DIFFERENTIATED THYROID CANCER: INITIAL MANAGEMENT
Goals of initial therapy of differentiated thyroid cancer are:
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 recurrence (
62-
64).
2.
To minimize treatment- and disease-related morbidity. The extent of surgery and the experience of the surgeon both play important roles in determining the risk of surgical complications (
65,
66).
3.
To permit accurate staging of the disease. Because disease stage can assist with prognostication, disease management and follow-up strategies, accurate postoperative staging is a crucial element in the management of patients with differentiated thyroid cancer (
67,
68).
4.
To facilitate postoperative treatment with radioactive iodine, where appropriate. For patients undergoing radioiodine remnant ablation, or radioiodine treatment of residual or metastatic disease, removal of all normal thyroid tissue is an important element of initial surgery (
69). Near-total or total thyroidectomy also may reduce the risk for recurrence within the contralateral lobe (
70).
5.
To permit accurate long-term surveillance for disease recurrence. Both radioiodine whole-body scanning and measurement of serum thyroglobulin are affected by residual normal thyroid tissue. Where these approaches are utilized for long-term monitoring, near-total or total thyroidectomy is required (
71).
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, thyrotropin suppression and external beam irradiation each play adjunctive roles in at least some patients (
71-
74).
What is the role of preoperative staging with diagnostic imaging and laboratory tests?
Neck imaging. Differentiated thyroid carcinoma (particularly papillary carcinoma) involves cervical lymph nodes in 20%-50% of patients in most series using standard pathologic techniques (
75-
79), and may be present even when the primary tumor is small and intrathyroidal (
37,
80). The frequency of micrometastases may approach 90%, depending on the sensitivity of the detection method (
81,
82). Preoperative ultrasound identifies suspicious cervical adenopathy in 20%-31% of cases, potentially altering the surgical approach (
83,
84), although prospective studies are needed.
Accurate staging is important in determining the prognosis and tailoring treatment for patients with differentiated thyroid cancer. However, unlike many tumor types, the presence of metastatic disease does not obviate the need for surgical excision of the primary tumor in differentiated thyroid cancer (
85). Because metastatic disease may respond to radioiodine therapy, removal of the thyroid as well as the primary tumor and accessible loco-regional disease remains an important component of initial treatment even in metastatic disease.
As ultrasound evaluation is uniquely operator dependent, alternative imaging procedures may be preferable in some clinical settings, though the sensitivity of computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) scan remain unknown in this setting. These alternative imaging modalities, as well as laryngoscopy and endoscopy, may also be useful in the assessment of large, rapidly growing, or invasive tumors, to assess the involvement of extrathyroidal tissues (
86,
87).
R21. Preoperative neck ultrasound for the contralateral lobe and cervical (central and bilateral) lymph nodes is recommended for all patients undergoing thyroidectomy for malignant cytologic findings on biopsy—Recommendation B
R22. Routine preoperative use of other imaging studies (CT, MRI, PET) is not recommended—Recommendation E
Measurement of serum thyroglobulin. There is some evidence that high preoperative concentrations of serum thyroglobulin may predict a higher sensitivity for post-operative surveillance with serum thyroglobulin (
88). Evidence that this impacts patient management or outcomes is not yet available.
R23. Routine preoperative measurement of serum thyroglobulin is not currently recommended—Recommendation E
What is the appropriate operation for differentiated thyroid cancer?
Surgical options for indeterminate biopsies or biopsies diagnostic of differentiated thyroid carcinoma. The goal 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. Surgical options for thyroid cancer should be limited to lobectomy, near-total thyroidectomy (removal of all grossly visible thyroid tissue, leaving only a small amount (<1 gram) of tissue adjacent to the insertion of the recurrent laryngeal nerve into the cricothyroid muscle), and total thyroidectomy (removal of all grossly visible thyroid tissue). Subtotal thyroidectomy, leaving more than 1 gram of tissue with the posterior capsule on the involved side, is an inappropriate operation for thyroid cancer (
89).
Surgery for a nondiagnostic biopsy, a biopsy suspicious for papillary cancer, a biopsy suggestive of "follicular neoplasm," including special consideration for patients with other risk factors. Among solitary thyroid nodules with an indeterminate ( "suspicious," "follicular neoplasm," or Hürthle cell neoplasm) biopsy, the risk of malignancy is approximately 20% (
90-
92). For solitary nodules that are repeatedly nondiagnostic on biopsy, the risk of malignancy is unknown but is probably closer to 5%-10% (
29).
R24. For patients with an isolated indeterminate solitary nodule who prefer a more limited surgical procedure, thyroid lobectomy is the recommended initial surgical approach—Recommendation C
R25. Because of an increased risk for malignancy, total thyroidectomy is indicated in patients with 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 (
32,
93,
94). Patients with 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 thyroidectomy—Recommendation A
Surgery for a biopsy diagnostic for malignancy. Near-total or total thyroidectomy is recommended if any of the following are present: the primary thyroid carcinoma is more than 1-1.5 cm, contralateral thyroid nodules, regional or distant metastases, patient has a personal history of radiation therapy to the head and neck, or a first-degree family history of differentiated thyroid cancer. Older age (>45 years) may also be a criterion for recommending near-total or total thyroidectomy because of higher recurrence rates in this age group (
62,
68,
69,
95,
96). Increased extent of primary surgery may improve survival for high-risk patients (
97-
99), while rates of recurrence are reduced by total- or near-total thyroidectomy even among low-risk patients (
68,
100,
101).
R26. For most patients with thyroid cancer, the initial surgical procedure should be a near-total or total thyroidectomy. Thyroid lobectomy alone may be sufficient treatment for small, low-risk, isolated, intrathyroidal papillary carcinomas in the absence of cervical nodal metastases—Recommendation A
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 (
75,
102). In many cases, these lymph nodes do not appear abnormal to inspection (
103). Bilateral central (compartment VI) node dissection may improve survival (compared to historic controls) and reduce the risk for nodal recurrence (
76,
103). This central compartment dissection can be achieved with low morbidity in experienced hands (
104-
107).
R27. Routine central-compartment (level VI) neck dissection should be considered for patients with papillary thyroid carcinoma and suspected Hürthle carcinoma. Near-total or total thyroidectomy without central node dissection may be appropriate for follicular cancer, and when followed by radioactive iodine therapy, may provide an alternative approach for papillary and Hüthle cell cancers—Recommendation B
Lymph nodes in the lateral neck (compartments II-IV) and posterior triangle (compartment V) may also be involved by thyroid cancer, most often in papillary and Hürthle cell carcinoma (
75,
108). For those patients in whom nodal disease is evident clinically, on preoperative ultrasound, or at the time of surgery, surgical resection may reduce the risk of recurrence and possibly mortality (
102,
109,
110). Functional compartmental en-bloc dissection is favored over selective dissection (berry picking) with limited data suggesting improved mortality (
64,
111-
113).
R28. Lateral neck compartmental lymph node dissection should be performed for patients with biopsy-proven metastatic cervical lymphadenopathy detected clinically or by imaging, especially when they are likely to fail radioactive iodine treatment based on lymph node size, number, or other factors, such as aggressive histology of the primary tumor—Recommendation B
Completion thyroidectomy. Completion thyroidectomy may be necessary when the diagnosis of malignancy is made after lobectomy for an indeterminate or nondiagnostic biopsy. Some patients with malignancy may require completion thyroidectomy to provide complete resection of multicentric disease (
114), and to allow radioiodine therapy. Most (
115,
116) but not all (
114) studies of papillary cancer have observed a higher rate of cancer in the opposite lobe when multifocal (≥2 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 (
117,
118).
R29. Completion thyroidectomy should be offered to those patients for whom a near-total or total thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. This includes all patients with thyroid cancer except those with small (<1 cm), intrathyroidal, node-negative, low-risk tumors—Recommendation B
R30. Ablation of the remaining lobe with radioactive iodine has been used as an alternative to completion thyroidectomy (
119). It is unknown whether this approach results in similar long term outcomes. Consequently, radioactive iodine ablation in lieu of completion thyroidectomy is not recommended—Recommendation E
What is the role of postoperative staging systems and which should be used?
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 differentiated thyroid carcinoma; (
2) to tailor decisions regarding postoperative adjunctive therapy, including radioiodine therapy and thyrotropin suppression, to 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 between health care professionals. Staging systems also allow evaluation of differing therapeutic strategies applied to comparable groups of patients in clinical studies.
AJCC/UICC TNM staging. Application of the AJCC/UICC classification system based on pTNM parameters is recommended for tumors of all types, including thyroid cancer (
67,
120), because it provides a useful shorthand method to describe the extent of the tumor (
121) (Table 2). 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 (
61,
62,
68,
98,
122-
125). 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 (
125). Nevertheless, each of the schemes allows accurate identification of the majority (70%-85%) of patients at low-risk of mortality, allowing the follow-up and management of these patients to be less intensive than the higher risk minority, who may benefit from a more aggressive management strategy.
R31. Because of its utility in predicting disease mortality, and its requirement for cancer registries, AJCC/UICC staging is recommended for all patients with differentiated thyroid cancer. The use of postoperative clinicopathologic staging systems is also recommended to improve prognostication and to plan follow-up for patients with differentiated thyroid carcinoma—Recommendation B
What is the role of postoperative radioiodine remnant ablation?
Postoperative radioiodine remnant ablation is increasingly being used to eliminate the post-surgical thyroid remnant. The goals of this treatment are to destroy residual thyroid tissue in an effort to decrease the risk for recurrent locoregional disease and to facilitate long-term surveillance with whole-body iodine scans and/or stimulated thyroglobulin measurements (
62,
63). A number of large, retrospective studies show a significant reduction in the rates of disease recurrence (
61,
98,
99,
126) and cause-specific mortality (
98,
99,
126-
128). However, other similar studies show no such benefit, at least among the majority of patients with papillary thyroid carcinoma, who are at the lowest risk for mortality (
68,
101,
128-
131). In those studies that show benefit, the advantage appears to be restricted to patients with larger tumors (>1.5 cm), or with residual disease after surgery, while lower risk patients do not show evidence for benefit (
68,
98,
132). No prospective studies have been performed to address this question (
128).
R32. Radioiodine ablation is recommended for patients with stages III and IV disease
(AJCC sixth edition; Table 2), all patients with stage II disease younger than age 45 years and most patients with stage II disease 45 years or older, and selected patients with stage I disease, especially those with multifocal disease, nodal metastases, extrathyroidal or vascular invasion, and/or more aggressive histologies—Recommendation B
How should patients be withdrawn from thyroid hormone prior to radioiodine ablation?
Remnant ablation (as well as subsequent monitoring for thyroid cancer persistence/recurrence using radioiodine whole-body scans (WBS) and/or serum thyroglobulin measurement) 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 more than 30 mU/L is associated with increased radioiodine uptake in tumors (
133), while studies using single-dose exogenous TSH suggest maximal thyrocyte stimulation at TSH levels between 51-82 mU/L (
134,
135). Endogenous TSH elevation can be achieved by two basic approaches to thyroid hormone withdrawal, stopping levothyroxine (LT
4) and switching to levotriiodothyronine (LT
3) for 2-4 weeks followed by withdrawal of triiodothyronine (T
3) for 2 weeks, or discontinuation of LT
4 for 3 weeks without use of T
3. Both methods of preparation can achieve serum TSH levels greater than 30 mU/L in greater than 90% of patients (
135-
144). These two approaches have not been directly compared for efficiency of patient preparation (efficacy of ablation, iodine uptake, thyroglobulin levels, disease detection, or symptoms). Other preparative approaches have been proposed, but have not been validated by other investigators (
145,
146).
R33. Patients undergoing radioiodine therapy or diagnostic testing can be prepared by LT
4 withdrawal for at least 3 weeks or T
3 treatment for 2-4 weeks and T
3 withdrawal for 2 weeks with measurement of serum TSH to determine timing of testing or therapy (TSH>30 mU/L)—Recommendation B
Should radioiodine scanning be performed before radioiodine ablation?
Radioiodine 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 (
147). Furthermore, there is an increasing trend to avoid pretherapy radioiodine scans altogether because of concerns over
131I-induced stunning of thyroid cancer (
148). Stunning is defined as a reduction in uptake of the
131I therapy dose induced by a pretreatment diagnostic dose. Stunning occurs most prominently with higher doses (5-10 mCi) of
131I (
149), with increasing time between the diagnostic dose and therapy (
150), and is not visually appreciated at lower doses (1-3 mCi). However, the accuracy of low-dose
131I scans has been questioned, and some have reported quantitatively the presence of stunning below the threshold of visual detection (
151). Although comparison studies show excellent concordance between
123I and
131I for tumor detection, optimal
123I activity and time to scan after
123I administration is not known (
152). Furthermore,
123I is expensive, is not universally available, its short half life (t
1/2=13 hours) makes handling this isotope more difficult (
153), and stunning may also occur though to a lesser degree than with
131I (
150). Determination of the thyroid bed uptake can be achieved using 10-100
µCi
131I.
R34. 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 radioiodine that is administered. If performed, pretherapy scans should utilize low-dose
131I (1-3 mCi) or
123I—Recommendation C
What activity of 131I should be used for remnant ablation?
Successful remnant ablation is usually defined as an absence of visible radioiodine uptake on a subsequent diagnostic radioiodine scan. Activities between 30 and 100 mCi of
131I generally show similar rates of successful remnant ablation (
154-
157), although there is a trend toward higher success rates with higher activities (
158).
R35. The minimum activity (30-100 mCi) necessary to achieve successful remnant ablation should be chosen, particularly for low-risk patients—Recommendation B
R36. 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 C
Can recombinant human thyrotropin (Thyrogen™) be used in lieu of thyroxine withdrawal for remnant ablation?
There is limited experience with the use of recombinant human thyrotropin (rhTSH) in radioiodine ablation of postsurgical thyroid remnants. Some patients, unable to tolerate hypothyroidism or unable to generate an elevated TSH, have undergone successful remnant ablation with rhTSH (
159,
160). Successful remnant ablation with 30 mCi
131I was equivalent after thyroxine withdrawal compared to rhTSH stimulation when the thyroxine therapy was stopped 1 day prior to the rhTSH injections and restarted the day after
131I therapy (
161). rhTSH is not approved in the United States for this indication, but it is approved in Europe.
R37. Remnant ablation can be performed following thyroxine withdrawal or rhTSH stimulation—Recommendation B
a
Is a low-iodine diet necessary before remnant ablation?
The efficacy of radioactive iodine depends on the radiation dose delivered to the thyroid tissue (
162). Low-iodine diets (<50
µg/d of dietary iodine) have been recommended prior to radioiodine therapy (
162-
164), to increase the effective radiation dose. Measurement of iodine excretion may be a useful way to identify patients whose iodine intake could interfere with radioiodine remnant ablation (
164).
R38. A low-iodine diet for 1-2 weeks is recommended for patients undergoing radioiodine remnant ablation, particularly for those patients with high iodine intake—Recommendation B
Should a posttherapy scan be performed after remnant ablation?
Posttherapy whole body iodine scanning is typically conducted approximately 1 week after radioactive iodine therapy to visualize metastases. Additional metastatic foci have been reported in 10%-26% of patients scanned after highdose radioiodine treatment compared to the diagnostic scan (
165,
166). 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% (
165-
167).
R39. A posttherapy scan is recommended after radioiodine remnant ablation. This is typically done 5-8 days after the therapeutic dose is administered, although published data supporting this time interval are lacking—Recommendation B
What is the role of TSH suppression therapy?
Differentiated thyroid cancer expresses the thyrotropin receptor on the cell membrane, and responds to TSH stimulation by increasing the expression of several thyroid-specific proteins (thyroglobulin, sodium iodide symporter) and by increasing the rates of cell growth. Suppression of TSH, using supraphysiologic doses of LT
4, is used commonly to treat patients with thyroid cancer in an effort to decrease the risk of recurrence (
73,
168). A recent meta-analysis supported the efficacy of TSH suppression therapy in preventing major adverse clinical events (relative risk [RR] = 0.73; confidence interval [CI] = 0.60-0.88; p <0.05) (
168).
What is the appropriate degree of initial TSH suppression?
Retrospective studies have demonstrated that TSH suppression to below 0.1 mU/L may improve outcomes in highrisk patients with thyroid cancer (
73,
169), although no such evidence of benefit has been documented in low-risk patients. 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, and increased risk of osteoporosis in postmenopausal women (
170).
R40. Initial thyrotropin suppression to below 0.1 mU/L is recommended for high-risk patients with thyroid cancer, 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—Recommendation B
Is there a role for adjunctive external beam irradiation or chemotherapy?
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 (
171). There are reports of responses among patients with locally advanced disease (
172,
173), and improved relapse-free and cause-specific survival (
174). It remains unknown whether external beam radiation might reduce reduce the risk for recurrence in the neck after adequate primary surgery and/or radioiodine treatment.
R41. The use of external beam irradiation 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 radioactive iodine would likely be ineffective—Recommendation B
Chemotherapy. There are no data to support the use of adjunctive chemotherapy in the management of differentiated thyroid cancer. Doxorubicin (adriamycin) may act as a radiation sensitizer in some tumors of thyroid origin (
175,
176), and could be considered for patients with locally advanced disease undergoing external beam radiation.
R42. There is no role for the routine adjunctive use of chemotherapy in patients with differentiated thyroid cancer—Recommendation F
