Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

[A4] Serum TSH with US and with or without scan

With the discovery of a thyroid nodule >1 cm in any diameter or diffuse or focal thyroidal uptake on ¹⁸FDG-PET scan, a serum TSH level should be obtained. If the serum TSH is subnormal, a radionuclide thyroid scan should be obtained to document whether the nodule is hyperfunctioning (i.e., tracer uptake is greater than the surrounding normal thyroid), isofunctioning or “warm” (i.e., tracer uptake is equal to the surrounding thyroid), or nonfunctioning (i.e., has uptake less than the surrounding thyroid tissue). Since hyperfunctioning nodules rarely harbor malignancy, if one is found that corresponds to the nodule in question, no cytologic evaluation is necessary. If overt or subclinical hyperthyroidism is present, additional evaluation is required. Higher serum TSH, even within the upper part of the reference range, is associated with increased risk of malignancy in a thyroid nodule (26).

Diagnostic thyroid US should be performed in all patients with a suspected thyroid nodule, nodular goiter, or radiographic abnormality; e.g., a nodule found incidentally on computed tomography (CT) or magnetic resonance imaging (MRI) or thyroidal uptake on ¹⁸FDG-PET scan. Thyroid US can answer the following questions: Is there truly a nodule that corresponds to the palpable abnormality? How large is the nodule? Does the nodule have benign or suspicious features? Is suspicious cervical lymphadenopathy present? Is the nodule greater than 50% cystic? Is the nodule located posteriorly in the thyroid gland? These last two features might decrease the accuracy of FNA biopsy performed with palpation (27,28). Also, there may be other thyroid nodules present that require biopsy based on their size and appearance (18,29,30). As already noted, FNA is recommended especially when the serum TSH is elevated because, compared with normal thyroid glands, the rate of malignancy in nodules in thyroid glands involved with Hashimoto's thyroiditis is as least as high or possibly higher (31,32).

[A5] Serum Tg measurement

Serum Tg levels can be elevated in most thyroid diseases and are an insensitive and nonspecific test for thyroid cancer (33).

[A6] Serum calcitonin measurement

The utility of serum calcitonin has been evaluated in a series of prospective, nonrandomized studies (34 –37). The data suggest that the use of routine serum calcitonin for screening may detect C-cell hyperplasia and medullary thyroid cancer at an earlier stage and overall survival may be improved. However, most studies rely on pentagastrin stimulation testing to increase specificity. This drug is no longer available in the United States, and there remain unresolved issues of sensitivity, specificity, assay performance and cost-effectiveness. A recent cost-effectiveness analysis suggested that calcitonin screening would be cost effective in the United States (38). 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 (39).

[A8] US for FNA decision making (see Table 3)

Various sonographic characteristics of a thyroid nodule have been associated with a higher likelihood of malignancy (43 –48). These include nodule hypoechogenicity compared to the normal thyroid parenchyma, increased intranodular vascularity, irregular infiltrative margins, the presence of microcalcifications, an absent halo, and a shape taller than the width measured in the transverse dimension. With the exception of suspicious cervical lymphadenopathy, which is a specific but insensitive finding, no single sonographic feature or combinations of features is adequately sensitive or specific to identify all malignant nodules. However, certain features and combination of features have high predictive value for malignancy. Furthermore, the most common sonographic appearances of papillary and follicular thyroid cancer differ. A PTC is generally solid or predominantly solid and hypoechoic, often with infiltrative irregular margins and increased nodular vascularity. Microcalcifications, if present, are highly specific for PTC, but may be difficult to distinguish from colloid. Conversely, follicular cancer is more often iso- to hyperechoic and has a thick and irregular halo, but does not have microcalcifications (49). Follicular cancers that are <2 cm in diameter have not been shown to be associated with metastatic disease (50).

Certain sonographic appearances may also be highly predictive of a benign nodule. A pure cystic nodule, although rare (<2% of all nodules), is highly unlikely to be malignant (47). In addition, a spongiform appearance, defined as an aggregation of multiple microcystic components in more than 50% of the nodule volume, is 99.7% specific for identification of a benign thyroid nodule (48,51,52). In a recent study, only 1 of 360 malignant nodules demonstrated this appearance (48) and in another report, a spongiform appearance had a negative predictive value for malignancy of 98.5% (52). Elastography is an emerging and promising sonographic technique that requires additional validation with prospective studies (53).

Routine FNA is not recommended for subcentimeter nodules. However, the presence of a solid hypoechoic nodule with microcalcifications is highly suggestive of PTC. Although most micropapillary carcinomas may be incidental findings, a subset may be more clinically relevant, especially those >5 mm in diameter (54). These include nodules that have abnormal lymph nodes detected clinically or with imaging at presentation (55,56). Therefore, after imaging a subcentimeter nodule with a suspicious appearance, sonographic assessment of lateral neck and central neck lymph nodes (more limited due to the presence of the thyroid) must be performed. Detection of abnormal lymph nodes should lead to FNA of the lymph node. Other groups of patients for whom consideration of FNA of a subcentimeter nodule may be warranted include those with a higher likelihood of malignancy (high risk history): 1) family history of PTC (57); 2) history of external beam radiation exposure as a child (58); 3) exposure to ionizing radiation in childhood or adolescence (59); 4) history of prior hemithyroidectomy with discovery of thyroid cancer; and 5) ¹⁸FDG-PET–positive thyroid nodules.

Mixed cystic–solid nodules and predominantly cystic with >50% cystic component are generally evaluated by FNA with directed biopsy of the solid component (especially the vascular component.) Cyst drainage may also be performed, especially in symptomatic patients.

[A10] Nondiagnostic cytology

Nondiagnostic biopsies are those that fail to meet specified criteria for cytologic adequacy that have been previously established (the presence of at least six follicular cell groups, each containing 10–15 cells derived from at least two aspirates of a nodule) (5). After an initial nondiagnostic cytology result, repeat FNA with US guidance will yield a diagnostic cytology specimen in 75% of solid nodules and 50% of cystic nodules (28). Therefore, such biopsies need to be repeated using US guidance (60) and, if available, on-site cytologic evaluation, which may substantially increase cytology specimen adequacy (61,62). However, up to 7% of nodules continue to yield nondiagnostic cytology results despite repeated biopsies and may be malignant at the time of surgery (63,64).

[A11] Cytology suggesting PTC

[A12] Indeterminate cytology (follicular or Hürthle cell neoplasm follicular lesion of undetermined significance, atypia)

Indeterminate cytology, reported as “follicular neoplasm” or “Hürthle cell neoplasm” can be found in 15–30% of FNA specimens (4) and carries a 20–30% risk of malignancy (42), while lesions reported as atypia or follicular lesion of undetermined significance are variably reported and have 5–10% risk of malignancy (42). While certain clinical features such as male sex and nodule size (>4 cm) (66), older patient age (67), or cytologic features such as presence of atypia (68) can improve the diagnostic accuracy for malignancy in patients with indeterminate cytology, overall predictive values are still low. Many molecular markers (e.g., galectin-3 (69), cytokeratin, BRAF) have been evaluated to improve diagnostic accuracy for indeterminate nodules (70 –72). Recent large prospective studies have confirmed the ability of genetic markers (BRAF, Ras, RET/PTC) and protein markers (galectin-3) to improve preoperative diagnostic accuary for patients with indeterminate thyroid nodules (69,73,74). Many of these markers are available for commercial use in reference laboratories but have not yet been widely applied in clinical practice. It is likely that some combination of molecular markers will be used in the future to optimize management of patients with indeterminate cytology on FNA specimens.

Recently, ¹⁸FDG-PET scanning has been utilized in an effort to distinguish those indeterminate nodules that are benign from those that are malignant (75 –78). ¹⁸FDG-PET scans appear to have relatively high sensitivity for malignancy but low specificity, but results vary among studies (79).

[A13] Benign cytology

[B4] Neck imaging

Differentiated thyroid carcinoma (particularly papillary carcinoma) involves cervical lymph nodes in 20–50% of patients in most series using standard pathologic techniques (45,129 –132), and may be present even when the primary tumor is small and intrathyroidal (133). The frequency of micrometastases may approach 90%, depending on the sensitivity of the detection method (134,135). However, the clinical implications of micrometastases are likely less significant compared to macrometastases. Preoperative US identifies suspicious cervical adenopathy in 20–31% of cases, potentially altering the surgical approach (136,137) in as many as 20% of patients (138,139). However, preoperative US identifies only half of the lymph nodes found at surgery, due to the presence of the overlying thyroid gland (140).

Sonographic features suggestive of abnormal metastatic lymph nodes include loss of the fatty hilus, a rounded rather than oval shape, hypoechogenicity, cystic change, calcifications, and peripheral vascularity. No single sonographic feature is adequately sensitive for detection of lymph nodes with metastatic thyroid cancer. A recent study correlated the sonographic features acquired 4 days preoperatively directly with the histology of 56 cervical lymph nodes. Some of the most specific criteria were short axis >5 mm (96%), presence of cystic areas (100%), presence of hyperechogenic punctuations representing either colloid or microcalcifications (100%), and peripheral vascularity (82%). Of these, the only one with sufficient sensitivity was peripheral vascularity (86%). All of the others had sensitivities <60% and would not be adequate to use as single criterion for identification of malignant involvement (140). As shown by earlier studies (141,142), the feature with the highest sensitivity was absence of a hilus (100%), but this had a low specificity of only 29%. The location of the lymph nodes may also be useful for decision-making. Malignant lymph nodes are much more likely to occur in levels III, IV, and VI than in level II (140,142). Figure 2 illustrates the delineation of cervical lymph node Levels I through VI.

OPEN IN VIEWER

FIG. 2.

Lymph node compartments separated into levels and sublevels. Level VI contains the thyroid gland, and the adjacent nodes bordered superiorly by the hyoid bone, inferiorly by the innominate (brachiocephalic) artery, and laterally on each side by the carotid sheaths. The level II, III, and IV nodes are arrayed along the jugular veins on each side, bordered anteromedially by level VI and laterally by the posterior border of the sternocleidomastoid muscle. The level III nodes are bounded superiorly by the level of the hyoid bone, and inferiorly by the cricoid cartilage; levels II and IV are above and below level III, respectively. The level I node compartment includes the submental and submandibular nodes, above the hyoid bone, and anterior to the posterior edge of the submandibular gland. Finally, the level V nodes are in the posterior triangle, lateral to the lateral edge of the sternocleidomastoid muscle. Levels I, II, and V can be further subdivided as noted in the figure. The inferior extent of level VI is defined as the suprasternal notch. Many authors also include the pretracheal and paratracheal superior mediastinal lymph nodes above the level of the innominate artery (sometimes referred to as level VII) in central neck dissection (166).

Confirmation of malignancy in lymph nodes with a suspicious sonographic appearance is achieved by US-guided FNA aspiration for cytology and/or measurement of Tg in the needle washout. This FNA measurement of Tg is valid even in patients with circulating Tg autoantibodies (143,144).

Accurate staging is important in determining the prognosis and tailoring treatment for patients with DTC. However, unlike many tumor types, the presence of metastatic disease does not obviate the need for surgical excision of the primary tumor in DTC (145). Because metastatic disease may respond to RAI therapy, removal of the thyroid as well as the primary tumor and accessible locoregional disease remains an important component of initial treatment even in metastatic disease.

As US evaluation is uniquely operator dependent, alternative imaging procedures may be preferable in some clinical settings, though the sensitivities of CT, MRI, and PET for the detection of cervical lymph node metastases are all relatively low (30–40%) (146). These alternative imaging modalities, as well as laryngoscopy and endoscopy, may also be useful in the assessment of large, rapidly growing, or retrosternal or invasive tumors to assess the involvement of extrathyroidal tissues (147,148).

[B5] Measurement of serum Tg

There is limited evidence that high preoperative concentrations of serum Tg may predict a higher sensitivity for postoperative surveillance with serum Tg (149). Evidence that this impacts patient management or outcomes is not yet available.

[B7] Surgery for a nondiagnostic biopsy, a biopsy suspicious for papillary cancer or suggestive of “follicular neoplasm” (including special consideration for patients with other risk factors)

Amongst solitary thyroid nodules with an indeterminate (“follicular neoplasm” or Hürthle cell neoplasm) biopsy, the risk of malignancy is approximately 20% (151 –153). The risk is higher with large tumors (>4 cm), when atypical features (e.g., cellular pleomorphism) are 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 (66,154,155). For solitary nodules that are repeatedly nondiagnostic on biopsy, the risk of malignancy is unknown but is probably closer to 5–10% (63).

[B8] Surgery for a biopsy diagnostic for malignancy

Near-total or total thyroidectomy is recommended if the primary thyroid carcinoma is >1 cm (156), there are contralateral thyroid nodules present or regional or distant metastases are present, the patient has a personal history of radiation therapy to the head and neck, or the patient has first-degree family history of DTC. Older age (>45 years) may also be a criterion for recommending near-total or total thyroidectomy even with tumors <1–1.5 cm, because of higher recurrence rates in this age group (112,116,122,123,157). Increased extent of primary surgery may improve survival for high-risk patients (158 –160) and low-risk patients (156). A study of over 50,000 patients with PTC found on multivariate analysis that total thyroidectomy significantly improved recurrence and survival rates for tumors >1.0 cm (156). When examined separately, even patients with 1.0–2.0 cm tumors who underwent lobectomy, had a 24% higher risk of recurrence and a 49% higher risk of thyroid cancer mortality (p = 0.04 and p < 0.04, respectively). Other studies have also shown that rates of recurrence are reduced by total or near total thyroidectomy among low-risk patients (122,161,162).

[B9] Lymph node dissection

Regional lymph node metastases are present at the time of diagnosis in 20–90% of patients with papillary carcinoma and a lesser proportion of patients with other histotypes (129,139). Although PTC lymph node metastases are reported by some to have no clinically important effect on outcome in low risk patients, a study of the Surveillance, Epidemiology, and End Results (SEER) database found, among 9904 patients with PTC, that lymph node metastases, age >45 years, distant metastasis, and large tumor size significantly predicted poor outcome on multivariate analysis (163). All-cause survival at 14 years was 82% for PTC without lymph node and 79% with lymph node metastases (p < 0.05). Another recent SEER registry study concluded that cervical lymph node metastases conferred an independent risk of decreased survival, but only in patients with follicular cancer and patients with papillary cancer over age 45 years (164). Also, the risk of regional recurrence is higher in patients with lymph node metastases, especially in those patients with multiple metastases and/or extracapsular nodal extension (165).

In many patients, lymph node metastases in the central compartment (166) do not appear abnormal preoperatively with imaging (138) or by inspection at the time of surgery. Central compartment dissection (therapeutic or prophylactic) can be achieved with low morbidity in experienced hands (167 –171), and may convert some patients from clinical N0 to pathologic N1a, upstaging patients over age 45 from American Joint Committee on Cancer (AJCC) stage I to III (172). A recent consensus conference statement discusses the relevant anatomy of the central neck compartment, delineates the nodal subgroups within the central compartment commonly involved with thyroid cancer, and defines the terminology relevant to central compartment neck dissection (173).

Comprehensive bilateral central compartment node dissection may improve survival compared to historic controls and reduce risk for nodal recurrence (174). In addition, selective unilateral paratracheal central compartment node dissection increases the proportion of patients who appear disease free with unmeasureable Tg levels 6 months after surgery (175). Other studies of central compartment dissection have demonstrated higher morbidity, primarily recurrent laryngeal nerve injury and transient hypoparathyroidism, with no reduction in recurrence (176,177). 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 Tg levels (178). Although some lymph node metastases may be treated with radioactive iodine, several treatments may be necessary, depending upon the histology, size, and number of metastases (179).

These recommendations (R27a–c) should be interpreted in light of available surgical expertise. For patients with small, noninvasive, apparently node-negative tumors, the balance of risk and benefit may favor simple near-total thyroidectomy with close intraoperative inspection of the central compartment with compartmental dissection only in the presence of obviously involved lymph nodes. This approach may increase the chance of future locoregional recurrence, but overall this approach may be safer in less experienced surgical hands.

Lymph nodes in the lateral neck (compartments II–V), level VII (anterior mediastinum), and rarely in Level I may also be involved by thyroid cancer (129,180). For those patients in whom nodal disease is evident clinically, on preoperative US and nodal FNA or Tg measurement, or at the time of surgery, surgical resection may reduce the risk of recurrence and possibly mortality (56,139,181). Functional compartmental en-bloc neck dissection is favored over isolated lymphadenectomy (“berry picking”) with limited data suggesting improved mortality (118,182 –184).

[B10] Completion thyroidectomy

Completion thyroidectomy may be necessary when the diagnosis of malignancy is made following lobectomy for an indeterminate or nondiagnostic biopsy. Some patients with malignancy may require completion thyroidectomy to provide complete resection of multicentric disease (185), and to allow RAI therapy. Most (186,187) but not all (185) studies of papillary cancer have observed a higher rate of cancer in the opposite lobe when multifocal (two or more foci), as opposed to unifocal, disease is present in the ipsilateral lobe. The surgical risks of two-stage thyroidectomy (lobectomy followed by completion thyroidectomy) are similar to those of a near-total or total thyroidectomy (188).

[B12] The role of postoperative staging

Postoperative staging for thyroid cancer, as for other cancer types, is used: 1) to permit prognostication for an individual patient with DTC; 2) to tailor decisions regarding postoperative adjunctive therapy, including RAI therapy and TSH suppression, to assess the patient's risk for disease recurrence and mortality; 3) to make decisions regarding the frequency and intensity of follow-up, directing more intensive follow-up towards patients at highest risk; and 4) to enable accurate communication regarding a patient among health care professionals. Staging systems also allow evaluation of differing therapeutic strategies applied to comparable groups of patients in clinical studies.

[B13] AJCC/UICC TNM staging

Application of the AJCC/International Union against Cancer (AJCC/UICC) classification system based on pTNM parameters and age is recommended for tumors of all types, including thyroid cancer (121,190), because it provides a useful shorthand method to describe the extent of the tumor (191) (Table 4). This classification is also used for hospital cancer registries and epidemiologic studies. In thyroid cancer, the AJCC/UICC stage does not take account of several additional independent prognostic variables and may risk misclassification of some patients. Numerous other schemes have been developed in an effort to achieve more accurate risk factor stratification, including CAEORTC, AGES, AMES, U of C, MACIS, OSU, MSKCC, and NTCTCS systems. (107,116,122,159,192 –195). These schemes take into account a number of factors identified as prognostic for outcome in multivariate analysis of retrospective studies, with the most predictive factors generally being regarded as the presence of distant metastases, the age of the patient, and the extent of the tumor. These and other risk factors are weighted differently among these systems according to their importance in predicting outcome, but no scheme has demonstrated clear superiority (195). Each of the schemes allows accurate identification of the majority (70–85%) of patients at low-risk of mortality (T1–3, M0 patients), allowing the follow-up and management of these patients to be less intensive than the higher-risk minority (T4 and M1 patients), who may benefit from a more aggressive management strategy (195). Nonetheless, none of the examined staging classifications is able to account for more than a small proportion of the uncertainty in either short-term, disease-specific mortality or the likelihood of remaining disease free (121,195,196). AJCC/IUCC staging was developed to predict risk for death, not recurrence. For assessment of risk of recurrence, a three-level stratification can be used:

Low-risk patients have the following characteristics: 1) no local or distant metastases; 2) all macroscopic tumor has been resected; 3) there is no tumor invasion of locoregional tissues or structures; 4) the tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma) or vascular invasion; 5) and, if ¹³¹I is given, there is no ¹³¹I uptake outside the thyroid bed on the first posttreatment whole-body RAI scan (RxWBS) (197 –199).

Since initial staging is based on clinico-pathologic factors that are available shortly after diagnosis and initial therapy, the AJCC stage of the patient does not change over time. However, depending on the clinical course of the disease and response to therapy, the risk of recurrence and the risk of death may change over time. Appropriate management requires an ongoing reassessment of the risk of recurrence and the risk of disease-specific mortality as new data are obtained during follow-up (206).

[B16] Can rhTSH (Thyrogen™) be used in lieu of thyroxine withdrawal for remnant ablation?

For most patients, including those unable to tolerate hypothyroidism or unable to generate an elevated TSH, remnant ablation can be achieved with rhTSH (235,236). A prospective randomized study found that thyroid hormone withdrawal and rhTSH stimulation were equally effective in preparing patients for ¹³¹I remnant ablation with 100 mCi with significantly improved quality of life (237). Another randomized study using rhTSH showed that ablation rates were comparable with 50 mCi compared to 100 mCi with a significant decrease (33%) in whole-body irradiation (238). Finally, a recent study has shown that ablation rates were similar with either withdrawal or preparation with rhTSH using 50 mCi of ¹³¹I (239). In addition, short-term recurrence rates have been found to be similar in patients prepared with thyroid hormone withdrawal or rhTSH (240). Recombinant human TSH is approved for remnant ablation in the United States, Europe, and many other countries around the world.

[B17] Should RAI scanning be performed before RAI ablation?

RAI WBS provides information on the presence of iodine-avid thyroid tissue, which may represent the normal thyroid remnant or the presence of residual disease in the postoperative setting. In the presence of a large thyroid remnant, the scan is dominated by uptake within the remnant, potentially masking the presence of extrathyroidal disease within locoregional lymph nodes, the upper mediastinum, or even at distant sites, reducing the sensitivity of disease detection (241). Furthermore, there is an increasing trend to avoid pretherapy RAI scans altogether because of its low impact on the decision to ablate, and because of concerns over ¹³¹I-induced stunning of normal thyroid remnants (242) and distant metastases from thyroid cancer (243). Stunning is defined as a reduction in uptake of the ¹³¹I therapy dose induced by a pretreatment diagnostic activity. Stunning occurs most prominently with higher activities (5–10 mCi) of ¹³¹I (244), with increasing time between the diagnostic dose and therapy (245), and does not occur if the treatment dose is given within 72 hours of the scanning dose (246). However, the accuracy of low-activity ¹³¹I scans has been questioned, and some research has reported quantitatively the presence of stunning below the threshold of visual detection (247). Although comparison studies show excellent concordance between ¹²³I and ¹³¹I for tumor detection, optimal ¹²³I activity and time to scan after ¹²³I administration are not known (248). Furthermore, ¹²³I is expensive, is not universally available, its short half life (t_½ = 13 hours) makes handling this isotope logistically more difficult (249), and stunning may also occur though to a lesser degree than with ¹³¹I (245). Furthermore, a recent study showed no difference in ablation rates between patients that had pretherapy scans with ¹²³I (81%) compared to those who had received diagnostic scans using 2 mCi of ¹³¹I (74%, p > 0.05) (250). Alternatively, determination of the thyroid bed uptake, without scanning, can be achieved using 10–100 μCi ¹³¹I.

[B18] What activity of ¹³¹I should be used for remnant ablation?

Successful remnant ablation is usually defined as an absence of visible RAI uptake on a subsequent diagnostic RAI scan or an undetectable stimulated serum Tg. Activities between 30 and 100 mCi of ¹³¹I generally show similar rates of successful remnant ablation (251 –254) and recurrence rates (213). Although there is a trend toward higher ablation rates with higher activities (255,256), a recent prospective randomized study found no significant difference in the remnant ablation rate using 30 or 100 mCi of ¹³¹I (257). Furthermore, there are data showing that 30 mCi is effective in ablating the remnant with rhTSH preparation (258). In pediatric patients, it is preferable to adjust the ablation activity according to the patient's body weight (259) or surface area (260).

[B19] Is a low-iodine diet necessary before remnant ablation?

The efficacy of radioactive iodine depends on the radiation dose delivered to the thyroid tissue (261). Low-iodine diets (<50 μg/d of dietary iodine) and simple recommendations to avoid iodine contamination have been recommended prior to RAI therapy (261 –263) to increase the effective radiation dose. A history of possible iodine exposure (e.g., intravenous contrast, amiodarone use) should be sought. Measurement of iodine excretion with a spot urinary iodine determination may be a useful way to identify patients whose iodine intake could interfere with RAI remnant ablation (263). Information about low-iodine diets can be obtained at the Thyroid Cancer Survivors Association website (www.thyca.org).

[B25] External beam irradiation

External beam irradiation is used infrequently in the management of thyroid cancer except as a palliative treatment for locally advanced, otherwise unresectable disease (274). There are reports of responses among patients with locally advanced disease (275,276) and improved relapse-free and cause-specific survival in patients over age 60 with extrathyroidal extension but no gross residual disease (277). It remains unknown whether external beam radiation might reduce the risk for recurrence in the neck following adequate primary surgery and/or RAI treatment in patients with aggressive histologic subtypes (278).

[B26] Chemotherapy

There are no data to support the use of adjunctive chemotherapy in the management of DTC. Doxorubicin may act as a radiation sensitizer in some tumors of thyroid origin (279), and could be considered for patients with locally advanced disease undergoing external beam radiation.

[C7] Diagnostic whole-body RAI scans

There are two main issues that affect the use of DxWBS during follow-up: stunning (described above) and accuracy. A DxWBS is most useful during follow-up when there is little or no remaining normal thyroid tissue. Disease not visualized on the DxWBS, regardless of the activity of ¹³¹I employed, may occasionally be visualized on the RxWBS images done after larger, therapeutic amounts of ¹³¹I (285,307 –310). Following RAI ablation, when the posttherapy scan does not reveal uptake outside the thyroid bed, subsequent DxWBS have low sensitivity and are usually not necessary in low-risk patients who are clinically free of residual tumor and have an undetectable serum Tg level on thyroid hormone and negative cervical US (197,285,309,311).

[C8] Cervical ultrasonography

Cervical ultrasonography is highly sensitive in the detection of cervical metastases in patients with DTC (139,290,312). Recent data suggest that measurement of Tg in the needle washout fluid enhances the sensitivity of FNA of cervical nodes that are suspicious on US (313,314). Cervical metastases occasionally may be detected by neck ultrasonography even when TSH-stimulated serum Tg levels remain undetectable (201,296).

[C9] ¹⁸FDG-PET scanning

For many years, the primary clinical application of ¹⁸FDG-PET scanning in thyroid cancer was to localize disease in Tg-positive (>10 ng/mL), RAI scan–negative patients (315). When used for this indication, insurance providers have usually required documentation that the patient had a follicular derived thyroid cancer with suppressed or stimulated Tg >10 ng/mL in the setting of a negative DxWBS. Still, the impact of ¹⁸FDG-PET imaging on biochemical cure, survival, or progression-free survival in this setting are not well defined.

More recently, publications provide data that support the use of ¹⁸FDG-PET scanning for indications beyond simple disease localization in Tg-positive, RAI scan–negative patients (315,316).

Current additional clinical uses of ¹⁸FDG-PET scanning may include:

Initial staging and follow-up of high-risk patients with poorly differentiated thyroid cancers unlikely to concentrate RAI in order to identify sites of disease that may be missed with RAI scanning and conventional imaging.

As can be seen from the list of indications above, low-risk patients are very unlikely to require ¹⁸FDG-PET scanning as part of initial staging or follow-up. Additionally, inflammatory lymph nodes, suture granulomas, and increased muscle activity are common causes of false-positive ¹⁸FDG-PET findings. Therefore, cytologic or histologic confirmation is required before one can be certain that an ¹⁸FDG-positive lesion represents metastatic disease.

The sensitivity of ¹⁸FDG-PET scanning may be marginally improved with TSH stimulation (especially in patients with low Tg values), but the clinical benefit of identifying these additional small foci is yet to be proven (316).

[C15] Dose and methods of administering ¹³¹I for locoregional or metastatic disease

Despite the apparent effectiveness of ¹³¹I therapy in many patients, the optimal therapeutic activity remains uncertain and controversial (334). There are three approaches to ¹³¹I therapy: empiric fixed amounts, therapy determined by the upper bound limit of blood and body dosimetry, and quantitative tumor dosimetry (335). Dosimetric methods are often reserved for patients with distant metastases or unusual situations such as renal insufficiency (336,337) or when therapy with rhTSH stimulation is deemed necessary. Comparison of outcome among these methods from published series is difficult (334). No prospective randomized trial to address the optimal therapeutic approach has been published. Arguments in favor of higher activities cite a positive relationship between the total ¹³¹I uptake per tumor mass and outcome (225), while others have not confirmed this relationship (338). In the future, the use of ¹²³I or ¹³¹I with modern SPECT/CT or ¹²⁴I PET-based dosimetry may facilitate whole-body and lesional dosimetry (339,340).

The maximum tolerated radiation absorbed dose (MTRD), commonly defined as 200 rads (cGy) to the blood, is potentially exceeded in a significant number of patients undergoing empiric treatment with various amounts of ¹³¹I. In one study (341) 1–22% of patients treated with ¹³¹I according to dosimetry calculations would have theoretically exceeded the MTRD had they been empirically treated with 100–300 mCi of ¹³¹I. Another study (342) found that an empirically administered ¹³¹I activity of 200 mCi would exceed the MTRD in 8–15% of patients younger than age 70 and 22–38% of patients aged 70 years and older. Administering 250 mCi empirically would have exceeded the MTRD in 22% of patients younger than 70 and 50% of patients 70 and older.

No randomized trial comparing thyroid hormone withdrawal therapy to rhTSH-mediated therapy for treatment of metastatic disease has been reported but there is, despite a growing body of nonrandomized studies regarding this use (343 –352), one small comparative study that showed the radiation dose to metastatic foci is lower with rhTSH than that following withdrawal (353). Many of these case reports and series report disease stabilization or improvement in some patients following rhTSH-mediated ¹³¹I therapy. The use of rhTSH does not eliminate and may even increase the possibility of rapid swelling of metastatic lesions (348,354 –356).

[C18] Treatment of pulmonary metastases

In the management of the patient with pulmonary metastases, key criteria for therapeutic decisions include 1) size of metastatic lesions (macronodular typically detected by chest radiography; micronodular typically detected by CT; lesions beneath the resolution of CT); 2) avidity for RAI and, if applicable, response to prior RAI therapy; and 3) stability (or lack thereof ) of metastatic lesions. Pulmonary pneumonitis and fibrosis are rare complications of high-dose radioactive iodine treatment. Dosimetry studies with a limit of 80 mCi whole-body retention at 48 hours and 200 cGy to the red bone marrow should be considered in patients with diffuse ¹³¹I pulmonary uptake (371). If pulmonary fibrosis is suspected, then appropriate periodic pulmonary function testing and consultation should be obtained. The presence of pulmonary fibrosis may limit the ability to further treat metastatic disease with RAI.

Macronodular pulmonary metastases may also be treated with RAI if demonstrated to be iodine avid. How many doses of RAI to give and how often to give it is a decision that must be individualized based on the disease response to treatment, the rate of disease progression in between treatments, age of the patient, the presence or absence of other metastatic lesions, and the availability of other treatment options including clinical trials (360,365).

[C19] Non–RAI-avid pulmonary disease

Radioiodine is of no benefit in patients with non–RAI-avid disease. In the setting of a negative diagnostic RAI scan, micronodular pulmonary metastases may demonstrate a positive posttreatment scan and measurable benefit to RAI therapy, whereas this is unlikely in the setting of macronodular metastases. In one study, administration of 200–300 mCi of RAI to 10 patients with pulmonary macrometastases who had negative 3 mCi diagnostic scans was associated with a fivefold increase in the median TSH-suppressed Tg, and death was reported in several patients within 4 years of treatment (374). Although not specifically limited to pulmonary lesions, patients with increasing volumes of ¹⁸FDG-avid disease seen on PET scans were less likely to respond to RAI and more likely to die during a 3-year follow-up compared with ¹⁸FDG-negative patients (375). Another study found that RAI therapy of metastatic lesions that were positive on ¹⁸FDG-PET scanning was of no benefit (376). In other studies of ¹⁸FDG-PET imaging, however, insufficient details exist in patients known to have pulmonary metastases to assess the utility of this modality to predict treatment response or prognosis (377). A study (378) that retrospectively examined the clinical course of 400 thyroid cancer patients with distant metastases who had undergone ¹⁸FDG-PET scanning found that although age, initial tumor stage, histology, Tg level, RAI uptake, and PET outcomes all correlated with survival by univariate analysis, only age and PET results were strong predictors of survival. There were significant inverse relationships between survival and both the glycolytic rate of the most active lesion and the number of ¹⁸FDG-avid lesions. The study found tumors that did not concentrate ¹⁸FDG had a significantly better prognosis after a median follow-up of about 8 years than did tumors that avidly concentrated ¹⁸FDG.

Most studies evaluating systemic therapy for metastatic disease have focused on patients with pulmonary metastases. Traditional cytotoxic chemotherapeutic agents, such as doxorubicin and cisplatin, are generally associated with no more than 25% partial response rates, complete remission has been rare, and toxicities from these treatments are considerable (379). Doxorubicin monotherapy, which remains the only treatment for metastatic thyroid carcinoma approved by the U.S. Food and Drug Administration, is occasionally effective when dosed appropriately (60–75 mg/m² every 3 weeks) (380 –383), but durable responses are uncommon. Most studies of combination chemotherapy show no increased response over single agent doxorubicin and increased toxicity (384). Some specialists recommend consideration of single agent doxorubicin or paclitaxel, or a combination of these agents, based on limited data in anaplastic thyroid carcinoma (385). One recent study evaluated the effect of combination chemotherapy (carboplatinum and epirubicin) under TSH stimulation (endogenous or rhTSH) (386), demonstrating an overall rate of complete and partial response of 37%. These data need to be confirmed prior to consideration for general use. Recently published phase II trials suggest that anti-angiogenic therapies may produce partial response rates of up to 31% and stabilize another 40–50% of patients with progressive metastatic disease (387 –391). Clinical benefit lasting at least 24 weeks was observed in about half of patients. 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. These side effects, although often mild and responsive to supportive care measures, justify suggesting that treatment with these agents should be limited to specialists experienced in their use. Similar results are also being reported with use of sunitinib, but phase II studies are still ongoing. Serum TSH levels may increase with the use of these agents. Serum TSH should be monitored, and the thyroxine dose increased as needed. Multiple other agents are in clinical trials, targeting pathways involved in angiogenesis, cell cycle regulation, and tumor differentiation.

If the patient qualifies for a clinical trial, they should consider bypassing traditional chemotherapy and moving directly to clinical trials. However, often patients cannot participate in clinical trials because of the time and expense required, or failure to meet strict eligibility criteria. Most available trials can be found listed at www.clinicaltrials.gov, www.nci.nih.gov, www.centerwatch.com, or www.thyroid.org.

[C20] Treatment of bone metastases

In the management of the patient with bone metastases, key criteria for therapeutic decisions include 1) the presence of or the risk for pathologic fracture, particularly in a weight-bearing structure; 2) risk for neurologic compromise from vertebral lesions; 3) presence of pain; 4) avidity of RAI uptake; and 5) potential significant marrow exposure from radiation arising from RAI-avid pelvic metastases.

[C21] Treatment of brain metastases

Brain metastases typically occur in older patients with more advanced disease and are associated with a poor prognosis (351). Surgical resection and external beam radiotherapy traditionally have been the mainstays of therapy (351,396). There are few data showing efficacy of RAI.