomplete response or recurrence — A structural incomplete response (or recurrence) is defined as evidence of structural or functional disease regardless of Tg or Tg antibody levels (table 5). These patients require imaging to identify extent of disease, biopsy to confirm diagnosis, and consideration for additional therapies [11,34].
Known sites of metastatic disease should be imaged by CT or MRI at 6- to 12-month intervals, depending on rate of progression. FDG-PET imaging can be useful to identify additional sites of disease if the Tg is rising over time without evidence of corresponding structural disease progression in the known sites of disease. Diagnostic radioiodine scanning should be performed to determine the radioiodine avidity of the structural disease.
For patients with bone metastasis, skeletal radiographs of lesions in weight-bearing bones are useful in assessing fracture risk. We seldom obtain routine bone scans in the evaluation of patients with bone metastasis from thyroid cancer. (See 'Other imaging' above.)
Serum TSH should be maintained <0.1 mU/L in patients with a structurally incomplete response. TSH goals are modified based on concurrent medical conditions that increase the risk of TSH suppression. (See 'Thyroid hormone suppression' above.)
Defining extent of disease — Highly sensitive detection tools (such as neck ultrasonography, CT scans, MRI, and highly sensitive serum thyroglobulin assays) (table 7) can identify very small volume persistent or recurrent disease that may not demand immediate intervention. Thus, we differentiate "detectable findings" from "actionable findings" [62]. 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
Subsequent evaluation and management depends on these factors as well as radioiodine avidity, FDG avidity, and specific pathology of the tumor.
Local disease
●Small volume cervical lymph nodes – 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) when the smallest diameter of the abnormal lymph node is ≥1 cm. FNA of smaller lymph nodes may be indicated if the abnormal lymph node is >0.8 cm in smallest diameter when located near critical structures in the central neck.
•FDG-PET negative and growing less than 3 to 5 mm – Persistent or recurrent local disease may not warrant active intervention if it is small volume (≤1 cm), stable, and the patient is asymptomatic. Ongoing monitoring for growth is required (table 7).
•FDG-PET positive or growing – Surgical resection is typically preferred for patients with clinically significant, low-volume, local disease, such as central neck lymph nodes ≥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 per year) or are significantly FDG-PET positive (standardized uptake value [SUV] 5 to 10).
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.
Where available, ablation therapies (eg radiofrequency, ethanol) are an alternative to surgery for small abnormal cervical lymph nodes [64-66].
●Large volume or invasive – For recurrence in the thyroid bed associated with soft-tissue, laryngeal, tracheal, or esophageal invasion, surgery is preferred if resectable. (See "Differentiated thyroid cancer: Surgical treatment", section on 'Surgery for invasive disease'.)
If disease is unresectable, options include radioiodine (for radioiodine-avid disease), systemic therapies, or external beam radiotherapy (EBRT). (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection' and "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy" and "Differentiated thyroid cancer: External beam radiotherapy".)
For small or large volume disease that is surgically resected, 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 [67]. However, recurrent disease that is FDG avid (positive on FDG-PET scanning) is unlikely to respond to even high-dose radioiodine therapy [68]. Furthermore, if the patient had an 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. Systemic therapy or EBRT are alternative options. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy" and "Differentiated thyroid cancer: External beam radiotherapy".)
Distant metastases
●Asymptomatic and slow growing or stable – Disease monitoring is an option for asymptomatic patients with indolent disease as long as there are no brain metastases [34].
●Symptomatic or growing
•Iodine avid – If radioiodine scans demonstrate uptake, radioiodine therapy is an option.
•Not iodine avid – If radioiodine scans do not demonstrate uptake, options include surgical resection if amenable, mutation-directed systemic therapy for unresectable disease, percutaneous radiofrequency ablation (where available, for metastases at sites other than brain), EBRT, clinical trials, best supportive care. (See "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy" and "Differentiated thyroid cancer: External beam radiotherapy".)
Surgery may be considered for patients with single distant metastases, including patients with a single bone metastasis [69], brain metastases [70], or limited pulmonary metastases [71]. The five-year survival for 31 patients with papillary cancer after thoracic metastasectomy was 64 percent [71], and radical surgical extirpation of isolated bone metastases is associated with improved survival [72].
●Additional treatments symptomatic bone metastases not amenable to radioiodine – In addition to therapies described above (eg, surgical resection, EBRT), other options for symptomatic bone metastases include embolization, or intravenous bisphosphonates or denosumab.
Palliative embolization may reduce symptoms or be used prior to surgery.
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 [73]. 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) [74,75]. (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 ligand [RANKL] 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 [34]. (See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors", section on 'Denosumab'.)
Indeterminate response — An indeterminate response is defined as 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 (table 5).
Approximately 15 to 20 percent of patients with an indeterminate response will develop structural disease [62]. In most patients, the nonspecific changes resolve or remain stable. Disease specific mortality is <1 percent.
Patients with an indeterminate response are monitored for the development of suspicious findings (table 7).
PROGNOSIS —
The vast majority of 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 4). (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
●Classification – Thyroid follicular epithelial-derived malignant neoplasms include follicular thyroid cancer, invasive encapsulated follicular subtype of papillary thyroid cancer, papillary thyroid cancer, oncocytic thyroid cancer, high-grade follicular cell-derived non-anaplastic thyroid cancer, and anaplastic thyroid cancer (table 1). Well-differentiated thyroid cancers include papillary, follicular, and oncocytic thyroid cancer as well as invasive encapsulated follicular variant papillary thyroid cancer (figure 1). (See 'Classification' above.)
●Surgical management – Surgery is the primary therapy for differentiated thyroid cancer.
•Preoperative imaging – All patients should have a preoperative ultrasound of the central and lateral neck lymph nodes in order to plan the surgical procedure. Additional cross-sectional 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 "Differentiated thyroid cancer: Surgical treatment", section on 'Choice of procedure'.)
•Postoperative thyroid hormone replacement – After initial thyroidectomy, levothyroxine is required to prevent hypothyroidism, and in most patients, to minimize potential thyroid-stimulating hormone (TSH) stimulation of tumor growth (algorithm 1). 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 levothyroxine 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 (table 2). 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. (See 'Initial risk stratification' above.)
●Management based on initial risk stratification – Subsequent management includes treatment with thyroid hormone-suppressive therapy (most patients) and radioiodine (high-risk and selected intermediate-risk patients). (See 'Management based on initial risk stratification' above.)
•Thyroid hormone suppression – The initial degree of TSH suppression is individualized based upon the extent of the disease and the likelihood of recurrence (table 2 and table 3).
-High-risk disease – For most patients with high-risk disease, we suggest an initial serum TSH goal of <0.1 mU/L (Grade 2C).
-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 after thyroidectomy (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 3.0 mU/L).
TSH goals for long-term follow-up are based on response to therapy assessments (table 5 and table 7) 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 2). Thyroid hormone suppression therapy should be monitored with serum TSH, measured annually and six to eight weeks after any levothyroxine dose adjustments. (See 'Thyroid hormone suppression' above.)
•Radioiodine – The decision to treat with radioiodine depends upon the risk of recurrence/persistent disease (table 2). Radioiodine is typically reserved for high-risk patients and selected intermediate-risk patients. (See "Differentiated thyroid cancer: Radioiodine treatment", section on 'Patient selection'.)
●Monitoring – Monitoring strategies are based upon the patient's ATA risk of recurrence (table 2 and table 3) and the reassessment of response to therapy at each follow-up visit (table 5 and table 7). (See 'Monitoring response to therapy' above and 'Dynamic risk stratification' above.)
For the detection of possible persistent/recurrent disease after thyroidectomy or lobectomy, we monitor neck ultrasound, 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 3 and table 7). (See 'Tests to monitor' above.)
●Ongoing management – Ongoing management is based upon response to therapy during the first one to two years of follow-up (table 5 and table 7). (See 'Ongoing management based on dynamic risk stratification' above and "Differentiated thyroid cancer: External beam radiotherapy" and "Differentiated thyroid cancer refractory to standard treatment: Systemic therapy".)
