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clinically node-negative PTC (cN0) and for most follicular cancers.
(Strong recommendation, Moderate-quality evidence) | 316 |
RECOMMENDATION 37
Therapeutic lateral neck compartmental lymph node dis- section should be performed for patients with biopsy-proven metastatic lateral cervical lymphadenopathy.
(Strong recommendation, Moderate-quality evidence) | 317 |
Regional lymph node metastases are present at the time of diagnosis in a majority of patients with papillary carcinomas and a lesser proportion of patients with follicular carcinomas (290,334,335). 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 SEER database found, among 9904 patients with PTC, that lymph node metastases, age >45 years, distant metastasis, and large tumor size significantly predicted poor overall survival outcome in a multivariate analysis (336). All-cause survival at 14 years was 82% for PTC without lymph node metastases and 79% with nodal metastases ( p < 0.05). Another SEER registry study concluded that cervical lymph node metastases con- ferred an independent risk of decreased survival, but only in patients with follicular cancer and patients with papillary cancer over age 45 years (337). However, characteristics of the lymph node metastases can further discriminate the risk of recurrence to the patient, especially in patients with clinically evident metastasis, multiple metastases, larger metastases, and/or extracapsular nodal extension (338,339), compared with those with more limited microscopic nodal disease (335). A recent comprehensive analysis of the National Cancer Data Base and SEER, however, showed a small but significantly increased risk of death for patients younger than 45 years with lymph node metastases compared with younger patients without involved lymph nodes, and that having incrementally more metastatic lymph nodes up to six involved nodes confers additional mortality risk in this age group (340). This study underlines the importance of rigorous preoperative screening for nodal metastases and potentially raises questions about current thyroid cancer staging systems. Common to all of these studies is the conclusion that the effect of the presence or absence of lymph node metastases on overall survival, if present, is small.
The cervical node sites are well-defined (341), and the
most common site of nodal metastases is in the central neck, which is cervical level VI (Fig. 3). A recent consensus con- ference statement describes 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 cen- tral compartment neck dissection (342). In many patients, lymph node metastases in this area do not appear abnormal on preoperative imaging (289,334,343–345) or by inspection at the time of surgery (335), defining a cN0 group.
The role of therapeutic lymph node dissection for treatment of thyroid cancer nodal metastases is well accepted for cN1 disease (336,346–348). However, the value of routine pro- phylactic level VI (central) neck dissection for cN0 disease remains unclear. Central compartment dissection (therapeutic
or prophylactic) can be achieved with low morbidity by ex- perienced thyroid surgeons (349–351). The value for an in- dividual patient depends upon the utility of the staging information to the treatment team in specific patient cir- cumstances (351,352). Based on limited and imperfect data, prophylactic dissection has been suggested to improve disease-specific survival (353), local recurrence (345,354), and post-treatment Tg levels (345,355). It has also been used to inform the use of adjuvant RAI (344,347,350,356) and improve the accuracy of the estimates of risk of recurrence (356–358). However, in several studies, prophylactic dis- section has shown no improvement in long-term patient outcome, while increasing the likelihood of temporary mor- bidity, including hypocalcemia, although prophylactic dis- section may decrease the need for repeated RAI treatments (334,346,347,349,359–364).
The removal of cN0 level VI lymph nodes detects a sub- stantial number of patients with pN1 disease; however, the direct effect of this on long-term outcome is small at best (365,366). The use of staging information for the planning of adjuvant therapy depends upon whether this information will affect the team-based decision-making for the individual patient. For these reasons, groups may elect to include pro- phylactic dissection for patients with some prognostic fea- tures associated with an increased risk of metastasis and recurrence (older or very young age, larger tumor size, multifocal disease, extrathyroidal extension, known lateral node metastases) to contribute to decision-making and dis- ease control (345,351,355). Alternatively, some groups may apply prophylactic level VI dissection to patients with better prognostic features if the patient is to have a bilateral thy- roidectomy, and if the nodal staging information will be used to inform the decision regarding use of adjuvant therapy (344,350,356). Finally, for some groups it appears reasonable to use a selective approach that applies level VI lymph node dissection at the time of initial operation only to patients with clinically evident disease based on preoperative physical exam, preoperative radiographic evaluation, or intraoperative demonstration of detectable disease (cN1) (335,359,367).
The information from prophylactic central neck dissection must be used cautiously for staging information. Since mi- croscopic nodal positivity occurs frequently, prophylactic dissection often converts patients from clinical N0 to path- ologic N1a, upstaging many patients over age 45 from American Joint Committee on Cancer (AJCC) stage I to stage III (334,344–347). However, microscopic nodal positivity does not carry the recurrence risk of macroscopic clinically detectable disease (335). Thus microscopic nodal upstaging may lead to excess RAI utilization and patient follow-up. Alternatively, the demonstration of uninvolved lymph nodes by prophylactic dissection may decrease the use of RAI for some groups (344,350,356). These effects may account for some of the existing extreme variability in utilization of RAI for thyroid cancer (368).
Studies of the BRAFV600E mutation have suggested an association between presence of the mutation and the risk of nodal disease (369–371), although results across all patients with papillary thyroid carcinoma are mixed (372–375). However, the presence of a BRAFV600E mutation has a limited PPV for recurrence and therefore, BRAFV600E mutation status in the primary tumor should not impact the decision for prophylactic central neck dissection (376). | 318 |
The preceding recommendations should be interpreted in light of available surgical expertise. For patients with small, noninvasive, cN0 tumors, the balance of risk and benefit may favor thyroid lobectomy and close intraoperative inspection of the central compartment, with the plan adjusted to total thyroidectomy with compartmental dissection only in the presence of involved lymph nodes.
Lymph nodes in the lateral neck (compartments II–V, Fig. 3), level VII (anterior mediastinum), and rarely in level I may also be involved by thyroid cancer (282,335,377,378). For patients in whom nodal disease is evident clinically on pre- operative US and nodal FNA cytology or Tg washout mea- surement or at the time of surgery, surgical resection by compartmental node dissection may reduce the risk of re- currence and possibly mortality (379–381). | 320 |
[B9] Completion thyroidectomy | 321 |
RECOMMENDATION 38
Completion thyroidectomy should be offered to pa- tients for whom a bilateral thyroidectomy would have been recommended had the diagnosis been available before the initial surgery. Therapeutic central neck lymph node dis- section should be included if the lymph nodes are clinically involved. Thyroid lobectomy alone may be sufficient treatment for low-risk papillary and follicular carcinomas.
(Strong recommendation, Moderate-quality evidence)
RAI ablation in lieu of completion thyroidectomy is not recommended routinely; however, it may be used to ablate the remnant lobe in selected cases.
(Weak recommendation, Low-quality evidence) | 322 |
Completion thyroidectomy may be necessary when the diagnosis of malignancy is made following lobectomy for an indeterminate or nondiagnostic biopsy. In addition, some patients with malignancy may require completion thyroidectomy to provide complete resection of multicentric disease and to allow for efficient RAI therapy. However, since intrathyroidal PTC or low-risk FTC can be managed with either lobectomy or total thyroidectomy (see Recommenda- tion 35B), a completion thyroidectomy is not always required. The surgical risks of two-stage thyroidectomy (lobectomy followed by completion thyroidectomy) are similar to those of a near-total or total thyroidectomy (382–384). The marginal utility of prophylactic lymph node dissection for cN0 disease argues against its application in re-operations.
Ablation of the remaining lobe with RAI has been used as an alternative to completion thyroidectomy (385,386). There are limited data regarding the long-term outcomes of this approach. The data suggest similar clinical out- comes with a slightly higher proportion of patients with persistent detectable Tg. This approach may be helpful in patients for whom completion thyroidectomy carries some increased risk and for whom a delay in the length of time required to achieve destruction of the normal thyroid, which follows RAI (as opposed to surgical resection), is acceptable. In one unblinded, multicenter, randomized controlled equivalence trial comparing dose activities in achieving successful ablation of a remaining lobe in pa- tients with T1b or T2 primary tumors, who had surgical
contraindications or declined completion thyroidectomy, the remnant ablation success rate was significantly higher using 100 mCi (75% success rate; 1 mCi = 37 MBq), compared with 30 mCi (54%), although mild to moderate short-term neck pain was more frequently reported in the high-dose group (66%) compared with the low-dose group (51%) (387). Prednisone treatment for neck pain was used more frequently in the high-dose group (36% of patients) than in the low-dose group. | 323 |
[B10] What is the appropriate perioperative approach to voice and parathyroid issues?
[B11] Preoperative care communication | 324 |
RECOMMENDATION 39
Prior to surgery, the surgeon should communicate with the patient regarding surgical risks, including nerve and parathyroid injury, through the informed consent process and communicate with associated physicians, including anesthesia personnel, regarding important findings elicited during the preoperative workup.
(Strong recommendation, Moderate-quality evidence) | 325 |
The preoperative consent process should include explicit discussion of the potential for temporary or permanent nerve injury (and its clinical sequelae, including voice change, swallowing disability, risk of aspiration, and tracheostomy) as well as hypoparathyroidism, bleeding, scarring, disease recurrence, need for additional postoperative treatment, and need for thyroid hormone and surveillance thyroid function tests. The conversation should be informed by the operating surgeon’s own rates of complications. Results of the preop- erative evaluation regarding extent of disease, risk stratifi- cation, and integrity of the airway should include results from imaging, cytology, and physical examination (388–392). | 326 |
[B12] Preoperative voice assessment | 327 |
RECOMMENDATION 40
All patients undergoing thyroid surgery should have preop- erative voice assessment as part of their preoperative physical examination. This should include the patient’s description of vocal changes, as well as the physician’s assessment of voice.
(Strong recommendation, Moderate-quality evidence) | 328 |
RECOMMENDATION 41
Preoperative laryngeal exam should be performed in all patients with
Preoperative voice abnormalities
(Strong recommendation, Moderate-quality evidence)
History of cervical or upper chest surgery, which places the RLN or vagus nerve at risk
(Strong recommendation, Moderate-quality evidence)
Known thyroid cancer with posterior extrathyroidal extension or extensive central nodal metastases
(Strong recommendation, Low-quality evidence) | 329 |
Voice alteration is an important complication of thyroid surgery affecting patients’ quality of life (with regard to voice, swallowing, and airway domains), and it can have medico-legal and cost implications (393–401).
Preoperative assessment provides a necessary baseline reference from which to establish perioperative expectations (402). Also, preoperative voice assessment may lead one to identify preoperative vocal cord paralysis or paresis, which provides presumptive evidence of invasive thyroid malig- nancy and is important in planning the extent of surgery and in perioperative airway management (403–405). Contralateral nerve injury at surgery in such patients could cause bilateral cord paralysis with airway implications.
Preoperative voice assessment should include the patient’s historical subjective response to questions regarding voice abnormalities or changes, as well as the physician’s objective assessment of voice, and should be documented in the medical record (Table 9) (406). Voice and laryngeal function may be further assessed through laryngoscopy, and the application of validated quality of life and auditory perceptual assessment voice instruments (402). It is important to appreciate that vocal cord paralysis, especially when chronic, may not be associated with significant vocal symptoms due to a variety of mecha- nisms, including contralateral vocal cord compensation. Voice assessment alone may not identify such individuals (402).
Incidence rates for preoperative vocal cord paresis or pa- ralysis for patients with benign thyroid disease at preoperative laryngoscopy range from 0% to 3.5% and up to 8% in patients with thyroid cancer (407–411). Finding vocal cord paralysis on preoperative examination strongly suggests the presence of locally invasive disease. Approximately 10%–15% of thyroid cancers present with extrathyroidal extension, with the most common structures involved including strap muscle (53%), the RLN (47%), trachea (30%), esophagus (21%), and larynx
(12%) (405,412–414).
Undiagnosed preoperative laryngeal nerve dysfunction conveys greater risk during total thyroidectomy of postop- erative bilateral nerve paralysis, respiratory distress, and need for tracheostomy. Also, preoperative identification of vocal cord paralysis is important because surgical algorithms in the management of the invaded nerve incorporate nerve func- tional status (415).
A laryngeal exam should be performed if the voice is ab- normal during preoperative evaluation. In addition, a patient | 331 |
Table 9. Preoperative Factors Which May
Be Associated with Laryngeal Nerve Dysfunction | 332 |
Factor Symptoms/signs | 333 |
History Voice abnormality, dysphagia, airway symptoms, hemoptysis, pain, rapid progression, prior operation in neck or upper chest
Physical exam Extensive, firm mass fixed to the
larynx or trachea
Imaging Mass extending to/beyond periphery of thyroid lobe posteriorly and/or tracheoesophageal infiltration, or bulky cervical adenopathy along the course of the RLN or vagus nerve
should have a laryngeal exam even if the voice is normal if he or she has a history of neck surgery that placed at risk either the RLN (such as past thyroid or parathyroid surgery) or the vagus nerve (such as carotid endarterectomy, cervical eso- phagectomy, and anterior approach to the cervical spine) or a history of prior external beam radiation to the neck. Correlation between vocal symptoms and actual vocal cord function is poor given the potential for variation in paralytic cord position, de- gree of partial nerve function, and contralateral cord function/ compensation; therefore, vocal symptoms may be absent in patients with vocal cord paralysis. Vocal cord paralysis may be present in 1.5% to 30% of such postsurgical patients; it can be asymptomatic in up to one-third (403,416–422).
A laryngeal exam is recommended in patients with the preoperative diagnosis of thyroid cancer if there is evidence for gross extrathyroidal extension of cancer posteriorly or extensive nodal involvement, even if the voice is normal. The laryngeal exam should be performed in the previously noted high-risk settings, but it can be performed in other patients based on the surgeon’s judgment. | 334 |
[B13] Intraoperative voice and parathyroid management | 335 |
RECOMMENDATION 42
Visual identification of the RLN during dissection is required in all cases. Steps should also be taken to preserve the external branch of the superior laryngeal nerve (EBSLN) during dissection of the superior pole of the thyroid gland.
(Strong recommendation, Moderate-quality evidence)
Intraoperative neural stimulation (with or without monitoring) may be considered to facilitate nerve identi- fication and confirm neural function.
(Weak recommendation, Low-quality evidence) | 336 |
RECOMMENDATION 43
The parathyroid glands and their blood supply should be preserved during thyroid surgery.
(Strong recommendation, Moderate-quality evidence) | 337 |
RLN injury rates are lower when the nerve is routinely visualized in comparison with surgeries in which the nerve is simply avoided (402,416,423). If the EBSLN can be visu- alized and preserved, that is ideal. If the EBSLN cannot be visually identified, steps should be taken to avoid the nerve; this can be done by staying close to the thyroid capsule at the superior pole and by skeletonizing the superior vascular pedicle. Intraoperative nerve monitoring can be used to fa- cilitate this dissection (419). Studies with or without in- traoperative nerve monitoring demonstrate similar patient outcomes with regard to nerve injury rates (420), but studies likely have been underpowered to detect statistically sig- nificant differences (413,424). A recent systematic meta- analysis of 20 randomized and nonrandomized prospective and retrospective studies suggested no statistically signifi- cant benefit of intraoperative neuromonitoring compared to visualization alone during thyroidectomy for the outcomes of overall, transient, or permanent RLN palsy when analyzed per nerve at risk or per patient (425). However, second- | 338 |
ary subgroup analyses of high-risk patients (including those | 339 |
with thyroid cancer) suggested statistically significant het- erogeneity (variability) in treatment effect for overall and transient RLN injury, when analyzed per nerve at risk. Several studies show that intraoperative nerve monitoring is more commonly utilized by higher volume surgeons to fa- cilitate nerve management, and several studies show im- proved rates of nerve paralysis with the use of neural monitoring in reoperative and complex thyroid surgery (401,426–430). Neural stimulation at the completion of lo- bectomy can be used as a test to determine the safety of contralateral surgery with avoidance of bilateral vocal cord paralysis, and it has been associated with a reduction of bi- lateral paralysis when loss of signal occurs on the first side (428,431–433). Given the complexity of monitoring sys- tems, training and observation of existing monitoring stan- dards are important to provide optimal benefit (424,434).
Typically, parathyroid gland preservation is optimized by gland identification via meticulous dissection (435,436). If the parathyroid(s) cannot be located, the surgeon should at- tempt to dissect on the thyroid capsule and ligate the inferior thyroid artery very close to the thyroid, since the majority of parathyroid glands receive their blood supply from this ves- sel. There are exceptions to this rule; for example, superior glands in particular may receive blood supply from the su- perior thyroid artery. If the parathyroid glands are inadver- tently or unavoidably removed (e.g., they are intrathyroidal, or require removal during a central lymph node dissection) or devascularized, confirmation of cancer-free parathyroid tis- sue should be performed, and then the glands can be auto- transplanted into the strap or sternocleidomastoid muscles. It is important to inspect the thyroidectomy and/or central lymphadenectomy specimen when removed and before sending it to pathology to look for parathyroid glands that can be rescued. | 341 |
[B14] Postoperative care | 342 |
RECOMMENDATION 44
Patients should have their voice assessed in the postoper- ative period. Formal laryngeal exam should be performed if the voice is abnormal
(Strong recommendation, Moderate-quality evidence) | 343 |
RECOMMENDATION 45
Important intraoperative findings and details of postoper- ative care should be communicated by the surgeon to the patient and other physicians who are important in the patient’s postoperative care.
(Strong recommendation, Low-quality evidence) | 344 |
Voice assessment should occur after surgery and should be based on the patient’s subjective report and physician’s ob- jective assessment of voice in the office (409). Typically this assessment can be performed at 2 weeks to 2 months after surgery. Early detection of vocal cord motion abnormalities after thyroidectomy is important for facilitating prompt in- tervention (typically through early injection vocal cord medialization), which is associated with better long-term outcome, including a lower rate of formal open thyroplasty repair (437–439). Many options exist for the management of RLN paralysis, including voice therapy, vocal cord injection
techniques, and open vocal cord medialization. Rates of vo- cal cord paralysis after thyroid surgery can only be assessed by laryngeal exam postoperatively.
Communication of intraoperative findings and postopera- tive care from the surgeon to other members of the patient’s thyroid cancer care team is critical to subsequent therapy and monitoring approaches. Important elements of communica- tion include (i) surgical anatomic findings, including RLN and parathyroid status (including nerve monitoring loss of signal information if monitoring is employed); (ii) surgical disease findings, including evidence for extrathyroidal spread, completeness of tumor resection, presence and dis- tribution of nodal disease; and (iii) postoperative status, in- cluding voice/laryngeal exam, laboratory data regarding calcium/parathyroid hormone levels and need for calcium and/or vitamin D supplementation, and the surgical pathol- ogy report (440). The surgeon should remain engaged in the patient’s pursuant care to facilitate appropriate communica- tion and may remain engaged subsequent to endocrinologic consultation depending on regional practice patterns. | 345 |
[B15] What are the basic principles of histopathologic evaluation of thyroidectomy samples? | 346 |
RECOMMENDATION 46
In addition to the basic tumor features required for AJCC/UICC thyroid cancer staging including status of resection margins, pathology reports should contain ad- ditional information helpful for risk assessment, such as the presence of vascular invasion and the number of in- vaded vessels, number of lymph nodes examined and in- volved with tumor, size of the largest metastatic focus to the lymph node, and presence or absence of extranodal extension of the metastatic tumor.
(Strong recommendation, Moderate-quality evidence)
Histopathologic variants of thyroid carcinoma associated with more unfavorable outcomes (e.g., tall cell, columnar cell, and hobnail variants of PTC; widely invasive FTC; poorly differentiated carcinoma) or more favorable out- comes (e.g., encapsulated follicular variant of PTC without invasion, minimally invasive FTC) should be identified during histopathologic examination and reported.
(Strong recommendation, Low-quality evidence)
Histopathologic variants associated with familial syndromes (cribriform-morular variant of papillary carci- noma often associated with FAP, follicular or papillary carcinoma associated with PTEN-hamartoma tumor syn- drome) should be identified during histopathologic ex- amination and reported.
(Weak recommendation, Low-quality evidence) | 347 |
Pathologic examination of thyroid samples establishes the diagnosis and provides important information for risk stratification of cancer and postsurgical patient manage- ment. Histopathologically, papillary carcinoma is a well- differentiated malignant tumor of thyroid follicular cells that demonstrates characteristic microscopic nuclear features. Although a papillary growth pattern is frequently seen, it is not required for the diagnosis. Follicular carcinoma is a | 348 |
well-differentiated malignant tumor of thyroid follicular cells that shows transcapsular and/or vascular invasion and lacks the diagnostic nuclear features of papillary carcinoma. Oncocytic (Hu¨rthle cell) follicular carcinoma shows the follicular growth pattern but is composed of cells with abundant granular eosin- ophilic cytoplasm, which has this appearance because of accu- mulation of innumerable mitochondria. This tumor is currently designated by the World Health Organization as a histopatho- logic variant of follicular carcinoma (441). However, oncocytic follicular carcinoma tumors have some differences in biological behavior as compared to the conventional type follicular carci- noma, such as the ability to metastasize to lymph nodes and a possibly higher rate of recurrence and tumor-related mortality (269,442,443). Moreover, a growing body of genetic evidence suggests that oncocytic tumors develop via unique molecular mechanisms and therefore represent a distinct type of well- differentiated thyroid cancer (444).
Traditionally, follicular carcinomas have been sub- divided into minimally invasive (encapsulated) and widely invasive. In this classification scheme, minimally invasive carcinomas are fully encapsulated tumors with microscop- ically identifiable foci of capsular or vascular invasion, whereas widely invasive carcinomas are tumors with extensive vascular and/or extrathyroidal, invasion. More recent approaches con- sider encapsulated tumors with only microscopic capsular in- vasion as minimally invasive, whereas angioinvasive tumors are placed into a separate category (445–447). Such an approach is preferable because it distinguishes encapsulated tumors with capsular invasion and no vascular invasion, which are highly indolent tumors with a mortality <5%, from angioinvasive fol- licular carcinomas, which have a mortality ranging from 5% to 30%, depending on the number of invaded blood vessels (448). In addition to establishing a diagnosis for each nodule in a thyroidectomy or lobectomy specimen, the pathology report must provide characteristics required for AJCC/UICC TNM staging, such as tumor size and presence of extrathyroidal extension and lymph node metastasis. Extrathyroidal exten- sion is defined as tumor extension into the adjacent tissues. It is subdivided into minimal, which is invasion into immediate perithyroidal soft tissues or sternothyroid muscle typically detected only microscopically (T3 tumors), and extensive, which is tumor invasion into subcutaneous soft tissues, lar- ynx, trachea, esophagus, or RLN (T4a tumors). The status of the resection (inked) margins should be reported as ‘‘in- volved’’ or ‘‘uninvolved’’ with tumor, since positive margins are generally associated with intermediate or high risk for
recurrence.
The size of the metastatic focus in a lymph node (335) and tumor extension beyond the capsule of a lymph node (338,449,450) affect cancer risk. Therefore, the pathology report should indicate the size of the largest metastatic focus to the lymph node and the presence or absence of extranodal tumor extension, as well as the number of examined and involved lymph nodes.
Additionally, the presence of vascular (blood vessel) in- vasion is an unfavorable prognostic factor (451–453) and should be evaluated and reported. Vascular invasion is di- agnosed as direct tumor extension into the blood vessel lu- men or a tumor aggregate present within the vessel lumen, typically attached to the wall and covered by a layer of en- dothelial cells. More rigid criteria for vascular invasion proposed by some authors also require the presence of a fibrin
thrombus attached to the intravascular tumor cells (453). The invaded blood vessels should not be located within the tumor nodule parenchyma, but rather in the tumor capsule or outside of it. Invasion of multiple (four or more) blood vessels ap- pears to entail poorer outcomes, particularly in follicular carcinomas (454–456). Therefore, the number of invaded blood vessels (less than four or more) should be stated in the pathology report.
More than 10 microscopic variants of papillary carcinoma have been documented (457). Some of them are associated with more aggressive or conversely more indolent tumor behavior and can contribute to risk stratification. The vari- ants with more unfavorable outcomes are the tall cell, co- lumnar cell, and hobnail variants. The tall cell variant is characterized by predominance (>50%) of tall columnar tu- mor cells whose height is at least three times their width. These tumors present at an older age and more advanced stage than classic papillary carcinoma (458–461) and dem- onstrate a higher recurrence rate and decreased disease- specific survival (458–460,462,463). Some studies found a higher rate of lymph node metastasis and poorer survival in patients with tall cell variant as compared to classic papillary carcinoma even in tumors without extrathyroidal extension, and this was independent of patient age and tumor size and stage (464,465). The BRAFV600E mutation is found in *80% of these tumors (156,466).
The columnar cell variant of papillary carcinoma is char- acterized by predominance of columnar cells with pro- nounced nuclear stratification (467,468). These tumors have a higher risk of distant metastases and tumor-related mor- tality, the latter seen mostly in patients with an advanced disease stage at presentation (467–470). The BRAFV600E mutation is found in one-third of these tumors (467).
Papillary carcinoma with prominent hobnail features is a rare, recently described variant characterized by the pre- dominance of cells with a hobnail appearance with apically placed nuclei and bulging of the apical cell surface (471,472). The BRAFV600E mutation is frequently found in these tumors (471,473). This variant of papillary carcinoma appears to be associated with frequent distant metastases (typically to lung) and increased risk of tumor-related death (471).
Other variants of papillary carcinoma, such as the solid variant and diffuse sclerosing variant, may be associated with a less favorable outcome, although the data remain conflict- ing. The solid variant tumors appear to be more frequently associated with distant metastases that are present in about 15% of cases, and with a slightly higher mortality rate, which was 10%–12% in two studies with 10 and 19 years mean follow-up (474,475). However, among children and adoles- cents with post-Chernobyl papillary carcinomas, which fre- quently were of the solid variant, the mortality was very low (<1%) during the first 10 years of follow-up (476,477). Im- portantly, the solid variant of papillary carcinoma should be distinguished from poorly differentiated thyroid carcinoma, with which it shares the insular, solid, and trabecular growth patterns. The distinction is based primarily on the preserva- tion of nuclear features and lack of necrosis and high mitotic activity in the solid variant, as outlined by the Turin diag- nostic criteria for poorly differentiated thyroid carcinoma (478). It is important to make the distinction because poorly differentiated thyroid carcinoma has a much poorer progno- sis, with the 5-year survival of 72% and 10-year survival of | 350 |
46% in a series of 152 patients diagnosed using the Turin criteria (479).
The prognostic implication of the diffuse sclerosing variant of papillary cancer remains controversial. This variant is characterized by diffuse involvement of the thyroid gland and a higher rate of local and distant metastases at presentation, and it has lower disease-free survival than classic papillary carcinoma (480–482). The frequency of distant metastases, predominantly affecting the lung, varies between reported series and is 10%–15% based on almost 100 published cases summa- rized by Lam and Lo in 2006 (483) and more recent reports. Nevertheless, the overall mortality appears to be low, with a disease-specific survival of approximately 93% at 10 years of follow-up. The diffuse sclerosing variant tends to be found in younger patients in whom response to treatment is high.
The encapsulated follicular variant of papillary carcinoma is, in contrast, associated with a low risk of recurrence, par- ticularly in the absence of capsular or vascular invasion. This variant is characterized by a follicular growth pattern with no papillae formation and total tumor encapsulation, and the diagnosis rests on the finding of characteristic nuclear fea- tures of papillary carcinoma. Although the encapsulated follicular variant of PTC shares the follicular growth pattern with the infiltrative, nonencapsulated follicular variant of PTC, these tumors differ in their molecular profiles and biological properties. The encapsulated follicular variant tumors frequently have RAS mutations, whereas nonencap- sulated follicular variants frequently harbor BRAFV600E mu- tations, similar to classic papillary carcinomas (484,485). Most of the encapsulated follicular variant papillary carci- nomas show no invasive growth, whereas in about one-third of cases tumor capsule invasion, vascular invasion, or both are found (486,487). Whereas in the past the encapsulated follicular variant was relatively rare, at the present time half to two-thirds of all follicular variant papillary carcinomas belong to this subtype (488). The behavior of these tumors is usually quite indolent. A summary of six studies that reported 107 cases of encapsulated follicular variant revealed 25% with lymph node metastases and 1% with distant metastases (489). Among these 107 patients, one died of disease and two were alive with disease, whereas the rest (97%) of the patients were alive and well with various follow-up periods. In a study of 61 cases of encapsulated follicular variant, lymph node metastases were observed in 5%, and there was no distant metastasis (486). With median follow-up of 11 years, one patient developed tumor recurrence, and this tumor had in- vasion. No adverse events were found in any of the encap- sulated and noninvasive tumors, including 31 patients treated with lobectomy only. Similarly, no evidence of recurrence was found in 61 out of 62 encapsulated or well-circumscribed follicular variant of PTC in another series of patients with a median follow-up of 9.2 years, and the only case that de- veloped recurrence had a positive resection margin after initial surgery (490). In another study of a cohort of thyroid tumors followed on average for 12 years, none of 66 patients with encapsulated follicular variant of papillary carcinoma died of disease (487). Despite a low probability, some pa- tients with encapsulated follicular variants may present with distant metastases, particularly to the bones, or develop me- tastasis on follow-up (491,492). Tumors prone to metastatic behavior often have a thick capsule and significant in- tratumoral fibrosis, and virtually all of them reveal vascular
invasion or invasion of the tumor capsule. Therefore, path- ologic evaluation of these tumors should include microscopic examination of the entire tumor capsule to rule out invasion, as well as careful evaluation of the tumor to rule out the presence of poorly differentiated carcinoma areas or other unfavorable diagnostic features such as tumor necrosis or high (‡3 per 10 high-power fields) mitotic activity (493). In the absence of these features, a completely excised nonin- vasive encapsulated follicular variant of papillary carcinoma is expected to have a very low risk of recurrence or extra- thyroidal spread, even in patients treated by lobectomy.
Similarly, excellent clinical outcomes are seen in FTCs that manifest only capsular invasion without vascular inva- sion (494–496). When vascular invasion is present, the tumor should no longer be designated as minimally invasive. However, some studies (456,494,497–500), although not all (496,501), suggest that only those follicular carcinomas that have a greater extent of vascular invasion (more than four foci of vascular invasion, or extracapsular vascular invasion) are associated with poorer outcomes.
Some histopathologic variants of thyroid carcinomas are important to recognize because of their association with fa- milial tumor syndromes (41,502). The cribriform-morular variant of papillary carcinoma is frequently seen in patients with FAP due to a germline mutation in the adenomatous polyposis coli (APC) gene (503,504). It is characterized by a prominent cribriform architecture and formation of whorls or morules composed of spindle cells. The presence of aberrant b-catenin immunoreactivity provides a strong evidence for this tumor variant (505–507). Approximately 40% of patients with this variant of papillary carcinoma are found to have FAP, whereas the rest have no evidence of the inherited disease (505,508). Although no microscopic tumor features can distinguish between familial and sporadic disease, tumor multifocality is more common in the setting of the familial disease (505,508). Since many patients with the cribriform- morular variant have FAP, and thyroid cancer can precede clinically detectable colonic abnormalities in *40% of pa- tients (508), this diagnosis should raise the possibility of the familial disease and prompt consideration for colonic ex- amination and genetic counseling.
Follicular carcinoma may develop as a manifestation of the PTEN hamartoma tumor syndrome, which is caused by a germline mutation in the PTEN gene (509–511). The histo- pathologic appearance of thyroid glands in these patients is very characteristic and should allow pathologists to suspect this syndrome (510,511). The glands typically have numer- ous sharply delineated, frequently encapsulated thyroid nodules that microscopically are well-delineated and cellular and have variable growth patterns (510–513). Individuals affected by this syndrome also have a high risk for benign and malignant tumors of the breast and endometrium, colon ha- martomas, and others, and in light of the characteristic ap- pearance of the thyroid gland in these patients, genetic counseling should be recommended.
Well-differentiated papillary and follicular cancers should be histologically distinguished from poorly differentiated carcinoma. Poorly differentiated carcinoma is an aggressive thyroid tumor characterized by a partial loss of the features of thyroid differentiation that occupies morphologically and behaviorally an intermediate position between well- differentiated papillary and follicular carcinomas and fully | 352 |
dedifferentiated anaplastic carcinoma. Another term used in the past for this tumor was ‘‘insular carcinoma.’’ Diagnostic criteria for poorly differentiated carcinoma are based on the consensus Turin proposal and include the following three features: (i) solid/trabecular/insular microscopic growth pattern, (ii) lack of well-developed nuclear features of pap- illary carcinoma, and (iii) convoluted nuclei (evidence for partial loss of differentiation in papillary cancer), tumor ne- crosis, or three or more mitoses per 10 high-power fields (514). Poorly differentiated carcinomas have significantly worse outcome as compared to well-differentiated PTC and FTC, with a 10-year survival of *50% (514–516). Pa- tient age over 45 years, larger tumor size, presence of ne- crosis, and high mitotic activity are additional factors that may influence a more unfavorable outcome in patients with poorly differentiated thyroid cancer (514,517). It is not clear if the proportion of poorly differentiated carcinoma areas within the cancer nodule directly correlates with prognosis. Several studies have reported similarly decreased survival in patients with poorly differentiated carcinoma constituting more than 50% of the tumor and in those in whom it was observed as a minor component (518,519). Tumors with in- sular, solid, or trabecular architecture, but lacking other di- agnostic features of poorly differentiated carcinoma, do not demonstrate such an aggressive behavior and therefore should not be considered as poorly differentiated. On the other hand, some studies suggest that the presence of a high mitotic rate (‡5 mitoses/10 high-power fields or Ki-67 labeling index
‡4%) or tumor necrosis predicts a less favorable outcome
irrespective of the presence of the solid/trabecular/insular growth pattern (520,521). | 354 |
[B16] What is the role of postoperative staging systems and risk stratification in the management of DTC?
[B17] Postoperative staging | 355 |
RECOMMENDATION 47
AJCC/UICC staging is recommended for all patients with DTC, based on its utility in predicting disease mortality, and its requirement for cancer registries.
(Strong recommendation, Moderate-quality evidence) | 356 |
Postoperative staging for thyroid cancer, as for other cancer types, is used (i) to provide prognostic information, which is of value when considering disease surveillance and therapeutic strategies, and (ii) to enable risk-stratified description of pa- tients for communication among health care professionals, tracking by cancer registries, and research purposes.
Accurate initial staging requires a detailed understanding of all pertinent risk stratification data, whether they were ob- tained as part of preoperative testing, during the operation(s), or as part of postoperative follow-up. It is also important to emphasize that in many cases the written pathology report of the surgical specimen does not convey critical risk factors such as preoperative vocal cord paralysis, extent of gross extra- thyroidal invasion, completeness of resection, or remaining gross residual disease. Without these critical pieces of infor- mation, it is likely that initial risk stratification will be inac- curate and potentially misleading. Details and suggestions for effectively communicating specific risk factors between health
care providers are outlined in a recent publication of the Sur- gical Affairs Committee of the ATA (440).
It is important to emphasize that the identification of a clinico-pathologic or molecular predictor of recurrence or mortality does not necessarily imply that more aggressive therapies (such as more extensive surgery, RAI therapy, aggressive thyroid hormone therapy with TSH suppres- sion, targeted therapies) will have a significant impact on clinical outcomes. Similarly, the absence of a risk factor does not mean that more aggressive therapies are not indicated. Intervention studies are required to determine which at-risk- patients may benefit from additional therapies or a more conservative management approach. Until appropriate treat- ment intervention studies are completed, the risk stratification information associated with a clinico-pathologic risk factor or with a molecular profiling can be used as a prognostic factor to guide follow-up management decisions such as the type and frequency of imaging and biochemical testing. | 357 |
[B18] AJCC/UICC TNM staging
Over the years, multiple staging systems have been de- veloped to predict the risk of mortality in patients with DTC (522). Each of the systems uses some combination of age at diagnosis, size of the primary tumor, specific tumor histol- ogy, and extrathyroidal spread of the tumor (direct extension of the tumor outside the thyroid gland, loco-regional metas- tases, and/or distant metastases) to stratify patients into one of several categories with differing risks of death from thyroid cancer. Recently, a nomogram was developed and validated using the SEER data base, which provides a mathematical approach to integrating these important clinical predictive features into a specific mortality risk estimate for an indi- vidual patient (523). Using an approach similar to the MACIS system from the Mayo Clinic (270), a quantitative approach based on histology, age, lymph node metastases, tumor size, and extrathyroidal extension utilizing TNM staging has re- cently been proposed and validated (524,525)
While none of the staging systems has been shown to be clearly superior to the other systems, several studies have demonstrated that the AJCC/UICC TNM system (Table 10) and the MACIS system consistently provide the highest proportion of variance explained (PVE, a statistical measure of how well a staging system can predict the outcome of interest) when applied to a broad range of patient cohorts (277,501,526–530), and they have been validated in retro- spective studies as well as prospectively in clinical practice. Unfortunately, none of the staging systems designed to predict mortality from thyroid cancer can account for more than a small proportion (5%–30%, corresponding to PVE values of 0.05–0.30) of the uncertainty associated with eventual death from thyroid cancer (277,501,526–530). This relative inability to accurately predict the risk of death from thyroid cancer for an individual patient may be related to the failure of current staging systems to adequately integrate the risk associated with other potentially important clinico- pathologic features such as the specific histology (well- differentiated thyroid cancer versus poorly differentiated thyroid cancer), molecular profile, size and location of distant metastases (pulmonary metastases versus bone metastases versus brain metastases), functional status of the metastases (RAI avid versus 18FDG-PET avid), and effectiveness of initial therapy (completeness of resection, effectiveness of | 358 |
Table 10. AJCC 7th Edition/TNM Classification System for Differentiated Thyroid Carcinoma
Definition
RAI, external beam radiation therapy or other systemic therapies). Furthermore, recent studies have questioned the use of the age of 45 years as a cutoff to upstage patients using | 360 |
the AJCC/UICC TNM system (340,531–533). | 361 |
T0 No evidence of primary tumor
T1a Tumor £1 cm, without extrathyroidal extension T1b Tumor >1 cm but £2 cm in greatest dimension,
without extrathyroidal extension
T2 Tumor >2 cm but £4 cm in greatest dimension, without extrathyroidal extension.
T3 Tumor >4 cm in greatest dimension limited to the thyroid
or
Any size tumor with minimal extrathyroidal extension (e.g., extension into sternothyroid muscle or perithyroidal soft tissues).
T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve.
T4b Tumor of any size invading prevertebral fascia
or encasing carotid artery or mediastinal vessels N0 No metastatic nodes
N1a Metastases to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes).
N1b Metastases to unilateral, bilateral, or contralateral cervical (levels I, II III, IV, or V) or retropharyngeal or superior mediastinal
lymph nodes (level VII)
M0 No distant metastases M1 Distant metastases | 362 |
Patient age <45 years old at diagnosis | 363 |
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, Seventh Edition (1077) published by Springer Science and Business Media LLC (http://www.springer.com).
Even though the various staging systems designed to predict mortality from thyroid cancer were developed and validated using cohorts that were either exclusively or predominantly PTC patients, several small studies have demonstrated that MACIS and AJCC/UICC TNM staging systems were also predictive in patients with FTC (501,534,535).
Currently, none of the mortality risk systems incorporate molecular testing results. This may need to be re-evaluated as studies emerge using molecular testing including BRAFV600E, TERT, and TP53 or combinations of markers. For example, in one study that analyzed more than 400 DTCs, the presence of a TERT mutation was found to be an independent predictor of mortality (hazard ratio [HR] 10.35 [95% CI 2.01–53.24]) for all differentiated cancers and for papillary carcinomas (154). These potential prognostic markers are promising, but re- quire further study. | 364 |
[B19] What initial stratification system should be used to estimate the risk of persistent/recurrent disease? | 365 |
RECOMMENDATION 48
The 2009 ATA Initial Risk Stratification System is recommended for DTC patients treated with thyroidec- tomy, based on its utility in predicting risk of disease re- currence and/or persistence.
(Strong recommendation, Moderate-quality evidence)
Additional prognostic variables (such as the extent of lymph node involvement, mutational status, and/or the degree of vascular invasion in FTC), not included in the 2009 ATA Initial Risk Stratification system may be used to further refine risk stratification for DTC as described in the following text (and in Fig. 4) in the Modified Initial Risk Stratification system. However, the incremental benefit of adding these specific prognostic variables to the 2009 In- itial Risk Stratification system has not been established.
(Weak recommendation, Low-quality evidence)
While not routinely recommended for initial postop- erative risk stratification in DTC, the mutational status of BRAF, and potentially other mutations such as TERT, have the potential to refine risk estimates when interpreted in the context of other clinico-pathologic risk factors.
(Weak recommendation, Moderate-quality evidence) | 366 |
Because the AJCC/TNM risk of mortality staging system does not adequately predict the risk of recurrence in DTC (536–539), the 2009 version of the ATA thyroid cancer guidelines proposed a three-tiered clinico-pathologic risk stratification system that classified patients as having low, intermediate, or high risk of recurrence (25). Low-risk pa- tients were defined as having intrathyroidal DTC with no evidence of extrathyroidal extension, vascular invasion, or metastases. Intermediate-risk patients demonstrated either microscopic extrathyroidal extension, cervical lymph node metastases, RAI-avid disease in the neck outside the thyroid | 367 |
FIG. 4. Risk of structural disease recurrence in patients without structurally identifiable disease after initial therapy. The risk of structural disease recurrence associated with selected clinico-pathological features are shown as a continuum of risk with percentages (ranges, approximate values) presented to reflect our best estimates based on the published literature reviewed in the text. In the left hand column, the three-tiered risk system proposed as the Modified Initial Risk Stratification System is also presented to demonstrate how the continuum of risk estimates informed our modifications of the 2009 ATA Initial Risk System (see Recommendation 48). *While analysis of BRAF and/or TERT status is not routinely recommended for initial risk stratification, we have included these findings to assist clinicians in proper risk stratification in cases where this information is available. FTC, follicular thyroid cancer; FV, follicular variant; LN, lymph node; PTMC, papillary thyroid microcarcinoma; PTC, papillary thyroid cancer. | 369 |
bed, vascular invasion, or aggressive tumor histology. High- risk patients had gross extrathyroidal extension, incomplete tumor resection, distant metastases, or inappropriate post- operative serum Tg values (Table 11).
The 2009 ATA risk stratification system was somewhat different than staging systems proposed by a European Consensus conference (540) and the Latin American Thyroid Society (LATS) (541) which classify patients as either being at very low risk (unifocal, intrathyroidal T1aN0M0), low risk (T1b N0M0, T2N0M0, or multifocal T1N0M0,), or high risk (any T3 or T4, any N1, or any M1). The European and LATS very low risk and low risk categories would be classified as ATA low risk, while the ETA high risk category would be subdivided between ATA intermediate risk (minor extra- thyroidal extension, N1 disease) and ATA high risk (gross extrathyroidal extension, M1, incomplete tumor resection).
Subsequent studies have retrospectively validated the 2009 ATA risk of recurrence staging system through analysis of independent datasets originating from three respective con- tinents (Table 12). These studies have reported the estimates of patients who subsequently had no evidence of disease (NED) in each ATA Risk Category after total thyroidectomy and RAI remnant ablation: (a) low risk, 78%–91% NED, (b) intermediate risk, 52%–64% NED, and (c) high risk, 31%– 32% NED (538,539,542,543). In these datasets, NED was | 371 |
defined as a stimulated Tg <1 ng/mL with no other radio- logical or clinical evidence of disease. Prospectively col- lected validation data for the ATA initial risk stratification system are needed.
Three additional studies, in which the ATA risk classifi- cation system was retrospectively evaluated, have also sug- gested that the ATA risk of recurrence model may be applied in low- and intermediate-risk patients in the absence of RAI remnant ablation (328,544,545). Over a median follow-up period that ranged from 5 to 10 years, structural disease re- currence was identified in less than 1%–2% of ATA low-risk patients and 8% of ATA intermediate-risk patients who un- derwent thyroid surgery without RAI ablation as the initial therapy (328,544,545).
The type of persistent disease also varies according to ATA initial risk stratification, with 70%–80% of the persis- tent disease in ATA low-risk patients manifested by abnor- mal serum Tg levels (suppressed or stimulated Tg >1 ng/mL) without structurally identifiable disease, while only 29%– 51% of the ATA intermediate-risk patients and 19%–21% of ATA high-risk patients are classified as having persistent disease only on the basis of biochemical abnormalities (538,539,543). With increasing ATA risk level, the RR of having structural persistent/recurrent disease increases. Thus, the ATA low-risk patients appear to have the highest RR of | 372 |
Table 11. ATA 2009 Risk Stratification System with Proposed Modifications
ATA low risk Papillary thyroid cancer (with all of the following):
No local or distant metastases;
All macroscopic tumor has been resected
No tumor invasion of loco-regional tissues or structures
The tumor does not have aggressive histology (e.g., tall cell, hobnail variant, columnar cell carcinoma)
131
If I is given, there are no RAI-avid metastatic foci outside the thyroid bed on | 373 |
ATA intermediate risk
the first posttreatment whole-body RAI scan
No vascular invasion
Clinical N0 or £5 pathologic N1 micrometastases (<0.2 cm in largest dimension)a Intrathyroidal, encapsulated follicular variant of papillary thyroid cancera
Intrathyroidal, well differentiated follicular thyroid cancer with capsular invasion and no or minimal (<4 foci) vascular invasiona
Intrathyroidal, papillary microcarcinoma, unifocal or multifocal, including BRAFV600E
mutated (if known)a
Microscopic invasion of tumor into the perithyroidal soft tissues
RAI-avid metastatic foci in the neck on the first posttreatment whole-body RAI scan Aggressive histology (e.g., tall cell, hobnail variant, columnar cell carcinoma) Papillary thyroid cancer with vascular invasion | 377 |
Clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimensiona Multifocal papillary microcarcinoma with ETE and BRAFV600E mutated (if known)a
ATA high risk Macroscopic invasion of tumor into the perithyroidal soft tissues (gross ETE) Incomplete tumor resection
Distant metastases
Postoperative serum thyroglobulin suggestive of distant metastases Pathologic N1 with any metastatic lymph node ‡3 cm in largest dimensiona
Follicular thyroid cancer with extensive vascular invasion (> 4 foci of vascular invasion)a
aProposed modifications, not present in the original 2009 initial risk stratification system. See sections [B19]–[B23] and Recommendation 48B. | 378 |
isolated thyroglobulinemia, which may be of less clinical significance than structural disease persistence or recurrence. Similar to what was seen with the staging systems designed to predict risk of mortality from thyroid cancer (see section [B18] above), the PVE by the ATA risk of recurrence system was suboptimal, ranging from 19% to 34% (538,542). More recently, a novel mathematical clinico-pathologic staging system from the University of Yonsei yielded similar results
with a PVE of 11.9% in predicting disease recurrence (546).
[B20] Potential impact of specific clinico-pathologic fea- tures on the risk estimates in PTC
As originally conceived, the ATA initial risk stratification system was a three-tiered system in which clinico-pathologic features available at the time of initial treatment were used to classify DTC patients as having either low, intermediate, or high risk of either recurrence or persistent disease. However, as with any categorical staging system, the risk of recurrence within the individual risk categories (low, intermediate, and | 379 |
Table 12. American Thyroid Association Risk Stratification System: Clinical Outcomes Following Total Thyroidectomy and Radioiodine Remnant Ablation or Adjuvant Therapy | 380 |
aBecause the ATA intermediate- and high-risk groups were merged into a single ‘‘high-risk’’ group in the series by Castagna et al. (542), risk of persistent/recurrent disease for these subgroups is not presented.
bProportion of patients with a biochemical incomplete response. Definition: suppressed Tg >1 ng/mL, TSH-stimulated Tg >10 ng/mL, or rising anti-Tg antibody levels in the absence of structural disease.
cProportion of patients with persistent/recurrent disease that is structural. Definition: structural disease that is either biopsy-proven or highly suspicious for disease with or without abnormal serum Tg.
ND, not determined. | 381 |
high) can vary depending on the specific clinical features of individual patients (Fig. 4). In addition, the three-tiered system did not specifically address the risk of recurrence associated with specific DTC histologies, multifocality, ge- notype, extent of vascular invasion, or extent of metastatic lymph node involvement.
For example, while intrathyroidal PTCs of all sizes are included in the ATA low-risk category, the risk of structural disease recurrence can vary from 1%–2% in unifocal papil- lary microcarcinomas, to 4%–6% in multifocal papil- lary microcarcinomas (141,147), to 5%–6% in 2–4 cm intrathyroidal PTC (547), and 8%–10% in intrathyroidal PTC
>4 cm (547). Similarly, while all DTC patients with loco- regional lymph node metastases were classified as having intermediate risk in the 2009 ATA risk stratification system, the risk of structural disease recurrence can vary from 4% in patients with fewer than five metastatic lymph nodes, to 5% if all involved lymph nodes are <0.2 cm, to 19% if more than five lymph nodes are involved, to 21% if more than 10 lymph nodes are involved, to 22% if macroscopic lymph node me- tastases are clinically evident (clinical N1 disease), and 27%– 32% if any metastatic lymph node is >3 cm (335,548). These risk estimates apply to both N1a and N1b disease because there are insufficient data to determine risk based on location within the neck independent of size, number of involved nodes, and extranodal extension. It is very likely that these risk estimates could vary depending on the types and extent of nodal dissections done in individual patients. As defined by the ATA surgical affairs committee task force on thyroid cancer nodal surgery, £5 pN1 micrometastases (<0.2 cm in largest dimension) are classified as lower risk N1 disease (<5% risk of recurrence) (335). Clinical N1 disease, more than five metastatic lymph nodes, or any metastatic lymph node >3 cm in largest dimension are classified as higher risk N1 disease (>20% risk of recurrence) (335). Identification of extranodal extension of the tumor through the metastatic lymph node capsule has also been associated with an in- creased risk of recurrent/persistent disease (338,450). It is difficult to estimate the risk associated with extension of the tumor through the capsule of involved lymph nodes because this histologic finding is tightly linked with both the number of involved lymph nodes (338,450) and invasion of the tumor through the thyroid capsule (450,549).
It is also important to differentiate the clinical significance of minor extrathyroidal extension (ATA intermediate risk) from gross extrathyroidal invasion of surrounding structures (ATA high risk). The risk of recurrence associated with minor extrathyroidal extension (pT3 disease manifest by minimal extrathyroidal extension) ranges from 3% to 9% (550–554), while the risk of recurrence in patients with gross extrathyroidal extension (pT4a disease involving the subcu- taneous soft tissues, larynx, trachea, esophagus, or RLN) ranges from 23% to 40% (537,550,552–555).
The encapsulated follicular variant of papillary thyroid carcinoma also appears to be associated with a low 10-year risk of recurrence (486,490,556). Only two recurrences were reported in the 152 patients (1.3% risk of recurrence) de- scribed in these three reports. No recurrences were described in the 42 patients that had encapsulated FVPTC without capsular or lymphovascular invasion in the series by Liu et al. (486). However, the study by Baloch et al. (556) included a single patient with encapsulated FVPTC that developed bone
metastasis despite not having lymphovascular invasion or lymph node metastases identified at the time of diagnosis. Therefore, intrathyroidal FVPTC is best classified as a low- risk tumor that is unlikely to recur or metastasize.
Well-differentiated FTCs demonstrating only capsular in- vasion (without vascular invasion) usually have an excellent prognosis with recurrence rates of 0%–7% and can be classi- fied as low-risk tumors (494–496). Encapsulated, minimally invasive FTC with only minor vascular invasion (small number of foci confined to intracapsular vessels) also appears to have a low recurrence rate of approximately 0%–5% (456,500). Furthermore, some studies (456,494,497–500), but not all (496,501), suggest a greater extent of vascular invasion (more than four foci of vascular invasion, or extracapsular vascular invasion) is associated with poorer outcomes even in en- capsulated FTCs. However, FTC is considered ATA high risk if extensive vascular invasion is present because the risk of the development of newly identified distant metastases is as high as 30%–55% (455,494,497,500).
In PTC, most (451–453,558–561), but not all (562) studies demonstrate that vascular invasion is associated with worse clinical outcomes. Recurrence rates were significantly higher if vascular invasion was present in the studies by Gardner et al. (16%–20% with vascular invasion, 3%–6% without), Nishida et al. (28% with vascular invasion, 15% without), and Falvo et al. (30% with vascular invasion, 5% without), but not in the studies by Furlan et al. (562) or Akslen et al. (559). Vascular invasion in PTC was also associated with higher rates of dis- tant metastases (453,561) and disease-specific mortality (559,560). | 383 |
[B21] Potential impact of BRAFV600E and other mutations on risk estimates in PTC
In a pooled univariate analysis of 1849 PTC patients, the presence of a BRAFV600E mutation was associated with in- creased disease-specific mortality, although this was not significantly associated with mortality in a multivariate analysis (370). However, a significant interaction between BRAFV600E mutation and several conventional clinico- pathological risk factors was seen, such that the risk of mortality was higher in patients with BRAF mutation com- pared to those with wild-type BRAF in the setting of lymph node metastases (11.1% vs. 2.6%, p < 0.001), distant metas- tases (51.5% vs. 18.2%, p < 0.001), AJCC stage IV disease (31.4% vs. 13%, p0.004), and age ‡45 years at diagnosis (8% vs. 1.9%, p < 0.001). In a systematic review and meta- analysis of 14 publications that included 2470 PTC patients from nine different countries, the BRAFV600E mutation was associated with a significantly higher risk of recurrence than BRAF wild-type tumors (24.9% vs. 12.6%, p < 0.00001 [95% CI 1.61–2.32]) (563). In the studies included in this meta- analysis, the risk of recurrence in BRAFV600E-positive tumors ranged from 11% to 40% (median 26.5%), while the risk of recurrence in BRAF wild-type tumors ranged from 2% to 36% (median 9.5%). Because the BRAFV600E mutation is tightly linked with the presence of aggressive histologic phenotypes, lymph node metastases, and extrathyroidal ex- tension, it is difficult to determine the proportion of risk that is attributable to the BRAF mutation versus that attributable to the other clinico-pathologic features. Some studies (564,565), but not all (566–568), have demonstrated that the BRAFV600E mutation is an independent predictor of risk of | 384 |
recurrence in multivariate analysis. Furthermore, a recent publication demonstrated a small, but statistically signifi- cant improvement in risk stratification if BRAF status was used in conjunction with the 2009 ATA initial risk stratifi- cation system (569). In a meta-analysis of 2167 patients, the presence of a BRAFV600E mutation had a sensitivity of 65% in identifying those tumors that subsequently recurred, but had a PPV of only 25% in predicting the risk of recur- rence (563). Unlike previous studies that were often small and primarily single-institution reports, a large multicen- ter pooled-data evaluation of 2099 patients (1615 women,
484 men, median age 45 years) demonstrated that the BRAFV600E mutation was significantly associated with the risk of recurrence in both classical PTC (20.7% vs. 12.4%, HR 1.46 [95% CI 1.08–1.99] after adjustment for multi- ple clinico-pathological features), and FVPTC (21.3% vs. 7.0%, HR 3.20 [95% CI 1.46–7.02] after adjustment for multiple clinico-pathological features). Based on these data, it appears that the BRAF status in isolation is not sufficient to substantially contribute to risk stratification in most patients. However, an incremental improvement in risk stratification can be achieved if the BRAF mutational status is considered in the context of other standard clinico-pathological risk factors. Since the clinical implications of this incremental improve- ment in risk stratification are not clear, we are not routinely recommending BRAF mutational evaluation for initial post- operative risk stratification in DTC.
The potential role of BRAF status in isolation as an aid to risk stratification in patients clinico-pathologically classi- fied as having ATA low risk is currently being evaluated. In a cohort of low-risk patients with intrathyroidal PTC (<4 cm, N0, M0; 33% with BRAF mutation), the overall risk of having structural disease recurrence over 5 years of follow up was 3% (565). However, BRAFV600E-mutated tumors had a recurrence rate of 8% (8 of 106) compared with only 1% (2 of 213) in BRAF wild-type tumors ( p = 0.003, Fisher’s exact). Furthermore, in multivariate analysis, the only clinico-pathological significant predictor of persistent disease after 5 years of follow-up was the presence of a BRAFV600E mutation. If these findings are verified in additional studies, it is possible that BRAF testing could be used to help further risk stratify patients with intrathyroidal PTC as having very low risk of recur- rence (BRAF wild-type) or intermediate risk of recurrence (BRAFV600E mutation).
The impact of BRAF status on the risk of recurrence in the very low-risk patients (intrathyroidal unifocal papillary mi- crocarcinomas <1 cm) appears to be small. Even though BRAF mutation is present in 30%–67% of papillary microcarcinomas (152,153,156,566,570–576), the overall clinical recurrence rate is quite low, ranging from 1% to 6% (274,566). In a series of 99 papillary microcarcinoma patients with an overall re- currence rate of 7%, no recurrences were detected in the pa- tients with a BRAFV600E mutation and intrathyroidal, unifocal tumors. Conversely, BRAFV600E-mutated multifocal PTMC with extrathyroidal extension demonstrated a 20% recurrence rate (150). Therefore, in the absence of data demonstrating that the BRAFV600E mutation is associated with increased structural recurrence in very low-risk tumors, we have classified in- trathyroidal papillary microcarcinomas (T1a, N0, M0) har- boring BRAFV600E mutations with no other worrisome features (such as extrathyroidal extension, aggressive histology, vas-
cular invasion, or lymph node metastases) as ATA low-risk tumors. The few patients (about 10% of PTMC patients) that demonstrate multifocal PTMC with extrathyroidal invasion and a BRAFV600E mutation would be considered as having ATA intermediate risk for recurrence. Based on these data, there appears to be little role for BRAF mutational testing as an aid to risk stratification in PTMC tumors that do not demon- strate other worrisome clinico-pathologic features.
More recent data suggest that aggressive behavior of a given thyroid carcinoma, including high probability of tumor recurrence, is likely when it harbors more than one known oncogenic mutation, and specifically a BRAF mutation co- occurring with a TERT promoter, PIK3CA, TP53, or AKT1 mutation (155–157,577). Such a combination of several mutations is seen in a much smaller fraction of PTC as compared with a 40%–45% incidence of BRAF mutations and is expected to serve as a more specific marker of unfa- vorable outcomes of PTC.
Two other molecular markers that appear to confer an increased risk of tumor recurrence and tumor-related mortality are TP53 and TERT mutations. TP53 mutations have been known to occur mostly in poorly differentiated and anaplastic thyroid cancers. However, more recent broad mutational analyses identified TP53 mutations in 2 of 57 (3.5%) well-differentiated PTC and 4 of 36 (11%) of well-differentiated FTC (578). Both PTCs in this series that were positive for TP53 mutations also showed muta- tions in BRAF (or BRAF and PIK3CA) and developed lung metastases. All four TP53-positive FTC (with no other coexisting mutations) were oncocytic, and three out of four of those were widely invasive FTC.
Finally, recent studies identified TERT promoter muta- tions as a likely predictor of more unfavorable outcomes for patients with thyroid cancer. TERT mutations were found in 7%–22% of PTC and 14%–17% of FTC, but with a signif- icantly higher prevalence in dedifferentiated thyroid can- cers (154,579–581). In some (154,579), but not all (580) reports, TERT mutations were found more often in PTC carrying a BRAF mutation. In the largest reported series (332 PTC and 70 FTC followed on average for 8 years), a TERT mutation was an independent predictor of disease- free survival (odds ratio [OR] 4.68 [95% CI 1.54–14.27])
and mortality (HR 10.35 [95% CI 2.01–53.24]) for well- differentiated thyroid cancer (154). Furthermore, the com- bination of a TERT mutation and a BRAF mutation within the same tumor was associated with a high risk of structural disease recurrence (155). These results, although pending confirmation in other studies, suggest that these molecular markers, alone or in combination, may be helpful for risk stratification of thyroid cancer and provide significantly more accurate risk assessment than BRAF mutational status taken in isolation. | 386 |
[B22] Potential impact of postoperative serum Tg on risk estimates
Several studies have demonstrated the clinical utility of a serum Tg measurement (either TSH stimulated or non- stimulated) obtained a few weeks after total thyroidectomy (postoperative Tg) and before RAI remnant ablation as a tool to aid in initial risk stratification and adjuvant therapy decision-making (See Recommendations 50B and 50C). Please see section [C6] for discussion of Tg measurements. | 387 |
[B23] Proposed modifications to the 2009 ATA initial risk stratification system
While the 2009 risk stratification system has proven to be a valuable tool for initial risk stratification in PTC, modifica- tions are required to better incorporate our new understanding regarding the risks associated with the extent of lymph node involvement, mutational status, and specific FTC histologies (Table 11). While the modified 2009 risk stratification system continues to classify intrathyroidal PTC without vascular invasion as low risk, the category was expanded to include patients with small-volume lymph node metastases (clinical N0 or £5 pathologic N1 micrometastases, <0.2 cm in largest dimension), intrathyroidal encapsulated follicular variant of PTC, intrathyroidal well-differentiated follicular cancer with capsular or minor vascular invasion (<4 vessels involved), and intrathyroidal papillary microcarcinomas that are either BRAF wild-type or BRAF mutated. Similarly, the modified 2009 intermediate-risk category continues to include patients with microscopic invasion of the tumor into perithyroidal soft tissues, vascular invasion, uptake outside the thyroid bed at the time of remnant ablation, and aggressive histologies, but it has been modified to include only a subset of patients with lymph node metastases (clinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimension and multifocal papillary microcarcinoma with extrathyroidal extension and BRAF mutated (if known). Finally, the high- risk category continues to include patients with macroscopic extrathyroidal extension, incomplete tumor resection, distant metastases, and postoperative serum Tg suggestive of distant metastases, but it has been expanded to include patients with large-volume lymph node involvement (any metastatic lymph node ‡3 cm in largest dimension), and FTC with ex- tensive vascular invasion (>4 foci of vascular invasion or extracapsular vascular invasion). While these modifications are based on our current literature review of the impact of the individual risk factors, future studies will be required to validate this proposed modification to determine if the ad- ditional modifying factors provide significant incremental improvement in risk stratification. | 389 |
[B24] Risk of recurrence as a continuum of risk
While the ATA initial risk stratification system provides a meaningful and valuable tool for predicting risk of recur- rence when used as a three-tiered categorical staging system, additional insights can be gained if one appreciates that the risk of structural disease recurrence is a continuum of risk that ranges from <1% in very low-risk patients to >50% in high-risk patients (see Fig. 4). Therefore, individualized management recommendations should be based not only on the categorical risk of recurrence estimate, but also on a more individualized estimate of risk in which the ATA low- and intermediate-risk categories are further characterized on the basis of respective clinical or pathologic features, such as the size of the primary tumor, number and size of loco- regional lymph node metastases (as well as extranodal ex- tension), specific histologic variant, vascular invasion, extent of extrathyroidal extension, or other potentially important factors.
While the risk estimates presented in this section may be useful in guiding initial treatment selections (extent of initial surgery, need for RAI ablation), it is important to recognize that these risk estimates likely reflect not only the tumor
biology, but also the impact of initial therapy, which varies from thyroid lobectomy to total thyroidectomy with varying extents of lymph node dissection, either with or without RAI ablation, across the various studies. Additional studies are needed to better define the risk of recurrence in most of these clinical scenarios in patients randomized to receive one of several initial treatment options (lobectomy versus total thyroidectomy, extent of lymph node dissection, with or without RAI ablation). | 390 |
[B25] How should initial risk estimates be modified over time? | 391 |
RECOMMENDATION 49
Initial recurrence risk estimates should be continually modified during follow-up, because the risk of recurrence and disease-specific mortality can change over time as a function of the clinical course of the disease and the re- sponse to therapy.
(Strong recommendation, Low-quality evidence) | 392 |
While initial staging systems provide important insights into an individual patient’s risk of recurrence and disease- specific mortality, they provide static, single-point estimates of risk based only on data available at the time of initial therapy. None of the currently available initial staging sys- tems are capable of using new data obtained during the course of follow-up to modify the initial risk estimate. For example, an ATA low-risk patient that demonstrates a rising serum Tg associated with cervical lymphadenopathy highly suspicious for recurrent disease at some point during follow-up would still be classified as ATA low risk despite the presence of clinical data demonstrating a high risk of recurrence. Con- versely, an ATA high-risk patient that remains NED over 30 years of appropriate follow-up would still be classified as ATA high risk despite having a risk of recurrence that is significantly lower than would have been predicted at the time of initial therapy.
Therefore, while the initial staging systems can be infor- mative in guiding therapeutic and early diagnostic follow-up strategy decisions, a risk stratification system that incorpo- rates individual response to therapy into a real-time, dynamic risk stratification scheme is needed to provide an individu- alized approach to ongoing management (582,583). One approach that has been proposed is to use the risk estimates from the initial staging systems to guide initial management recommendations and then to incorporate a response-to- therapy assessment during follow-up to modify these initial risk estimates in an ongoing, dynamic process (584).
Multiple studies have now shown that many patients ini- tially classified as intermediate or high risk of recurrence using initial staging systems can be reclassified as having a subsequent low risk of recurrence based on having an ex- cellent response to initial therapy (538,539,542,586–601). Furthermore, the PVE values associated with staging sys- tems that incorporated response-to-therapy variables into revised risk estimates were significantly higher (62%–84%) than those seen with initial staging systems (<30%) (538,542). These data indicate that long-term outcomes can be more reliably predicted using systems that adjust to new data over time. | 393 |
[B26] Proposed terminology to classify response to ther- apy and clinical implications
All clinical, biochemical, imaging (structural and func- tional), and cytopathologic findings obtained during follow- up should be used to redefine the clinical status of the patient and to assess their individual response to therapy. Ideally, the global consideration of the composite findings of such an assessment would allow for the disease status to be classified into one of several discrete response to therapy risk strata as proposed by Tuttle et al. (538,582). Potential challenges in applying this specific system in routine clinical practice in- clude lack of validation in specific subgroups of patients (such as those who had less than total thyroidectomy or those not treated with RAI), the lack of published prospective data utilizing this system in clinical care, and some inconsistency with other authors in classifying the significance of varying levels of detectable Tg levels or imaging findings.
The response to therapy restaging system was also not designed or specifically tested by developers to guide specific therapeutic decisions on primary therapy (such as use of adjuvant treatment) because it has been designed for use after primary therapy is completed. Prospective studies of the value of this system for guiding extent of primary treatment, including adjuvant treatment decisions, are needed. How- ever, given that there is emerging evidence that such a re- classification system has potential to be of great importance in ongoing clinical care of DTC patients after primary treatment, the details are described herein.
It is acknowledged that appropriate clinical application of such a system is highly dependent on the availability of high-quality biochemical testing and structural, and func- tional imaging with appropriate interpretation (e.g., stan- dardized radiologic reporting). Therefore, applicability may be limited in settings where these procedures are not avail- able or feasible.
The concept and initial validation of the four response-to- therapy categories presented here were described by Tuttle et al. (538) and modified in Vaisman et al. (328). As origi- nally conceived, these clinical outcomes described the best response to initial therapy during the first 2 years of follow-up (538,582), but they are now being used to describe the clin- ical status at any point during follow-up.
Excellent response: no clinical, biochemical, or structural evidence of disease
Biochemical incomplete response: abnormal Tg or rising anti-Tg antibody levels in the absence of local-
izable disease. Please see section [C6] for discussion of Tg measurements.
Structural incomplete response: persistent or newly identified loco-regional or distant metastases
Indeterminate response: nonspecific biochemical or structural findings that cannot be confidently classified
as either benign or malignant. This includes patients with stable or declining anti-Tg antibody levels without definitive structural evidence of disease.
The majority of published studies examining response to therapy in DTC have been performed in populations of pa- tients whose primary treatment consisted of total thyroidec- tomy and RAI ablation. While the following sections will provide the details of multiple studies examining response to therapy, a simplified overview of the clinical implications of
the response-to-therapy reclassification system in patients treated with total thyroidectomy and RAI ablation, based on the research from Tuttle et al. (538,539) and supported by other studies, is described in Table 13. Specific suggestions with regard to the application of response-to-therapy as- sessments in patients treated with total thyroidectomy with- out RAI ablation or with thyroid lobectomy have recently been published by Momesso et al. (602). | 395 |
[B27] Excellent response: no clinical, biochemical, or structural evidence of disease after initial therapy (remission, NED)
These patients have no clinical, biochemical, or structural evidence of disease identified on risk-appropriate follow-up studies (Table 13). If a total thyroidectomy and RAI abla- tion were done, an excellent response was usually defined as a TSH-stimulated Tg of <1 ng/mL in the absence of struc- tural or functional evidence of disease (and in the absence of anti-Tg antibodies) (538,539,542,586–601). An excellent response to initial therapy is achieved in 86%–91% of ATA low-risk patients, 57%–63% of ATA intermediate-risk patients, and 14%–16% of ATA high-risk patients (538,539,542).
In 20 retrospective studies, the risk of recurrence over 5–10 years of follow-up ranged from 1% to 4% (median 1.8%) in patients who had an excellent response to therapy by 6–18 months after total thyroidectomy and RAI remnant ablation (538,539,542,586–601,603).
The potential impact of this reclassification is the most dramatic in the two-thirds of ATA intermediate-risk patients who achieve an excellent response and therefore have their risk of having recurrent/persistent disease decreased from 36%–43% (predicted by initial ATA risk stratification) to 1%– 2% (predicted by response-to-therapy reclassification) (538,539). Because of the very low risk of structural disease recurrence in ATA low risk patients (1%–3%), reclassification based on an excellent response to therapy has less practical implications than in the intermediate- and high-risk patients.
While many of the studies reviewed primarily low-risk DTC patients (586,588,595–598,601), the same low risk of recurrence following achievement of excellent response to therapy was seen in other studies that had substantial numbers of intermediate-risk patients (538,539,542,587,591,592,604). Furthermore, most studies also demonstrate that the few high-risk patients that achieve an excellent response to therapy also have subsequent recurrence rates in the 1%– 2% range (542,593,594,600). The one exception is the 14% risk of recurrence seen in the few ATA high-risk patients that achieved remission in a series from Memorial Sloan- Kettering Cancer Center (538), which is likely due to the known referral bias of unusual and very high-risk cases. Nonetheless, high-risk patients that achieve an excellent response to therapy may require somewhat more intense follow-up than ATA low- and intermediate-risk patients demonstrating an excellent response to therapy. It is im- portant to note that patients at intermediate to high risk of recurrence may require additional structural or functional imaging to rule out disease that may not be detected by US and Tg measurements prior to being classified as having an excellent response (602). The details for choice of follow-up tests are found in another section of these guidelines [C4– C13], (Figs. 5–8). | 396 |
Table 13. Clinical Implications of Response to Therapy Reclassification in Patients with Differentiated Thyroid Cancer Treated with Total Thyroidectomy and Radioiodine Remnant Ablation
Category Definitionsa Clinical outcomes Management implications | 397 |
Excellent response | 398 |
Biochemical incomplete response | 400 |
Structural incomplete response | 404 |
Indeterminate response
Negative imaging
and either
Suppressed Tg <0.2 ng/mLb
or
TSH-stimulated Tg <1 ng/mLb
Negative imaging
and
Suppressed Tg ‡1 ng/mLb
or
Stimulated Tg ‡10 ng/mLb
or
Rising anti-Tg antibody levels | 407 |
Structural or functional evidence of disease With any Tg level
With or without anti-Tg antibodies | 409 |
Nonspecific findings on imaging studies
Faint uptake in thyroid bed on RAI scanning
Nonstimulated Tg detectable, but <1 ng/mL
Stimulated Tg detectable, but <10 ng/mL
or
Anti-Tg antibodies stable or declining in the absence of structural or functional disease
1%–4% recurrencec
<1% disease specific deathc | 411 |
At least 30% spontaneously evolve to NEDd
20% achieve NED after additional therapya
20% develop structural diseasea
<1% disease specific deatha | 412 |
50%–85% continue to have persistent disease despite additional therapye
Disease specific death rates as high as 11% with loco-regional metastases and 50% with structural distant metastasesa | 414 |
15%–20% will have structural disease identified during follow-upa
In the remainder, the nonspecific changes are either stable,
or resolvea
<1% disease specific deatha
An excellent response to therapy should lead to an early decrease in the intensity and frequency of follow up and the degree of TSH suppression
If associated with stable or declining serum Tg values, a biochemical incomplete response should lead to continued observation with ongoing TSH suppression in most patients. Rising Tg or anti-Tg antibody values should
prompt additional investigations and potentially additional therapies.
A structural incomplete response may lead to additional treatments or ongoing observation depending on multiple clinico-pathologic factors including the size, location, rate of growth, RAI avidity, 18FDG avidity, and specific pathology of the structural lesions.
An indeterminate response should lead to continued observation with appropriate serial imaging of the nonspecific lesions and serum Tg monitoring.
Nonspecific findings that become suspicious over time can be further evaluated with additional imaging or biopsy. | 415 |
NED denotes a patient as having no evidence of disease at final follow-up.
aReferences (538,539).
bIn the absence of anti-Tg antibodies.
cReferences (538,539,542,586–593,595–601,1078).
dReferences (598,599,617–621).
eReferences (328,607,626,627,898). | 417 |
While most studies have assessed response to therapy using TSH-stimulated Tg values obtained 6–18 months after initial therapy (538,539,542,586,588–590,593–595,597–600), at least
15 other studies have evaluated the response to surgical therapy using a stimulated Tg obtained at the time of RAI remnant ablation (605). Patients demonstrating an excellent response to therapy at this very early time point have a very low risk of disease recurrence (605).
Four additional studies used nonstimulated sensitive Tg assays to define an excellent response to therapy at various time points after initial therapy with total thyroidectomy and RAI remnant ablation (587,595,601,606). A recurrence rate of 1.5% was seen in a cohort of 589 DTC patients who had a nonstimulated Tg <0.27 ng/mL at 3 months after initial therapy (595). Malandrino et al. (587) reported recurrence rates of 0%
in low-risk patients, 1% in intermediate-risk patients, and 2.7% in high-risk patients who demonstrated nonstimulated Tg values <0.15 ng/mL at 9–18 months after initial therapy. Smallridge et al. (606) described a 4.3% recurrence rate in 163 low- to intermediate-risk DTC patients with nonstimulated Tg
<0.1 ng/mL, measured a median of 1.8 years after initial sur- gery. Finally, Giovanella et al. (601) reported a 1.6% recur- rence rate over 5–6 years of follow-up in 185 low-risk patients who had a nonstimulated Tg of <0.2 ng/mL and normal post- operative neck US 6 months after remnant ablation.
Further studies are needed to refine the precise Tg value cutoff used to define what should be an excellent response to therapy in patients treated with total thyroidectomy with or without RAI remnant ablation. In addition to determining whether TSH-stimulated Tg values are clinically helpful in | 418 |
FIG. 5. Clinical decision- making and management recommendations in ATA low-risk DTC patients that have undergone total thy- roidectomy. R, recommen- dation in text. | 425 |
FIG. 6. Clinical decision- making and management recommendations in ATA low risk DTC patients that have undergone less than total thyroidectomy (lobectomy or lobectomy with isthmu- sectomy). R, recommenda- tion in text. | 438 |
FIG. 7. Clinical decision-making and management recommendations in ATA intermediate risk DTC pa- tients that have undergone total thyroidectomy. R, recommendation in text. | 452 |
patients at very low risk for recurrence, Tg cut points need to be defined for patients whose primary treatment consisted of thy- roid lobectomy or total thyroidectomy without RAI ablation.
In summary, once a patient achieves an excellent response to therapy, the initial risk of recurrence estimate should be modified and the patient reclassified as having a subsequent very low risk of recurrence. This reclassification into a very low risk of recurrence status can occur as early as several weeks (or several months) after initial therapy and is appli- cable to all DTC patients initially stratified as ATA low or intermediate risk of recurrence and to the few ATA high-risk patients that achieve an excellent response to therapy. Ap- propriate reclassification into the excellent response category with its very low risk of recurrence should lead to re- evaluation of intensity of diagnostic surveillance procedures and treatment, as discussed in other sections of these clinical practice guidelines [C4–C13] (Figs. 5–8). | 461 |
[B28] Biochemical incomplete response: abnormal Tg values in the absence of localizable disease
These patients have persistently abnormal suppressed and/ or stimulated Tg values or rising anti-Tg antibodies without | 462 |
structural evidence of disease that can be detected using risk- appropriate structural and functional imaging (Table 13). Please see section [C6] for discussion of Tg measurements. Previous studies have used nonstimulated Tg values of >1 ng/mL or TSH-stimulated Tg values of >10 ng/mL to define a bio- chemical incomplete response to therapy in patients treated with total thyroidectomy and RAI ablation (538,539,542). These studies used Tg assays with variable functional sen- sitivities, so this definition may change over time, especially for the nonstimulated Tg values.
A biochemical incomplete response is not an uncommon outcome and is seen in 11%–19% of ATA low-risk patients, 21%–22% of ATA intermediate-risk patients, and 16%–18% of ATA high-risk patients (538,539).
Clinical outcomes in these patients are usually very good, with as many as 56%–68% being classified as having NED at final follow-up, while 19%–27% continue to have persis- tently abnormal Tg values without structural correlate, and only 8%–17% developing structurally identifiable disease over 5–10 years follow-up (538,539,607). No deaths have been reported in patients with a biochemical incomplete re- sponse to therapy followed for up to 10 years (539,607). | 463 |
FIG. 8. Clinical decision- making and management recommendations in ATA high risk DTC patients that have undergone total thy- roidectomy and have no gross residual disease re- maining in the neck. R, rec- ommendation in text. | 470 |
Anti-Tg antibody levels measured over time in the same assay can provide clinically useful information (608). Rising anti-Tg antibody titers (or new appearance of anti-Tg anti- bodies) are associated with an increased risk of disease re- currence (609–614). Conversely, patients rendered free of disease with initial therapy will usually demonstrate a decline in anti-Tg antibody titers over several years (611,615,616).
Vaisman et al. (607) further demonstrated that the transi- tion to NED status occurred without any additional RAI or surgical therapy (beyond LT4 suppressive therapy) in 34% of patients classified as having a biochemical incomplete re- sponse to initial therapy. These observations are consistent with several previous studies that have demonstrated that abnormal serum Tg values can gradually decline over time without additional RAI or surgical therapy, in the absence of structurally identifiable disease (598,599,617,617–621).
A small percentage of patients with a biochemical in- complete response to therapy will demonstrate progressive increases in the nonstimulated Tg values over time. In pa- tients treated with total thyroidectomy and RAI remnant ablation, clinically significant increases in unstimulated se- rum Tg values over time as described by Tg doubling times (<1 year, 1–3 years, or >3 years) (622) or rate of rise in unstimulated Tg of ‡0.3 ng/mL/year over time (623), identify patients at increased risk of developing structurally identifi- able loco-regional or distant metastases.
Just as with the excellent response to therapy category, additional studies are needed to more precisely define what
Tg levels define an incomplete biochemical response to therapy. The specific cut point that defines an ‘‘abnormal Tg’’ is dependent on the corresponding TSH value, the amount of residual normal thyroid tissue after thyroidectomy, whether or not RAI ablation was performed, and the duration of time since ablation, because Tg values often decline for months to years after ablation. To define a biochemical incomplete re- sponse, previous studies have used nonstimulated Tg values of >5 ng/mL at 6 months (624), nonstimulated Tg values
>1 ng/mL more than 12 months after ablation (538,539,542),
or TSH-stimulated Tg values >10 ng/mL more than 1 year after ablation (538,539). The precise Tg value for defining a biochemical incomplete response to therapy in patients treated with lobectomy or total thyroidectomy without ablation has not been adequately defined. In addition, some studies also classified patients with persistent or rising anti-Tg antibodies in the absence of structurally identifiable disease as having a biochemical incomplete response to therapy (538,539,625).
In summary, a biochemical incomplete response is seen in approximately 15%–20% of DTC patients. Fortunately, many of these patients are eventually reclassified as having NED at final follow-up, often without any additional RAI or surgical treatments. | 477 |
[B29] Structural incomplete response: persistent or newly identified loco-regional or distant metastases
These patients have structural or functional (RAI scan,
18FDG-PET) evidence of loco-regional or distant metastases | 478 |
(538,539,607). This category includes both patients with biopsy-proven disease and also patients in whom structural or functional disease is identified, which is highly likely to be metastatic disease based on the clinical scenario (Table 13). A structural incomplete response to initial therapy is seen in 2%–6% of ATA low-risk patients, 19%–28% of ATA intermediate-risk patients, and 67%–75% of ATA high-risk patients (538,539).
Despite additional treatments, the majority of patients classified as having a structural incomplete response will have persistent structural and/or biochemical evidence of persistent disease at final follow-up (539,607). Depending on the definition used to describe patients as free from disease, higher rates of remission (29%–51%) have been described following surgical intervention for patients with persistent/ recurrent loco-regional disease (626–628). While no deaths were reported over a follow-up period that extended to 15 years in patients with biochemical incomplete response to therapy, death from disease was seen in 11% of patients with a loco-regional incomplete response and in 57% of patients with structurally identifiable distant metastases (539,607).
In summary, a structural incomplete response to initial therapy identifies a cohort of DTC patients that may not be cured with additional therapies and consequently demon- strate the highest risk of disease-specific mortality of any of the response-to-therapy categories. Persistent/recurrent loco- regional structural disease may have a higher likelihood of responding to additional treatments and has significantly lower disease-specific mortality rates than persistent/recur- rent distant metastases. | 480 |
[B30] Indeterminate response: biochemical or structural findings that cannot be classified as either benign or malig- nant (acceptable response)
Patients with an indeterminate response have biochemical, structural, or functional findings that cannot be confidently classified as either excellent response or persistent disease (328,538,539,606,629) (Table 13). Rather than forcing these patients into either the excellent or incomplete response-to- therapy categories, some investigators have recommended a separate category for these patients so that they can be con- tinued to be carefully observed, with selected patients iden- tified for further evaluation with testing designed to establish the presence or absence of disease (538,539).
For example, this category includes patients with sub- centimeter avascular thyroid bed nodules or atypical cervical lymph nodes that have not been biopsied, faint uptake in the thyroid bed with undetectable stimulated Tg on follow-up imaging, or nonspecific abnormalities on functional or cross- sectional imaging. Also included in this category are patients with nonstimulated Tg values that are detectable but <1 ng/ mL, TSH-stimulated Tg values between 1 and 10 ng/mL, and stable or declining Tg antibodies in the same assay over time in the absence of structural disease (538,539).
This issue was exemplified in a recent study evaluating the prognostic value of a highly sensitive Tg assay in which the response to therapy could not be definitively established in 16 patients that had small indeterminate pulmonary micro- nodules without other evidence for persistent disease (606). A similar situation arises when trying to determine the re- sponse to therapy in the 34% of patients that demonstrated nonspecific subcentimeter thyroid bed nodules after total
thyroidectomy (629). Similarly, it is often difficult to be certain whether or not very low-level detectable Tg values represent persistent disease or simply remnant normal thyroid cells remaining after initial therapy.
An indeterminate response to initial therapy is seen in 12%– 29% of ATA low-risk patients, 8%–23% of ATA intermediate- risk patients, and 0%–4% of ATA high-risk patients (538,539). The clinical outcomes in patients with an indeterminate re- sponse to therapy are intermediate between patients with an excellent response and those with incomplete responses. Two series have demonstrated that only 13%–20% of patients with an indeterminate response to therapy are reclassified as per- sistent/recurrent disease over approximately 10 years of follow- up. In the remaining 80%–90% of patients, the nonspecific findings either remain stable or resolve with observation alone. In summary, the majority of patients with an indeterminate response to therapy remain disease-free during prolonged follow-up. However, up to 20% of these patients will even- tually have biochemical, functional, or structural evidence of
disease progression and may require additional therapies. | 481 |
[B31] Using risk stratification to guide disease surveillance and therapeutic management decisions
Risk stratification is the cornerstone of individualized thyroid cancer management. Initial risk estimates are useful to guide the wide variety of clinical management decisions that need to be made around the time of initial diagnosis and treatment. As described in this document, initial manage- ment decisions are largely made by balancing the estimates of the risk of recurrence and the risk of disease-specific mortality with the potential benefits and risks of proposed therapies. However, in clinical practice many other risk estimates can also significantly influence surveillance and therapeutic decision-making, including the risk of failing initial therapy, the risk of having non–RAI-avid disease, the risk of disease recurring without making appreciable amounts of serum Tg, the risk of adjuvant RAI therapy, the risk of additional thyroid surgery, the risk of additional lymph node surgery, the risk of external beam radiation therapy, and the risk of systemic therapy. Individual manage- ment recommendations require that the risks and benefits of potential surveillance and therapeutic management decisions be carefully evaluated in the context of the specific clinico- pathologic features of each patient.
Nonetheless, initial risk estimates can be used to guide rec- ommendations with regard to the extent of thyroid surgery, the need for and extent of cervical lymph node dissection, the need for and the dose of administered activities of RAI, the need for and degree of TSH suppression, the need for and details of external beam radiation therapy, the need for and types of systemic therapy, the need for and types of studies required for initial staging, and the intensity and type of follow- up studies required for evaluating response to therapy in the early years following initial therapy. This approach tailors the aggressiveness of intervention and follow-up to the specific risks associated with the tumor in an individual patient.
In summary, this risk-adapted management approach uti- lizes initial risk estimates to guide early surveillance and therapeutic management decisions. These initial manage- ment plans are then modified over time as additional data accumulate and allow for restratification based on individ- ual response to therapy. This system tailors the extent and | 482 |
intensity of therapy and follow-up studies to real-time risk estimates that evolve over time for individual patients. | 484 |
[B32] Should postoperative disease status
be considered in decision-making for RAI therapy for patients with DTC? | 485 |
RECOMMENDATION 50
Postoperative disease status (i.e., the presence or ab- sence of persistent disease) should be considered in de- ciding whether additional treatment (e.g., RAI, surgery, or other treatment) may be needed.
(Strong recommendation, Low-quality evidence)
Postoperative serum Tg (on thyroid hormone therapy or after TSH stimulation) can help in assessing the per- sistence of disease or thyroid remnant and predicting po- tential future disease recurrence. The Tg should reach its nadir by 3–4 weeks postoperatively in most patients.
(Strong recommendation, Moderate-quality evidence)
The optimal cutoff value for postoperative serum Tg or state in which it is measured (on thyroid hormone therapy or after TSH stimulation) to guide decision-making re- garding RAI administration is not known.
(No recommendation, Insufficient evidence)
Postoperative diagnostic RAI WBSs may be useful when the extent of the thyroid remnant or residual disease cannot be accurately ascertained from the surgical report or neck ultrasonography, and when the results may alter the decision to treat or the activity of RAI that is to be administered. Identification and localization of uptake foci may be enhanced by concomitant single photon emission computed tomography–computed tomography (SPECT/ CT). When performed, pretherapy diagnostic scans should utilize 123I (1.5–3 mCi) or a low activity of 131I (1–3 mCi), with the therapeutic activity optimally administered within 72 hours of the diagnostic activity.
(Weak recommendation, Low-quality evidence) | 486 |
Postoperative disease status is a relevant consideration in postoperative treatment decision-making after initial con- sideration of clinic-pathologic stage. Evaluation of postop- erative disease status may be performed by a number of means including serum Tg, neck ultrasonography, and iodine radioisotope scanning. There are currently no RCTs com- paring any particular postoperative diagnostic strategy with the intention of modulating decision-making on RAI remnant ablation or RAI treatment for DTC. | 487 |
[B33] Utility of postoperative serum Tg in clinical decision- making
Serum Tg measurements (with anti-Tg antibodies), with or without neck US, are frequently performed as part of the early postoperative evaluation. Please see section [C6] for dis- cussion of Tg measurements. The predictive value of the postoperative Tg value will be significantly influenced by a wide variety of factors including the amount of residual thyroid cancer and/or normal thyroid tissue, the TSH level at the time of Tg measurement, the functional sensitivity of the Tg assay,
the Tg cutoff used for analysis, the individual risk of having RAI-avid loco-regional or distant metastasis, the time elapsed since total thyroidectomy, and/or the sensitivity of the post- therapy scanning technique (SPECT/CT vs. planar imaging).
Multiple studies have confirmed an increase risk of re- currence following total thyroidectomy and RAI remnant ablation in patients that had a postoperative TSH-stimulated Tg >1–2 ng/mL at the time of ablation (596,605,630–637). In multivariate analysis, the postoperative Tg is often found to be an independent predictor of persistent or recurrent disease (596,630,631,636,637). Furthermore, the risk of having re- current or persistent disease increases as the postoperative Tg rises (634,636). Using receiver operator curve analyses, thyroid hormone withdrawal postoperative Tg values be- tween 20 and 30 ng/mL achieve the optimal balance of sen- sitivity and specificity for predicting recurrent or persistent disease (638–640). Furthermore, high postoperative stimu- lated Tg values (>10–30 ng/mL) are also associated with poorer survival (636,639,641). Conversely, postoperative stimulated Tg values less than 1–2 ng/mL are strong predic- tors of remission (634,636). Even in ATA low- and intermediate-risk patients that did not receive RAI remnant ablation, a nonstimulated postoperative Tg <1 ng/mL was associated with excellent clinical outcomes and recurrence rates <1% (642). The median follow-up in this study was 62 months (2–116 months). Therefore, a postoperative serum Tg can provide valuable information with regard to the likeli- hood of achieving remission or having persistent or recurrent disease in response to an initial therapy.
A postoperative Tg <10 ng/mL may not distinguish be- tween nodal disease and thyroid remnant, when evaluated using concurrent RAI scans with SPECT/CT (643). In one of the prospective studies mentioned previously, a postop- erative Tg threshold of >5 ng/mL was suggested as an in- dication for RAI treatment (633). However, in a recent retrospective review of consecutive low-risk patients trea- ted with total thyroidectomy without RAI, an unstimulated Tg of ‡2 ng/mL with a concomitant median TSH level of
0.48 mIU/L was reported to detect all patients with disease
recurrence (76 patients followed for a median of 2.5 years) (644). Thus, there is some uncertainty as to what degree of postoperative stimulated or unstimulated thyroglobulinemia (with or without neck US interpretation) may be appropriate to prompt RAI treatment. Moreover, detection of unex- plained inappropriate thyroglobulinemia may prompt con- sideration of further investigation for its cause (e.g., imaging studies).
The postoperative Tg can also be used to predict the likelihood of identifying RAI-avid metastatic thyroid cancer outside the thyroid bed on the posttherapy scan at the time of remnant ablation. No uptake outside the thyroid bed was identified in 63 low-risk patients with a nonstimulated post- operative Tg of <0.4 ng/mL (630) or in 132 low-risk patients with a thyroid hormone withdrawal Tg of <1 ng/mL (645). However, RAI-avid metastatic foci outside the thyroid bed were detected in 12% of intermediate-risk patients with a suppressed Tg of <0.6 ng/mL (646), 5.6% of intermediate/ high risk patients with a suppressed Tg of <1 .0 ng/mL (647), and 6.3% of intermediate/high-risk patients with a thyroid hormone withdrawal stimulated Tg of <2 ng/mL (648). The likelihood of finding RAI-avid metastatic disease on the post- therapy scan is substantially lower (2.8%) if the postoperative | 488 |
Tg is undetectable in three different Tg assays than if it is undetectable only in a single assay (30%) (649). Con- versely, the likelihood of identifying either loco-regional or distant metastases on the posttherapy scan increases as either the suppressed or stimulated Tg values rise above 5–10 ng/mL (631,646,647,650). Therefore, neither a stim- ulated or suppressed postoperative Tg of <1 ng/mL can completely eliminate the possibility that a posttherapy RAI scan will identify metastatic foci outside the thyroid bed. However, postoperative Tg values greater than 5–10 ng/mL increase the likelihood of identifying RAI-avid metastatic disease on the posttherapy scan.
The postoperative serum Tg value can also be used to predict the likelihood of successful remnant ablation. Post- operative thyroid hormone withdrawal stimulated Tg values
>5–6 ng/mL were associated with higher rates of failed ab- lation after administered activities of both 30 mCi (651) and 100 mCi (652). A TSH-stimulated Tg >6 ng/mL was asso- ciated with a 5-fold greater risk of failing ablation after an activity of 30 mCi administered after preparation with thy- roid hormone withdrawal (651).
It does appear that a postoperative Tg value (either TSH- stimulated or nonstimulated) is an important prognostic factor that can be used to guide clinical management. Given a disappearance half-life of 1–3 days (653–658), the postop- erative Tg should reach its nadir by 3–4 weeks postopera- tively in nearly all patients. In low-risk patients, a suppressed or stimulated Tg <1 ng/mL is very reassuring and further confirms classification of the patients as being at low risk. In intermediate-risk patients, postoperative Tg values <1 ng/mL are reassuring, but do not completely rule out the presence of small-volume RAI-avid metastatic disease. However, even without RAI ablation, many intermediate risk patients have excellent clinical outcomes. Therefore, it is not clear that additional therapy is required in these intermediate-risk pa- tients with postoperative Tg values <1 ng/mL even though small-volume RAI-avid disease may still be present after thyroidectomy.
On the other hand, postoperative Tg values (stimulated or nonstimulated) greater than 10–30 ng/mL increase the like- lihood of having persistent or recurrent disease, failing initial RAI ablation, having distant metastases, and dying of thyroid cancer. Therefore, postoperative Tg values >10 ng/mL will likely lead to additional evaluations and possibly even ad- ditional therapies.
With regard to decision-making on the need for RAI remnant ablation, it appears that the postoperative serum Tg value will be more helpful in identifying patients that may benefit from RAI ablation rather than in identifying patients that do not require ablation. For example, a postoperative Tg value >5–10 ng/mL may lead to selection of RAI ablation in an ATA low-risk patient or ATA intermediate-risk patient that otherwise would not have required RAI ablation (selective use) in order to improve initial staging and facilitate follow- up. Conversely, in high-risk patients, a postoperative Tg value
<1 ng/mL does not rule out RAI-avid disease and therefore is unlikely to alter the decision to proceed with RAI ablation. | 490 |
[B34] Potential role of postoperative US in conjunction with postoperative serum Tg in clinical decision-making
In a prospective study of 218 DTC patients, Lee et al. (659) reported that a stimulated Tg <2 ng/mL after thyroid hormone
withdrawal (with goal TSH of >30 mIU/L), at the time of administration of 100–200 mCi of 131I (for remnant ablation or treatment), was associated with the following NPVs for biochemical or structural recurrence at 6–12 months: 98.4% for ATA low-risk patients, 94.1% for ATA intermediate-risk patients, and 50% in the ATA high-risk group. They further reported that the NPVs increased to 97.2%, and 100% for ATA intermediate- and high-risk patients, respectively, when the stimulated Tg values were combined with negative neck US findings at baseline (with no change in low-risk patients). Similar significant decreases in the risk of recurrence were seen when ATA intermediate- and high-risk patients had a normal postoperative neck US (660). | 491 |
[B35] Role of postoperative radioisotope diagnostic scan- ning in clinical decision-making
Iodine radioisotope diagnostic testing may include 131I or 123I diagnostic imaging with or without SPECT-CT, and/or RAI uptake measurements. Postoperative RAI planar imaging (123I or 131I, with or without SPECT-CT) has been reported to yield information that could alter clinical management (such as altering disease status assessment) in 25%–53% of patients, as reported in single-center, retrospective studies (643,661,662). However, in a multivariate analysis of retrospective data, Hu et al. (663) reported that the use of 5 mCi of 131I between4 and 11 days prior to remnant ablation was independently associated with an increased risk of remnant ablation failure. In contrast, in a smaller retrospective study, the administration of 3–5 mCi of 131I for scanning 2–5 days prior to ablation in 37 patients was not associated with any significant reduction in remnant abla- tion success, compared to no pretherapy scanning in 63 patients (131I therapeutic activity of 100–200 mCi used in both groups) (664). A possible relationship between 131I diagnostic scan activity on remnant ablation success was suggested in another retrospective study, in which success was lower following the use of 3 mCi as compared to 1 mCi of 131I, 9 days before therapeutic administration of 100 mCi (665). In two small RCTs, there was no significant impact of 131I scanning compared to 123I scanning on the rate of successful remnant ablation (666,667). The timing of whole-body diagnostic scans following administration of radioisotopes in reviewed studies ranged from about 24 to 72 hours for 131I (643,662, 663,665–667) and was 24 hours for 123I (661,662,666). The tailoring of RAI therapeutic activity according to RAI neck uptake (measured 24 hours after administration of 1 mCi of 131I) was associated with a lower rate of remnant ablation success than fixed dosing, in another single-center retrospective observational study (668). Furthermore, in a multivariate analysis of retrospective data (adjusted for rel- evant risk factors), Verburg et al. (669) reported that the use of 1 mCi of 131I for calculation of RAI neck uptake 2 days before remnant ablation was independently associated with an increased risk of remnant ablation failure, although Yap and Murby showed that 1.1 mCi 131I diagnostic scans did not adversely affect the success of ablation or recurrence rate at 3 years (670).
There continues to be discussion on the utility of postoper- ative iodine radioisotope diagnostic scanning (with or without SPECT/CT) in guiding RAI therapeutic decision-making. Valuable information on disease status, remnant uptake, and the presence of residual RAI-avid disease may be obtained by such testing, which could alter management and potentially | 492 |
benefit outcome. Questions regarding the potentially negative impact of such scans with 131I on RAI therapeutic efficacy for successful remnant ablation (‘‘stunning’’) may be mitigated or avoided by the use of either low-activity 131I (1–3 mCi) or alternative isotopes such as 123I. | 494 |
[B36] What is the role of RAI (including remnant ablation, adjuvant therapy, or therapy
for persistent disease) after thyroidectomy in the primary management of DTC? | 495 |
RECOMMENDATION 51 (details in Table 14)
RAI remnant ablation is not routinely recommended after thyroidectomy for ATA low-risk DTC patients. Consideration of specific features of the individual patient that could modulate recurrence risk, disease follow-up implications, and patient preferences are relevant to RAI decision-making.
(Weak recommendation, Low-quality evidence)
RAI remnant ablation is not routinely recommended after lobectomy or total thyroidectomy for patients with unifocal papillary microcarcinoma, in the absence of other adverse features.
(Strong recommendation, Moderate-quality evidence)
RAI remnant ablation is not routinely recommended after thyroidectomy for patients with multifocal papillary microcarcinoma in absence of other adverse features. Consideration of specific features of the individual patient that could modulate recurrence risk, disease follow-up implications, and patient preferences are relevant to RAI decision-making.
(Weak recommendation, Low-quality evidence)
RAI adjuvant therapy should be considered after total thyroidectomy in ATA intermediate-risk level DTC patients.
(Weak recommendation, Low-quality evidence)
RAI adjuvant therapy is routinely recommended after total thyroidectomy for ATA high risk DTC patients
(Strong recommendation, Moderate-quality evidence) | 496 |
Subsets and Splits