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s f u la b l a t i o no far e m a i n i n gl o b ei np a - tients with T1b or T2 primary tumors, who had surgicalcontraindications 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 moderateshort-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 usedmore frequently in the high-dose group (36% of patients) than in the low-dose group. [B10] What is the appropriate perioperative approach to voice and parathyroid issues? [B11] Preoperative care communication &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, includinganesthesia personnel, regarding important findings elicited during the preoperative workup. (Strong recommendation, Moderate-quality evidence) 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 functiontests. 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). [B12] Preoperative voice assessment &RECOMMENDATION 40 All patients undergoing thyroid surgery should have preop- erative voice assessment as part of their preoperative physicalexamination. This should include the patient’s description of vocal changes, as well as the physician’s assessment of voice. (Strong recommendation, Moderate-quality |
evidence) &RECOMMENDATION 41 Preoperative laryngeal exam should be performed in all patients with (A) Preoperative voice abnormalities(Strong recommendation, Moderate-quality evidence)(B) History of cervical or upper chest surgery, which places the RLN or vagus nerve at risk (Strong recommendation, Moderate-quality evidence)(C) Known thyroid cancer with posterior extrathyroidal extension or extensive central nodal metastases (Strong recommendation, Low-quality evidence)ATA THYROID NODULE/DTC GUIDELINES 35 |
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 havemedico-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 toidentify preoperative vocal cord paralysis or paresis, which provides presumptive evidence of invasive thyroid malig- nancy and is important in planning the extent of surgery andin 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 medicalrecord (Table 9) (406). Voice and laryngeal function may be further assessed through laryngoscopy, and the application of validated quality of |
life and auditory perceptual assessmentvoice 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 preoperativelaryngoscopy 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 oflocally 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 themanagement 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 patientshould 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 thevagus 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 poorgiven 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 inpatients 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. Thelaryngeal 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. [B13] Intraoperative voice and parathyroid management &RECOMMENDATION 42 (A) Visual identification of the RLN during dissection isrequired in all cases. Steps should also be taken to preservethe external branch of the superior laryngeal nerve (EBSLN) during dissection of the superior pole of the thyroid gland. (Strong recommendation, Moderate-quality evidence)(B) Intraoperative neural stimulation (with or without monitoring) may be considered to facilitate nerve identi-fication and confirm neural function. (Weak recommendation, Low-quality evidence) &RECOMMENDATION 43 The parathyroid glands and their |
blood supply should be preserved during thyroid surgery. (Strong recommendation, Moderate-quality evidence) 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 bevisually 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 vascularpedicle. 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 studieslikely have been underpowered to detect statistically sig- nificant differences (413,424). A recent systematic meta- analysis of 20 randomized and nonrandomized prospectiveand retrospective studies suggested no statistically signifi- cant benefit of intraoperative neuromonitoring compared to visualization alone |
during thyroidectomy for the outcomesof overall, transient, or permanent RLN palsy when analyzedper nerve at risk or per patient (425). However, second- ary subgroup analyses of high-risk patients (including thoseTable 9.Preoperative Factors Which May Be Associated with Laryngeal Nerve Dysfunction Factor Symptoms/signs History Voice abnormality, dysphagia, airway symptoms, hemoptysis,pain, rapid progression, prioroperation 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 alongthe course of the RLN or vagusnerve36 HAUGEN ET AL. |
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 ismore 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 neuralmonitoring 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 ofcontralateral 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 inferiorthyroid 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, superiorglands 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) ordevascularized, confirmation of cancer-free parathyroid tis- sue should be performed, and then the glands can be auto- transplanted into the strap or sternocleidomastoid muscles. Itis important to inspect the thyroidectomy and/or central lymphadenectomy specimen when removed and before sending it to pathology to look for parathyroid glands that canbe rescued. [B14] Postoperative care &RECOMMENDATION 44 Patients should have their voice assessed in the postoper-ative period. Formal laryngeal exam should be |
performedif the voice is abnormal (Strong recommendation, Moderate-quality evidence) &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 thepatient’s postoperative care. (Strong recommendation, Low-quality evidence) 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 abnormalitiesafter thyroidectomy is important for facilitating prompt in- tervention (typically through early injection vocal cord medialization), which is associated with better long-termoutcome, 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 injectiontechniques, 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) surgicaldisease 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 regardingcalcium/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 thepatient’s pursuant care to facilitate appropriate communica- tion and may remain engaged subsequent to endocrinologic consultation depending on regional practice patterns. [B15] What are the basic principles of histopathologic evaluation of thyroidectomy samples? &RECOMMENDATION 46 (A) 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)(B) Histopathologic variants of thyroid carcinoma associated with more unfavorable outcomes (e.g., tall cell, columnarcell, and hobnail variants of PTC; widely invasive FTC; poorly differentiated carcinoma) or more favorable out- comes (e.g., encapsulated follicular variant of PTC withoutinvasion, minimally invasive FTC) should be identified during histopathologic examination and reported. (Strong recommendation, Low-quality evidence)(C) Histopathologic variants associated with familial syndromes (cribriform-morular variant of papillary carci-noma often associated with FAP, follicular or papillarycarcinoma associated with PTEN-hamartoma tumor syn- |
drome) should be identified during histopathologic ex- amination and reported. (Weak recommendation, Low-quality evidence) Pathologic examination of thyroid samples establishes the diagnosis and provides important information for riskstratification of cancer and postsurgical patient manage- ment. Histopathologically, papillary carcinoma is a well- differentiated malignant tumor of thyroid follicular cells thatdemonstrates characteristic microscopic nuclear features.Although a papillary growth pattern is frequently seen, it is not required for the diagnosis. Follicular carcinoma is aATA THYROID NODULE/DTC GUIDELINES 37 |
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 currentlydesignated by the World Health Organization as a histopatho- logic variant of follicular carcinoma (441). However, oncocytic follicular carcinoma tumors have some differences in biologicalbehavior 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 evidencesuggests 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 invasivecarcinomas are fully encapsul ated tumors with microscop- ically identifiable foci of capsular or vascular invasion, whereas widely invasive carcinomas are tumors with extensive vascularand/or extrathyroidal, invasi on. More recent approaches con- sider encapsulated tumors with only microscopic capsular in- vasion as minimally invasive, whereas angioinvasive tumors areplaced into a separate category (445–447). Such an approach ispreferable 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 extrathyroidalextension 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 typicallydetected only microscopically (T3 tumors), and extensive , which is tumor invasion into subcutaneous soft tissues, lar- ynx, trachea, esophagus, or RLN (T4a tumors). The status ofthe resection (inked) margins should be reported as ‘‘in- volved’’ or ‘‘uninvolved’’ with tumor, since positive margins are generally associated with intermediate or high risk forrecurrence. 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 pathologyreport 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 andinvolved lymph nodes. Additionally, the presence of vascular (blood vessel) in- vasion is an unfavorable prognostic factor (451–453) andshould 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 fibrinthrombus 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 outsideof 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 thepathology report. More than 10 microscopic variants of papillary carcinoma have been documented (457). Some of them are associatedwith 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 ischaracterized 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 advancedstage 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 ahigher 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 BRAF V600Emutation 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 apicallyplaced nuclei and bulging of the apical cell surface (471,472).TheBRAF V600Emutation 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 witha 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 about15% 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 bedistinguished 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 of38 HAUGEN ET AL. |
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 ischaracterized 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 offollow-up. The diffuse sclerosing variant tends to be found inyounger 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 thediagnosis rests on the finding of characteristic nuclear fea- tures of papillary carcinoma. Although the encapsulated follicular variant of PTC shares the follicular growth patternwith the infiltrative, nonencapsulated follicular variant of PTC, these tumors differ in their molecular profiles and biological properties. The encapsulated follicular varianttumors frequently have RAS mutations, whereas nonencap- sulated follicular variants frequently harbor BRAF V600Emu- 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 encapsulatedfollicular 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 isusually quite |
indolent. A summary of six studies that reported107 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 twowere 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 nodemetastases 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 recurrencewas found in 61 out of 62 encapsulated or well-circumscribedfollicular 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 afterinitial 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 carcinomadied 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 vascularinvasion 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 thepresence 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 tumorshould 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 thathave 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-morularvariant 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 ormorules composed of spindle cells. The presence of aberrant b-catenin immunoreactivity provides a strong evidence for this tumor variant (505–507). Approximately 40% of patientswith 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 featurescan 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 precedeclinically 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 agermline 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 suspectthis syndrome (510,511). The glands typically have numer- ous sharply delineated, frequently encapsulated thyroid nodules that microscopically are well-delineated and cellularand have variable growth patterns (510–513). Individualsaffected 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 featuresof thyroid differentiation that occupies morphologically and behaviorally an intermediate position between well- differentiated papillary and follicular carcinomas and fullyATA THYROID NODULE/DTC GUIDELINES 39 |
dedifferentiated anaplastic carcinoma. Another term used in the past for this tumor was ‘‘insular carcinoma.’’ Diagnostic criteria for poorly differentiated carcinoma are based on theconsensus Turin proposal and include the following threefeatures: (i) solid/trabecular/insular microscopic growth pattern, (ii) lack of well-developed nuclear features of pap- illary carcinoma, and (iii) convoluted nuclei (evidence forpartial loss of differentiation in papillary cancer), tumor ne- crosis, or three or more mitoses per 10 high-power fields (514). Poorly differentiated carcinomas have significantlyworse 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 thatmay 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 areaswithin the cancer nodule directly correlates with prognosis. Several studies have reported similarly decreased |
survival in patients with poorly differentiated carcinoma constitutingmore 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/insulargrowth pattern (520,521). [B16] What is the role of postoperative staging systems and risk stratification in the management of DTC? [B17] Postoperative staging &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) Postoperative staging for |
thyroid cancer, as for other cancer types, is used (i) to provide prognostic information, which is ofvalue 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 suchas 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 healthcare |
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 ormortality 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 stratificationinformation 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 andfrequency of imaging and biochemical testing. [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 atdiagnosis, 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 ofseveral categories with differing risks of death from thyroid cancer. Recently, a nomogram was developed and validated using the SEER data base, which provides a mathematicalapproach 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 MACISsystem 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 ofinterest) 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 PVEvalues of 0.05–0.30) of the uncertainty associated witheventual 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 tothe 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 metastasesversus brain metastases), functional status of the metastases (RAI avid versus 18FDG-PET avid), and effectiveness of initial therapy (completeness of resection, effectiveness of40 HAUGEN ET AL. |
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 usingthe AJCC/UICC TNM system (340,531–533). Even though the various staging systems designed to predict mortality from thyroid cancer were developed and validated using cohorts that were either exclusively or predominantlyPTC patients, several small studies have demonstrated that MACIS and AJCC/UICC TNM st aging 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 BRAF V600E, TERT , and TP53 or combinations of markers. For example, in one study that analyzed more than 400 DTCs, the presence of aTERT mutation was found to be an independent predictor of mortality (hazard ratio [HR] 10.35 [95% CI 2.01–53.24]) forall differentiated cancers and |
for papillary carcinomas (154). These potential prognostic markers are promising, but re- quire further study. [B19] What initial stratification system should be used to estimate the risk of persistent/recurrent disease? &RECOMMENDATION 48 (A) 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)(B) 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 tofurther 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 ofadding these specific prognostic variables to the 2009 In-itial Risk Stratification system has not been established. (Weak recommendation, Low-quality evidence)(C) 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) 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 riskstratification 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 noevidence of extrathyroidal extension, vascular invasion, or metastases. Intermediate-risk patients demonstrated either microscopic extrathyroidal extension, cervical lymph nodemetastases, RAI-avid disease in the neck outside the thyroidTable 10. AJCC 7 th Edition /TNM Classification System for Differentiated Thyroid Carcinoma Definition 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 orAny size tumor with minimal extrathyroidalextension (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 recurrentlaryngeal nerve. T4b Tumor of any size invading prevertebral fascia or encasing carotid artery or mediastinal vessels N0 No metastatic nodesN1a 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) orretropharyngeal or superior mediastinal lymph nodes (level VII) M0 No distant metastases M1 Distant metastases Patient age <45 years old at diagnosis I Any T Any N M0 II Any T |
Any N M1 Patient age ‡45 years old at diagnosis I T1a N0 M0 T1b N0 M0 II T2 N0 M0III T1a N1a M0 T1b N1a M0T2 N1a M0T3 N0 M0 T3 N1a M0 IVa T1a N1b M0 T1b N1b M0 T2 N1b M0T3 N1b M0 T4a N0 M0 T4a N1a M0T4a N1b M0 IVb T4b Any N M0IVc Any T Any N M1 Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (1077) published by Springer Science and Business Media LLC(http://www.springer.com).ATA THYROID NODULE/DTC GUIDELINES 41 |
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 ThyroidSociety (LATS) (541) which classify patients as either beingat 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 LATSvery 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 ofindependent 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 wasdefined 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 appliedin low- and intermediate-risk patients in the absence of RAIremnant 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-riskpatients |
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 persistentdisease 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 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 riskwith percentages (ranges, approximate values) presented |
to reflect our best estimates based on the published literaturereviewed 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 wherethis information is available. FTC, follicular thyroid cancer; FV, follicular variant; LN, lymph node; PTMC, papillary thyroid microcarcinoma; PTC, papillary thyroid cancer.42 HAUGEN ET AL. |
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). Morerecently, 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, orhigh 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, andTable 11. ATA 2009 Risk Stratification System with Proposed Modifications ATA low risk Papillary thyroid cancer (with all of the following): /C15No local or distant metastases; /C15All macroscopic tumor has been resected /C15No tumor invasion of loco-regional tissues or structures /C15The tumor does not have aggressive histology (e.g., tall cell, hobnail variant, columnar cell carcinoma) /C15If131I is given, there are no RAI-avid metastatic foci outside the thyroid bed on the first posttreatment whole-body RAI scan /C15No vascular invasion /C15Clinical 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 ATA intermediate riskMicroscopic 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 invasionClinical N1 or >5 pathologic N1 with all involved lymph nodes <3 cm in largest dimensiona Multifocal papillary microcarcinoma with ETE and BRAFV600Emutated (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 metastasesPathologic 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. Table 12.American Thyroid Association Risk Stratification System: Clinical Outcomes Following Total Thyroidectomy and Radioiodine Remnant Ablation or Adjuvant Therapy ATA risk Study NED, %Biochemical incomplete, %bStructural incomplete, %c Low Tuttle et al. (538) 86 11 3 Castagna |
et al. (542) 91 NDaNDa Vaisman et al. (539) 88 10 2 Pitoia et al. (543) 78 15 7 IntermediateaTuttle et al. (538) 57 22 21 Vaisman et al. (539) 63 16 21 Pitoia et al. (543) 52 14 34 High Tuttle et al. (538) 14 14 72 Vaisman et al. (539) 16 12 72 Pitoia et al. (543) 31 13 56 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.ATA THYROID NODULE/DTC GUIDELINES 43 |
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 recurrenceassociated 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 havingintermediate 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% ifall 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 becausethere 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 theserisk estimates could vary depending on the types and extentof 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 lymphnode>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 metastaticlymph 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 becausethis 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 grossextrathyroidal 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 werereported 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 withoutcapsular 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 bonemetastasis 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 havea 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 (morethan four foci of vascular invasion, or extracapsular vascularinvasion) 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 ofthe 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). [B21] Potential impact of BRAFV600Eand other mutations on risk estimates in PTC In a pooled univariate analysis of 1849 PTC patients, the presence of a BRAFV600Emutation was associated with in- creased disease-specific mortality, although this was notsignificantly associated with mortality in a multivariateanalysis (370). However, a significant interaction between BRAF V600Emutation and several conventional clinico- pathological risk factors was seen, such that the risk ofmortality 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 BRAFV600Emutation was associated with a significantly higher risk of recurrence thanBRAF 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 ofrecurrence in BRAF wild-type tumors ranged from 2% to 36% (median 9.5%). Because the BRAFV600Emutation is tightly linked with the presence of aggressive histologicphenotypes, 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 BRAFV600Emutation is an independent predictor of risk of44 HAUGEN ET AL. |
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 BRAFV600Emutation had a sensitivity of 65% in identifying those tumors that subsequently recurred, buthad 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 BRAF V600Emutation 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 formultiple 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 c a nb ea c h i e v e di ft h e 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 cli nico-pathologically classi- fied as having ATA low risk is currently being evaluated. Ina 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 offollow up was 3% (565). However, BRAF V600E-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 BRAFV600Emutation. 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 (BRAFV600Emutation). 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 recurrencerate 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 BRAF V600Emutation and intrathyroidal, unifocal tumors. Conversely, BRAFV600E-mutated multifocal PTMC with extrathyroidal extension demonstrated a 20% recurrencerate (150). Therefore, in the absence of data demonstrating that theBRAFV600Emutation is associated with increased structural recurrence in very low-risk tumors, we have classified in-trathyroidal papillary microcarcinomas (T1a, N0, M0) har- boring BRAF V600E 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 invasionand a BRAFV600Emutation 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 tumorrecurrence, is likely when it harbors more than one known oncogenic mutation, and specifically a BRAF mutation co- occurring with a TERT promoter, PIK3CA ,TP53 ,o rAKT1 mutation (155–157,577). Such a combination of severalmutations 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-relatedmortality are TP53 andTERT mutations. TP53 mutations have been known to occur mostly in poorly differentiated and anaplastic thyroid cancers. However, more recentbroad 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 seriesthat were positive for TP53 mutations also showed muta- tions in BRAF (orBRAF |
andPIK3CA ) and developed lung metastases. All four TP53 -positive FTC (with no other coexisting mutations) were oncocytic, and three out of fourof those were widely invasive FTC. Finally, recent studies identified TERT promoter muta- tions as a likely predictor of more unfavorable outcomes forpatients 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), aTERT 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 structuraldisease recurrence (155). These results, although pending confirmation in other studies, suggest that these molecular markers, alone or in combination, may be helpful for riskstratification of thyroid cancer and provide significantlymore accurate risk assessment than BRAF mutational status t a k e ni ni s o l a t i o n . [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 toolto aid in initial risk stratification and adjuvant therapy decision-making (See Recommendations 50B and 50C). Please see section [C6] for discussion of Tg measurements.ATA THYROID NODULE/DTC GUIDELINES 45 |
[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 includepatients with small-volume lymph node metastases (clinicalN0 or £5 pathologic N1 micrometastases, <0.2 cm in largest dimension), intrathyroidal encapsulated follicular variant of PTC, intrathyroidal well-differentiated follicular cancer withcapsular 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 atthe time of remnant ablation, and aggressive histologies, butit 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 macroscopicextrathyroidal extension, incomplete tumor resection, distant metastases, and postoperative serum Tg suggestive of distant metastases, but it has been expanded to include patients withlarge-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 modificationsare 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. [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 amore 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 importantfactors. While the risk estimates presented in this section may be useful in guiding initial treatment selections (extent of initialsurgery, need for RAI ablation), it is important to recognizethat these risk estimates likely reflect not only the tumorbiology, 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 RAIablation, across the various studies. Additional studies areneeded 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 totalthyroidectomy, extent of lymph node dissection, with or without RAI ablation). [B25] How should initial risk estimates be modified over time? &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) 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 initialtherapy. 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 Tgassociated 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 ofclinical 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 asATA high risk despite having a |
risk of recurrence that issignificantly 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, dynamicrisk 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 estimatesfrom the initial staging systems to guide initial management recommendations and then to incorporate a response-to- therapy assessment during follow-up to modify these initialrisk 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 asubsequent 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.46 HAUGEN ET AL. |
[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 anassessment 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 datautilizing 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 ofadjuvant treatment) because it has been designed for use afterprimary 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 primarytreatment, the details are described herein. It is acknowledged that appropriate clinical application of such a system is highly dependent on the availability ofhigh-quality biochemical testing and structural, and func- tional imaging with appropriate interpretation (e.g., stan- dardized radiologic reporting). Therefore, applicability maybe 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 Tuttleet 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. /C15Excellent response: no clinical, biochemical, or structural evidence of disease /C15Biochemical 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. /C15Structural incomplete response: persistent or newly identified loco-regional or distant metastases /C15Indeterminate 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 withoutdefinitive 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 totherapy, a simplified overview of the clinical implications ofthe 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 suggestionswith 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 recentlybeen published by Momesso et al. (602). [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 aTSH-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 excellentresponse 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 6–18months 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 from36%–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%), reclassificationbased 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 numbersof 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 totherapy 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 excellentresponse 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 USand Tg measurements prior to being classified as having anexcellent response (602). The details for choice of follow-up tests are found in another section of these guidelines [C4– C13], (Figs. 5–8).ATA THYROID NODULE/DTC GUIDELINES 47 |
While most studies have assessed response to therapy using TSH-stimulated Tg values obtained 6–18 months after initialtherapy (538,539,542,586,588–590,593–595,597–600), at least15 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 totherapy 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 of1.5% was seen in a cohort of 589 DTC patients who had anonstimulated 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 Tgvalues <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 totherapy in patients treated with total thyroidectomy with orwithout RAI remnant ablation. In addition to determining whether TSH-stimulated Tg values are clinically helpful inTable 13.Clinical Implications of Response to Therapy Reclassification in Patients with Differentiated Thyroid Cancer Treated with Total Thyroidectomy and Radioiodine Remnant Ablation Category DefinitionsaClinical outcomes Management implications Excellent responseNegative imaging and eitherSuppressed Tg <0.2 ng/mLb or |
TSH-stimulated Tg <1 ng/mLb1%–4% recurrencec <1% disease specific deathcAn excellent response to therapy should lead to an earlydecrease in the intensity and frequency of follow up and the degree of TSH suppression Biochemical incomplete responseNegative imaging and Suppressed Tg ‡1 ng/mLb or Stimulated Tg ‡10 ng/mLb or Rising anti-Tg antibody levelsAt least 30% spontaneously evolve to NEDd 20% achieve NED after additional therapya 20% develop structural diseasea <1% disease specific deathaIf associated with stable or declining serum Tg values, a biochemical incompleteresponse should lead tocontinued observation with ongoing TSH suppression in most patients. Rising Tg oranti-Tg antibody values shouldprompt additional investigations and potentially additional therapies. Structural incompleteresponseStructural or functional evidence of diseaseWith any Tg levelWith or without anti-Tg antibodies50%–85% continue to have persistent disease despiteadditional therapy e Disease specific death rates as high as 11% with loco-regional metastases and 50% withstructural distant metastasesaA structural incomplete response may lead to additional |
treatmentsor ongoing observation dependingon multiple clinico-pathologic factors including the size, location, rate of growth, RAIavidity, 18FDG avidity, and specific pathology of the structural lesions. Indeterminate responseNonspecific 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 absenceof structural or functional disease15%–20% will have structural disease identified during follow-upa In the remainder, the nonspecific changes are either stable, or resolvea <1% disease specific deathaAn indeterminate response should lead to continued observation with appropriate serial imagingof the nonspecific lesions andserum Tg monitoring. Nonspecific findings that become suspicious over timecan be further evaluated withadditional imaging or biopsy. 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).48 HAUGEN ET AL. |
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. FIG. 6. Clinical decision- making and management recommendations in ATA low riskDTC patients that have undergone less than totalthyroidectomy (lobectomy or lobectomy with isthmu- sectomy). R, recommenda-tion in text. 49 |
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 bemodified 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 severalweeks (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 proceduresand treatment, as discussed in other sections of these clinical practice guidelines |
[C4–C13] (Figs. 5–8). [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 withoutstructural 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 >1n g / m L 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, especiallyfor 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, andonly 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). FIG. 7. Clinical decision-making and management recommendations inATA intermediate risk DTC pa- tients that have undergone totalthyroidectomy. R, recommendation in text.50 HAUGEN ET AL. |
Anti-Tg antibody levels measured over time in the same assay can provide clinically useful information (608). Risinganti-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 declinein 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 orsurgical therapy (beyond LT 4suppressive therapy) in 34% of patients classified as having a biochemical incomplete re- sponse to initial therapy. These observations are consistentwith several previous studies that have demonstrated thatabnormal 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 whatTg 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 ofresidual 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 toyears 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 abiochemical incomplete response to therapy in patients treatedwith lobectomy or total thyroidectomy without ablation has not been adequately defined. In addition, some studies also classified patients with persistent or rising anti-Tg antibodiesin 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 orsurgical treatments. [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 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.ATA THYROID NODULE/DTC GUIDELINES 51 |
(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 bemetastatic 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-riskpatients (538,539). Despite additional treatments, the majority of patients classified as having a structural incomplete response willhave 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 describedfollowing 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 15years 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 patientswith structurally identifiable distant metastases (539,607). In summary, a structural incomplete response to initial therapy identifies a cohort of DTC patients that may not becured 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 ofresponding to additional treatments and has significantly lower disease-specific mortality rates than persistent/recur- rent distant metastases. [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 confidentlyclassified 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 aseparate 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 establishthe presence or absence of disease (538,539). For example, this category includes patients with sub- centimeter avascular thyroid bed nodules or atypical cervicallymph 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 patientswith 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 timein 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 theresponse 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 totalthyroidectomy (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 thyroidcells 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. Twoseries 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 nonspecificfindings either remain stable or resolve with observation alone. In summary, |
the majority of patients with an indeterminate response to therapy remain disease-free during prolongedfollow-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. [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 decisionsthat need to be made around the time of initial diagnosis andtreatment. 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-specificmortality with the potential benefits and risks of proposed therapies. However, in clinical practice many other risk estimates can also significant ly 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 appreciableamounts of serum Tg, the risk of adjuvant RAI therapy, therisk 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 anddetails of external beam radiation therapy, the need for andtypes 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 theearly 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 and52 HAUGEN ET AL. |
intensity of therapy and follow-up studies to real-time risk estimates that evolve over time for individual patients. [B32] Should postoperative disease status be considered in decision-making for RAI therapy for patients with DTC? &RECOMMENDATION 50 (A) 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, orother treatment) may be needed. (Strong recommendation, Low-quality evidence)(B) 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 itsnadir by 3–4 weeks postoperatively in most patients. (Strong recommendation, Moderate-quality evidence)(C) 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)(D) 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 alterthe 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 emissioncomputed tomography–computed tomography (SPECT/ CT). When performed, pretherapy diagnostic scans should utilize 123I (1.5–3 mCi) or a low activity of131I (1–3 mCi), with the therapeutic activity optimally administered within72 hours of the diagnostic activity. (Weak recommendation, Low-quality evidence) 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 ofmeans including serum Tg, neck ultrasonography, and iodine radioisotope scanning. There are currently no RCTs com- paring any particular postoperative diagnostic |
strategy withthe intention of modulating decision-making on RAI remnantablation or RAI treatment for DTC. [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 earlypostoperative evaluation. Please see section [C6] for dis- cussion of Tg measurements. The predictive value of the postoperative Tg value will be significantly influenced by awide variety of factors including the amount of residual thyroidcancer 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 |