Key Points
- Differentiated thyroid cancer (DTC), which includes papillary and follicular cancer, comprises the vast majority (90%) of all thyroid cancers.
- Preoperative neck US is recommended for all patients undergoing thyroid surgery for malignant or suspicious FNA cytology or molecular findings (recommendation 32)
- Preoperative cross-sectional imaging (CT or MRI) is recommended for patients with clinical suspicion of advanced disease (recommendation 33)
- Patients with thyroid cancer that is 1-4 cm and no preoperative evidence of clinically apparent lymph nodes or extrathyroidal extension can be treated with thyroidectomy or lobectomy (recommendation 35)
- Perioperative voice assessment is important in management of patients with DTC (recommendations 39-45)
- For uniform reporting and appropriate risk assessment, pathology reports should include TNM status, unfavorable or favorable histopathologic variants, assessment of vascular invasion, number of LN examined and involved as well as size of largest involved LN and assessment of extranodal invasion (recommendation 46)
- The ATA Initial Risk Stratification System is recommended for patients with DTC (recommendation 48)
- ATA defined response to therapy should be continually assessed to determine the ongoing risk of recurrence (recommendations 49, 62 and 63)
- Radioiodine (RAI) should be considered as remnant ablation, adjuvant therapy or therapy, and many patients with low risk disease do not require RAI remnant ablation (recommendation 51)
- In patients with low and intermediate risk DTC, preparation for RAI ablation or adjuvant therapy with rhTSH is an acceptable alternative to thyroid hormone withdrawal (recommendation 54)
- Lower administered RAI activities (approximately 30 mCi) are generally favored for patients with ATA low risk and intermediate risk disease with lower risk features (recommendation 55)
- Monitoring approaches and TSH targets should be modified by the ATA response to therapy re-classification (recommendations 62-70)
- RAI-refractory DTC is classified (recommendation 91)
- Patients with RAI-refractory DTC should be carefully evaluated for ongoing monitoring (on TSH-suppressive thyroid hormone therapy), directed therapy (including surgery, radiation or thermal ablation), approved systemic therapy or entry into a clinical trial (recommendations 92-96)
- Patients considered for kinase inhibitor therapy should be carefully counseled on the benefits and risks of therapy and carefully monitored during therapy (recommendations 96-98)
Differentiated Thyroid Cancer
Guideline Grading System
| Strength of Recommendation | Quality of Evidence | ||
|---|---|---|---|
| SR | Strong Recommendation | H | High-quality evidence |
| WR | Weak Recommendation | M | Moderate-quality evidence |
| NR | No Recommendation | L | Low-quality evidence |
| I | Insufficient evidence | ||
- 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)
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)
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) - 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)
B) Routine preoperative 18FDG-PET scanning is NOT recommended. (SR-L) - Routine preoperative measurement of serum Tg or Tg antibodies is NOT recommended. (WR-L)
Table 1. Ultrasound Features of Lymph Nodes Predictive of Malignant Involvement
| Sign | Reported sensitivity % | Reported specificity % |
|---|---|---|
| Microcalcifications | 5–69 | 93–100 |
| Cystic aspect | 10–34 | 91–100 |
| Peripheral vascularity | 40–86 | 57–93 |
| Hyperechogenicity | 30–87 | 43–95 |
| Round shape | 37 | 70 |
Table 2. AJCC 7th edition/TNM Classification System for Differentiated Thyroid Carcinoma
| Primary tumor (T) | |||
|---|---|---|---|
| T0 | No evidence of primary tumor | ||
| T1a | Tumor ≤1 cm, without extrathyroidal extension | ||
| T1b | Tumor >1 cm but ≤2 cm in greatest dimension, without extrathyroidal extension | ||
| T2 | Tumor >2 cm but ≤4 cm in greatest dimension, without extrathyroidal extension. | ||
| T3 | Tumor >4 cm in greatest dimension limited to the thyroid -or- Any size tumor with minimal extrathyroid extension (e.g., extension into sternothyroid muscle or perithyroidal soft tissues). | ||
| T4a | Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. | ||
| T4b | Tumor of any size invading prevertebral fascia or encasing carotid artery or mediastinal vessels | ||
| Regional Lymph Nodes (N) | |||
| N0 | No metastatic nodes | ||
| N1a | Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) | ||
| N1b | Metastases to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII) | ||
| Distant metastases (M) | |||
| M0 | No distant metastasis | ||
| M1 | Distant metastasis | ||
| Patient age < 45 years old at diagnosis | |||
| I | Any T | Any N | M0 |
| II | Any T | Any N | M1 |
| Patient age ≥ 45 years old at diagnosis | |||
| I | T1a | N0 | M0 |
| T1b | N0 | M0 | |
| II | T2 | N0 | M0 |
| III | T1a | N1a | M0 |
| T1b | N1a | M0 | |
| T2 | N1a | M0 | |
| T3 | N0 | M0 | |
| T3 | N1a | M0 | |
| IVa | T1a | N1b | M0 |
| T1b | N1b | M0 | |
| T2 | N1b | M0 | |
| T3 | N1b | M0 | |
| T4a | N0 | M0 | |
| T4a | N1a | M0 | |
| T4a | N1b | M0 | |
| IVb | T4b | Any N | M0 |
| IVc | Any T | Any N | M1 |
Treatment
- 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)
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)
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) - 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)
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)
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) - Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. (SR-M)
- 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)
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) - 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)
- 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)
- Preoperative laryngeal exam should be performed in all patients with:
A) Preoperative voice abnormalities (SR-M)
B) History of cervical or upper chest surgery, which places the RLN or vagus nerve at risk (SR-M)
C) Known thyroid cancer with posterior extrathyroidal extension or extensive central nodal metastases. (SR-L) - 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)
B) Intraoperative neural stimulation (with or without monitoring) may be considered to facilitate nerve identification and confirm neural function. (WR-L)
Table 3. Pre-operative Factors Which May Be Associated With Laryngeal Nerve Dysfunction
| History | Voice abnormality, dysphagia, airway symptoms, hemoptysis, pain, rapid progression, prior operation in neck or upper chest. |
|---|---|
| Physical Exam | Extensive, firm mass fixed to the larynx or trachea. |
| Imaging | Mass extending to/beyond periphery of thyroid lobe posteriorly and/or tracheoesophageal infiltration, or bulky cervical adenopathy along the course of the RLN or vagus nerve. |
- The parathyroid glands and their blood supply should be preserved during thyroid surgery. (SR-HM)
- Patients should have their voice assessed in the post-operative period. Formal laryngeal exam should be performed if the voice is abnormal. (SR-M)
- 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)
- 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)
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)
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) - 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)
- 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)
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)
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)
Table 4. Best Response to Therapy
| Excellent response | No clinical, biochemical or structural evidence of disease. |
|---|---|
| Biochemical incomplete response | Abnormal thyroglobulin or rising anti-thyroglobulin antibody levels in the absence of localizable disease. |
| Structural incomplete response | Persistent or newly identified locoregional or distant metastases. |
| Indeterminate response | Non-specific biochemical or structural findings which cannot be confidently classified as either benign or malignant. This includes patients with stable or declining anti-thyroglobulin antibody levels without definitive structural evidence of disease. |
