Laszlo Hegedus, Paolo Vitti, and the AACE/AME/ETA Task Force on Thyroid Nodules (see Appendix)

^a These guidelines are based on Endocr Pract. 2006 Jan-Feb;12(1):63-102. Used with permission.

The authors have no conflicts of interest to disclose.

Correspondence to:
Hossein Gharib, MD
Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, 200 First St SW, Rochester, MN 55905, USA
Email: gharib.hossein@mayo.edu

Note of the Authors
Medical Guidelines for Clinical Practice have been developed by AACE to assist health care professionals in medical decision making for specific clinical conditions. Most of the content herein is based on literature reviews. In areas of uncertainty, professional judgment was applied. These guidelines are a working document that reflects the state of the field at the time of publication. Because rapid changes in this area are expected, periodic revisions are inevitable. We encourage medical professionals to use this information in conjunction with their best clinical judgment. Any decision by practitioners to apply these guidelines must be made in light of local resources and individual patient circumstances.

ABSTRACT
This document was prepared as a collaborative effort between the American Association of Clinical Endocrinologists (AACE), the Italian Association of Clinical Endocrinologists (AME), and the European Thyroid Association (ETA). This guideline covers diagnostic and therapeutic aspects of thyroid nodular disease but not thyroid cancer management.
The AACE protocol for standardized production of clinical practice guidelines was followed to rate the evidence level of each reference (on a scale of 1 to 4) and to link the guidelines to the strength of recommendations on the basis of grade designations A (action based on strong evidence) through D (action not based on any evidence or not recommended). The best evidence level (BEL), corresponding to the best conclusive evidence found, accompanies the recommendation grade. All recommendations resulted from a consensus among the AACE, AME, and ETA primary writers and were influenced by input from the Task Force members and reviewers. Some recommendations were upgraded or downgraded on the basis of expert opinion. In these cases, subjective factors such as clinical experience, cost, risks, and regional availability of specific technologies and expertise took priority over the reported BEL.
The use of high-resolution ultrasonography (US), sensitive thyrotropin (TSH) assay, and fine-needle aspiration (FNA) biopsy is the basis for management of thyroid nodules. Thyroid scintigraphy is not necessary for diagnosis in most cases. However, it may be warranted in patients with a low serum TSH value or a multinodular gland, to detect functional autonomy, most common in iodine-deficient areas. Measurement of serum TSH is the best initial laboratory test of thyroid function and should be followed by measurement of free thyroxine and triiodothyronine if the TSH value is decreased, and of anti–thyroid peroxidase antibodies if the TSH value is above the normal range. A single, nonstimulated calcitonin measurement can be used in the initial work-up of thyroid nodules and is recommended before thyroid nodule surgery.
Although thyroid nodules are a common incidental finding, US should not be performed as a screening test. Most patients with thyroid nodules are asymptomatic, but the absence of symptoms does not rule out malignancy; thus, clinical and US risk factors for malignant disease should always be reviewed. All patients with a palpable thyroid nodule or with clinical risk factors should undergo US examination.
Thyroid FNA biopsy is best performed under US guidance because of the increase in diagnostic accuracy of the procedure. US-guided FNA (UGFNA) biopsy is recommended for nodules <10 mm if clinical information or US features are suspicious. Cytologic smears or liquid-based cytology should be interpreted by a pathologist with specific experience. A classification scheme in 5 cytologic diagnostic categories is recommended for the cytologic report: nondiagnostic, benign, follicular lesion, suspicious, or malignant. Currently, no single cytochemical or genetic marker is specific and sensitive enough to replace the morphologic diagnosis of follicular lesion or suspicious for neoplasm. However, use of these markers may be considered in selected cases. Hormone determination on washout from FNA biopsy may increase the diagnostic accuracy of FNA biopsy in suspicious node metastasis or hyperplastic parathyroid glands. US-guided core-needle biopsy should be reserved for patients with neck masses and uncertain FNA biopsy diagnosis.
Patients with benign thyroid nodules should undergo clinical and US follow-up. Symptomatic goiters, whether euthyroid or hyperthyroid, may be treated surgically or with radioiodine. Although we do not recommend routine levothyroxine suppressive therapy, it may be considered for small nodular goiters in young patients living in iodine-deficient regions. Percutaneous ethanol injection is useful in the treatment of benign cystic thyroid lesions. Symptomatic patients with benign nodules who decline surgery or who are at surgical risk may benefit from US-guided thermal ablation.
Malignant or suspicious nodules should be treated surgically. Preoperative evaluation with US and UGFNA biopsy is recommended for appropriate surgical planning.
Suggestions for thyroid nodule management during pregnancy and childhood are also presented.

Key-words and abbreviations: AFTN = autonomously functioning thyroid nodule; BEL = best evidence level; CNB = core-needle biopsy; CT = computed tomography; EL = evidence level; FNA = fine-needle aspiration; LNB = large-needle biopsy; MEN2 = multiple endocrine neoplasia type 2; MeSH = Medical Subject Headings; MNG = multinodular goiter; MRI = magnetic resonance imaging; MTC = medullary thyroid carcinoma; PEI = percutaneous ethanol injection; PLA = percutaneous laser ablation; PTC = papillary thyroid carcinoma; RFA = radiofrequency ablation; rhTSH = recombinant human TSH; TPOAb = anti–thyroid peroxidase antibody; TRAb = anti–TSH-receptor antibody; TSH = thyrotropin (thyroid-stimulating hormone); UGFNA = US-guided FNA; US = ultrasonography, ultrasonographic

Contents
1. Thyroid Nodules: The Scope of the Problem
2. Clinical Evaluation and Diagnosis
2.1. History and Physical Examination
2.1.1. History
2.1.2. Symptoms and signs
2.2. Thyroid Incidentaloma
2.3. Key Recommendations
3. US and Other Diagnostic Imaging Studies
3.1. When to Perform Thyroid US
3.2. US Criteria for FNA Biopsy of Palpable Nodules
3.3. US Criteria for FNA Biopsy of Impalpable Nodules and Nodular Goiters
3.4. US-Elastography
3.5. US Contrast Media
3.6. Other Imaging Techniques
3.7. Key Recommendations
4. Thyroid Biopsy “ 14
4.1. Thyroid FNA Biopsy
4.2. Cytologic Diagnosis
4.3. FNA Biopsy Results
4.4. Large-Needle and Core-Needle Biopsy
4.5. Key Recommendations
5. Laboratory Evaluation
5.1. Assessment of Thyroid Function
5.2. TSH Assay
5.3. Serum Free Thyroxine and Free Triiodothyronine
5.4. Antibody Assays
5.5. Thyroglobulin Assay
5.6. Calcitonin Assay
5.7. Key Recommendations
6. Radionuclide Scanning
6.1. Thyroid Scintigraphy
6.2. Diagnostic Accuracy
6.3. Indications for Thyroid Scintigraphy
6.4. Key Recommendations
7. Management and Therapy
7.1. Nondiagnostic Nodules by FNA Biopsy (Class 1)
7.2. Benign Nodules by FNA Biopsy (Class 2)
7.2.1. Follow-up or levothyroxine suppressive therapy
7.2.2. Surgical indications
7.2.3. US-guided minimally invasive procedures
7.2.3.1. Percutaneous ethanol injection
7.2.3.2. Thermal ablation
7.2.4. Radioiodine treatment for hyperfunctioning nodules
7.2.5. Radioiodine treatment for nodular goiter
7.2.6. Recombinant human TSH–stimulated radioiodine for nontoxic goiter
7.3. Follicular Lesions by FNA Biopsy (Class 3)
7.4. Suspicious Nodules by FNA Biopsy (Class 4)
7.5. Malignant Nodules by FNA Biopsy (Class 5)
7.6. Key Recommendations
8. Pregnancy and Childhood
8.1. Thyroid Nodule During Pregnancy
8.2. Effects of Pregnancy on Nodular Thyroid Disease
8.3. Management and Therapy
8.3.1. Benign thyroid nodule
8.3.2. Follicular or suspicious thyroid nodule
8.3.3. Malignant thyroid nodule
8.4. Thyroid Nodules in Children
8.5. Key Recommendations
9. Methods
9.1. Development and Use of the Guidelines: Methods of Bibliographic Research
9.2. Levels of Evidence and Grading of Recommendations
10. Standards for Diagnostic and Therapeutic Procedures in Patients With Thyroid Nodules
10.1. Ultrasonography
10.1.1. Requirements for US equipment
10.1.2. Requirements for US training
10.1.3. Thyroid US method
10.1.4. Preoperative US study of the neck
10.1.5. Color and power Doppler US examination
10.1.6. US reporting
10.1.7. Documentation
10.1.8. New technology
10.2. Thyroid Biopsy
10.2.1. Counseling, informed consent, and request form
10.2.2. Procedure for palpation-guided FNA biopsy
10.2.3. Procedure for UGFNA biopsy
10.2.4. Hormone determination on FNA biopsy washout
10.2.5. LNB and CNB
10.3. Cytologic Diagnosis and Reporting
10.3.1. Preparation of FNA biopsy material for routine evaluation
10.3.1.1. Direct smears on slides
10.3.1.2. Liquid-based cytology
10.3.1.3. Cell block
10.3.2. Classification schemes for cytologic diagnosis
10.3.2.1. Class 1: nondiagnostic
10.3.2.2. Class 2: benign
10.3.2.3. Class 3: follicular lesion
10.3.2.4. Class 4: suspicious
10.3.2.5. Class 5: malignant
10.3.3. Additional studies
10.4. Laboratory Standards
10.4.1. Thyrotropin
10.4.2. Plasma total thyroxine and total triiodothyronine
10.4.3. Free thyroxine and free triiodothyronine
10.4.4. Anti–thyroid peroxidase antibodies
10.4.5. Antithyroglobulin antibodies
10.4.6. Anti-TSH receptor antibodies
10.4.7. Thyroglobulin
10.4.8. Calcitonin
10.5. Radioiodine Treatment
10.6. US-Guided Interventional Procedures
10.6.1. PEI of cystic lesions
10.6.2. Thermal ablation procedures
10.6.2.1. Percutaneous laser thermal ablation
10.6.2.2. Other thermal ablation procedures
11. References
12. Appendix
13. Executive Summary

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