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Guideline Summary
Guideline Title
Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.
Bibliographic Source(s)
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19(11):1167-214. [434 references] PubMed External Web Site Policy
Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM, The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006 Feb;16(2):109-42. [301 references]

Scope

Disease/Condition(s)

Thyroid nodules and differentiated thyroid cancer

Guideline Category
Diagnosis
Evaluation
Management
Treatment
Clinical Specialty
Endocrinology
Oncology
Radiation Oncology
Surgery
Intended Users
Physicians
Guideline Objective(s)
  • To update the 2006 recommendations for the management of patients with thyroid nodules and differentiated thyroid cancer
  • To assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer
Target Population

Patients with thyroid nodules and differentiated thyroid cancer

Interventions and Practices Considered

Evaluation

  1. Serum thyrotropin (TSH) (with radionuclide thyroid scan if abnormal)
  2. Thyroid sonography
  3. Serum thyroglobulin (Tg) (Note: currently not recommended)
  4. Serum calcitonin (Note: no recommendation for or against use can be made)
  5. Fine needle aspiration (FNA), with ultrasound guidance when applicable, including close observation or surgical excision (cystic nodules)
  6. Specific molecular markers
  7. Fluorodeoxyglucose positron emission tomography (FDG-PET) (Note: no recommendation for or against use can be made)
  8. 123I thyroid scan
  9. Technetium 99mTc pertechnetate scan
  10. Serial ultrasound (US) examinations
  11. Routine suppression therapy of benign nodules (Note: currently not recommended)

Treatment/Management

  1. Preoperative ultrasound staging (Note: routine preoperative use of other imaging studies, including computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET] is not currently recommended)
  2. Ultrasound-guided FNA, as applicable
  3. Surgery
    • Lobectomy or near-total/total thyroidectomy
    • Therapeutic and prophylactic central-compartment neck dissection
    • Therapeutic lateral neck compartmental lymph node dissection
    • Completion thyroidectomy
  4. Ablation with radioactive iodine, including pre-therapy scans and/or measurement of thyroid bed uptake and post-therapy scan
  5. Low iodine diet (for patients undergoing radioactive iodine remnant ablation)
  6. American Joint Committee on Cancer/International Union against Cancer (AJCC/UICC) staging
  7. TSH suppression therapy
  8. External beam irradiation
  9. Chemotherapy (Note: currently not recommended)
  10. Periodic follow-up of serum thyroglobulin levels
  11. Post-treatment whole body radioiodine scan (RxWBS) and diagnostic whole body radioiodine scan (DxWBS)
  12. Cervical ultrasonography follow-up
  13. Recombinant human thyrotropin (rhTSH)-mediated therapy
  14. Surgical resection of metastases
  15. Referral to clinical trials
Major Outcomes Considered
  • Sensitivity and specificity of diagnostic tests
  • Disease-related morbidity and mortality
  • Disease recurrence/metastatic spread

Methodology

Methods Used to Collect/Select the Evidence
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
Description of Methods Used to Collect/Select the Evidence

Relevant articles were identified by searching MEDLINE using the following search terms: {THRYOID NODULE/diagnosis, drug therapy, surgery, therapy, ultrasonography} or {CANCER} or {CARCINOMA} and {THYROID} and {FOLLICULAR CARCINOMA} or {PAPILLARY CACINOMA} and {FOLLOW-UP} and {TREATMENT} and {RECURRENCE}. All English language papers published between 1995 and December 2004 were reviewed and categorized in tabular form by date, author, subject, and whether it represented a randomized controlled trial, meta-analysis, or clinical case series. Relevant review articles, book chapters, and pre-1995 articles were also supplied by taskforce members.

2009 Update

Relevant articles on thyroid cancer were identified using the same search criteria employed for the original guidelines. Individual task force members submitted suggestions for clarification of prior recommendations, as well as new information derived from studies published since 2004. Relevant literature continued to be reviewed through December 2008.

Number of Source Documents

Not stated

Methods Used to Assess the Quality and Strength of the Evidence
Expert Consensus (Committee)
Rating Scheme for the Strength of the Evidence

Not applicable

Methods Used to Analyze the Evidence
Review of Published Meta-Analyses
Systematic Review
Description of the Methods Used to Analyze the Evidence

Not stated

Methods Used to Formulate the Recommendations
Expert Consensus
Description of Methods Used to Formulate the Recommendations

In recognition of the changes that have taken place in the overall management of these clinically important problems, the American Thyroid Association (ATA) appointed a taskforce to re-examine the current strategies that are used to diagnose and treat thyroid nodules and differentiated thyroid cancer (DTC), and to develop clinical guidelines using principles of evidence-based medicine. Members of the taskforce included experts in thyroid nodule and thyroid cancer management with representation from the fields of endocrinology, surgery, and nuclear medicine.

To begin the revision process, a half-day meeting was held on June 2, 2007. The Taskforce was broadened to include European experts and a head and neck surgeon. Three subsequent half-day meetings were held on October 5, 2007; July 13, 2008; and October 5, 2008, to review these suggestions and for additional comments to be considered. The meeting in July 2008 also included a meeting with six additional surgeons in an effort to produce guidelines related to central neck dissection that would be as authoritative as possible. The organization of management guideline recommendations is shown in Table 1 in the original guideline document. It was agreed to continue to categorize the published data and strength of recommendations using a modified schema proposed by the United States (U.S.) Preventive Services Task Force.

Rating Scheme for the Strength of the Recommendations

Strength of Panelists' Recommendations Based on Available Evidence

Rating Definition
A Strongly recommends. The recommendation is based on good evidence that the service or intervention can improve important health outcomes. Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes.
B Recommends. The recommendation is based on fair evidence that the service or intervention can improve important health outcomes. The evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes.
C Recommends. The recommendation is based on expert opinion.
D Recommends against. The recommendation is based on expert opinion.
E Recommends against. The recommendation is based on fair evidence that the service or intervention does not improve important health outcomes or that harms outweigh benefits.
F Strongly recommends against. The recommendation is based on good evidence that the service or intervention does not improve important health outcomes or that harms outweigh benefits.
I Recommends neither for nor against. The panel concludes that the evidence is insufficient to recommend for or against providing the service or intervention because evidence is lacking that the service or intervention improves important health outcomes, the evidence is of poor quality, or the evidence is conflicting. As a result, the balance of benefits and harms cannot be determined.

Adapted from the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality.

Cost Analysis

A recent cost-effectiveness analysis suggested that calcitonin screening would be cost effective in the United States. However, the prevalence estimates of medullary thyroid cancer in this analysis included patients with C-cell hyperplasia and micromedullary carcinoma, which have an uncertain clinical significance. If the unstimulated serum calcitonin determination has been obtained and the level is greater than 100 pg/mL, medullary cancer is likely present.

Method of Guideline Validation
Comparison with Guidelines from Other Groups
External Peer Review
Internal Peer Review
Description of Method of Guideline Validation

The final document was approved by the American Thyroid Association (ATA) Board of Directors and endorsed (in alphabetical order) by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology, British Association of Head and Neck Oncologists (BAHNO), The Endocrine Society, European Association for Cranio-Maxillo-Facial Surgery (EACMFS), European Association of Nuclear Medicine (EANM), European Society of Endocrine Surgeons (ESES), European Society for Paediatric Endocrinology (ESPE), International Association of Endocrine Surgeons (IAES), and Latin American Thyroid Society (LATS).

Other groups, including the American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons, the British Thyroid Association and The Royal College of Physicians, and the National Comprehensive Cancer Network, have previously developed guidelines that have provided somewhat conflicting recommendations due to the lack of high quality evidence from randomized controlled trials. The European Thyroid Association has published consensus guidelines for the management of differentiated thyroid cancer (DTC). The European Association of Nuclear Medicine has also recently published consensus guidelines for radioiodine (RAI) therapy of DTC. The ATA guidelines taskforce used a strategy similar to that employed by the National Institutes of Health for its Consensus Development Conferences.

Recommendations

Major Recommendations

Definitions for the strength of the recommendations (A–F, I) are presented at the end of the "Major Recommendations" field.

Thyroid Nodules

Evaluation

Laboratory Tests and Imaging Modalities

R1. Measure serum thyrotropin (TSH) in the initial evaluation of a patient with a thyroid nodule. If the serum TSH is subnormal, a radionuclide thyroid scan should be performed using either technetium 99mTc pertechnetate or 123I. Recommendation rating: A

R2. Thyroid sonography should be performed in all patients with known or suspected thyroid nodules. Recommendation rating: A

R3. Routine measurement of serum thyroglobulin (Tg) for initial evaluation of thyroid nodules is not recommended. Recommendation rating: F

R4. The panel cannot recommend either for or against the routine measurement of serum calcitonin. Recommendation rating: I

Fine Needle Aspiration (FNA) Biopsy

R5. (a) FNA is the procedure of choice in the evaluation of thyroid nodules. Recommendation rating: A

(b) Ultrasound (US) guidance for FNA is recommended for those nodules that are nonpalpable, predominantly cystic, or located posteriorly in the thyroid lobe. Recommendation rating: B

Cytopathological Interpretation of FNA Samples

R6. (a) US guidance should be used when repeating the FNA procedure for a nodule with an initial nondiagnostic cytology result. Recommendation rating: A

(b) Partially cystic nodules that repeatedly yield nondiagnostic aspirates need close observation or surgical excision. Surgery should be more strongly considered if the cytologically nondiagnostic nodule is solid. Recommendation rating: B

R7. If a cytology result is diagnostic of or suspicious for papillary thyroid cancer (PTC), surgery is recommended (Gharib, Goellner, & Johnson, 1993). Recommendation rating: A

R8. (a) The use of molecular markers (e.g., BRAF, RAS, RET/PTC, Pax8-PPAR gamma, or galectin-3) may be considered for patients with indeterminate cytology on FNA to help guide management. Recommendation rating: C

(b) The panel cannot recommend for or against routine clinical use of fluorodeoxyglucose positron emission tomography (FDG-PET) scan to improve diagnostic accuracy of indeterminate thyroid nodules. Recommendation rating: I

R9. If the cytology reading reports a follicular neoplasm, a 123I thyroid scan may be considered, if not already done, especially if the serum TSH is in the low-normal range. If a concordant autonomously functioning nodule is not seen, lobectomy or total thyroidectomy should be considered. Recommendation rating: C

R10. If the reading is "suspicious for papillary carcinoma" or "Hürthle cell neoplasm," a radionuclide scan is not needed, and either lobectomy or total thyroidectomy is recommended, depending on the lesion's size and other risk factors. Recommendation rating: A

R11. If the nodule is benign on cytology, further immediate diagnostic studies or treatment are not routinely required. Recommendation rating: A

R12 (a) In the presence of two or more thyroid nodules >1 cm, those with a suspicious sonographic appearance (see text and Table 3 in original guideline document) should be aspirated preferentially. Recommendation rating: B

(b) If none of the nodules has a suspicious sonographic appearance and multiple sonographically similar coalescent nodules with no intervening normal parenchyma present, the likelihood of malignancy is low and it is reasonable to aspirate the largest nodules only and observe the others with serial US examinations. Recommendation rating: C

R13. A low or low-normal serum TSH concentration may suggest the presence of autonomous nodule(s). A technetium 99mTc pertechnetate or 123I scan should be performed and directly compared to the US images to determine functionality of each nodule >1 to 1.5 cm. FNA should then be considered only for those isofunctioning or nonfunctioning nodules, among which those with suspicious sonographic features should be aspirated preferentially. Recommendation rating: B

Follow-up

Long-term Follow-up

R14. (a) It is recommended that all benign thyroid nodules be followed with serial US examinations 6 to 18 months after the initial FNA. If nodule size is stable (i.e., no more than a 50% change in volume or <20% increase in at least two nodule dimensions in solid nodules or in the solid portion of mixed cystic–solid nodules), the interval before the next follow-up clinical examination or US may be longer, e.g., every 3 to 5 years. Recommendation rating: C

(b) If there is evidence for nodule growth either by palpation or sonographically (more than a 50% change in volume or a 20% increase in at least two nodule dimensions with a minimal increase of 2 mm in solid nodules or in the solid portion of mixed cystic–solid nodules), the FNA should be repeated, preferably with US guidance. Recommendation rating: B

R15. 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. Recommendation rating: B

Medical Therapy

R16. Routine suppression therapy of benign thyroid nodules in iodine sufficient populations is not recommended. Recommendation rating: F

R17. Patients with growing nodules that are benign after repeat biopsy should be considered for continued monitoring or intervention with surgery based on symptoms and clinical concern. There are no data on the use of levothyroxine (LT4) in this subpopulation of patients. Recommendation rating: I

Children

R18. The diagnostic and therapeutic approach to one or more thyroid nodules in a child should be the same as it would be in an adult (clinical evaluation, serum TSH, US, FNA). Recommendation rating: A

Pregnant Women

R19. For euthyroid and hypothyroid pregnant women with thyroid nodules, FNA should be performed. For women with suppressed serum TSH levels that persist after the first trimester, FNA may be deferred until after pregnancy and cessation of lactation, when a radionuclide scan can be performed to evaluate nodule function. Recommendation rating: A

R20. (a) A nodule with cytology indicating PTC discovered early in pregnancy should be monitored sonographically and if it grows substantially (as defined above) by 24 weeks' gestation, surgery should be performed at that point. However, if it remains stable by midgestation or if it is diagnosed in the second half of pregnancy, surgery may be performed after delivery. In patients with more advanced disease, surgery in the second trimester is reasonable. Recommendation rating: C

(b) In pregnant women with FNA that is suspicious for or diagnostic of PTC, consideration could be given to administration of LT4 therapy to keep the TSH in the range of 0.1 to 1 mU/L. Recommendation rating: C

Differentiated Thyroid Cancer (DTC)—Initial Management

Initial Therapy

Preoperative Staging

R21. Preoperative neck US for the contralateral lobe and cervical (central and especially lateral neck compartments) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant cytologic findings on biopsy. US-guided FNA of sonographically suspicious lymph nodes should be performed to confirm malignancy if this would change management. Recommendation rating: B

R22. Routine preoperative use of other imaging studies (computed tomography [CT], magnetic resonance imaging [MRI], positron emission tomography [PET]) is not recommended. Recommendation rating: E

R23. Routine preoperative measurement of serum Tg is not recommended. Recommendation rating: E

Appropriate Operation

R24. For patients with an isolated indeterminate solitary nodule who prefer a more limited surgical procedure, thyroid lobectomy is the recommended initial surgical approach. Recommendation rating: C

R25. (a) Because of an increased risk for malignancy, total thyroidectomy is indicated in patients with indeterminate nodules who have large tumors (>4 cm), when marked atypia is seen on biopsy, when the biopsy reading is "suspicious for papillary carcinoma," in patients with a family history of thyroid carcinoma, and in patients with a history of radiation exposure. Recommendation rating: A

(b) Patients with indeterminate nodules who have bilateral nodular disease, or those who prefer to undergo bilateral thyroidectomy to avoid the possibility of requiring a future surgery on the contralateral lobe, should also undergo total or near-total thyroidectomy. Recommendation rating: C

R26. For patients with thyroid cancer >1 cm, the initial surgical procedure should be a near-total or total thyroidectomy unless there are contraindications to this surgery. Thyroid lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal papillary carcinomas in the absence of prior head and neck irradiation or radiologically or clinically involved cervical nodal metastases. Recommendation rating: A

R27*. (a) Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. Recommendation rating: B

(b) Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4). Recommendation rating: C

(c) Near-total or total thyroidectomy without prophylactic central neck dissection may be appropriate for small (T1 or T2), noninvasive, clinically node-negative PTCs and most follicular cancer. Recommendation rating: C

R28. Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. Recommendation rating: B

*R27a, 27b, 27c, and 28 were developed in collaboration with an ad hoc committee of endocrinologists, otolaryngology–head and neck surgeons, and endocrine surgeons. (See the "Composition of Group That Authored the Guideline" field for more details.)

R29. Completion thyroidectomy should be offered to those patients for whom a near-total or total thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. This includes all patients with thyroid cancer except those with small (<1 cm), unifocal, intrathyroidal, node-negative, low-risk tumors. Therapeutic central neck lymph node dissection should be included if the lymph nodes are clinically involved. Recommendation rating: B

R30. Ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy (Randolph & Daniels, 2002). It is unknown whether this approach results in similar long-term outcomes. Consequently, routine radioactive iodine ablation in lieu of completion thyroidectomy is not recommended. Recommendation rating: D

Postoperative Staging Systems

R31. Because of its utility in predicting disease mortality, and its requirement for cancer registries, American Joint Commission on Cancer/International Union Against Cancer (AJCC/UICC) staging is recommended for all patients with DTC. The use of postoperative clinico-pathologic staging systems is also recommended to improve prognostication and to plan follow-up for patients with DTC. Recommendation rating: B

Postoperative Radioiodine (RAI) Remnant Ablation

R32. (a) RAI ablation is recommended for all patients with known distant metastases, gross extrathyroidal extension of the tumor regardless of tumor size, or primary tumor size >4 cm even in the absence of other higher risk features.

(b) RAI ablation is recommended for selected patients with 1- to 4-cm thyroid cancers confined to the thyroid, who have documented lymph node metastases, or other higher risk features (see preceding paragraphs) when the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer. Recommendation rating: C (for selective use in higher risk patients)

(c) RAI ablation is not recommended for patients with unifocal cancer <1 cm without other higher risk features (see preceding paragraphs). Recommendation rating: E

(d) RAI ablation is not recommended for patients with multifocal cancer when all foci are <1 cm in the absence other higher risk features (see preceding paragraphs). Recommendation rating: E

Preparation for RAI Ablation

R33. Patients undergoing RAI therapy or diagnostic testing can be prepared by LT4 withdrawal for at least 2 to 3 weeks or LT3 treatment for 2 to 4 weeks and LT3 withdrawal for 2 weeks with measurement of serum TSH to determine timing of testing or therapy (TSH >30 mU/L). Thyroxine therapy (with or without LT3 for 7 to 10 days) may be resumed on the second or third day after RAI administration. Recommendation rating: B

R34. Remnant ablation can be performed following thyroxine withdrawal or recombinant human thyrotropin (rhTSH) stimulation. Recommendation rating: A

R35. Pretherapy scans and/or measurement of thyroid bed uptake may be useful when the extent of the thyroid remnant cannot be accurately ascertained from the surgical report or neck ultrasonography, or when the results would alter either the decision to treat or the activity of RAI that is administered. If performed, pretherapy scans should utilize 123I (1.5 to 3 mCi) or low-activity 131I (1 to 3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity. Recommendation rating: C

R36. The minimum activity (30 to 100 mCi) necessary to achieve successful remnant ablation should be utilized, particularly for low-risk patients. Recommendation rating: B

R37. If residual microscopic disease is suspected or documented, or if there is a more aggressive tumor histology (e.g. tall cell, insular, columnar cell carcinoma), then higher activities (100 to 200 mCi) may be appropriate. Recommendation rating: C

R38. A low-iodine diet for 1 to 2 weeks is recommended for patients undergoing RAI remnant ablation, particularly for those patients with high iodine intake. Recommendation rating: B

Posttherapy Scan

R39. A posttherapy scan is recommended following RAI remnant ablation. This is typically done 2 to 10 days after the therapeutic dose is administered, although published data supporting this time interval are lacking. Recommendation rating: B

Postsurgery and RAI Therapy

TSH Suppression Therapy

R40. Initial thyrotropin suppression to below 0.1 mU/L is recommended for high-risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly below the lower limit of normal (0.1 to 0.5 mU/L) is appropriate for low-risk patients. Similar recommendations apply to low-risk patients who have not undergone remnant ablation, i.e., serum TSH 0.1 to 0.5 mU/L. Recommendation rating: B

External Beam Irradiation and Chemotherapy

R41. The use of external beam irradiation to treat the primary tumor should be considered in patients over age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective. The sequence of external beam irradiation and RAI therapy depends on the volume of gross residual disease and the likelihood of the tumor being RAI responsive. Recommendation rating: B

R42. There is no role for the routine adjunctive use of chemotherapy in patients with DTC. Recommendation rating: F

Differentiated Thyroid Cancer: Long-term Management

Serum Thyroglobulin (Tg) Measurements

R43. Serum Tg should be measured every 6 to 12 months by an immunometric assay that is calibrated against the Certified Reference Material (CRM)-457 standard. Ideally, serum Tg should be assessed in the same laboratory and using the same assay, during follow-up of patients with DTC who have undergone total or near-total thyroidectomy with or without thyroid remnant ablation. Thyroglobulin antibodies should be quantitatively assessed with every measurement of serum Tg. Recommendation rating: A

R44. Periodic serum Tg measurements 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 during TSH suppression or stimulation 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. Recommendation rating: B

R45. (a) In low-risk patients who have had remnant ablation and negative cervical US and undetectable TSH-suppressed Tg within the first year after treatment, serum Tg should be measured after thyroxine withdrawal or rhTSH stimulation approximately 12 months after the ablation to verify absence of disease. Recommendation rating: A

(b) Low-risk patients who have had remnant ablation, negative cervical US, and undetectable TSH-stimulated Tg can be followed primarily with yearly clinical examination and Tg measurements on thyroid hormone replacement. Recommendation rating: B

Diagnostic Whole-body RAI Scans (DxWBS), Ultrasound, and Other Imaging Techniques

R46. After the first posttreatment whole-body RAI scan (RxWBS) performed following RAI remnant ablation, low-risk patients with an undetectable Tg on thyroid hormone with negative antithyrogolublin antibodies and a negative US do not require routine DxWBS during follow-up. Recommendation rating: F

R47. DxWBS, either following thyroid hormone withdrawal or rhTSH, 6 to 12 months after remnant ablation may be of value in the follow-up of patients with high or intermediate risk of persistent disease (see risk stratification system under AJCC/UICC tumor-node-metastasis [TNM] staging in the original guideline document), but should be done with 123I or low activity 131I. Recommendation rating: C

R48. (a) Following surgery, cervical ultrasound to evaluate the thyroid bed and central and lateral cervical nodal compartments should be performed at 6 to 12 months and then periodically, depending on the patients' risk for recurrent disease and Tg status. Recommendation rating: B

(b) If a positive result would change management, ultrasonographically suspicious lymph nodes greater than 5 to 8 mm in the smallest diameter should be biopsied for cytology with Tg measurement in the needle washout fluid. Recommendation rating: A

(c) Suspicious lymph nodes less than 5 to 8 mm in largest diameter may be followed without biopsy with consideration for intervention if there is growth or if the node threatens vital structures. Recommendation rating: C

(d) In addition to its proven role in the localization of disease in Tg-positive, RAI scan–negative patients, FDG-PET scanning may be employed 1) 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, 2) as a prognostic tool in patients with metastatic disease to identify those patients at highest risk for rapid disease progression and disease-specific mortality, and 3) as an evaluation of posttreatment response following systemic or local therapy of metastatic or locally invasive disease. Recommendation rating: C

Long-term Thyroxine Suppression Therapy

R49. (a) In patients with persistent disease, the serum TSH should be maintained below 0.1 mU/L indefinitely in the absence of specific contraindications. Recommendation rating: B

(b) In patients who are clinically and biochemically free of disease but who presented with high risk disease, consideration should be given to maintaining TSH-suppressive therapy to achieve serum TSH levels of 0.1 to 0.5 mU/L for 5 to 10 years. Recommendation rating: C

(c) In patients free of disease, especially those at low risk for recurrence, the serum TSH may be kept within the low normal range (0.3 to 2 mU/L). Recommendation rating: B

(d) In patients who have not undergone remnant ablation who are clinically free of disease and have undetectable suppressed serum Tg and normal neck US, the serum TSH may be allowed to rise to the low normal range (0.3 to 2 mU/L). Recommendation rating: C

Management of Metastatic Disease

Surgical Management

R50. (a) Therapeutic comprehensive compartmental lateral and/or central neck dissection, sparing uninvolved vital structures, should be performed for patients with persistent or recurrent disease confined to the neck. Recommendation rating: B

(b) Limited compartmental lateral and/or central compartmental neck dissection may be a reasonable alternative to more extensive comprehensive dissection for patients with recurrent disease within compartments having undergone prior comprehensive dissection and/or external beam radiotherapy. Recommendation rating: C

R51. When technically feasible, surgery for aerodigestive disease is recommended in combination with RAI and/or external beam radiotherapy. Recommendation rating: B

RAI Therapy for Locoregional or Distant Metastatic Disease

R52. (a) In the treatment of locoregional or metastatic disease, no recommendation can be made about the superiority of one method of RAI administration over another (empiric high dose versus blood and/or body dosimetry versus lesional dosimetry). Recommendation rating: I

(b) Empirically administered amounts of 131I exceeding 200 mCi that often potentially exceed the maximum tolerable tissue dose should be avoided in patients over age 70 years. Recommendation rating: A

R53. There are currently insufficient outcome data to recommend rhTSH-mediated therapy for all patients with metastatic disease being treated with 131I. Recommendation rating: D

R54. Recombinant human (rh)TSH-mediated therapy may be indicated in selected patients with underlying comorbidities 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. Recommendation rating: C

Lithium in 131I Therapy

R55. 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. Recommendation rating: I

Distant Metastatic Disease

Pulmonary Metastases

R56. Pulmonary micrometastases should be treated with RAI therapy, and repeated every 6 to 12 months as long as disease continues to concentrate RAI and respond clinically, because the highest rates of complete remission are reported in these subgroups (Ronga et al., 2004; Schlumberger et al., 1996; Ilgan et al., 2004; Hod et al., 2005). Recommendation rating: A

R57. The selection of RAI activity to administer for pulmonary micrometastases can be empiric (100 to 200 mCi) or estimated by dosimetry to limit whole-body retention to 80 mCi at 48 hours and 200 cGy to the red bone marrow. Recommendation rating: B

R58. RAI-avid macronodular metastases should be treated with RAI and treatment should 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 to 200 mCi) or estimated by lesional dosimetry or dosimetry to limit whole-body retention to 80 mCi at 48 hours and 200 cGy to the red bone marrow. Recommendation rating: B

R59. (a) Evidence of benefit of routine treatment of non–RAI-avid pulmonary metastases is insufficient to recommend any specific systemic therapy. For many patients, metastatic disease is slowly progressive and patients can often be followed conservatively on TSH-suppressive therapy with minimal evidence of radiographic or symptomatic progression. For selected patients, however, other treatment options need to be considered, such as metastasectomy, endobronchial laser ablation, or external beam radiation for palliation of symptomatic intrathoracic lesions (e.g., obstructing or bleeding endobronchial masses), and pleural or pericardial drainage for symptomatic effusions. Referral for participation in clinical trials should be considered. Recommendation rating: C

(b) Referral for participation in clinical trials should be considered for patients with progressive or symptomatic metastatic disease. For those patients who do not participate in clinical trials, treatment with tyrosine kinase inhibitors should be considered. Recommendation rating: B

Bone Metastases

R60. Complete surgical resection of isolated symptomatic metastases has been associated with improved survival and should be considered, especially in patients <45 years old with slowly progressive disease (Bernier et al., 2001; Zettinig et al., 2002). Recommendation ratings: B

R61. RAI therapy of iodine-avid bone metastases has been associated with improved survival and should be employed (Bernier et al., 2001; Schlumberger et al., 1996), although RAI is rarely curative. The RAI activity administered can be given empirically (100 to 200 mCi) or determined by dosimetry (Maxon et al., 1983). Recommendation rating: B

R62. When skeletal metastatic lesions arise in locations where acute swelling may produce severe pain, fracture, or neurologic complications, external radiation and the concomitant use of glucocorticoids to minimize potential TSH-induced and/or radiation-related tumor expansion should be strongly considered (Luster et al., 2005). Recommendation rating: C

R63. Painful lesions that cannot be resected can also be treated by several options individually or in combination, including RAI, external beam radiotherapy, intra-arterial embolization (Eustatia-Rutten et al., 2003; Van Tol et al., 2000), radiofrequency ablation (Posteraro, Dupuy, & Mayo-Smith, 2004), periodic pamidronate or zoledronate infusions (with monitoring for development of possible mandibular osteonecrosis) (Vitale et al., 2001), or vertebroplasty or kyphoplasty (Masala et al., 2003). While many of these modalities have been shown to relieve bone pain in cancer, they have not necessarily been reported to have been used in thyroid cancer patients. Recommendation rating: C

R64. Evidence is insufficient to recommend treatment of asymptomatic, non–RAI-responsive, stable lesions that do not threaten nearby critical structures. Recommendation rating: I

Brain Metastases

R65. Complete surgical resection of central nervous system (CNS) metastases should be considered regardless of RAI avidity, because it is associated with significantly longer survival. Recommendation rating: B

R66. CNS lesions that are not amenable to surgery should be considered for external beam irradiation. Optimally, very targeted approaches (such as radiosurgery) are employed to limit the radiation exposure of the surrounding brain tissue. Whole brain and spine irradiation could be considered if multiple metastases are present. Recommendation rating: C

R67. If CNS metastases do concentrate RAI, then RAI could be considered. If RAI is being considered, prior external beam radiotherapy and concomitant glucocorticoid therapy are strongly recommended to minimize the effects of a potential TSH-induced increase in tumor size and the subsequent inflammatory effects of the RAI (Luster et al., 2005). Recommendation rating: C

Complications of RAI Therapy

R68. The evidence is insufficient to recommend for or against the routine use of preventive measures to prevent salivary gland damage after RAI therapy. Recommendation rating: I

R69. Patients with xerostomia are at increased risk of dental caries and should discuss preventive strategies with their dentists. Recommendation rating: C

R70. Surgical correction should be considered for nasolacrimal outflow obstruction, which often presents as excessive tearing (epiphora) but also predisposes to infection. Recommendation rating: B

Second Malignancies and Leukemia

R71. Because there is no evidence demonstrating a benefit of more intensive screening, all thyroid cancer patients should be encouraged to seek age-appropriate screenings for cancer according to routine health maintenance recommendations. Patients who receive a cumulative 131I activity in excess of 500 to 600 mCi should be advised that they may have a small excess risk of developing leukemia and solid tumors in the future. Recommendation rating: C

Bone Marrow

R72. Patients receiving therapeutic doses of RAI should have baseline complete blood cell (CBC) and assessment of renal function. Recommendation rating: C

Effect of RAI on Gonadal Function and in Nursing Women

R73. Women receiving RAI therapy should avoid pregnancy for 6 to 12 months. Recommendation rating: C

R74. (a) Radioactive iodine should not be given to nursing women. Depending on the clinical situation, RAI therapy could be deferred until a time when lactating women have stopped breast-feeding for at least 6 to 8 weeks. Recommendation rating: B

(b) Dopaminergic agents might be useful in decreasing breast exposure in recently lactating women, although caution should be exercised given the risk of serious side effects associated with their routine use to suppress postpartum lactation. Recommendation rating: C

Tg-positive, RAI–negative Patients

R75. Empiric radioactive iodine therapy (100 to 200 mCi) might be considered in patients with elevated (Tg levels after T4 withdrawal of 10 ng/mL or higher, or a level of 5 ng/mL or higher after rhTSH stimulation) or rising serum Tg levels in whom imaging has failed to reveal a potential tumor source. If the posttherapy scan is negative, no further RAI therapy should be administered. Recommendation rating: C

R76. If persistent nonresectable disease is localized after an empiric dose of RAI, and there is objective evidence of significant tumor reduction, then RAI therapy should 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. Recommendation rating: C

R77. In the absence of structurally evident disease, stimulated serum Tg <10 ng/mL with thyroid hormone withdrawal or <5 ng/mL with rhTSH can be followed with continued LT4 therapy alone, reserving additional therapies for those patients with rising serum Tg levels over time or other evidence of structural disease progression. Recommendation rating: C

Patients with Negative RxWBS

R78. (a) If an empiric dose (100 to 200 mCi) of RAI fails to localize the persistent disease, fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scanning should be considered, especially in patients with unstimulated serum Tg levels >10 to 20 ng/mL or in those with aggressive histologies, in order to localize metastatic lesions that may require treatment or continued close observation (Wang et al., 1999; Helal et al., 2001). Recommendation rating: B

(b) Tg-positive, RxWBS-negative patients with disease that is incurable with surgery and is structurally evident or visualized on FDG-PET/CT scan can be managed with thyroid hormone suppression therapy, external beam radiotherapy, chemotherapy, radiofrequency ablation, chemo-embolization, or monitoring without additional therapy if stable. Clinical trials should also be considered. Recommendation rating: C

R79. Tg-positive, RxWBS-negative patients with no structural evidence of disease can be followed with serial structural imaging studies and serial Tg measurements, with both performed more frequently if the Tg level is rising. When and how often to repeat FDG-PET/CT imaging in this setting is less certain. Recommendation rating: C

External Beam Radiotherapy

R80. External beam radiation should be used in the management of unresectable gross residual or recurrent cervical disease, painful bone metastases, or metastatic lesions in critical locations likely to result in fracture, neurological, or compressive symptoms that are not amenable to surgery (e.g., vertebral metastases, CNS metastases, selected mediastinal or subcarinal lymph nodes, pelvic metastases) (Brierley et al., 2005). Recommendation rating: B

Definitions:

Strength of Panelists' Recommendations Based on Available Evidence

Rating Definition
A Strongly recommends. The recommendation is based on good evidence that the service or intervention can improve important health outcomes. Evidence includes consistent results from well-designed, well-conducted studies in representative populations that directly assess effects on health outcomes.
B Recommends. The recommendation is based on fair evidence that the service or intervention can improve important health outcomes. The evidence is sufficient to determine effects on health outcomes, but the strength of the evidence is limited by the number, quality, or consistency of the individual studies; generalizability to routine practice; or indirect nature of the evidence on health outcomes.
C Recommends. The recommendation is based on expert opinion.
D Recommends against. The recommendation is based on expert opinion.
E Recommends against. The recommendation is based on fair evidence that the service or intervention does not improve important health outcomes or that harms outweigh benefits.
F Strongly recommends against. The recommendation is based on good evidence that the service or intervention does not improve important health outcomes or that harms outweigh benefits.
I Recommends neither for nor against. The panel concludes that the evidence is insufficient to recommend for or against providing the service or intervention because evidence is lacking that the service or intervention improves important health outcomes, the evidence is of poor quality, or the evidence is conflicting. As a result, the balance of benefits and harms cannot be determined.

Adapted from the U.S. Preventive Services Task Force, Agency for Healthcare Research and Quality.

Clinical Algorithm(s)

Clinical algorithms are provided in the original guideline document for the following:

  • Evaluation of patients with one or more thyroid nodules
  • Initial follow-up of patients with differentiated thyroid carcinoma
  • Longer term follow-up of patients with differentiated thyroid carcinoma
  • Considerations for empiric treatment with radioiodine

Evidence Supporting the Recommendations

References Supporting the Recommendations
Type of Evidence Supporting the Recommendations

The type of supporting evidence is specifically stated for each recommendation (see the "Major Recommendations" field).

Benefits/Harms of Implementing the Guideline Recommendations

Potential Benefits

Appropriate management of patients with thyroid nodules and differentiated thyroid cancer

Potential Harms
  • False-negative and false-positive results of diagnostic tests
  • Complications of percutaneous ethanol injection (PEI) include mild to moderate local pain, flushing, dizziness, and dysphonia.
  • There may be a higher rate of complications in pregnant women undergoing thyroid surgery compared with nonpregnant women.
  • Studies of central compartment dissection have demonstrated higher morbidity, primarily recurrent laryngeal nerve injury and transient hypoparathyroidism, with no reduction in recurrence. In another study, comprehensive (bilateral) central compartment dissection demonstrated higher rates of transient hypoparathyroidism compared to selective (unilateral) dissection with no reduction in rates of undetectable or low thyroglobulin (Tg) levels.
  • Adverse effects of serum thyrotropin (TSH) suppression may include the known consequences of subclinical thyrotoxicosis, including exacerbation of angina in patients with ischemic heart disease, increased risk for atrial fibrillation in older patients, and increased risk of osteoporosis in postmenopausal women.
  • External beam radiation is associated with some morbidity.
  • The use of recombinant human thyrotropin (rhTSH) does not eliminate and may even increase the possibility of rapid swelling of metastatic lesions.
  • Pulmonary pneumonitis and fibrosis are rare complications of high-dose radioactive iodine treatment.
  • The orally available anti-angiogenic tyrosine kinase inhibitors (axitinib, motesanib, and sorafenib) have numerous common side effects, including hypertension, diarrhea, fatigue, skin rashes and erythema, and weight loss, and various drug-specific toxicities have been reported as well.
  • While radioiodine (RAI) appears to be a reasonably safe therapy, it is associated with a cumulative dose-related low risk of early- and late-onset complications such as salivary gland damage, dental caries, nasolacrimal duct obstruction, and secondary malignancies.
  • Published data indicate that when administered activities are selected to remain below 200 cGy to the bone marrow, minimal transient effects are noted in white blood cell (WBC) and platelet counts. However, persistent mild decrements in white blood count and/or platelets are not uncommon in patients who have received multiple RAI therapies. Furthermore, radiation to the bone marrow is impacted by several factors, including renal function.
  • Temporary amenorrhea/oligomenorrhea lasting 4 to 10 months occurs in 20% to 27% of menstruating women after 131I therapy for thyroid cancer.
  • Ovarian damage from RAI therapy may result in menopause occurring approximately 1 year earlier than the general population, but this result was not associated with cumulative dose administered or the age at which the therapy was given. In men, RAI therapy may be associated with a temporary reduction in sperm counts and elevated serum follicle-stimulating hormone (FSH) levels. Higher cumulative doses (500 to 800 mCi) in men are associated with an increased risk of persistent elevation of serum FSH levels, but fertility and risks of miscarriage or congenital abnormalities in subsequent pregnancies are not changed with moderate RAI activities (~200 mCi).

Contraindications

Contraindications

Radionuclide scan is contraindicated in pregnant women.

Qualifying Statements

Qualifying Statements
  • The medical opinions expressed are those of the authors; none were dictated by the American Thyroid Association (ATA).
  • It is the authors' goal in formulating these guidelines, and the ATA's goal in providing support for the development of these guidelines, that they assist in the clinical care of patients, and share what the authors believe is current, rational, and optimal medical practice. In some circumstances, it may be apparent that the level of care recommended may be best provided in limited centers with specific expertise. Finally, it is not the intent of these guidelines to replace individual decision making, the wishes of the patient or family, or clinical judgment.

Implementation of the Guideline

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools
Clinical Algorithm
For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

Institute of Medicine (IOM) National Healthcare Quality Report Categories

IOM Care Need
Getting Better
Living with Illness
IOM Domain
Effectiveness

Identifying Information and Availability

Bibliographic Source(s)
American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Pacini F, Schlumberger M, Sherman SI, Steward DL, Tuttle RM. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009 Nov;19(11):1167-214. [434 references] PubMed External Web Site Policy
Adaptation

Not applicable: The guideline was not adapted from another source.

Date Released
2006 Feb (revised 2009 Nov)
Guideline Developer(s)
American Thyroid Association - Professional Association
Source(s) of Funding

American Thyroid Association

Guideline Committee

American Thyroid Association Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer

Composition of Group That Authored the Guideline

Taskforce Members: David S. Cooper (Chair), The Johns Hopkins University School of Medicine, Baltimore, Maryland; Gerard M. Doherty, University of Michigan Medical Center, Ann Arbor, Michigan; Bryan R. Haugen, University of Colorado Health Sciences Center, Denver, Colorado; Richard T. Kloos, The Ohio State University, Columbus, Ohio; Stephanie L. Lee, Boston University Medical Center, Boston, Massachusetts; Susan J. Mandel, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; Ernest L. Mazzaferri, University of Florida College of Medicine, Gainesville, Florida; Bryan McIver, The Mayo Clinic, Rochester, Minnesota; Furio Pacini, The University of Siena, Siena, Italy; Martin Schlumberger, Institute Gustave Roussy, Paris, France; Steven I. Sherman, University of Texas M.D. Anderson Cancer Center, Houston, Texas; David L. Steward, University of Cincinnati Medical Center, Cincinnati, Ohio; and R. Michael Tuttle, Memorial Sloan-Kettering Cancer Center, New York, New York

Note: Recommendations 27a, 27b, 27c, and 28 were developed in collaboration with an ad hoc committee of endocrinologists (David S. Cooper, M.D., Richard T. Kloos, M.D., Susan J. Mandel, M.D., M.P.H., and R. Michael Tuttle, M.D.), otolaryngology–head and neck surgeons (Gregory Randolph, M.D., David Steward, M.D., David Terris, M.D. and Ralph Tufano, M.D.), and endocrine surgeons (Sally Carty, M.D., Gerard M. Doherty, M.D., Quan-Yang Duh, M.D., and Robert Udelsman, M.D., M.B.A.)

Financial Disclosures/Conflicts of Interest

These guidelines were funded by the American Thyroid Association (ATA) without support from any commercial sources.

GMD is a consultant for MedTronic ENT. BRH has received honoraria from Genzyme and grant/research support from Veracyte. RTK has received grant/research support from Genzyme, Bayer-Onyx, Eisai, and Veracyte; is a consultant for Genzyme, Bayer-Onyx, Abbott, and Veracyte; and is on the Speakers Bureau for Genzyme and Abbott. He has received no honoraria for commercial speaking since November 2006 and all commercial consulting since that time has been approved by the ATA Board of Directors and the ATA Ethics Committee and has been without financial compensation. SLL has received grant/research support from Bayer and is a consultant for Abbott, Onyx, and Bayer. SJM has received grant/research support from Veracyte and has been a CME speaker for Genzyme. ELM is on the Speakers Bureau for Genzyme. FP has received grant/research support from Amgen, Exelixis, and AstraZeneca and is a consultant and on the Speakers Bureau for Genzyme. MS has received grant/research support from Genzyme, Amgen, AstraZeneca, Bayer, Exelixis, and Eisai; is a consultant for Genzyme, AstraZeneca, Bayer, and Exelixis; and is on the Speakers Bureau for Genzyme, AstraZeneca, and Exelixis. SIS has received grant/research support from Genzyme, Amgen, AstraZeneca, and Eisai; is a consultant for AstraZeneca, Eisai, Exelixis, Plexxikon, Oxigene, Semalore, Celgene, and Eli Lilly; is on the Speakers Bureau for Genzyme; and has received honoraria from Abbott. DLS has received grant/research support from Veracyte, Wyeth, AstraZeneca, and Gyrus. RMT is a consultant for Genzyme, Abbott, and Eli Lilly, and has received honoraria from Genzyme and Abbott. DSC and BM report that no competing financial interests exist.

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, Mazzaferri EL, McIver B, Sherman SI, Tuttle RM, The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2006 Feb;16(2):109-42. [301 references]

Guideline Availability

Electronic copies: Available in Portable Document Format (PDF) from the American Thyroid Association Web site External Web Site Policy.

Print copies: Available from American Thyroid Association, 6066 Leesburg Pike, Suite 550, Falls Church, VA 22041.

Availability of Companion Documents

None available

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI on November 30, 2006. This NGC summary was updated by ECRI Institute on May 6, 2010.

Copyright Statement

This NGC summary is based on the original guideline, which is subject to the guideline developer's copyright restrictions.

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