[B1] DIFFERENTIATED THYROID CANCER: INITIAL MANAGEMENT GUIDELINES

Differentiated thyroid cancer, arising from thyroid follicular epithelial cells, accounts for the vast majority of thyroid cancers. Of the differentiated cancers, papillary cancer comprises about 85% of cases compared to about 10% that have follicular histology, and 3% that are Hürthle cell or oxyphil tumors (110). In general, stage for stage, the prognoses of PTC and follicular cancer are similar (107,110). Certain histologic subtypes of PTC have a worse prognosis (tall cell variant, columnar cell variant, diffuse sclerosing variant), as do more highly invasive variants of follicular cancer. These are characterized by extensive vascular invasion and invasion into extrathyroidal tissues or extensive tumor necrosis and/or mitoses. Other poorly differentiated aggressive tumor histologies include trabecular, insular, and solid subtypes (111). In contrast, minimally invasive follicular thyroid cancer, is characterized histologically by microscopic penetration of the tumor capsule without vascular invasion, and carries no excess mortality (112–115).

[B2] Goals of initial therapy of DTC

The goals of initial therapy of DTC are follows:

  1. To remove the primary tumor, disease that has extended beyond the thyroid capsule, and involved cervical lymph nodes. Completeness of surgical resection is an important determinant of outcome, while residual metastatic lymph nodes represent the most common site of disease persistence/recurrence (116–118).
  2. To minimize treatment-related morbidity. The extent of surgery and the experience of the surgeon both play important roles in determining the risk of surgical complications  (119,120)
  3. To permit accurate staging of the disease. Because disease staging can assist with initial prognostication, disease management, and follow-up strategies, accurate postoperative staging is a crucial element in the management of patients with DTC (121,122).
  4. To facilitate postoperative treatment with radioactive iodine, where appropriate. For patients undergoing RAI remnant ablation, or RAI treatment of residual or metastatic disease, removal of all normal thyroid tissue is an important element of initial surgery (123). Near total or total thyroidectomy also may reduce the risk for recurrence within the contralateral lobe (124).
  5. To permit accurate long-term surveillance for disease recurrence. Both RAI whole-body scanning (WBS) and measurement of serum Tg are affected by residual normal thyroid tissue. Where these approaches are utilized for long-term monitoring, near-total or total-thyroidectomy is required (125).
  6. To minimize the risk of disease recurrence and metastatic spread. Adequate surgery is the most important treatment variable influencing prognosis, while radioactive iodine treatment, TSH suppression, and external beam irradiation each play adjunctive roles in at least some patients (125–128).

[B3] What is the role of preoperative staging with diagnostic imaging and laboratory tests?

[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.

 

 

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).

  • RECOMMENDATION 21
    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

     

  • RECOMMENDATION 22
    Routine preoperative use of other imaging studies (CT, MRI, PET) is not recommended. Recommendation rating: E

[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.

  • RECOMMENDATION 23
    Routine preoperative measurement of serum Tg is not recommended. Recommendation rating: E

[B6] What is the appropriate operation for indeterminate thyroid nodules and DTC?    The goals of thyroid surgery can include provision of a diagnosis after a nondiagnostic or indeterminate biopsy, removal of the thyroid cancer, staging, and preparation for radioactive ablation and serum Tg monitoring. Surgical options to address the primary tumor should be limited to hemithyroidectomy with or without isthmusectomy, near-total thyroidectomy (removal of all grossly visible thyroid tissue, leaving only a small amount [<1 g] of tissue adjacent to the recurrent laryngeal nerve near the ligament of Berry), and total thyroidectomy (removal of all grossly visible thyroid tissue). Subtotal thyroidectomy, leaving >1 g of tissue with the posterior capsule on the uninvolved side, is an inappropriate operation for thyroid cancer (150).

[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).

  • RECOMMENDATION 24
    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
     
  • RECOMMENDATION 25
    1. 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
    2. 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

[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).

  • RECOMMENDATION 26
    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

[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).

  • RECOMMENDATION 27*
    1. 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
    2. 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
    3. 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

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).

  • RECOMMENDATION 28*
    Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy. Recommendation rating: B

[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).

  • RECOMMENDATION 29
    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

     

  • RECOMMENDATION 30
    Ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy (189). 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

[B11] What is the role of postoperative staging systems and which should be used?

[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 131Iis given, there is no 131I uptake outside the thyroid bed on the first posttreatment whole-body RAI scan (RxWBS) (197–199).
  • Intermediate-risk patients have any of the following: 1) microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery; 2) cervical lymph node metastases or 131I uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation (200,201); or 3) tumor with aggressive histology or vascular invasion (202–204).
  • High-risk patients have 1) macroscopic tumor invasion, 2) incomplete tumor resection, 3) distant metastases, and possibly 4) thyroglobulinemia out of proportion to what is seen on the posttreatment scan (205).

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).

TABLE 4. TNM CLASSIFICATION SYSTEM FOR DIFFERENTIATED THYROID CARCINOMA

 

Definition

T1

Tumor diameter 2 cm or smaller

 

T2

Primary tumor diameter >2 to 4 cm

 

T3

Primary tumor diameter >4 cm limited to the thyroid or with minimal extrathyroidal extension

 

T4a

Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve

 

T4b

Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

 

TX

Primary tumor size unknown, but without extrathyroidal invasion

 

N0

No metastatic nodes

 

N1a

Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes)

 

N1b

Metastasis to unilateral, bilateral, contralateral cervical or superior mediastinal nodes

 

NX

Nodes not assessed at surgery

 

M0

No distant metastases

 

M1

Distant metastases

 

MX

Distant metastases not assessed

 

Stages

 

 

 

Patient age <45 years

Patient age 45 years or older

Stage I

Any T, any N, M0

T1, N0, M0

Stage II

Any T, any N, M1

T2, N0, M0

Stage III

 

T3, N0, M0

 

 

T1, N1a, M0

 

 

T2, N1a, M0

 

 

T3, N1a, M0

Stage IVA

 

T4a, N0, M0

 

 

T4a, N1a, M0

 

 

T1, N1b, M0

 

 

T2, N1b, M0

 

 

T3, N1b, N0

 

 

T4a, N1b, M0

Stage IVB

 

T4b, Any N, M0

Stage IVC

 

Any T, Any N, M1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois.
The original source for this material is the AJCC Cancer Staging Manual, Sixth Edition (435).

 RECOMMENDATION 31
Because of its utility in predicting disease mortality, and its requirement for cancer registries, 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

[B14] What is the role of postoperative RAI remnant ablation?   Postoperative RAI remnant ablation is increasingly being used to eliminate the postsurgical thyroid remnant (122). Ablation of the small amount of residual normal thyroid remaining after total thyroidectomy may facilitate the early detection of recurrence based on serum Tg measurement and/or RAI WBS. Additionally, the posttherapy scan obtained at the time of remnant ablation may facilitate initial staging by identifying previously undiagnosed disease, especially in the lateral neck. Furthermore, from a theoretical point of view, this first dose of RAI may also be considered adjuvant therapy because of the potential tumoricidal effect on persistent thyroid cancer cells remaining after appropriate surgery in patients at risk for recurrence or disease specific mortality. Depending on the risk stratification of the individual patient, the primary goal of the first dose of RAI after total thyroidectomy may be 1) remnant ablation (to facilitate detection of recurrent disease and initial staging), 2) adjuvant therapy (to decrease risk of recurrence and disease specific mortality by destroying suspected, but unproven metastatic disease), or 3) RAI therapy (to treat known persistent disease). While these three goals are closely interrelated, a clearer understanding of the specific indications for treatment will improve our ability to select patients most likely to benefit from RAI after total thyroidectomy, and will also influence our recommendations regarding choice of administered activity for individual patients. Supporting the use of RAI as adjuvant therapy, a number of large, retrospective studies show a significant reduction in the rates of disease recurrence (107,159,160,207) and cause-specific mortality (159,160,207–209). However, other similar studies show no such benefit, at least among the majority of patients with PTC, who are at the lowest risk for mortality (110,122,162,209–212). In those studies that show benefit, the advantage appears to be restricted to patients with tumors >1.5 cm, or with residual disease following surgery, while lower-risk patients do not show evidence for benefit (122,159,213). The National Thyroid Cancer Treatment Cooperative Study Group (NTCTCSG) report (214) of 2936 patients found after a median follow-up of 3 years, that near-total thyroidectomy followed by RAI therapy and aggressive thyroid hormone suppression therapy predicted improved overall survival of patients with NTCTCSG stage III and IV disease, and was also beneficial for patients with NTCTCSG stage II disease. No impact of therapy was observed in patients with stage I disease. It should be noted that the NTCTCSG staging criteria are similar but not identical to the AJCC criteria. Thus, older patients with microscopic extrathyroidal extension are stage II in the NTCTCSG system, but are stage III in the AJCC system. There are recent data suggesting a benefit of RAI in patients with more aggressive histologies (215). There are no prospective randomized trials that have addressed this question (209). Unfortunately, many clinical circumstances have not been examined with regard to the efficacy of RAI ablative therapy. Table 5 presents a framework for deciding whether RAI is worthwhile, solely based on the AJCC classification, and provides the rationale for therapy and the strength of existing evidence for or against treatment.

TABLE 5. MAJOR FACTORS IMPACTING DECISION MAKING IN RADIOIODINE REMNANT ABLATION

 

 

Expected benefit

 

 

Factors

Description

Decreased risk of death

Decreased risk of recurrence

May facilitate initial staging and follow-up

RAI ablation usually recommended

Strength of evidence

T1

1 cm or less, intrathyroidal or microscopic multifocal

No

No

Yes

No

E

 

1–2 cm, intrathyroidal

No

Conflicting dataa

Yes

Selective usea

I

T2

>2–4 cm, intrathyroidal

No

Conflicting dataa

Yes

Selective usea

C

T3

>4 cm

 

 

 

 

 

 

<45 years old

No

Conflicting dataa

Yes

Yes

B

 

≥45 years old

Yes

Yes

Yes

Yes

B

 

Any size, any age, minimal extrathyroidal extension

No

Inadequate dataa

Yes

Selective usea

I

T4

Any size with gross extrathyroidal extension

Yes

Yes

Yes

Yes

B

Nx,N0

No metastatic nodes documented

No

No

Yes

No

I

N1

<45 years old

No

Conflicting dataa

Yes

Selective usea

C

 

>45 years old

Conflicting data

Conflicting dataa

Yes

Selective usea

C

M1

Distant metastasis present

Yes

Yes

Yes

Yes

A

aBecause of either conflicting or inadequate data, we cannot recommend either for or against RAI ablation for this entire subgroup. However, selected patients within this subgroup with higher risk features may benefit from RAI ablation (see modifying factors in the text).

In addition to the major factors listed in Table 5, several other histological features may place the patient at higher risk of local recurrence or metastases than would have been predicted by the AJCC staging system. These include worrisome histologic subtypes (such as tall cell, columnar, insular, and solid variants, as well as poorly differentiated thyroid cancer), the presence of intrathyroidal vascular invasion, or the finding of gross or microscopic multifocal disease. While many of these features have been associated with increased risk, there are inadequate data to determine whether RAI ablation has a benefit based on specific histologic findings, independent of tumor size, lymph node status, and the age of the patient. Therefore, while RAI ablation is not recommended for all patients with these higher risk histologic features, the presence of these features in combination with size of the tumor, lymph node status, and patient age may increase the risk of recurrence or metastatic spread to a degree that is high enough to warrant RAI ablation in selected patients. However, in the absence of data for most of these factors, clinical judgment must prevail in the decision-making process. For microscopic multifocal papillary cancer, when all foci are <1 cm, recent data suggest that RAI is of no benefit in preventing recurrence (216,217).

Nonpapillary histologies (such as follicular thyroid cancer and Hürthle cell cancer) are generally regarded as higher risk tumors. Expert opinion supports the use of RAI in almost all of these cases. However, because of the excellent prognosis associated with surgical resection alone in small follicular thyroid cancers manifesting only capsular invasion (without vascular invasion (so-called “minimally invasive follicular cancer”), RAI ablation may not be required for all patients with this histological diagnosis (112).

  • RECOMMENDATION 32
    1. 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 (see Table 5 for strength of evidence).
    2. RAI ablation is recommended for selected patients with 1–4 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 (see Table 5 for strength of evidence for individual features). Recommendation rating: C (for selective use in higher risk patients)
    3. RAI ablation is not recommended for patients with unifocal cancer <1 cm without other higher risk features (see preceding paragraphs). Recommendation rating: E
    4. 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

[B15] How should patients be prepared for RAI ablation?   (see Fig. 3) Remnant ablation requires TSH stimulation. No controlled studies have been performed to assess adequate levels of endogenous TSH for optimal ablation therapy or follow-up testing. Noncontrolled studies suggest that a TSH of >30 mU/L is associated with increased RAI uptake in tumors (218), while studies using single dose exogenous TSH suggest maximal thyrocyte stimulation at TSH levels between 51 and 82 mU/L (219, 220). However, the total area under the TSH curve, and not simply the peak serum TSH concentration, is also potentially important for optimal RAI uptake by thyroid follicular cells. Endogenous TSH elevation can be achieved by two basic approaches to thyroid hormone withdrawal, stopping LT4 and switching to LT3 for 2–4 weeks followed by withdrawal of LT3 for 2 weeks, or discontinuation of LT4 for 3 weeks without use of LT3. Both methods of preparation can achieve serum TSH levels >30 mU/Lin >90% of patients (220–229). These two approaches have not been directly compared for efficiency of patient preparation (efficacy of ablation, iodine uptake, Tg levels, disease detection), although a recent prospective study showed no difference in hypothyroid symptoms between these two approaches (230). Other preparative methods have been proposed, but have not been validated by other investigators (231,232). Children with thyroid cancer achieve adequate TSH elevation within 14 days of LT4 withdrawal (233). A low serum Tg level at the time of ablation has excellent negative predictive value for absence of residual disease, and the risk of persistent disease increases with higher stimulated Tg levels (198,205,234).

 

     
 

FIG. 3. Algorithm for initial follow-up of patients with differentiated thyroid carcinoma.
aEBRT, external beam radiotherapy. The usual indication for EBRT is macroscopic unresectable tumor in a patient older than 45 years; it is not usually recommended for children and adults less than age 45.
bNeck ultrasonography of operated cervical compartments is often compromised for several months after surgery.
cTg, thyroglobulin with anti-thyroglobulin antibody measurement; serum Tg is usually measured by immunometric assay and may be falsely elevated for several weeks by injury from surgery or by heterophile antibodies, although a very high serum Tg level after surgery usually indicates residual disease.
dSome clinicians suspect residual disease when malignant lymph nodes, or tumors with aggressive histologies (as defined in the text) have been resected, or when there is a microscopically positive margin of resection.
erhTSH is recombinant human TSH and is administered as follows: 0.9mg rhTSH i.m. on two consecutive days, followed by 131I therapy on the third day.
fTHW is levothyroxine and=or triiodothyronine withdrawal.
gSee text for exceptions regarding remnant ablation. The smallest amount of 131I necessary to ablate normal thyroid remnant tissue should be used. DxWBS (diagnostic whole-body scintigraphy) is not usually necessary at this point, but may be performed if the outcome will change the decision to treat with radioiodine and=or the amount of administered activity.
hRxWBS is posttreatment whole-body scan done 5 to 8 days after therapeutic 131I administration.
iUptake in the thyroid bed may indicate normal remnant tissue or residual central neck nodal metastases.

 
  • RECOMMENDATION 33
    Patients undergoing RAI therapy or diagnostic testing can be prepared by LT4 withdrawal for at least 2–3 weeks or LT3 treatment for 2–4 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 7–10 days) may be resumed on the second or third day after RAI administration. Recommendation rating: B

[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.

  • RECOMMENDATION 34
    Remnant ablation can be performed following thyroxine withdrawal or rhTSH stimulation. Recommendation rating: A

[B17] Should RAI scanning be performed before RAI ablation?   RAI WBS provides information on the presence of io-dine-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 131Iinduced 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 (t½ = 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 pre-therapy 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.

  • RECOMMENDATION 35
    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 (1.5–3 mCi) or low-activity 131I (1–3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity. Recommendation rating: C

[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).

  • RECOMMENDATION 36
    The minimum activity (30–100 mCi) necessary to achieve successful remnant ablation should be utilized, particularly for low-risk patients. Recommendation rating: B

     

  • RECOMMENDATION 37
    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 (100–200 mCi) may be appropriate. Recommendation rating: C

[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).

  • RECOMMENDATION 38
    A low-iodine diet for 1–2 weeks is recommended for patients undergoing RAI remnant ablation, particularly for those patients with high iodine intake. Recommendation rating: B

[B20] Should a posttherapy scan be performed following remnant ablation?   Posttherapy whole-body iodine scanning is typically conducted approximately 1 week after RAI therapy to visualize metastases. Additional metastatic foci have been reported in 10–26% of patients scanned following high-dose RAI treatment compared with the diagnostic scan (264,265). The new abnormal uptake was found most often in the neck, lungs, and mediastinum, and the newly discovered disease altered the disease stage in approximately 10% of the patients, affecting clinical management in 9–15% (264–266). Iodine 131 single photon emission computed tomography (SPECT)/CT fusion imaging may provide superior lesion localization after remnant ablation, but it is still a relatively new imaging modality (267).

  • RECOMMENDATION 39
    A posttherapy scan is recommended following RAI remnant ablation. This is typically done 2–10 days after the therapeutic dose is administered, although published data supporting this time interval are lacking. Recommendation rating: B

[B21] Postsurgery and RAI therapy early management of DTC

[B22] What is the role of TSH suppression therapy?   DTC expresses the TSH receptor on the cell membrane and responds to TSH stimulation by increasing the expression of several thyroid specific proteins (Tg, sodium-iodide symporter) and by increasing the rates of cell growth (268). Suppression of TSH, using supra-physiologic doses of LT4, is used commonly to treat patients with thyroid cancer in an effort to decrease the risk of recurrence (127,214,269). A meta-analysis supported the efficacy of TSH suppression therapy in preventing major adverse clinical events (RR = 0.73; CI = 0.60–0.88; p < 0.05) (269).

[B23] What is the appropriate degree of initial TSH suppression?   Retrospective and prospective studies have demonstrated that TSH suppression to below 0.1 mU/Lmay improve outcomes in high-risk thyroid cancer patients (127,270), though no such evidence of benefit has been documented in low-risk patients. A prospective cohort study (214) of 2936 patients found that overall survival improved significantly when the TSH was suppressed to undetectable levels in patients with NTCTCSG stage III or IV disease and suppressed to the subnormal to undetectable range in patients with NTCTCSG stage II disease; however, in the latter group there was no incremental benefit from suppressing TSH to undetectable levels. Suppression of TSH was not beneficial in patients with stage I disease. In another study, there was a positive association between serum TSH levels and the risk for recurrent disease and cancer-related mortality (271). Adverse effects of 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 (272), and increased risk of osteoporosis in postmenopausal women (273).

  • RECOMMENDATION 40
    Initial TSH 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 (0.1–0.5 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 0.1–0.5 mU/L. Recommendation rating: B

[B24] Is there a role for adjunctive external beam irradiation or chemotherapy?

[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).

  • RECOMMENDATION 41
    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

[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.

  • RECOMMENDATION 42
    There is no role for the routine adjunctive use of chemotherapy in patients with DTC. Recommendation rating: F



*R27a, 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.)