Last updated December 16, 2022

Thyroid Nodules and Differentiated Thyroid Cancer -- Differentiated Cancer

Thyroid Nodules

Diagnosis

1. Screening people with familial follicular cell-derived differentiated thyroid cancer may lead to an earlier diagnosis of thyroid cancer, but the panel cannot recommend for or against ultrasound screening since there is no evidence that this would lead to reduced morbidity or mortality. (NR, I)
623
2.
A) Serum TSH should be measured during the initial evaluation of a patient with a thyroid nodule. (SR, M)
623
B) If the serum TSH123 is subnormal, a radionuclide (preferably I) thyroid scan should be performed. (, )
623
C) If the serum TSH is normal or elevated, a radionuclide scan should NOT be performed as the initial imaging evaluation. (SR, M)
623
3. Routine measurement of serum Tg for initial evaluation of thyroid nodules is NOT recommended. (SR, M)
623
4. The panel cannot recommend either for or against routine measurement of serum calcitonin in patients with thyroid nodules. (NR, I)
623
5. A) Focal 18FDG-PET uptake within a sonographically confirmed thyroid nodule conveys an increased risk of thyroid cancer, and fine needle aspiration is recommended for those nodules >1 cm. (SR, M)
623
5. B) Diffuse 18FDG-PET uptake, in conjunction with sonographic and clinical evidence of chronic lymphocytic thyroiditis, does not require further imaging or fine needle aspiration. (SR, M)
623
6. Thyroid sonography with survey of the cervical lymph nodes should be performed in all patients with known or suspected thyroid nodules. (SR, H)
623
7. FNA is the procedure of choice in the evaluation of thyroid nodules, when clinically indicated. (SR, H)
623
8. Thyroid nodule diagnostic FNA is recommended for (Figure 2, Table 1):
A) Nodules >1cm in greatest dimension with high suspicion sonographic pattern. (SR, M)
623
B) Nodules >1 cm in greatest dimension with intermediate suspicion sonographic. (SR, L)
623
C) Nodules >1.5 cm in greatest dimension with low suspicion sonographic pattern. (WR, L)
623
Thyroid nodule diagnostic FNA may be considered for (Figure 2, Table 1):
D) Nodules >2 cm in greatest dimension with very low suspicion sonographic pattern (e.g., – spongiform). Observation without FNA is also a reasonable option. (WR, M)
623
Thyroid nodule diagnostic FNA is not required for (Figure 2, Table 1):
E) Nodules that do not meet the above criteria. (SR, M)
623
F) Nodules that are purely cystic. (SR, M)
623
9. Thyroid nodule FNA cytology should be reported using diagnostic groups outlined in the Bethesda System for Reporting Thyroid Cytopathology (http://ajcp.ascpjournals.org/cgi/pmidlookup?view=long&pmid=20660341). (SR, M)
623
10. A) For a nodule with an initial nondiagnostic cytology result, FNA should be repeated with US guidance and, if available, on-site cytologic evaluation (SR, M)
623
10. B) Repeatedly nondiagnostic nodules without a high suspicion sonographic pattern require close observation or surgical excision for histopathologic diagnosis. (WR, L)
623
10. C) Surgery should be considered for histopathologic diagnosis if the cytologically nondiagnostic nodule has a high suspicion sonographic pattern, growth of the nodule (greater than 20% in two dimensions) is detected during ultrasound surveillance, or clinical risk factors for malignancy are present. (WR, L)
623
11. If the nodule is benign on cytology, further immediate diagnostic studies or treatment are not required. (SR, H)
623
12. If a cytology result is diagnostic for primary thyroid malignancy, surgery is generally recommended. (SR, M)
623
13. If molecular testing is being considered, patients should be counseled regarding the potential benefits and limitations of testing, and about the possible uncertainties in the therapeutic and long-term clinical implications of results. (SR, L)
623
14. If intended for clinical use, molecular testing should be performed in CLIA/CAP (Clinical Laboratory Improvement Amendments/College of American Pathologists) certified molecular laboratories, or international equivalent, as reported quality assurance practices may be superior compared to other settings. (SR, L)
623
15. A) For nodules with AUS/FLUS cytology, after consideration of worrisome clinical and sonographic features, investigations such as repeat FNA or molecular testing may be used to supplement malignancy risk assessment in lieu of proceeding directly with a strategy of either surveillance or diagnostic surgery. Informed patient preference and feasibility should be considered in clinical decision-making. (WR, M)
623
15. B) If repeat FNA cytology and/or molecular testing are not performed or inconclusive, either surveillance or diagnostic surgical excision may be performed for an AUS/FLUS thyroid nodule, depending on clinical risk factors, sonographic pattern, and patient preference. (SR, L)
623
16. A) Diagnostic surgical excision is the long-established standard of care for the management of follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) cytology nodules. However, after consideration of clinical and sonographic features, molecular testing may be used to supplement malignancy risk assessment data, in lieu of proceeding directly with surgery. Informed patient preference and feasibility should be considered in clinical decision-making. (WR, M)
623
16. B) If molecular testing is either not performed or inconclusive, surgical excision may be considered for removal and definitive diagnosis of an FN/SFN thyroid nodule. (SR, L)
623
17. A) If the cytology is reported as suspicious for papillary carcinoma (SUSP), surgical management should be similar to that of malignant cytology, depending on clinical risk factors, sonographic features, patient preference, and possibly results of mutational testing (if performed). (SR, L)
623
17. B) After consideration of clinical and sonographic features, mutational testing for BRAF or the 7-gene mutation marker panel (BRAF, RAS, RET/PTC, PAX8/PPAR γ) may be considered in nodules with SUSP cytology if such data would be expected to alter surgical decision-making. (WR, M)
623
18. 18FDG-PET imaging is not routinely recommended for the evaluation of thyroid nodules with indeterminate cytology. (WR, M)
623

Treatment

19. When surgery is considered for patients with a solitary, cytologically indeterminate nodule, thyroid lobectomy is the recommended initial surgical approach. This approach may be modified based on clinical or sonographic characteristics, patient preference and/or molecular testing when performed. (SR, M)
623
20. A) Because of increased risk for malignancy, total thyroidectomy may be preferred in patients with indeterminate nodules which are cytologically suspicious for malignancy, positive for known mutations specific for carcinoma, sonographically suspicious, large (>4 cm), or in patients with familial thyroid carcinoma or history of radiation exposure, if completion thyroidectomy would be recommended based on the indeterminate nodule being malignant following lobectomy. (SR, M)
623
20. B) Patients with indeterminate nodules who have bilateral nodular disease, those with significant medical comorbidities, or those who prefer to undergo bilateral thyroidectomy to avoid the possibility of requiring a future surgery on the contralateral lobe, may undergo total or near-total thyroidectomy, assuming completion thyroidectomy would be recommended if the indeterminate nodule proved malignant following lobectomy. (WR, L)
623
21. A) Patients with multiple thyroid nodules >1 cm should be evaluated in the same fashion as patients with a solitary nodule >1 cm, excepting that each nodule >1 cm carries an independent risk of malignancy and therefore multiple nodules may require FNA (SR, M)
623
21. B) When multiple nodules >1 cm are present, those with a suspicious sonographic pattern (Table 1, Figure 2) should be aspirated preferentially. FNA should be performed preferentially based upon nodule sonographic pattern and respective size cut-off (Table 1, Figure 2). (SR, M)
623
21. C) If none of the nodules has a high or moderate suspicion sonographic pattern, and multiple sonographically similar very low or low suspicion pattern nodules coalesce with no intervening normal parenchyma, the likelihood of malignancy is low and it is reasonable to aspirate only the largest nodules (>2 cm) or continue surveillance without FNA while observing the others with serial US examinations. (WR, L)
623
22. A low or low-normal serum TSH123 concentration in patients with multiple nodules may suggest that some nodule(s) may be autonomous. In such cases, a radionuclide (preferably I) thyroid scan should be considered and directly compared to the US images to determine functionality of each nodule >1 cm. FNA should then be considered only for those isofunctioning or nonfunctioning nodules, among which those with high suspicion sonographic pattern should be aspirated preferentially. (WR, L)
623
23. Given the low false negative rate of US-guided FNA cytology and the higher yield of missed malignancies based upon nodule sonographic pattern rather than growth, the follow up of thyroid nodules with benign cytology diagnoses should be determined by risk stratification based upon ultrasound pattern.
A) Nodules with high suspicion US pattern: repeat USA) Nodules with high suspicion US pattern: repeat USA) Nodules with high suspicion US pattern: repeat USA) Nodules with high suspicion US pattern: repeat USA) Nodules with high suspicion US pattern: repeat USA) Nodules with high suspicion US pattern: repeat USA) Nodules with high suspicion US pattern: repeat US and US-guided FNA within 12 months. (SR, M)
623
B) Nodules with low to intermediate suspicion US pattern: repeat US at 12–24 months. If sonographic evidence of growth (20% increase in at least two nodule dimensions with a minimal increase of 2 mm or more than a 50% change in volume) or development of new suspicious sonographic features, the FNA could be repeated or observation continued with repeat US, with repeat FNA in case of continued growth. (WR, L)
623
C) Nodules with very low suspicion US pattern (including spongiform nodules): The utility of surveillance US and assessment of nodule growth as an indicator for repeat FNA to detect a missed malignancy is limited. If US is repeated, it should be done at >24 months. (WR, L)
623
24. Nodules may be detected on US that do not meet criteria for FNA at initial imaging (Recommendation 8). The strategy for sonographic follow-up of these nodules should be based upon the nodule’s sonographic pattern.
A) Nodules with high suspicion US pattern: repeat US in 6–12 months (WR, L)
623
B) Nodules with sonographic features of low to intermediate suspicion US pattern: consider repeat US at 12–24 months. (WR, L)
623
C) Nodules >1 cm with very low suspicion US pattern (including spongiform nodules) and pure cyst: the utility and time interval of surveillance US for risk of malignancy is not known. If US is repeated, it should be at >24 months (NR, I)
623
D) Nodules <1 cm with very low suspicion US pattern (including spongiform nodules) and pure cysts do not require routine sonographic follow-up (WR, L)
623
E) Nodules <5 mm without high suspicion US pattern do not require routine sonographic FU and if repeated, the US should be performed at ≥24 months (WR, L)
623
25. Routine TSH suppression therapy for benign thyroid nodules in iodine sufficient populations is not recommended. Though modest responses to therapy can be detected, the potential harm outweighs benefit for most patients. (SR, H)
623
26. Individual patients with benign, solid or mostly solid nodules should have adequate iodine intake. If inadequate dietary intake is found or suspected, a daily supplement (containing 150 mcg iodine) is recommended. (SR, M)
623
27. A) Surgery may be considered for growing nodules that are benign after repeat FNA if they are large (>4 cm), causing compressive or structural symptoms, or based upon clinical concern. (WR, L)
623
27. B) Patients with growing nodules that are benign after FNA should be regularly monitored. Most asymptomatic nodules demonstrating modest growth should be followed without intervention. (SR, L)
623
28. Recurrent cystic thyroid nodules with benign cytology should be considered for surgical removal or percutaneous ethanol injection (PEI) based on compressive symptoms and cosmetic concerns. Asymptomatic cystic nodules may be followed conservatively. (WR, L)
623
29. There are no data to guide recommendations on the use of thyroid hormone therapy in patients with growing nodules that are benign on cytology (NR, I)
623
30. A) FNA of clinically relevant thyroid nodules should be performed in euthyroid and hypothyroid pregnant women. (SR, M)
623
30. B) For women with suppressed serum TSH levels that persist beyond 16 weeks gestation, FNA may be deferred until after pregnancy and cessation of lactation. At that time, a radionuclide scan can be performed to evaluate nodule function if the serum TSH remains suppressed. (SR, M)
623
31. A) PTC discovered by cytology in early pregnancy should be monitored sonographically. If it grows substantially before 24–26 weeks gestation, or if US reveals cervical lymph nodes that are suspicious for metastatic disease, surgery should be considered during pregnancy. However, if the disease remains stable by midgestation, or if it is diagnosed in the second half of pregnancy, surgery may be deferred until after delivery. (WR, L)
623
31. B) In pregnant women with FNA that is suspicious for or diagnostic of PTC, thyroid hormone therapy to keep the serum TSH 0.1–1.0mU/L is recommended. (WR, L)
623

Differentiated Thyroid Cancer

32. A) Preoperative neck US for cervical (central and especially lateral neck compartments) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant or suspicious for malignancy cytologic or molecular findings. ( SR , M )
623
32. B) US-guided FNA of sonographically suspicious lymph nodes >8–10 mm in the smallest diameter should be performed to confirm malignancy if this would change management. ( SR , M )
623
32. C) The addition of FNA-Tg washout in the evaluation of suspicious cervical lymph nodes is appropriate in select patients, but interpretation may be difficult in patients with an intact thyroid gland. ( WR , L )
623
33. A) Preoperative use of cross-sectional imaging studies (CT-MRI) with intravenous contrast is recommended as an adjunct to ultrasound for patients with clinical suspicion for advanced disease including invasive primary tumor, or clinically apparent multiple or bulky lymph node involvement. ( SR , L )
623
33. B) Routine preoperative 18FDG-PET scanning is NOT recommended. ( SR , L )
623
34. Routine preoperative measurement of serum Tg or Tg antibodies is NOT recommended. ( WR , L )
623

Treatment

35. A) For patients with thyroid cancer >4 cm or with gross extrathyroidal extension (clinical T4) or clinically apparent metastatic disease to nodes (clinical N1) or distant sites (clinical M1), the initial surgical procedure should include a near-total or total thyroidectomy and gross removal of all primary tumor unless there are contraindications to this procedure. ( SR , M )
623
35. B) For patients with thyroid cancer >1 cm and <4 cm without extrathyroidal extension and without clinical evidence of any lymph node metastases (cN0), the initial surgical procedure can be either a bilateral procedure (near-total or total thyroidectomy) or a unilateral procedure (lobectomy). Thyroid lobectomy alone may be sufficient initial treatment for low risk papillary and follicular carcinomas. However, the treatment team may choose total thyroidectomy to enable RAI therapy or to enhance follow-up based upon disease features and/or patient preferences. ( SR , M )
623
35. C) If surgery is chosen for patients with thyroid cancer <1 cm without extrathyroidal extension and cN0, the initial surgical procedure should be a thyroid lobectomy unless there are clear indications to remove the contralateral lobe. Thyroid lobectomy alone is sufficient treatment for small, unifocal, intrathyroidal carcinomas in the absence of prior head and neck irradiation, familial thyroid carcinoma, or clinically detectable cervical nodal metastases. (SR, M)
623
36. A) Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. (SR, M)
623
36. B) Prophylactic central-compartment neck dissection (ipsilateral or bilateral) should be considered in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes (cN0) who have advanced primary tumors (T3 or T4), clinically involved lateral neck nodes (cN1b), or if the information will be used to plan further steps in therapy. ( WR , L )
623
36. C) Thyroidectomy without prophylactic central neck dissection is appropriate for small (T1 or T2), noninvasive, clinically node-negative PTC (cN0) and for most follicular cancers. (SR, M)
623
37. Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. (SR, M)
623
38. A) Completion thyroidectomy should be offered to those patients for whom a bilateral thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. Therapeutic central neck lymph node dissection should be included if the lymph nodes are clinically involved. Thyroid lobectomy alone may be sufficient treatment for low risk papillary and follicular carcinomas. (SR, M)
623
38. B) Radioactive iodine ablation in lieu of completion thyroidectomy is not recommended routinely. However, it may be used to ablate the remnant lobe in selected cases. (WR, L)
623
39. Prior to surgery, the surgeon should communicate with the patient regarding surgical risks, including nerve and parathyroid injury, through the informed consent process and communicate with associated physicians, including anesthesia personnel, regarding important findings elicited during the preoperative workup. ( SR , M )
623
40. All patients undergoing thyroid surgery should have preoperative voice assessment as part of their pre-operative physical examination. This should include the patient’s description of vocal changes, as well as the physician’s assessment of voice. ( SR , M )
623
A) Preoperative voice abnormalities (SR, M)
623
B) History of cervical or upper chest surgery, which places the RLN or vagus nerve at risk (SR, M)
623
C) Known thyroid cancer with posterior extrathyroidal extension or extensive central nodal metastases. (SR, L)
623
42. A) Visual identification of the recurrent laryngeal nerve (RLN) during dissection is required in all cases. Steps should also be taken to preserve the external branch of the superior laryngeal nerve (EBSLN) during dissection of the superior pole of the thyroid gland. (SR, M)
623
42. B) Intraoperative neural stimulation (with or without monitoring) may be considered to facilitate nerve identification and confirm neural function. (WR, L)
623
43. The parathyroid glands and their blood supply should be preserved during thyroid surgery. (SR)

High Moderate-quality evidence

623
44. Patients should have their voice assessed in the post-operative period. Formal laryngeal exam should be performed if the voice is abnormal. ( SR , M )
623
45. Important intraoperative findings and details of post-operative care should be communicated by the surgeon to the patient and other physicians who are important in the patient’s post-operative care. ( SR , L )
623
46. A) In addition to the basic tumor features required for AJCC/UICC thyroid cancer staging including status of resection margins, pathology reports should include additional information helpful for risk assessment including the presence of vascular invasion and the number of invaded vessels, number of lymph nodes examined and involved with tumor, size of the largest metastatic focus to the lymph node, and presence or absence of extranodal extension of the metastatic tumor. (SR, M)
623
46. B) Histopathologic variants of thyroid carcinoma associated with more unfavorable (e.g. tall cell, columnar cell, and hobnail variants of PTC; widely invasive FTC; poorly differentiated carcinoma) or more favorable (e.g. encapsulated follicular variant of PTC without invasion, minimally-invasive FTC) outcome should be identified during histopathologic examination and reported. (SR, L)
623
46. C) Histopathologic variants associated with familial syndromes (cribriform-morular variant of papillary carcinoma often associated with familial adenomatous polyposis, PTEN-hamartoma tumor syndrome associated follicular or papillary carcinoma) should be identified during histopathologic examination and reported. ( WR , L )
623
47. AJCC/UICC staging is recommended for all patients with DTC based on its utility in predicting disease mortality and its requirement for cancer registries. ( SR , M )
623
48. A) The 2009 ATA Initial Risk Stratification System (Cooper DS et al. Thyroid 2009;19:1167–1214) is recommended for DTC patients treated with thyroidectomy, based on its utility in predicting risk of disease recurrence and/or persistence. ( SR , M )
623
48. B) Additional prognostic variables (such as the extent of lymph node involvement, mutational status, and/or the degree of vascular invasion in follicular thyroid cancer) not included in the 2009 ATA Initial Risk Stratification system may be used to further refine risk stratification for DTC as described below (and in Fig 4) in the Modified Initial Risk Stratification system. However, the incremental benefit of adding these specific prognostic variables to the 2009 Initial Risk Stratification system has not been established. ( WR , L )
623
48. C) While not routinely recommended for initial post-operative risk stratification in DTC, the mutational status of BRAF, and potentially other mutations such as TERT, have the potential to refine risk estimates when interpreted in the context of other clinico-pathologic risk factors. ( WR , M )
623

DTC: Long-Term Management and Advanced Cancer Management

49. Initial recurrence risk estimates should be continually modified during follow-up because the risk of recurrence and disease specific mortality can change over time as a function of the clinical course of the disease and the response to therapy. ( SR , L )
623
50. A) Post-operative disease status (i.e. the presence or absence of persistent disease) should be considered in deciding whether additional treatment (e.g. radioactive iodine, surgery, or other treatment) may be needed. (SR, L)
623
50. B) Post-operative serum thyroglobulin (on thyroid hormone therapy or after TSH stimulation) can help in assessing the persistence of disease or thyroid remnant and predicting potential future disease recurrence. The Tg should reach its nadir by 3–4 weeks post-operatively in most patients. ( SR , M )
623
50. C) The optimal cut-off value for post-operative serum thyroglobulin or state in which it is measured (on thyroid hormone therapy or after TSH stimulation) to guide decision-making regarding RAI administration is not known. ( NR , I )
623
50. D) Post-operative diagnostic radioiodine whole-body scans may be useful when the extent of the thyroid remnant or residual disease cannot be accurately ascertained from the surgical report or neck ultrasonography, and when the results may alter the decision to treat, or the activity of RAI that is to be administered. Identification and localization of uptake foci may be enhanced by concomitant SPECT/CT123. When performed, pretherapy diagnostic scans should utilize I (1.5–3 mCi) or a low activity of 131I (1–3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity. ( WR , L )
623
51. A) RAI remnant ablation is not routinely recommended after thyroidectomy for ATA low risk DTC patients. Consideration of specific features of the individual patient that could modulate recurrence risk, disease follow-up implications, and patient preferences are relevant to RAI decision-making. ( WR , L )
623
51. B) RAI remnant ablation is not routinely recommended after lobectomy or total thyroidectomy for patients with unifocal papillary microcarcinoma in the absence of other adverse features. ( SR , M )
623
51. C) RAI remnant ablation is not routinely recommended after thyroidectomy for patients with multi-focal papillary microcarcinoma in absence of other adverse features. Consideration of specific features of the individual patient that could modulate recurrence risk, disease followup implications and patient preferences are relevant to RAI decision-making. ( WR , L )
623
51. D) RAI adjuvant therapy should be considered after total thyroidectomy in ATA intermediate risk level differentiated thyroid cancer patients. ( WR , L )
623
51. E) RAI adjuvant therapy is routinely recommended after total thyroidectomy for ATA high risk differentiated thyroid cancer patients. ( SR , M )
623
52. The role of molecular testing in guiding post-operative RAI use has yet to be established. Therefore no molecular testing to guide post-operative RAI use can be recommended at this time. ( NR , I )
623
53. A) If thyroid hormone withdrawal is planned prior to RAI therapy or diagnostic testing, levothyroxine should be withdrawn for 3–4 weeks. Liothyronine (LT3) may be substituted for levothyroxine in the initial weeks if levothyroxine is withdrawn for ≥4 weeks, and in such circumstances LT3 should be withdrawn for ≥2 weeks. Serum TSH should be measured prior to radioisotope administration to evaluate the degree of TSH elevation. ( SR , M )
623
53. B) A goal TSH of >30 mIU/L has been generally adopted in preparation for RAI therapy or diagnostic testing, but there is uncertainty relating to the optimum TSH level associated with improvement in long-term outcomes. ( WR , L )
623
54. A) In patients with ATA low risk and ATA intermediate risk DTC without extensive lymph node involvement (i.e. T1–T3, N0/Nx/N1a, M0) in whom radioiodine remnant ablation or adjuvant therapy is planned, preparation with rhTSH stimulation is an acceptable alternative to thyroid hormone withdrawal for achieving remnant ablation, based on evidence of superior short-term quality of life, non-inferiority of remnant ablation efficacy, and multiple consistent observations suggesting no significant difference in long-term outcomes. ( SR , M )
623
54. B) In patients with ATA intermediate risk DTC who have extensive lymph node disease (multiple clinically-involved LN) in absence of distant metastases, preparation with rhTSH stimulation may be considered as an alternative to thyroid hormone withdrawal, prior to adjuvant radioactive iodine treatment. ( WR , L )
623
54. C) In patients with ATA high risk DTC with attendant higher risks of disease-related mortality and morbidity, more controlled data from long-term outcome studies are needed before recombinant human thyrotropin preparation for RAI adjuvant treatment can be recommended. ( NR , I )
623
54. D) In patients with DTC of any risk level with significant co-morbidity that may preclude thyroid hormone withdrawal prior to iodine radioiodine administration, recombinant human thyrotropin preparation should be considered. Significant co-morbidity may include:

a) a significant medical or psychiatric condition that could be acutely exacerbated with hypothyroidism leading to a serious adverse event, or
b) inability to mount an adequate endogenous TSH response with thyroid hormone withdrawal.

( SR , L )
623
55. A) If radioactive iodine remnant ablation is performed after total thyroidectomy for ATA low risk thyroid cancer or intermediate risk disease with lower risk features (i.e., low volume central neck nodal metastases with no other known gross residual disease nor any other adverse features), a low administered dose activity of approximately 30 mCi is generally favored over higher administered dose activities. ( SR , H )
623
55. B) Higher administered activities may need to be considered for patients receiving less than a total or near-total thyroidectomy where a larger remnant is suspected or where adjuvant therapy is intended. ( WR , L )
623
56. When RAI is intended for initial adjuvant therapy to treat suspected microscopic residual disease, administered activities above those used for remnant ablation ≤150 mCi are generally recommended (in absence of known distant metastases). It is uncertain whether routine use of higher administered activities ( >150 mCi) in this setting will reduce structural disease recurrence for T3 and N1 disease. ( WR , L )
623
57. A low-iodine diet for approximately 1–2 weeks should be considered for patients undergoing RAI remnant ablation or treatment. ( WR , L )
623
58. A post-therapy whole-body scan (with or without single-photon emission tomography/computed tomography [SPECT-CT]) is recommended after RAIemission tomography/computed tomography [SPECT-CT]) is recommended after RAI remnant ablation or treatment to inform disease staging and document the RAI-avidity of any structural disease. ( SR , L )
623
59. A) For high-risk thyroid cancer patients, initial TSH suppression to below 0.1 mU/L is recommended. ( SR , M )
623
55. B) For intermediate-risk thyroid cancer patients, initial TSH suppression to 0.1–0.5 mU/L is recommended. ( WR , L )
623
55. C) For low risk patients who have undergone remnant ablation and have undetectable serum Tg levels, TSH may be maintained at the lower end of the reference range (0.5–2 mU/L) while continuing surveillance for recurrence. Similar recommendations hold for low-risk patients who have not undergone remnant ablation and have undetectable serum Tg levels. (WR, L)
623
55. D) For low risk patients who have undergone remnant ablation and have low level serum Tg levels, TSH may be maintained at or slightly below the lower limit of normal (0.1–0.5 mU/L) while continuing surveillance for recurrence. Similar recommendations hold for low-risk patients who have not undergone remnant ablation, although serum Tg levels may be measurably higher, and continued surveillance for recurrence applies. ( WR , L )
623
55. E) For low risk patients who have undergone lobectomy, TSH may be maintained in the mid to lower reference range (0.5–2 mU/L) while continuing surveillance for recurrence. Thyroid hormone therapy may not be needed if patients can maintain their serum TSH in this target range. (WR, L)
623
60. There is no role for routine adjuvant external beam radiation therapy to the neck in patients with DTC after initial complete surgical removal of the tumor. ( SR , L )
623
61. There is no role for routine systemic adjuvant therapy in patients with DTC (beyond RAI and/or TSH suppressive therapy using levothyroxine). ( SR , L )
623
62. A) Serum thyroglobulin should be measured by an assay that is calibrated against the CRM457 standard. Thyroglobulin antibodies should be quantitatively assessed with every measurement of serum Tg. Ideally, serum Tg and Tg antibodies should be assessed longitudinally in the same laboratory and using the same assay for a given patient. ( SR , H )
623
62. B) During initial follow-up, serum Tg on thyroxine therapy should be measured every 6–12 months. More frequent Tg measurements may be appropriate for ATA high risk patients. ( SR , M )
623
62. C) In ATA low and intermediate risk patients that achieve an excellent response to therapy, the utility of subsequent Tg testing is not established. The time interval between serum Tg measurements can be lengthened to at least ≥12–24 months. ( WR , L )
623
62. D) Serum TSH should be measured at least every 12 months in all patients on thyroid hormone therapy. (SR)

Moderate-Low-quality evidence

623
62. E) ATA high risk patients (regardless of response to therapy) and all patients with biochemical incomplete, structural incomplete, or indeterminate response should continue to have Tg measured at least every 6–12 months for several years. ( WR , L )
623
63. A) In ATA low-risk and intermediate-risk patients who have had remnant ablation or adjuvant therapy and negative cervical US, serum Tg should be measured at 6–18 months on thyroxine therapy with a sensitive Tg assay (<0.2 ng/ml) or after TSH stimulation to verify absence of disease (excellent response). ( SR , M )
623
63. B) Repeat TSH stimulated Tg testing is not recommended for low and intermediate risk patients with an excellent response to therapy. ( WR , L )
623
63. C) Subsequent TSH stimulated Tg testing may be considered in patients with an indeterminate, biochemical incomplete or structural incomplete response following either additional therapies or a spontaneous decline in Tg values on thyroid hormone therapy over time in order to reassess response to therapy. ( WR , L )
623
64. Periodic serum Tg measurements on thyroid hormone therapy and neck ultrasonography should be considered during follow-up of patients with DTC who have undergone less than total thyroidectomy and in patients who have had a total thyroidectomy but not RAI ablation. While specific cutoff levels of Tg that optimally distinguish normal residual thyroid tissue from persistent thyroid cancer are unknown, rising Tg values over time are suspicious for growing thyroid tissue or cancer. ( SR , L )
623
65. A) Following surgery, cervical US to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6–12 months and then periodically, depending on the patient’s risk for recurrent disease and Tg status. ( SR , M )
623
65. B) If a positive result would change management, ultrasonographically suspicious lymph nodes 8–10 mm in the smallest diameter should be biopsied for cytology with Tg measurement in the needle washout fluid. ( SR , L )
623
65. C) Suspicious lymph nodes <8–10 mm in smallest diameter may be followed without biopsy with consideration for FNA or intervention if there is growth or if the node threatens vital structures. ( WR , L )
623
65. D) Low-risk patients who have had remnant ablation, negative cervical US, and a low serum Tg on thyroid hormone therapy in a sensitive assay (<0.2 ng/ml) or after TSH-stimulation (Tg <1 ng/ml) can be followed primarily with clinical examination and Tg measurements on thyroid hormone replacement. ( WR , L )
623
66. After the first post-treatment WBS performed following RAI remnant ablation or adjuvant therapy, low-risk and intermediate-risk patients (lower risk features) with an undetectable Tg on thyroid hormone with negative antithyroglobulin antibodies and a negative US (excellent response to therapy) do not require routine diagnostic WBS during follow-up. ( SR , M )
623
67. A) Diagnostic WBS, either following thyroid hormone withdrawal or rhTSH, 6–12 months after remnant ablation adjuvant RAI123 therapy can be useful in the follow-up of patients with high or intermediate risk (higher risk features) of persistent disease and should be done with I or low activity 131I. ( SR , L )
623
67. B) SPECT-CT radioiodine imaging is preferred over planar imaging in patients with uptake on planar imaging to better anatomically localize the radioiodine uptake and distinguish between likely tumors and nonspecific uptake. ( WR , M )
623
68. A) FDG-PET scanning should be considered in high risk 18DTC patients with elevated serum Tg (generally >10 ng/ml) with negative radioiodine imaging. ( SR , M )
623
68. B) 18FDG-PET scanning may also be considered

a) as part of initial staging in poorly differentiated thyroid cancers and invasive Hürthle cell carcinomas, especially those with other evidence of disease on imaging or because of elevated serum Tg levels,

b) as a prognostic tool in patients with metastatic disease to identify lesions and patients at highest risk for rapid disease progression and disease-specific mortality, and

c) as an evaluation of posttreatment response following systemic or local therapy of metastatic or locally invasive disease.

( WR , L )
623
69. A) Cross-sectional imaging of the neck and upper chest (CT, MRI) with intravenous contrast should be considered

a) in the setting of bulky and widely distributed recurrent nodal disease where ultrasound may not completely delineate disease,

b) in the assessment of possible invasive recurrent disease where potential aerodigestive tract invasion requires complete assessment or

c) when neck ultrasound is felt to be inadequately visualizing possible neck nodal disease (high Tg, negative neck US).

( SR , M )
623
69. B) CT imaging of the chest without intravenous contrast (imaging pulmonary parenchyma) or with intravenous contrast (to include the mediastinum) should be considered in high risk DTC patients with elevated serum Tg (generally >10 ng/ml) or rising Tg antibodies with or without negative radioiodine imaging. ( SR , M )
623
69. C) Imaging of other organs including MRI brain, MR skeletal survey, and/or CT or MRI of the abdomen should be considered in high risk DTC patients with elevated serum Tg (generally >10 ng/ml) and negative neck and chest imaging who have symptoms referable to those organs or who are being prepared for TSH-stimulated RAI therapy (withdrawal or rhTSH) and may be at risk for complications of tumor swelling. ( SR , L )
623
70. A) In patients with a structural or biochemical incomplete response to therapy, the serum TSH should be maintained below 0.1 mU/L indefinitely in the absence of specific contraindications. ( SR , M )
623
70. B) In patients with a biochemical incomplete response to therapy, the serum TSH should be maintained between 0.1–0.5 mU/L, taking into account the initial ATA risk classification, Tg level, Tg trend over time, and risk of TSH suppression. ( WR , L )
623
70. C) In patients with an excellent (clinically and biochemically free of disease) or indeterminate response to therapy but who presented with high risk disease, consideration should be given to maintaining thyroid hormone therapy to achieve serum TSH levels of 0.1–0.5 mU/L for ≤5 years after which the degree of TSH suppression can by reduced with continued surveillance for recurrence. ( WR , L )
623
70. D) In patients with an excellent (clinically and biochemically free of disease) or indeterminate response to therapy, especially those at low risk for recurrence, the serum TSH may be kept within the low reference range (0.5–2 mU/L). ( SR , M )
623
70. E) In patients who have not undergone remnant ablation or adjuvant therapy who demonstrate an excellent or indeterminate response to therapy with a normal neck US and low or undetectable suppressed serum Tg, and Tg or TgAb that are not rising, the serum TSH can be allowed to rise to the low reference range (0.5–2 mU/L). ( WR , L )
623
71. Therapeutic compartmental central and/or lateral neck dissection in a previously operated compartment, sparing uninvolved vital structures, should be performed for patients with biopsy-proven persistent or recurrent disease for central neck nodes ≥8 mm and lateral neck nodes ≥10 mm in the smallest dimension which can be localized on anatomic imaging. ( SR , M )
623
72. When technically feasible, surgery for aerodigestive invasive disease is recommended in combination with RAI and/or external beam radiotherapy. ( SR , M )
623
73. A) Although there are theoretical advantages to dosimetric approaches to the treatment of loco-regional or metastatic disease, no recommendation can be made about the superiority of one method of RAI administration over another (empiric high activity vs. blood and/or body dosimetry vs. lesional dosimetry). ( NR , I )
623
73. B) Empirically administered amounts of 131I exceeding 150 mCi that often potentially exceed the maximum tolerable tissue dose should be avoided in patients >70 years. (SR, M)
623
74. There are currently insufficient outcome data to recommend rhTSH-mediated therapy for all patients with distant metastatic disease being treated with 131I. ( NR , I )
623
75. Recombinant human TSH–mediated therapy may be indicated in selected patients with underlying co-morbidities making iatrogenic hypothyroidism potentially risky, in patients with pituitary disease who are unable to raise their serum TSH, or in patients in whom a delay in therapy might be deleterious. Such patients should be given the same or higher activity that would have been given had they been prepared with hypothyroidism or a dosimetrically determined activity. ( SR , L )
623
76. Since there are no outcome data that demonstrate a better outcome of patients treated with lithium as an adjunct to 131I therapy, the data are insufficient to recommend lithium therapy. ( NR , I )
623
77. A) Pulmonary micrometastases should be treated with RAI therapy repeated every 6–12 months as long as disease continues to concentrate RAI and respond clinically, because highest rates of complete remission are reported in these subgroups. ( SR , M )
623
77. B) The selection of RAI activity to administer for pulmonary micrometastases can be empiric (100–200 mCi, or 100–150 mCi for patients >70 yo) or estimated by dosimetry to limit whole-body retention to 80 mCi at 48 hours and 200 cGy to the bone marrow. ( SR , M )
623
78. Radioiodine-avid macronodular metastases may be treated with RAI, and treatment may be repeated when objective benefit is demonstrated (decrease in the size of the lesions, decreasing Tg), but complete remission is not common and survival remains poor. The selection of RAI activity to administer can be made empirically (100–200 mCi) or by lesional dosimetry or whole-body dosimetry if available in order to limit whole-body retention to 80 mCi at 48 hours and 200 cGy to the bone marrow. ( WR , L )
623
79. A) RAI therapy of iodine-avid bone metastases has been associated with improved survival and should be employed, although RAI is rarely curative. ( SR , M )
623
79. B) The RAI activity administered can be given empirically (100–200 mCi) or determined by dosimetry. ( WR , L )
623
80. In the absence of structurally evident disease, patients with stimulated serum Tg <10 ng/mL with thyroid hormone withdrawal or <5 ng/mL with rhTSH (indeterminate response) can be followed without empiric RAI therapy on with continued thyroid hormone therapy alone, reserving additional therapies for those with rising serum Tg levels over time or other evidence of structural disease progression. ( WR , L )
623
81. Empiric (100–200 mCi) or dosimetrically-determined radioactive iodine therapy may be considered in patients with more significantly elevated serum Tg levels, rapidly rising serum Tg levels or rising Tg18 antibody levels, in whom imaging (anatomic neck/chest imaging and/or FDG-PET/CT) has failed to reveal a tumor source that is amenable to directed therapy. The risk of high cumulative administered activities of RAI must be balanced against uncertain long-term benefits. If empiric RAI therapy is given and the post-therapy scan is negative, the patient should be considered to have RAI-refractory disease and no further RAI therapy should be administered. ( WR , L )
623
82. If persistent nonresectable disease is localized after an empiric dose of RAI and there is objective evidence of significant tumor reduction, then consideration can be made for RAI therapy to be repeated until the tumor has been eradicated or the tumor no longer responds to treatment. The risk of repeated therapeutic doses of RAI must be balanced against uncertain long-term benefits. ( WR , L )
623
83. The evidence is insufficient to recommend for or against the routine use of measures to prevent salivary gland damage after RAI therapy. ( NR , L )
623
84. Patients with xerostomia are at increased risk of dental caries and should discuss preventive strategies with their dental/oral health professional dentist. ( WR , L )
623
85. Surgical correction should be considered for nasolacrimal outflow obstruction, which often presents as excessive tearing (epiphora) but also predisposes to infection. ( SR , L )
623
86. Although patients should be counseled on the risks of second primary malignancy (SPM) with RAI treatment for DTC, the absolute increase in risk of developing second primary malignancy attributable to RAI treatment is considered small and does not warrant specific screening for SPMs to any extent greater than age-appropriate general population health screening. ( WR , L )
623
87. Patients receiving therapeutic doses of RAI should have baseline complete blood count (CBC) and assessment of renal function. ( WR , L )
623
88. Women of childbearing age receiving RAI therapy should have a negative screening evaluation for pregnancy prior to RAI administration and avoid pregnancy for 6–12 months after receiving RAI.
623
89. Radioactive iodine should not be given to nursing women. Depending on the clinical situation, RAI123 therapy could be deferred until lactating women have stopped breast-feeding or pumping for at least 3 months. A diagnostic I or low dose 131I scan should be considered in recently lactating women to detect breast uptake that may warrant deferral of therapy. ( SR , L )
623
90. Men receiving cumulative radioiodine activities >400 mCi should be counseled on potential risk of infertility. ( SR , M )
623
91. Radioiodine-refractory structurally-evident DTC is defined classified in patients with appropriate TSH stimulation and iodine preparation in four basic ways:

A) The malignant/metastatic tissue does not ever concentrate radioiodine (no uptake outside the thyroid bed at the first diagnostic or therapeutic WBS).

B) The tumor tissue loses the ability to concentrate radioiodine after previous evidence of RAI-avid disease (in the absence of stable iodine contamination).

C) Radioiodine is concentrated in some lesions but not in others.

D) Metastatic disease progresses despite significant concentration of radioiodine.
When a patient with DTC is classified as refractory to radioiodine, there is no indication for further radioiodine treatment. ( WR , L )
623
92. A) Patients with I refractory metastatic 131DTC that is asymptomatic, stable or minimally progressive, not likely to develop rapidly progressive, clinically significant complications, and do not have indications for directed therapy can be monitored on TSH-suppressive thyroid hormone therapy with serial radiographic imaging every 3–12 months. ( WR , L )
623
92. B) BRAF or other mutational testing is not routinely recommended for prognostic purposes in patients with radioiodine-refractory, progressive, locally advanced or metastatic DTC. ( WR , M )
623
93. A) Both stereotactic radiation and thermal ablation (RFA and cryoablation) show a high efficacy in treating individual distant metastases with relatively few side effects and may be considered as valid alternatives to surgery. ( WR , M )
623
93. B) Stereotactic radiation or thermal ablation should be considered prior to initiation of systemic treatment when individual distant metastases are symptomatic or at high risk of local complications. ( SR , M )
623

94. While surgical resection and stereotactic external beam radiotherapy are the mainstays of therapy for CNS metastases, RAI can be considered if CNS metastases concentrate RAI. If RAI is being considered, stereotactic external beam radiotherapy and concomitant glucocorticoid therapy are recommended prior to RAI metastases concentrate RAI. If RAI is being considered, stereotactic external beam radiotherapy and concomitant glucocorticoid therapy are recommended prior to RAI therapy to minimize the effects of a potential TSH-induced increase in tumor size and RAI-induced inflammatory response.

( WR , L )
623
95. Patients should be considered for referral to participate in prospective therapeutic clinical trials based upon specific eligibility requirements for given studies and the likelihood that the patient may or may not benefit from study participation. Clinicians considering referral of patients for trials should review available treatment options and eligibility criteria, preferably through discussions with trial center personnel and review of trial materials at the website www.clinicaltrials.org. (SR, M)
623
96. A) Kinase inhibitor therapy should be considered in RAI-refractory DTC patients with metastatic, rapidly progressive, symptomatic and/or imminently threatening disease not otherwise amenable to local control using other approaches. Kinase inhibitors that are FDA-approved for differentiated thyroid carcinoma or other available kinase inhibitors (preferably within the context of therapeutic clinical trials) can be considered since the impact of these agents on overall survival and quality of life remains to be defined. ( WR , M )
623
96. B) Patients who are candidates for kinase inhibitor therapy should be thoroughly counseled on the potential risks and benefits of this therapy as well as alternative therapeutic approaches including best supportive care. Appropriate informed consent should be obtained and documented in the medical record prior to initiation of any therapy, regardless of whether the patient is being treated in the context of a clinical trial. ( SR , L )
623
97. Patients who have disease progression while on initial kinase inhibitor therapy without prohibitive adverse effects should be considered for second-line kinase inhibitor therapy. Ideally, such therapy should be undertaken within the context of therapeutic clinical trials. ( WR , L )
623
98. Active surveillance: Proactive monitoring and timely intervention in response to emergent toxicities are critical components of management in patients receiving kinase inhibitor therapy. ( SR , L )
623
99. Agents without established efficacy in DTC should be used only primarily within the context of therapeutic clinical trials. ( SR , L )
623
100. Cytotoxic chemotherapy can be considered in RAI-refractory DTC patients with metastatic, rapidly progressive, symptomatic, and/or imminently threatening disease not otherwise amenable to control through other approaches including kinase inhibitors. Too few data exist to recommend specific cytotoxic regimens, and use within the context of a therapeutic clinical trial is preferred. ( WR , L )
623
101. Bisphosphonate or denosumab therapy should be considered in patients with diffuse and/or symptomatic bone metastases from RAI-refractory DTC, either alone or concomitantly with other systemic therapies. Adequate renal function (bisphosphonates) and calcium and vitamin D25 level (bisphosphonates and denosumab) should be documented prior to each dose, and dental evaluation should take place before initial use. ( SR , M )
623

Recommendation Grading

Overview

Title

Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer

Authoring Organization

Publication Month/Year

January 12, 2016

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Document Objectives

Our objective in these guidelines is to inform clinicians, patients, researchers, and health policy makers about the best available evidence (and its limitations), relating to the diagnosis and treatment of adult patients with thyroid nodules and DTC. 

Target Patient Population

Adults with DTC

Inclusion Criteria

Female, Male, Adult, Older adult

Health Care Settings

Ambulatory, Hospital, Operating and recovery room, Outpatient, Radiology services

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Counseling, Assessment and screening, Diagnosis, Prevention, Management, Treatment

Keywords

differentiated thyroid cancer (DTC), thyroid nodules, DTC, Thyroid Cancer