NCCN临床实践指南：甲状腺癌（2024.V5）

指南内分泌与代谢· 甲状腺疾病 · 2024

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The search results were narrowed by selecting studies in humans published in English.

Sensitive/Inclusive Language Usage

NCCN Guidelines strive to use language that advances the goals of equity, inclusion, and representation. NCCN Guidelines endeavor to use language that is person-first; not stigmatizing; anti-racist, anti-classist, antimisogynist, anti-ageist, anti-ableist, and anti-weight-biased; and inclusive of individuals of all sexual orientations and gender identities. NCCN Guidelines incorporate non-gendered language, instead focusing on organ-specific recommendations. This language is both more accurate and more inclusive and can help fully address the needs of individuals of all sexual orientations and gender identities. NCCN Guidelines will continue to use the terms men, women, female, and male when citing statistics, recommendations, or data from organizations or sources that do not use inclusive terms. Most studies do not report how sex and gender data are collected and use these terms interchangeably or inconsistently. If sources do not differentiate gender from sex assigned at birth or organs present, the information is presumed to predominantly represent cisgender individuals. NCCN encourages researchers to collect more specific data in future studies and organizations to use more inclusive and accurate language in their future analyses.

# Differentiated Thyroid Carcinoma Clinical Presentation and Diagnosis

Differentiated Thyroid Carcinoma Clinical Presentation and Diagnosis

Differentiated (ie, papillary, follicular, oncocytic) thyroid carcinoma is usually asymptomatic for long periods and commonly presents as a solitary thyroid nodule. However, evaluating all nodules for malignancy is difficult, because benign nodules are so prevalent and because thyroid carcinoma is so uncommon. 1, 48, 49 Moreover, both benign and malignant thyroid nodules are usually asymptomatic, giving no clinical clue to their diagnosis. About 50% of the malignant nodules are discovered during a routine physical examination, by serendipity on imaging studies, or during surgery for benign disease. 50 The other 50% are often first noticed by the patient, usually as an asymptomatic nodule. 1, 48 ne-needle aspiration (FNA) with ultrasound guidance is the procedure of choice for evaluating suspicious thyroid nodules. 3, 49, 51 [54] [55] Although > 50% of all malignant nodules are asymptomatic, the pretest probability of malignancy in a nodule increases considerably when signs or symptoms are present. 56, 57 For example, the likelihood that a nodule is malignant increases about 7-fold if it is very firm, fixed to adjacent structures, rapidly growing, associated with enlarged regional lymph nodes, causes vocal cord paralysis, or symptoms of invasion into neck structures are present. 57, 58 Family history of thyroid cancer is also indicative of malignancy. If two or more of these features are present, the likelihood of thyroid cancer is virtually assured; however, this is a rare situation. 58 A patient's age and gender also affect the probability of malignancy. Other factors that increase the suspicion of malignancy include: 1) a history of head and neck irradiation; 2) a history of diseases NCCN Guidelines Version 5.2024 Thyroid Carcinoma MS-5 associated with thyroid carcinoma, such as familial adenomatous polyposis (FAP, formerly called Gardner syndrome), Carney complex, Cowden syndrome, and multiple endocrine neoplasia (MEN) types 2A or 2B; 3) evidence of other thyroid cancer-associated diseases or syndromes, such as hyperparathyroidism, pheochromocytoma, marfanoid habitus, and mucosal neuromas (suggestive of MEN2B), which make the presence of medullary carcinoma more likely; or 4) the presence of suspicious findings detected by imaging, such as focal fluorodeoxyglucose (FDG) uptake on PET or central hypervascularity, irregular border, and/or microcalcifications on ultrasound. 3, 59 r recommendations regarding evaluation of a thyroid nodule that is known or suspected on an exam or from incidental imaging in adults, see guidelines published by the American Thyroid Association (ATA). 3 In 2015, the ATA updated its guidelines on the management of thyroid nodules and thyroid cancer; its comprehensive guidelines also discuss ultrasound and FNA. 3 A statement from the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) committee, which is based on the Breast Imaging Reporting and Data System (BI-RADS) classification for breast cancer, was published in 2017 and also includes recommendations for management of thyroid nodules based on ultrasound findings. 60 Good concordance has been demonstrated between the TI-RADS and Bethesda classification systems. 61 A systematic review including 12 studies with 13,000 patients and 14,867 thyroid nodules showed pooled sensitivity values of 0.89 (95% CI, 0.80-0.95) for the ATA guidelines and 0.84 (95% CI, 0.76-0.89) for ACR TI-RADS for risk stratification of thyroid nodules. 62 Specificity values were much lower: 0.46 (95% CI, 0.29-0.63) for the ATA guidelines and 0.67 (95% CI, 0.56-0.76) for ACR TI-RADS.

# FNA and Molecular Diagnostic Results

FNA and Molecular Diagnostic Results

Cytologic examination of an FNA specimen is typically categorized as: category I: nondiagnostic; category II: benign; category III: atypia of undetermined significance (AUS); category IV: follicular neoplasm or oncocytic neoplasm; category V: suspicious for malignancy; or category VI: malignancy (includes papillary, medullary, anaplastic, or lymphoma). These diagnostic categories for FNA results reflect the 2023 Bethesda System for Reporting Thyroid Cytopathology. 63 The NCCN Guidelines for Thyroid Carcinoma no longer provide management recommendations for nodules classified as Bethesda I and Bethesda II. Pathology and cytopathology slides should be reviewed at the treating institution by a pathologist with expertise in the diagnosis of thyroid disorders. Although FNA is a very sensitive test-particularly for papillary carcinoma-falsenegative results are sometimes obtained; therefore, a reassuring FNA should not override worrisome clinical or radiographic findings. 64, 65 stimated mean risk of malignancy, inclusive of NIFTP, is 22% (range, 13%-30%) for Bethesda III, 30% (range 23%-34%) for Bethesda IV, 74% (range 67%-83%) for Bethesda V, and 97% (range 97%-100%) for Bethesda VI. 63 If excluding NIFTP, estimated mean risk of malignancy for Bethesda III, IV, V, and VI decrease to 16%, 23%, 65%, and 94%, respectively. 63 lecular diagnostic testing to detect individual mutations (eg, BRAF V600E, RET/PTC, RAS, PAX8/PPAR gamma) or pattern recognition approaches using molecular classifiers may be useful in the evaluation of FNA samples that are indeterminate to assist in management decisions. 66- 76 The BRAF V600E mutation occurs in about 45% of patients with papillary carcinoma and is the most common mutation. 77 6] [87] The NCCN Panel recommends consideration of molecular diagnostic testing for these indeterminate groups. 88, 89 storically, studies have shown that molecular diagnostics do not perform well for oncocytic carcinoma. 86, 90, 91 However, modern genomic classifiers have shown promise for diagnosis of oncocytic carcinoma, with sensitivity values ranging from 88.9% to 92.9% and specificity values ranging from 58.8% to 69.3% for detecting oncocytic carcinoma. 92, 93 Molecular diagnostic testing may include multigene assays or individual mutational analysis. In addition to their utility in diagnostics, molecular markers are beneficial for making decisions about targeted therapy options for advanced disease and for informing eligibility for some clinical trials. In addition, the presence of some mutations may have prognostic importance.

Follicular lesions are potentially premalignant lesions with a very low, but unknown, malignant potential if not surgically resected. Clinical risk factors, sonographic patterns, and patient preference can help determine whether nodule surveillance or surgery is appropriate for these patients. Guidance regarding nodule surveillance from the ATA and the ACR TI-RADS should be followed, though neither the ATA nor TI-RADS provide nodule surveillance recommendations for nodules with indeterminate cytology. 3, 60 A systematic review including 27 studies that evaluated repeat FNA in AUS nodules showed that 48% (95% CI, 43%-54%) of nodules were reclassified as benign, with a negative predictive value (NPV) > 96%. 94 FNA may be repeated for AUS, especially if molecular diagnostics are technically inadequate.

Rather than proceeding to immediate surgical resection to obtain a definitive diagnosis for these indeterminate FNA cytology groups (follicular lesions), patients can be followed with nodule surveillance if the application of a specific molecular diagnostic test (in conjunction with clinical and ultrasound features) results in a predicted risk of malignancy that is comparable to the rate seen in cytologically benign thyroid FNAs (approximately ≤5%). It is important to note that the predictive value of molecular diagnostics may be significantly influenced by the pretest probability of disease associated with the various FNA cytology groups. Furthermore, in the cytologically indeterminate groups, the risk of malignancy from FNA can vary widely between institutions. 95, 96 Because the published studies have focused primarily on adult patients with thyroid nodules, the diagnostic utility of molecular diagnostics in pediatric patients remains to be defined. Therefore, proper implementation of molecular diagnostics into clinical care requires an understanding of both the performance characteristics of the specific molecular test and its clinical meaning across a range of pre-test disease probabilities. 89, 97 ditional immunohistochemical (IHC) studies (eg, calcitonin) may occasionally be required to confirm the diagnosis of medullary carcinoma. 98 Oncocytic carcinoma can sometimes mimic medullary carcinoma cytologically and on frozen section. Sometimes it can be difficult to discriminate between anaplastic carcinoma and other primary thyroid malignancies (ie, medullary carcinoma, thyroid lymphoma) or poorly differentiated cancer metastatic to the thyroid. 99 Metastatic renal carcinoma can mimic follicular neoplasm, melanoma can mimic medullary carcinoma, and metastatic lung cancer can mimic anaplastic carcinoma. 98 athology synoptic reports (protocols), such as those from the College of American Pathologists (CAP), are useful for reporting results from examinations of surgical specimens. The CAP protocol was updated in June 2017 and reflects the 8 th edition of the AJCC Staging Manual (see

Protocol for the Examination of Specimens From Patients With

Carcinomas of the Thyroid Gland on the CAP website). 10, 100 llicular and oncocytic neoplasms are rarely diagnosed by FNA, because the diagnostic criterion for these malignancies requires demonstration of

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vascular or capsular invasion. 38, 49, 64, 101 Nodules that yield an abundance of follicular cells with little or no colloid are nearly impossible to categorize as benign or malignant on the basis of FNA. 102 Repeat FNA will not resolve the diagnostic dilemma. However, molecular diagnostic testing may be useful for follicular neoplasms (see FNA Results in the NCCN Guidelines for Thyroid Carcinoma). 56, 89, 103 some patients with follicular lesions, serum TSH level and thyroid iodine-123 or technetium-99m scanning may identify patients with an autonomously functioning or "hot" nodule who often may be spared surgery, because the diagnosis of follicular adenoma (ie, benign) is highly likely. 3, 104 Patients who are clinically euthyroid with a low TSH and a hot nodule on thyroid imaging should be evaluated and treated for thyrotoxicosis as indicated even when cytology is suspicious for follicular neoplasm. Those with a hypofunctional (cold or warm) nodule and with suspicious clinical and sonographic features should proceed to surgery (see FNA Results in the NCCN Guidelines for Thyroid Carcinoma). 2, 3 hose patients with an increased or normal TSH and with cytology suspicious for follicular or oncocytic neoplasm should undergo diagnostic lobectomy, unless molecular diagnostic testing predicts a low risk of malignancy. In patients with follicular or oncocytic neoplasm on FNA who are selected for thyroid surgery in order to obtain a definitive diagnosis, total thyroidectomy is recommended for bilateral disease, unilateral disease > 4 cm (especially in individuals AMAB), invasive cancer, metastatic cancer, or if the patient prefers this approach.

When a diagnosis of thyroid carcinoma is promptly established using FNA, the tumor is often confined to the thyroid or has metastasized only to regional nodes; thus, patients can be cured. However, 5% to 10% of patients with papillary, follicular, or oncocytic carcinoma have tumors that aggressively invade structures in the neck or have produced distant metastases. Such cancers are difficult to cure.

Recurrence of Differentiated Thyroid Carcinoma

Depending on initial therapy and other prognostic variables, about 75% of patients with differentiated thyroid carcinoma show tumor recurrences during the first 5 years following treatment, with the remaining recurrences occur within 8 years after treatment. 105 Although not usually fatal, a recurrence in the neck is serious and must be regarded as the first sign of a potentially lethal outcome. 106, 107 In one retrospective multicenter Italian study, including 1020 patients with papillary thyroid cancer who underwent thyroidectomy, recurrences were observed in 1.4%, all of which were located in the cervical lymph nodes or in the thyroid bed. 105 Distant metastases were observed in 3.2%.

It is important to recognize that the poor outcomes in this study were probably related to the manner in which the recurrence was diagnosed. In the past, disease recurrence was heralded by symptoms or palpable disease on physical examination, reflecting relatively large-volume disease recurrence. However, tools that are highly sensitive for detecting disease (eg, sensitive Tg assays, high-resolution neck ultrasound) appear to have resulted in earlier detection of disease recurrence, which is now often found in the first 2 to 5 years of follow-up. 3, 108 These nonpalpable, smallvolume lymph node recurrences often show little evidence of disease progression over many years and do not appear to be associated with an increase in mortality. However, this age cut-off had led to overstaging and, hence, overtreatment. A more up-to-date analysis from an NCCN Member Institution showed that an age cut-off of 55 years predicted the presence of distant metastasis. 112 e disparity between cancer-related mortality and the frequency of tumor recurrence probably accounts for most of the disagreements among clinicians concerning optimal treatment for patients with differentiated thyroid carcinoma. How clinicians assess the importance of tumor recurrence (as opposed to cancer-specific survival) accounts for much of the debate surrounding the influence of age on the treatment plan for children and young adults. A systematic review including five studies showed that risk of tumor enlargement in patients with PTC undergoing active surveillance was negatively associated with age. 113 ildren typically present with more advanced disease and have more tumor recurrences after therapy than adults, yet their prognosis for survival is good. 114, 115 Although the prognosis of children with thyroid carcinoma is favorable for long-term survival (90% at 20 years), the standardized mortality ratio is 8-fold higher than predicted. 116 Some clinicians believe that young age imparts such a favorable influence on survival that it overshadows the behavior expected from the characteristics of the tumor. 8] [119] However, most physicians treating the disease believe that tumor stage and its histologic features should be as significant as the patient's age in determining treatment. 13, 114, 120, 121 rognosis is less favorable in individuals AMAB than in individuals AFAB, but the difference is usually small. 13, 119 One study found that gender was an independent prognostic variable for survival and that the risk of death from cancer was about twice as high in individuals AMAB than in individuals AFAB. 13 Because of this risk factor, individuals AMAB with thyroid carcinoma-especially those who are ≥55 years-may be regarded with special concern. 112

Familial Syndromes

Familial, non-medullary carcinoma accounts for about 5% of PTCs and, in some cases, may be clinically more aggressive than the sporadic form. 122, 123 For patients to be considered as having familial papillary carcinoma, most studies require at least three first-degree relatives to be diagnosed with papillary carcinoma because the finding of cancer in a single first-degree relative may just be a chance event. Microscopic familial papillary carcinoma tends to be multifocal and bilateral, often with vascular invasion, lymph node metastases, and high rates of recurrence and distant metastases. 124 Other familial syndromes associated with papillary carcinoma are FAP 125 and Carney complex (multiple neoplasia and lentiginosis syndrome, which affects endocrine glands). 126 The prognosis for patients with all of these syndromes is not different from the prognosis of those with spontaneously occurring papillary carcinoma. For patients with papillary carcinoma, if histology demonstrates cribriformmorular variant, then FAP screening should be done.

Follicular thyroid cancer is a feature of some inherited cancer syndromes associated with significant clinical implications for the patient and relatives. The most common of these is Cowden syndrome (CS)/PTEN hamartoma tumor syndrome (PHTS). personal or family history of multiple other cancers, may be candidates for genetic testing for germline mutations in other hereditary cancer genes.

Tumor Variables Affecting Prognosis

7] [138] [139] The CAP protocol provides definitions of vascular invasion and other terms (see Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland on the CAP website). 100 In patients with sporadic medullary carcinoma, a somatic RET oncogene mutation confers an adverse prognosis. 140 A meta-analysis including 13 studies showed that programmed death ligand 1 (PD-L1) expression is associated with lower disease-free survival (DFS) (hazard ratio [HR], 3.37; 95% CI, 2.54-4.48; P < .00001) and overall survival (OS) (HR, 2.52; 95% CI, 1.20-5.32; P = .01) in patients with thyroid cancer. 141 nother meta-analysis including 15 studies also showed a significant association between PD-L1 expression and lower DFS (HR, 1.90; 95% CI, 1.33-2.70; P < .001), but OS was not significantly associated with PD-L1 expression. 142 Subgroup analyses showed that the association between PD-L1 expression and DFS was significant for papillary carcinoma (HR, 2.18; 95% CI, 1.08-4.39), but not for poorly differentiated thyroid carcinoma or ATC (HR, 1.63; 95% CI, 0.62-4.32).

Histology

Although survival rates with typical papillary carcinoma are quite good, cancer-specific mortality rates vary considerably with certain histologic subsets of tumors. 1 A well-defined tumor capsule, which is found in about 10% of PTCs, is a particularly favorable prognostic indicator. [145] NIFTP, formerly known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), is characterized by its follicular growth pattern, encapsulation or clear demarcation of the tumor from adjacent tissue with no invasion, and nuclear features of papillary carcinoma. 146, 147 8] [149] [150] [151] NIFTP was re-classified in 2016 to prevent overtreatment of this indolent tumor type as well as the psychological consequences of a cancer diagnosis on the patient. 146, 147 AP updated its protocols with NIFTP in the June 2017 version. 100 A systematic review including 29 studies showed that the pooled prevalence rates of NIFTP within EFVPTC and PTC were 43.5% (95% CI, 33.5%-54.0%) and 4.4% (95% CI, 2.0%-9.0%), respectively, based on the revised 2016 diagnostic criteria. 152 A 2021 meta-analysis including 50 retrospective studies published between 2016 and 2021 showed that the incidence of NIFTP among PTCs or other thyroid malignancies was 6.0% (95% CI, 4.4%-8.2%). 153 ile molecular diagnostic testing may be useful for diagnosing NIFTP in the future, currently available tests were not validated using NIFTP samples. 5] [156] [157] However, multiple studies investigating the performance of molecular diagnostics for this subtype have reported that most thyroid nodules histologically diagnosed as NIFTP NCCN Guidelines Version 5.2024 Thyroid Carcinoma MS-10 are classified as "suspicious" by one specific molecular test, possibly leading to more aggressive surgical treatment than is necessary. 158, 159 herefore, the validation of molecular diagnostics with NIFTP samples will be necessary to ensure that the tests are accurately classifying these subtypes.

Follicular thyroid carcinoma is typically a solitary encapsulated tumor that may be more aggressive than papillary carcinoma. It usually has a microfollicular histologic pattern. It is identified as cancer by follicular cell invasion of the tumor capsule and/or blood vessels. The latter has a worse prognosis than capsular penetration alone. 160 Many follicular thyroid carcinomas are minimally invasive tumors, exhibiting only slight tumor capsular penetration without vascular invasion. They closely resemble follicular adenomas and are less likely to produce distant metastases or to cause death. 161 FNA or frozen section study cannot differentiate a minimally invasive follicular thyroid carcinoma from a follicular adenoma. 49, 101 Therefore, the tumor is often simply referred to as a "follicular neoplasm" by the cytopathologist (see Nodule Evaluation in the NCCN Guidelines for Thyroid Carcinoma). 64 The diagnosis of follicular thyroid carcinoma is assigned only after analysis of the permanent histologic sections-obtained from diagnostic lobectomy or thyroidectomy-shows tumor capsule invasion by follicular cells.

Highly invasive follicular thyroid carcinomas are much less common; they are sometimes recognized at surgery by their invasion of surrounding tissues and extensive invasion of blood vessels. Up to 80% of these cancers metastasize, causing death in about 20% of patients, often within a few years of diagnosis. 129 The poor prognosis is closely related to older age at diagnosis, advanced tumor stage, and larger tumor size. 13 The mortality rates for papillary and follicular thyroid carcinomas are similar in patients of comparable age and disease stage. Patients with either cancer have an excellent prognosis if the tumors are confined to the thyroid, are small, and are minimally invasive. However, patients with either papillary or follicular thyroid carcinoma have far less favorable outcomes if their disease is highly invasive or they develop distant metastases. 13, 162 en oncocytic cells constitute most (or all) of the mass of a malignant tumor, the disease is often classified as oncocytic carcinoma. Previously considered a variant of follicular thyroid carcinoma, the World Health Organization (WHO) and AJCC reclassified Hürthle cell carcinoma as a separate entity in 2017. 10, 163 In 2022, the term "Hürthle cell" was replaced with "oncocytic carcinoma." 164 Oncocytic carcinomas tend to be aggressive and associated with poor prognosis. 165, 166 However, a retrospective Japanese study (N = 558) has shown that there is not a significant difference in prognosis between oncocytic and follicular thyroid carcinomas. 167 cocytic carcinomas are characterized by somatic mutations in the RAS/RAF/MAPK and PIK/AKT/MTOR pathways, and in EIF1AX, TERT, and DAXX. Other unique alterations associated with these cancers include mitochondrial DNA variations and copy number alterations. 168 Benign and malignant oncocytic carcinomas usually cannot be discriminated by FNA or frozen section examination, although large ( > 4 cm) tumors are more likely to be malignant than smaller ones. 169 Similar to follicular thyroid carcinoma, the diagnosis of oncocytic carcinoma is only assigned after analysis of the permanent histologic sections-obtained from diagnostic lobectomy or thyroidectomy-shows tumor capsule invasion by oncocytic cells.

Primary Tumor Size

PTCs < 1 cm, termed "incidentalomas" or "microcarcinomas," are typically found incidentally after surgery for benign thyroid conditions. Their cancerspecific mortality rates are near zero. 170 The risk of recurrence in papillary microcarcinomas ranges from 1% to 2% in unifocal papillary microcarcinomas, and from 4% to 6% in multifocal papillary

MS-11 microcarcinomas. 171, 172 Other small PTCs become clinically apparent. For example, about 20% of microcarcinomas are multifocal tumors that commonly metastasize to cervical lymph nodes. Some researchers report a 60% rate of nodal metastases from multifocal microcarcinomas, 173 which may be the presenting feature and also may be associated with distant metastases. 170 Otherwise, small ( < 1.5 cm) papillary or follicular carcinomas confined to the thyroid almost never cause distant metastases. Furthermore, recurrence rates after 30 years are one third of those associated with larger tumors; the 30-year cancer-specific mortality is 0.4% compared to 7% (P < .001) for tumors ≥1.5 cm. 13 There is a linear relationship between tumor size and recurrence or cancer-specific mortality for both papillary and follicular carcinomas. 13 cal Tumor Invasion Up to 10% of differentiated thyroid carcinomas invade through the outer border of the gland and grow directly into surrounding tissues, increasing both morbidity and mortality. The local invasion may be microscopic or gross; it can occur with both papillary and follicular carcinomas. 13, 174 ecurrence rates are two times higher with locally invasive tumors, and as many as 33% of patients with such tumors die of cancer within a decade. 13, 175 mph Node Metastases Regional lymph node metastases are most commonly located in the central neck. 3 They are generally associated with worse prognosis in patients with differentiated thyroid cancer, but this association is influenced by other factors such as age. ] [178] Evidence is less consistent for younger patients. A large retrospective study including 47,902 patients aged < 45 years who underwent surgery for stage I PTC showed that cervical lymph node metastases was associated with worse survival outcomes (HR, 1.32; 95% CI, 1.04-1.67; P = .021 for National Cancer Database [NCDB] data; HR, 1.29; 95% CI, 1.08-1.56; P = .006 for SEER data). 179 Another retrospective study showed that, among patients aged < 45 years, lymph node involvement was not associated with survival for papillary carcinoma, though increased risk of death was observed for follicular carcinoma. 177 It is important to note that age cut-offs used in these studies were based on previous editions of AJCC staging, as these cut-offs for age at diagnosis for staging increased from 45 to 55 in 2017 (see section above on Age, Stage, and Sex at Diagnosis). 10 Studies examining the association between number of involved lymph nodes and disease outcomes have been inconsistent. One review showed that, among patients with regional node metastasis, number of positive nodes was associated with risk of recurrence. 180 This study emphasized the correlation between the size and number of metastatic lymph nodes and risk of recurrence. Identification of fewer than 5 sub-centimeter metastatic lymph nodes was associated with a low risk of recurrence. Conversely, structural disease recurrence rates of more than 20% to 30% were seen in large-volume lymph node metastases ( > 3 cm, or > 5-10 involved lymph nodes). Another study of patients aged < 45 years showed that number of involved nodes ≤6 nodes was associated with reduced survival. 179 There was no additional mortality risk observed with > 6 nodes.

Another study showed an association between lymph node ratio (metastatic lymph nodes to total lymph nodes) and disease-specific mortality in patients (N = 10,955) with papillary carcinoma who underwent thyroidectomy with lymph node dissection (HR, 4.33; 95% CI, 1.68-11.18; P < .01). 181

Distant Metastases

Distant metastases are the principal cause of death from papillary and follicular carcinomas. 182, 183 About 50% of these metastases are present at the time of diagnosis. 129 Distant metastases occur even more often in NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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patients with oncocytic carcinoma (35%) and in those patients who are > 40 years at diagnosis. 184, 185 Among iodine-123 patients in 13 studies, the sites of reported distant metastases were lung (49%), bone (25%), both lung and bone (15%), and the central nervous system (CNS) or other soft tissues (10%). [186] [187] Some pulmonary metastases are compatible with long-term survival. 188 or example, one study found that when distant metastases were confined to the lung, > 50% of the patients were alive and free of disease at 10 years, whereas no patients with skeletal metastases survived that long. 189 he survival rates are highest in young patients with diffuse lung metastases seen only on iodine-131 imaging and not on xray. 187, 189, 190 [186] Tumor Staging

The NCCN Guidelines for Thyroid Carcinoma do not use TNM (tumor, node, metastasis) stages as the primary determinant of management. Instead, many characteristics of the tumor and patient play important roles in these NCCN Guidelines. Many specialists in thyroid cancer also follow this paradigm. When treating differentiated thyroid carcinoma, many clinicians place a stronger emphasis on potential morbidity than on mortality (see Surgical Complications in this Discussion). The current 2017 AJCC staging guidelines (8 th edition) for thyroid carcinoma may be useful for prognosis (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma). 10 Many studies (including those described in this Discussion) have been based on AJCC-TNM staging from earlier editions, such as the 5 th edition 191 and not the 6 th , 7 th , or 8 th editions. 10, 192, 193 A 2017 study including 1613 patients with resected differentiated thyroid cancer showed that the 8 th edition may be superior to the 7 th edition for predicting DSS, since fewer patients were categorized as stage III and IV under the 8 th edition staging. 194

Prognostic Scoring Strategies

Several staging and clinical prognostic scoring strategies use patient age > 40 years as a major feature to identify cancer mortality risk from differentiated thyroid carcinoma. 117, 192, 193, 195, 196 These strategies include the EORTC, TNM 7 th edition, AMES (Age, Metastases, Extent, and Size), and AGES (Age, tumor Grade, Extent, and Size). All of these strategies effectively distinguish between patients at low and high risk. 197 With incrementally worsening MACIS (Metastasis, Age, Completeness of resection, Invasion, and Size) scores of less than 6, 6 to 6.99, 7 to 7.99, and 8+, however, the 20-year survival rates were 99%, 89%, 56%, and 24%, respectively. 117 fortunately, a study that classified 269 patients with papillary carcinoma according to five different prognostic paradigms found that some patients in the lowest risk group from each approach died of cancer. 120 This is particularly true of classification schemes that simply categorize patients dichotomously as low or high risk. 192, 198 The AJCC TNM staging approach (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma), which is perhaps the most widely used indicator of prognosis, classifies tumors in all patients < 55 years as stage I or stage II, even those with distant metastases. Although it predicts cancer mortality reasonably well, 199, 200 TNM staging was not established as a predictor of recurrence and therefore does not accurately forecast the recurrences that often occur in patients who developed thyroid carcinoma when they were young. Two studies have shown the poor predictive value of most staging approaches for thyroid carcinoma, including the TNM system. 195, 201 three-tiered staging system-low, intermediate, high-that uses clinicopathologic features to risk stratify with regard to the risk of NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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3] [204] [205] This staging system effectively risk stratifies patients with regard to the risk of recurrence, risk of persistent disease after initial therapy, risk of having persistent structural disease, likelihood of achieving remission in response to initial therapy, and likelihood of being in remission at final follow-up. In another approach, emphasis has been placed on evaluation of response to therapy using a dynamic risk assessment approach in which the initial risk estimates are modified during follow-up as additional data are accumulated. 206 This allows ongoing reassessment of risk and allows the management paradigm to be better tailored to realistic estimates of risk that may change substantially over time.

Surgical Management of Differentiated Thyroid Carcinoma

Ipsilateral Lobectomy Versus Total Thyroidectomy

Most NCCN Panel Members recommend total thyroidectomy for patients with biopsy-proven papillary carcinoma under the following circumstances: T3 or larger, clinical N1 disease, M1 disease, aggressive subtype, significant radiation exposure, significant family history, or coexistent thyroid disease. Of all of these clinical features, tumor size is the most debated and is the feature where there is not uniform agreement. Decisions about ipsilateral lobectomy versus total thyroidectomy should be individualized and done in consultation with the patient. 207 A retrospective cohort study including 88 patients with encapsulated well-differentiated thyroid carcinoma > 4 cm surgically resected from 1995 to 2021 showed a 10-year DFS and DSS of 100%, respectively. 208 No local, regional, or distant recurrence was observed in this patient sample, including those treated with lobectomy without RAI. Circumstances in which lobectomy is not recommended are detailed in the NCCN Guidelines. This debate reflects the limitations of prognostic scoring 119 and the morbidity often associated with total thyroidectomy performed outside of major cancer centers. Patients treated at the Mayo Clinic Comprehensive Cancer Center for low-risk PTCs (MACIS score ≤3.99) had no improvement in survival rates after undergoing procedures more extensive than ipsilateral lobectomy. Thus, the authors concluded that more aggressive surgery was indicated only for those with higher MACIS scores. 209 ncer-specific mortality and recurrence rates after unilateral or bilateral lobectomy were assessed in patients with papillary carcinoma considered to be low risk by AMES criteria. 210 No significant differences were found in cancer-specific mortality or distant metastasis rates between the two groups. A 2020 retrospective multicenter study from Spain that evaluated the 2015 ATA recommendation that low-risk papillary carcinoma between 1 cm and 4 cm could receive lobectomy as clinically indicated found that 57.5% of patients who received total thyroidectomy between 2000 and 2017 would have needed thyroidectomy if they had first undergone lobectomy only. 211 3] [214] [215] [216] The large thyroid remnant remaining after unilateral lobectomy, however, may complicate long-term follow-up with serum Tg determinations and whole body iodine-131 imaging. Panel members recommend lobectomy (without RAI ablation) for patients with papillary carcinoma who have incidental small-volume pathologic N1A metastases ( < 5 involved nodes with no metastasis < 2 mm). 217 CN Panel Members believe that lobectomy alone is adequate treatment for papillary microcarcinomas provided the patient has not been exposed to radiation, has no other risk factors, and has a tumor ≤1 cm that is unifocal and confined to the thyroid without vascular invasion (see Primary Treatment in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).

Completion Thyroidectomy

Completion thyroidectomy is recommended when RAI is anticipated or if long-term follow-up is planned with serum Tg determinations and with (or without) whole body iodine-131 imaging. Completion thyroidectomy has a complication rate similar to that of total thyroidectomy. Completion thyroidectomy is recommended for any of the following: positive resection margins, gross extrathyroidal extension, macroscopic multifocal disease (ie, > 1 cm), macroscopic nodal metastases, confirmed contralateral disease, or vascular invasion. 3 Note that "gross extrathyroidal extension" refers to spread of the primary tumor outside of the thyroid capsule with invasion into the surrounding structures such as strap muscles, trachea, larynx, vasculature, esophagus, and/or recurrent laryngeal nerve. 134, 221, 222 lood vessel invasion of < 4 vessels does not require completion thyroidectomy in follicular and oncocytic thyroid carcinomas. In patients with local or distant tumor recurrence after lobectomy, cancer is found in > 60% of the resected contralateral lobes. 223 ccoli et al studied irradiated children from Chernobyl who developed thyroid carcinoma and were treated by lobectomy; they found that 61% had unrecognized lung or lymph node metastases that could only be identified after completion thyroidectomy. 121 In another study, patients who underwent completion thyroidectomy within 6 months of their primary operation developed significantly fewer lymph node and hematogenous recurrences, and they survived significantly longer than did those in whom the second operation was delayed for more than 6 months. 224

Surgical Complications

EN_PAPER

NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Panel Disclosures ð Endocrinology Þ Internal medicine † Medical oncology Ф Nuclear medicine ζ Otolaryngology ≠ Pathology ¥ Patient advocacy § Radiation/Radiation oncology ¶ Surgery/Surgical oncology * Writing Committee Member Continue

NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Panel Disclosures ð Endocrinology Þ Internal medicine † Medical oncology Ф Nuclear medicine ζ Otolaryngology ≠ Pathology ¥ Patient advocacy § Radiation/Radiation oncology ¶ Surgery/Surgical oncology * Writing Committee Member Continue

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NCCN Guidelines Index Table of Contents Discussion

UPDATES

Abstract

Continued PAP-7 (Also for FOLL-6, ONC-6) • Lobectomy, management, no evidence of disease, bullet 2: Neck ultrasound annually, and then as clinically indicated every 3-5 years if stable. Also for Total thyroidectomy without RAI, no evidence of disease. PAP-8 • Footnote added: Interpretation of rising or new Tg ab is assay dependent and best performed as a radioimmunoassay and with a consistent assay for interpretation of trends. (Also for FOLL-7 and ONC-7) PAP-10 (Also for PAP-11, PAP-12, FOLL-9, FOLL-10, FOLL-11, ONC-9, ONC-10, and ONC-11) • Column 2, bullet 2: For advanced, progressive, or threatening disease, genomic somatic ... • Footnote added: Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors. FOLL-3 • Footnote added: Differentiated high-grade carcinoma includes follicular thyroid carcinoma with ≥5 mitoses per 2 mm 2 and/or tumor necrosis. FOLL-6 • Footnote added: Follicular thyroid carcinoma does not spread to lymph nodes, but, however, could spread to soft tissue within in the neck. ONC-1 • FNA Results, Oncocytic follicular neoplasm (Bethesda IV) • Footnote a modified: The diagnosis of oncocytic carcinoma, formerly known as Hurthle cell carcinoma, requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. ONC-3 • Footnote added: Differentiated high-grade carcinoma includes oncocytic carcinoma with ≥5 mitoses per 2 mm 2 and/or tumor necrosis. MEDU-1 • Diagnostic procedures Bullet 5: Screen for germline RET proto-oncogene mutations PV (exons 10, 11, 13-16); genetic counseling may be indicated Bullet 8: Additional cross-sectional imaging as indicated for metastatic disease Bullet 8, sub-bullet 2: Consider Ga-68 DOTATATE PET/CT; if not available, consider bone scan and/or skeletal whole body MRI • Footnotes Removed: Imaging may be indicated based on high burden of disease, calcitonin > 500 pg/mL, or elevated CEA levels g modified: Prior to germline testing, all patients should be offered genetic counseling either by their physician or a genetic counselor. Surgical intervention should not be delayed while awaiting test results. MEDU-2 • Additional workup, bullet 3 modified: Screen for germline RET proto-oncogene mutations PV (exons 10, 11, 13-16); genetic counseling may be indicated • Footnote i modified: If initial thyroid surgery was less than a total thyroidectomy, additional surgical intervention (eg, completion thyroidectomy ± central neck dissection) may not be necessary unless there is a positive germline RET mutation PV or radiographic evidence of disease (ie, biopsy-proven residual neck disease).

THYR-2

Consider lobectomy or total thyroidectomy (depending on molecular results) b for definitive diagnosis/treatment or Nodule surveillance g,j TREATMENT g a Bethesda v3 terminology for Bethesda IV is follicular neoplasm or oncocytic follicular neoplasm, and the estimated risk of malignancy, inclusive of NIFTP, is mean 30% (range, 23%-34%). b The diagnosis of follicular carcinoma or oncocytic carcinoma requires evidence of either vascular or capsular invasion, which cannot be determined by FNA. Molecular diagnostics may be useful to allow reclassification of follicular lesions (ie, follicular neoplasm, AUS) as either more or less likely to be benign or malignant based on the genetic profile. If molecular testing suggests papillary thyroid carcinoma, especially in the case of BRAF V600E, see PAP-1. Given the challenges of cytology to explicitly diagnose MTC in limited samples, molecular tests may be used to identify them. If molecular testing, in conjunction with clinical and ultrasound features, predicts a risk of malignancy comparable to the risk of malignancy seen with a benign FNA cytology (approximately 5% or less), consider nodule surveillance. Molecular markers should be interpreted with caution and in the context of clinical, radiographic, and cytologic features of each individual patient. If molecular diagnostics are technically inadequate or not done, then repeat FNA. c Estimated risk of malignancy is mean 22% (range, 13%-30%) inclusive of NIFTP. g TI-RADS (https://www.jacr.org/article/S1546-1440 (17)30186-2/pdf) or ATA (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739132/pdf/thy.2015.0020.pdf). j Clinical risk factors, sonographic patterns, and patient preference can help determine whether nodule surveillance or surgery is appropriate.

Diagnostic categories for FNA results reflect NCI state of the science conference, the Bethesda Classification. Ali q Principles of Radiation and RAI Therapy (THYR-C). r If higher than expected uptake (residual thyroid uptake or distant metastasis) change dose accordingly. s A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. z While pre-ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre-ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI-avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased glomerular filtration rate (GFR). Patients on dialysis require special handling. No uptake

KNOWN OR SUSPECTED DISTANT METASTATIC DISEASE

q Principles of Radiation and RAI Therapy (THYR-C). z While pre-ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre-ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI-avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. aa To evaluate macroscopic metastatic foci for potential alterative therapies (eg, surgical resection, EBRT) to prevent invasion/compression of vital structures or pathologic fracture either as a result of disease progression or TSH stimulation. bb Thyrotropin alfa may be used for elderly patients for when prolonged hypothyroidism may be risky. cc Consider 24-hour urine iodine. dd If suspicion of pulmonary metastasis, chest CT can be done without contrast.

• Consider

RAI adjuvant therapy q and post-treatment imaging (whole body RAI scan, q consider PET scan) • Consider other local therapies (EBRT, q etc) as primary therapy or postoperative for structural metastatic disease

No evidence of disease

PAP-8

l Principles of TSH Suppression (THYR-A). ee In selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated Tg and consider concomitant diagnostic RAI imaging. ff Interpretation of rising or new Tg ab is assay dependent and best performed as a radioimmunoassay and with a consistent assay for interpretation of trends. l Principles of TSH Suppression (THYR-A). q Principles of Radiation and RAI Therapy (THYR-C). gg Generally, a tumor is considered iodine-responsive if follow-up iodine-123 or low-dose iodine-131

(1-3 mCi) whole body diagnostic imaging done 6-12 months after iodine-131 treatment is negative or shows decreasing uptake compared to pre-treatment scans. It is recommended to use the same preparation and imaging method used for the pre-treatment scan and therapy. Favorable response to iodine-131 treatment is additionally assessed through change in volume of known iodine-concentrated lesions by CT/MRI, and by decreasing unstimulated or stimulated Tg levels.

TREATMENT OF LOCALLY RECURRENT, ADVANCED, AND/OR METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY

l Principles of TSH Suppression (THYR-A). q Principles of Radiation and RAI Therapy (THYR-C). jj Ethanol ablation, cryoablation, RFA, etc. kk Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B). ll Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive, category 2B], or dabrafenib [BRAF positive, category 2B] ) can be considered if clinical trials are not available or appropriate. mm Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. nn Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors. oo Selpercatinib is also FDA approved for pediatric patients two years of age and older.

Structurally

TREATMENT OF METASTATIC DISEASE NOT AMENABLE TO RAI THERAPY pp

q Principles of Radiation and RAI Therapy (THYR-C). jj Ethanol ablation, cryoablation, RFA, etc. kk Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B). ll Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive, category 2B], or dabrafenib [BRAF positive, category 2B] ) can be considered if clinical trials are not available or appropriate. mm Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered.

nn Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors. oo Selpercatinib is also FDA approved for pediatric patients two years of age and older. pp RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. qq Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. An FDA-approved biosimilar is an appropriate substitute for denosumab.

CNS metastases

q Principles of Radiation and RAI Therapy (THYR-C). kk Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B). ll Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive, category 2B], or dabrafenib [BRAF positive, category 2B] ) can be considered if clinical trials are not available or appropriate. mm Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. nn Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors. oo Selpercatinib is also FDA approved for pediatric patients two years of age and older. pp RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. qq Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. An FDA-approved biosimilar is an appropriate substitute for denosumab. rr After consultation with neurosurgery and radiation oncology, data on the efficacy of lenvatinib or sorafenib for patients with brain metastases have not been established. ss Tyrosine kinase inhibitor (TKI) therapy should be used with caution in otherwise untreated CNS metastases due to bleeding risk. -C ). u While pre-ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre-ablation diagnostic scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high risk of having RAI-avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis require special handling. v To evaluate macroscopic metastatic foci for potential alterative therapies (such as surgical resection and/or EBRT) to prevent invasion/compression of vital structures or pathologic fracture either as a result of disease progression or TSH stimulation.

w Thyrotropin alfa may be used for elderly patients for whom prolonged hypothyroidism may be risky.

x Consider 24-hour urine iodine. y If suspicion of pulmonary metastasis, chest CT can be done without contrast. ii Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies were small and underpowered. jj Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors. kk Selpercatinib is also FDA approved for pediatric patients two years of age and older. c Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling (THYR-E). h If initial thyroid surgery was less than a total thyroidectomy, additional surgical intervention (eg, completion thyroidectomy ± central neck dissection) may not be necessary unless there is a positive germline RET PV or radiographic evidence of disease (ie, biopsy-proven residual neck disease). i Prior to germline testing, all patients should be offered genetic counseling either by their physician or a genetic counselor.

FOLL-9

Primary Treatment (MEDU-4)

a In view of the risks of thyroidectomy in very young children, referral to a surgeon and team experienced in pediatric thyroid surgery is advised. b Evidence of pheochromocytoma should be evaluated and treated appropriately before proceeding to the next step on the pathway in patients for whom results from RET mutation testing

have not yet been received. c Germline mutation should prompt specific mutation testing in subsequent family members and genetic counseling. See Principles of Cancer Risk Assessment and Counseling (THYR-E). j The timing of prophylactic thyroidectomy generally depends on the aggressiveness of the inherited RET PV. Codon M918T mutations are considered highest risk and codon 634 and A883F mutations are considered high risk, with MTC usually presenting at a younger age, whereas other RET PVs associated with MEN2A or FMTC are generally moderate risk. Prophylactic thyroidectomy may be delayed in patients with less high-risk RET PVs that have later onset of MTC, provided the annual basal calcitonin measurement is normal, the annual ultrasound is unremarkable, there is no history of aggressive MTC in the family, and the family is in agreement. (Brandi ML, et

Continue disease monitoring

o The likelihood of significant residual disease with an undetectable basal calcitonin is very low. p NCCN Guidelines for Survivorship. q Page PHEO-1 from the NCCN Guidelines for Neuroendocrine and Adrenal Tumors. r It is unlikely that there will be radiographic evidence of disease when calcitonin is less than 150 pg/mL. s Imaging may be indicated based on high burden of disease, calcitonin > 500 pg/mL, or elevated CEA levels.

PRINCIPLES OF THYROID-STIMULATING HORMONE (TSH) SUPPRESSION

THYR-A

• Because TSH is a trophic hormone that can stimulate the growth of cells derived from thyroid follicular epithelium, the use of levothyroxine to maintain low TSH levels is considered optimal in treatment of patients with papillary, follicular, or oncocytic carcinoma. However, data are lacking to permit precise specification of the appropriate serum levels of TSH.

THYR-B PRINCIPLES OF KINASE INHIBITOR THERAPY IN ADVANCED THYROID CARCINOMA 1-7

• Oral kinase inhibitors demonstrate clinically significant activity in randomized, placebo-controlled clinical trials in locally recurrent unresectable and metastatic MTC and in radioiodine-refractory differentiated thyroid cancer (DTC).

• When considering kinase inhibitor therapy for individual patients, several factors should be considered. Kinase inhibitor therapy can be associated with improved progression-free survival, but is not curative. Kinase inhibitor therapy is expected to cause side effects that may have a significant effect on quality of life. The natural history of MTC and DTC is quite variable with rates of disease progression ranging from a few months to many years.

• The pace of disease progression should be factored into treatment decisions. Patients with very indolent disease who are asymptomatic may not be appropriate for kinase inhibitor therapy, particularly if the side effects of treatment will adversely affect the patient's quality of life, whereas patients with more rapidly progressive disease may benefit from kinase inhibitor therapy, even if they have drug-induced side effects.

• Optimal management of kinase inhibitor side effects is essential. Where available, guidelines outlining the management of the dermatologic, hypertensive, and gastrointestinal side effects of kinase inhibitors can be used; side effects have been fatal. In addition, dose modification may be required, including dose holds and dose reductions.

• Molecular testing has been shown to be beneficial when making targeted therapy decisions, particularly related to drug therapies or clinical trial participation. In addition, the presence of some mutations may have prognostic importance. 1 5 Brose MS, Frenette CT, Keefe SM, Stein SM. Management of sorafenib-related adverse events: a clinician's perspective. Semin Oncol 2014;41 Suppl 2:S1-S16. 6 Carhill AA, Cabanillas ME, Jimenez C, et al. The noninvestigational use of tyrosine kinase inhibitors in thyroid cancer: establishing a standard for patient safety and monitoring. J Clin Endocrinol Metab 2013;98:31-42. 7

THYR-C 1 OF 5

PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY IODINE-131 ADMINISTRATION General Principles

Patients may be withdrawn from thyroid hormone to allow adequate elevation of TSH ( > 30 mU/l), 1 or prepared using two consecutive daily intramuscular injections of thyrotropin alfa for initial iodine-131 ablation of post-surgical gland remnant and/or treatment of locoregional residual or recurrent disease.

• Preparation with hormone withdrawal: duration of time off thyroid hormone depends on the extent of thyroidectomy and approach to hormone replacement in the initial postoperative setting. Because of the half-life of endogenous thyroid hormone, 4-6 weeks are required for clearance following total thyroidectomy. Consequently, if no thyroid hormone is given following total thyroidectomy in a patient who is euthyroid endogenous TSH levels should be sufficiently elevated ( > 30) in 3-6 weeks.

• Thyroid hormone withdrawal is preferred for most patients with distant metastatic disease based on the likelihood of augmentation of the delivered radiation dose. While thyrotropin alfa is not FDA-approved for treatment of distant metastases, it has been studied in this setting in retrospective cohorts and its use may be considered. 2,3

• Regardless of preparation method, an iodine-restricted diet is recommended for 7-14 days prior to iodine-131 therapy. A review of recent clinical history is advised to confirm the absence of recent iodinated contrast administration, amiodarone therapy over the past year, or long-acting iodine contaminants. Dietary supplements such as fish oil and daily multivitamins containing iodine should also be withheld over this period. Most common contrast media for CT require a 2-month period between contrast administration and iodine scintigraphy for adequate washout. If available, a 24-hour urine collection should be performed to confirm a normal free iodine ( < 100 mcg/24 h) prior to the initiation of the iodine-restricted diet. The diet involves a 10-to 14-day reduction in intake of iodized salt, seafood, and dairy products with the intention of optimizing the sensitivity of diagnostic examinations and the efficacy of potential therapies that may follow. Excellent resource information can be found at ThyCa.org and LIDLifeCommunity.org.

• Documentation of negative pregnancy test or infertility status is required for female patients of reproductive age prior to administration of radioiodine therapy.

• Adherence to all local, state, and national regulatory guidelines including signed informed consent and signed written directive from an authorized user should be confirmed.

• Written guidelines for minimizing exposure to others should be provided for patient signature, as per national and state regulatory requirements.

• Pre-treatment radioiodine imaging may be considered and a post-treatment iodine-131 whole body scan should be performed in all cases.

• Pre-therapy whole body scans may be obtained using 2-4 mCi iodine-123 or 1-2 mCi iodine-131. Iodine-123 avoids stunning and has favorable imaging characteristics. Low activity (1-3 mCi) iodine-131 minimizes stunning and has a longer physical half-life that will permit delayed imaging to improve lesion detection while permitting dosimetry in cases where dose maximization is considered. If iodine-131 is utilized then the time between the scanning and therapy doses should ideally by < 48 to 72 hours to avoid "stunning" from the diagnostic dose.

• Patients with high ( > 1000 mCi) cumulative lifetime administered activities should be monitored for myelosuppression and potential long-term toxicities, and although rare this should be considered in a risk-benefit analysis for use of RAI, as with any other therapy.

• Other organizations have defined RAI-refractory disease as: no RAI uptake on a diagnostic RAI scan; no RAI uptake present on an RAI scan done several days after RAI therapy; RAI uptake present in some but not other tumor foci; metastatic or disease progression of differentiated thyroid cancer despite RAI uptake; and metastatic or disease progression of differentiated thyroid cancer despite cumulative iodine-131 activity of > 22.2 GBq (600 mCi). 27 ferences on THYR-C 5 of 5

THYR-C 4 OF 5

PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY EXTERNAL BEAM RADIATION THERAPY Dose and Fractionation

Little evidence exists for appropriate treatment volumes for thyroid carcinoma. 6] [17] [18] [19] [20] [21] The treating radiation oncologist should use clinical judgment to determine the appropriate volumes, doses, and fractionation for each patient.

Differentiated

PRINCIPLES OF ACTIVE SURVEILLANCE FOR LOW-RISK PAPILLARY THYROID CANCER

Definition of Active Surveillance

• A treatment plan that involves closely watching a patient's condition but not giving any treatment unless there are changes in test results that show the condition is getting worse.

Evidence for Active

See the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic for the following: No evidence of primary tumor T1

Tumor ≤2 cm or less in greatest dimension limited to the thyroid T1a Tumor ≤1 cm in greatest dimension limited to the thyroid T1b Tumor > 1 cm but ≤2 cm in greatest dimension limited to the thyroid T2

Tumor > 2 cm but ≤4 cm in greatest dimension limited to the thyroid T3

Tumor ≥4 cm or with extrathyroidal extension T3a Tumor ≥4 cm in greatest dimension limited to the thyroid T3b Tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles)

T4

Advanced disease T4a Moderately advanced disease; tumor of any size with gross extrathyroidal extension into the nearby tissues of the neck, including subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Very advanced disease; tumor of any size with extension toward the spine or into nearby large blood vessels, gross extrathyroidal extension invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels

NCCN Categories of Evidence and Consensus Category 1

Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate. Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3

Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate. All recommendations are category 2A unless otherwise indicated.

NCCN Categories of Preference

Preferred intervention

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate, affordability.

Other recommended intervention

Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data; or significantly less affordable for similar outcomes.

Useful in certain circumstances

Other interventions that may be used for selected patient populations (defined with recommendation).

All recommendations are considered appropriate.

CAT

Overview Epidemiology

2] [3] Nodules are even more prevalent when the thyroid gland is examined at autopsy or surgery, or when using ultrasonography; 50% of the thyroids studied have nodules, which are almost always benign. 2, 4 New nodules develop at a rate of about 0.1% per year, beginning in early life, but they develop at a much higher rate (approximately 2% per year) after exposure to head and neck irradiation. 5, 6 hyroid nodules are approximately four times more common in individuals assigned female at birth (AFAB) than in individuals assigned male at birth (AMAB).

By contrast, thyroid carcinoma is uncommon. For the U.S. population, the lifetime risk of being diagnosed with thyroid carcinoma is 1.2%. 7 It is estimated that approximately 44,020 new cases of thyroid carcinoma will be diagnosed in the United States in 2024. 8 As with thyroid nodules, thyroid carcinoma occurs two to three times more often in individuals AFAB than in individuals AMAB. Thyroid carcinoma is currently the eighth most common malignancy diagnosed in individuals AFAB. 8 The disease is also diagnosed more often in white North Americans than in African Americans. The main histologic types of thyroid carcinoma are: 1) differentiated (including papillary, follicular, and oncocytic); 2) medullary; and 3) anaplastic, which is an aggressive undifferentiated tumor. Of 63,324 patients diagnosed with thyroid carcinoma from 2011 to 2015, 89.8% had papillary carcinoma, 4.5% had follicular carcinoma, 1.8% had oncocytic carcinoma, 1.6% had medullary carcinoma, and 0.8% had anaplastic carcinoma. 7 A population-based study of data collected by the International Agency for Research on Cancer from 1998 to 2012 showed that the global incidence of papillary thyroid carcinoma (PTC) increased during this time. 9 rtality rates for thyroid carcinoma are, in general, very low. Differentiated thyroid carcinomas usually have an excellent prognosis with 10-year survival rates exceeding 90% to 95%. 10, 11 In contrast, anaplastic thyroid carcinoma (ATC) is almost uniformly lethal. However, since differentiated thyroid carcinomas represent more than 95% of all cases, most thyroid carcinoma deaths are from papillary, follicular, and oncocytic carcinomas. In 2024, it is estimated that approximately 2170 cancer deaths will occur among persons with thyroid carcinoma in the United States. 8 3] [14] Although the estimated incidence of thyroid carcinoma previously increased by an average of ~5% annually between 2004 and 2013, the incidence rate has since stabilized, likely due to more conservative indications for thyroid biopsy and the reclassification of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). 15 3] [24] [25] [26] [27] [28] [29] [30] [31] The stable age-and genderadjusted mortality rate for thyroid carcinoma contrasts distinctly with the declining rates for other solid tumors in adults. 32, 33 A cohort study of 2000-2016 data from U.S. cancer registries showed an increase in incidence of aggressive PTC. 34 In addition, an analysis of 1992-2018 SEER data showed that there is no evidence of an improvement in disease-specific survival (DSS) in patients with distantly metastatic differentiated thyroid cancer. 35 e NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ) for Thyroid Carcinoma address management for the different types of thyroid carcinomas including papillary, follicular, oncocytic, medullary, and anaplastic carcinoma. Additional sections in these NCCN Guidelines ®

Managing Differentiated Thyroid Carcinoma

Managing differentiated (ie, papillary, follicular, oncocytic) thyroid carcinoma can be a challenge, because until recently, few prospective randomized trials of treatment have been done. 36, 37 Most of the information about treatment comes from studies of large cohorts of patients for whom therapy has not been randomly assigned. This accounts for much of the disagreement about managing differentiated carcinoma. Nonetheless, most patients can be cured of this disease when properly treated by experienced physicians and surgeons. 38 The treatment of choice is surgery, followed by radioactive iodine (RAI) ablation (iodine-131) in selected patients and thyroxine therapy in most patients. 11

The most common significant complications of thyroidectomy are hypoparathyroidism and recurrent laryngeal nerve injury, which occur more frequently after total thyroidectomy. 225 Transient clinical hypoparathyroidism postoperatively is common in adults 226 and children 121, 227 undergoing total thyroidectomy. One study reported hypocalcemia in 5.4% of patients immediately after total thyroidectomy, persisting in only 0.5% of patients 1 year later. 228 Another study reported a 3.4% incidence of long-term recurrent laryngeal nerve injury and a 1.1% incidence of permanent hypocalcemia. 229 Superior laryngeal nerve injury is under-reported and negatively impacts voice projection and high pitch range. When experienced surgeons perform thyroidectomies, complications occur at a lower rate. A study of 5860 patients found that surgeons who performed more than 100 thyroidectomies a year had the lowest overall complication rate (4.3%), whereas surgeons who performed fewer than 10 thyroidectomies a year had four times as many complications. 230

Radioactive Iodine-Diagnostics and Treatment

Diagnostic Whole Body Imaging and Thyroid Stunning

When indicated, diagnostic whole body iodine-131 imaging is recommended after surgery to assess the completeness of thyroidectomy and to assess whether residual disease is present (see RAI Being Considered Based on Clinicopathologic Features in the NCCN Guidelines for Papillary, Follicular, and Oncocytic Carcinoma). However, a phenomenon termed "stunning" may occur when imaging doses of iodine-131 induce follicular cell damage. 231 Stunning decreases uptake in the thyroid remnant or metastases, thus impairing the therapeutic efficacy of subsequent iodine-131. 232 To avoid or reduce the stunning effect, the following have been suggested: 1) the use of small doses of iodine-131 dose. 233 Iodine-123 is more expensive, and smaller iodine-131 doses have reduced sensitivity when compared with larger iodine-131 doses. 231, 232, 234 n addition, a large thyroid remnant may obscure detection of residual disease with iodine-131 imaging. Some experts recommend that diagnostic iodine-131 imaging be avoided completely with decisions based on the combination of tumor stage and serum Tg. 231 Other experts advocate that whole body iodine-131 diagnostic imaging may alter therapy, for example: 1) when unsuspected metastases are identified; or 2) when an unexpectedly large remnant is identified that requires additional surgery or a reduction in RAI dosage to avoid substantial radiation thyroiditis. 3, 231, 235, 236 If iodine contrast agent was used with imaging, then RAI should not begin for at least 2 months after the procedure in order to allow for free iodine levels to decrease and thus allow for optimal RAI uptake. 237, 238 te that diagnostic imaging is used less often for patients at low risk. A false-negative pretreatment scan is possible and should not prevent use of RAI if otherwise indicated (see Eligibility for Postoperative Radioactive Iodine in this Discussion, below). For known or suspected distant metastatic disease, diagnostic whole body iodine-123 or iodine-131 imaging before postoperative RAI may be considered.

Eligibility for Postoperative Radioactive Iodine

The NCCN Panel recommends a selective use approach to postoperative RAI administration. The three general, but overlapping, functions of postoperative RAI administration include: 1) remnant ablation, which may help in surveillance for recurrent disease (see below); 2) adjuvant therapy to try to eliminate suspected micrometastases; or 3) RAI therapy to treat known persistent disease. The NCCN Guidelines have three different pathways for postoperative RAI administration based on clinicopathologic factors: 1) RAI typically recommended; 2) RAI selectively recommended; and 3) RAI not typically recommended (see Clinicopathologic Factors in the NCCN Guidelines for Papillary, Follicular, and Oncocytic Carcinoma).

Postoperative RAI is typically recommended for patients at high risk of having persistent disease remaining after total thyroidectomy and includes patients with any of the following factors: 1) gross extrathyroidal extension;

2) postoperative unstimulated Tg > 10 ng/mL; 3) ≥6 lymph node micrometastases or bulky lymph nodes (based on surgical pathology); 4) significant N1b disease; or 5) differentiated high-grade carcinoma. For papillary carcinoma, vascular invasion is an indication for postoperative RAI. In the case of follicular or oncocytic carcinoma, extensive vascular invasion (≥4 foci) is another indication for postoperative RAI.

Postoperative RAI is also frequently recommended for patients with known/suspected distant metastases at presentation (see Clinicopathologic Factors in the NCCN Guidelines for Papillary, Follicular, and Oncocytic Carcinoma).

0] [241] The NCCN Panel does not routinely recommend RAI for patients with all of the following factors: 1) either unifocal (≤2 cm) or multifocal papillary microcarcinomas (classic subtype, all foci ≤1 cm) confined to the thyroid; 2) no detectable anti-Tg antibodies; and 3) postoperative unstimulated Tg < 1 ng/mL or stimulated Tg < 2 ng/mL. RAI would also not be recommended if a postoperative ultrasound was done (eg, if preoperative imaging was incomplete) and was negative. Minimal extrathyroidal extension alone does not warrant postoperative RAI. Guidelines from the ATA list very similar indications for NCCN Guidelines Version 5.2024 Thyroid Carcinoma

MS-16

postoperative RAI use and also provide specific guidance regarding the safe use of RAI in the outpatient setting. 3, 242 stoperative Administration of RAI

As stated above (see Eligibility for Postoperative Radioactive Iodine), use of postoperative RAI administration is dependent on risk for recurrence.

Evidence shows that patients with low risk for recurrence do not benefit from adjuvant RAI therapy. 243 However, low-dose RAI (ie, remnant ablation dose) may be used to destroy a thyroid remnant in order to facilitate an undetectable Tg. For patients with intermediate and high risk for recurrence, adjuvant RAI therapy is given with the goal of reducing the risk for recurrence. It is not necessary for there to be suspected disease at time of adjuvant RAI treatment, although it is suspected that recurrence is microscopic disease that progresses later. Finally, RAI therapy may also be used to treat known or suspected structural disease.

Previously, it was reported that postoperative RAI was associated with decreased OS in patients with stage I thyroid cancer, although the deaths seemed unrelated to thyroid cancer. 244 Longer follow-up suggests that OS is not decreased or increased in these patients. 245 However, a 2011 study reported that the incidence of secondary malignancies, such as leukemia and salivary gland malignancies, has increased in patients with low-risk thyroid cancer (ie, T1N0) who received adjuvant RAI. 246 8] [249] [250] A study of 21,870 patients at intermediate-risk with differentiated thyroid cancer found that postoperative adjuvant RAI improved OS (P < .001) and was associated with a 29% reduction in the risk of death after adjustment for demographic and clinical factors (HR, 0.71; 95% CI, 0.62-0.82; P < .001). 250 phase 3 randomized controlled trial (RCT) including 730 patients with differentiated thyroid cancer that was low risk (defined as multifocal pT1a or pT1b; N0 or Nx; no extrathyroidal extension) showed that receiving no postoperative RAI after thyroidectomy was noninferior to postoperative RAI administration for functional, structural, and biological abnormalities at 3 years. 243 A long-term-study (n = 1298) found that OS is not improved in patients who receive RAI ablation. 251 Reasons favoring remnant ablation include: 1) simplified patient follow-up, because elimination of thyroid bed uptake prevents misinterpretation of it as disease; 2) elimination of normal tissue as a source of Tg production, which facilitates identification of patients who are free of disease and may simplify their care while promoting early identification of those with residual cancer; and 3) elimination of normal tissue, which may eliminate the nidus for continued confounding anti-Tg antibody production. Conversely, others argue that most recurrences can be easily detected with neck ultrasound and that serum Tg levels are often quite low after a total thyroidectomy.

Thyroid hormone withdrawal is an option for increasing uptake from RAI treatment. However, two retrospective studies showed that patients with distantly metastatic RAI-avid differentiated thyroid cancer who received recombinant human TSH (rhTSH) in preparation for RAI treatment did not differ significantly in treatment response or survival, compared to patients who received RAI treatment after thyroid hormone withdrawal. 252, 253 uration of time off thyroid hormone depends on the extent of thyroidectomy and approach to hormone replacement in the initial postoperative setting. Guidance for preparing the patient and managing iodine-131 administration can be found in the Principles of Radiation and Radioactive Iodine Therapy: Iodine-131 Administration in the NCCN Guidelines for Thyroid Carcinoma.

If RAI ablation is used, the NCCN Guidelines recommend 30 mCi of iodine-131 for RAI ablation in patients at low risk based on randomized trials (category 1). 36, 37, 254 This same ablation dose-30 mCi-may be NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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considered in patients at slightly higher risk (category 2B). 255 RAI ablation is not recommended in patients at very low risk.

RAI therapy for thyroid cancer carries the risk of possible adverse effects including salivary gland dysfunction, lacrimal gland dysfunction, transient gonadal dysfunction, and secondary primary malignancies. 256 The possible benefits of RAI should be weighed with the risk of adverse effects as part of treatment decision-making. 257 Adverse effects may be minimized by using lower doses of RAI. 36 storically, the three methods of determining iodine-131 therapy activities (doses) have included: empiric fixed doses, quantitative dosimetry, and upper bound limits that are set by blood dosimetry. 3, 231, 258, 259 Most patients at NCCN Member Institutions receive postoperative RAI based on empiric fixed dosing; a few centers use a combination of blood dosimetry and quantitative lesional dosimetry. In the past, hospitalization was required to administer therapeutic doses of iodine-131 > 30 mCi (1110 MBq). However, iodine-131 therapy with high doses ( > 200 mCi) is best done in medical centers with experience using high doses. Dosimetry can be used to determine the maximal safe dose for treatment of unresectable, largevolume, iodine-concentrating, residual, or recurrent disease.

Administration of a fixed dose of iodine-131 is the most widely used and simplest method. Most clinics use this method regardless of the percentage uptake of iodine-131 in the remnant or metastatic lesion. Patients with uptake in tumor are routinely treated with large, fixed amounts of iodine-131. Lymph node metastases may be treated with about 100 to 175 mCi (3700-6475 MBq) of iodine-131. Cancer growing through the thyroid capsule (and incompletely resected) is treated with 150 to 200 mCi (5550-7400 MBq). Patients with distant metastases are usually treated with 100 to 200 mCi (3700-7400 MBq) of iodine-131, which typically will not induce radiation sickness or produce serious damage to other structures but may exceed generally accepted safety limits to the blood in patients who are older and in those with impaired kidney function. 260, 261 Diffuse pulmonary metastases that concentrate ≥50% of the diagnostic dose of iodine-131 (which is very uncommon) are treated with ≤150 mCi of iodine-131 (5550 MBq) to avoid lung injury, which may occur when > 80 mCi remains in the whole body 48 hours after treatment. Guidance relating to pediatric patients, patients desiring pregnancy, or patients with end-stage renal disease on hemodialysis can be found in the Principles of Radiation and Radioactive Iodine Therapy: Iodine-131 Administration in the NCCN Guidelines for Thyroid Carcinoma.

Post-treatment Iodine-131 Imaging

When iodine-131 therapy is given, whole body iodine-131 imaging should be performed several days later to document iodine-131 uptake by the tumor. Post-treatment whole body iodine-131 imaging should be done, primarily because ≤25% of images show lesions that may be clinically important, which were not detected by the diagnostic imaging. 258 In a study of pre-treatment and post-treatment imaging, the two differed in 27% of the treatment cycles, but only 10% of the post-treatment imaging showed clinically significant new foci of metastatic disease. 262 Post-treatment imaging was most likely to reveal clinically important new information in patients < 45 years who had received iodine-131 therapy in the past. Conversely, in older patients and patients who had not previously received iodine-131 therapy, post-treatment imaging rarely yielded new information that altered the patient's prognosis. 262 PET scan is indicated for patients with a negative whole body scan who have suspected structural disease based on other imaging methods and/or elevated Tg to a degree that would indicate distant metastasis. 263

Assessment and Management After Initial Treatment

Serum Tg determinations, neck ultrasound, and whole body iodine-131 imaging detect recurrent or residual disease in most patients who have undergone total thyroid ablation. 264 In contrast, neither serum Tg nor whole NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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body iodine-131 imaging is specific for thyroid carcinoma in patients who have not undergone thyroidectomy and remnant ablation.

Measuring Serum Tg and Anti-Tg Antibodies

Evaluation of serum Tg and anti-Tg antibody levels is helpful for the purpose of obtaining a postoperative baseline. Serum Tg measurement is the best means of detecting thyroid tissue, including carcinoma. Serum Tg levels vary in response to the increase in serum TSH after thyroid hormone withdrawal or TSH stimulation. Serum Tg generally does not increase as much after thyrotropin alfa as after withdrawal of thyroid hormone.

Using current Tg assays, patients treated with RAI with measurable serum Tg levels during TSH suppression and those with stimulated Tg levels > 2 ng/mL are likely to have residual/recurrent disease that may be localized in almost 50% promptly and in an additional 30% over the next 3 to 5 years. 265 About 6% of patients who had total thyroidectomy and RAI with detectable serum Tg levels (which are < 2 ng/mL but > 0.5 ng/mL after stimulation) will have recurrences over the next 3 to 5 years, whereas only about 2% of patients with completely undetectable serum Tg after stimulation will have recurrences over the next 3 to 5 years. The long-term clinical significance is uncertain for disease only detected by minimally elevated Tg levels after stimulation. A 2022 systematic review showed that, among patients who have not had RAI due to low risk of recurrence, Tg levels remain low and stable, indicating that a low cut-off (eg, 1-2.5 ng/mL) may be useful for these patients. 266 a study of 116 patients with anti-Tg antibodies before thyroidectomy, antibodies remained detectable for ≤20 years in some patients without detectable thyroid tissue, and the median time to disappearance of antibodies was 3 years. 267 Patients with persistently undetectable serum Tg and anti-Tg antibody levels have longer DFS when compared with patients who have detectable levels. 268 nctional sensitivity ≤0.1 ng/mL for Tg and ≤0.9 ng/mL for TgAb are reported for newer generation assays, compared to 1.0 ng/mL for Tg and 20 ng/mL for TgAb for older generation assays. 269, 270 Tg measurements may also be obtained without stimulating TSH using ultrasensitive assays (ie, second-generation Tg immunometric assays [TgIMAs]). 270, 271 With the availability of next-generation assays, it is now widely accepted that stimulated Tg is no longer necessary. 2] [273] These antibodies typically falsely lower the Tg value in immunochemiluminometric assays (ICMAs) and immunoradiometric assays (IRMAs), while raising the value in older radioimmunoassays. The conditions for TSH-stimulated, whole body iodine-131 imaging stipulate using 4-mCi iodine-131 doses (based on the trial) 274 and an imaging time of 30 minutes or until 140,000 counts are obtained.

Recombinant Human TSH

During follow-up, periodic withdrawal of thyroid hormone therapy has been used to increase the serum TSH concentrations sufficiently to stimulate thyroid tissue so that serum Tg measurements with (or without) iodine-131 imaging could be performed to detect residual thyroid tissue or carcinoma. However, patients dislike thyroid hormone withdrawal, because it causes symptomatic hypothyroidism. An alternative to thyroid hormone withdrawal is the administration of thyrotropin alfa intramuscularly, which stimulates thyroidal iodine-131 uptake and Tg release while the patient continues thyroid hormone suppressive therapy and avoids symptomatic hypothyroidism. 275 Administration of thyrotropin alfa is well tolerated; nausea (10.5%) and transient mild headache (7.3%) are its main adverse effects. 274 It is associated with significantly fewer symptoms and dysphoric mood states than hypothyroidism induced by thyroid hormone withdrawal. 275 CCN Guidelines Version 5.2024 Thyroid Carcinoma

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An international study was performed to assess the effects of two rhTSH dosing schedules on whole body iodine-131 imaging and serum Tg levels when compared with imaging and Tg levels obtained after thyroid hormone withdrawal. 274 Data showed that the combination of rhTSHstimulated whole body imaging and serum Tg measurements detected 100% of metastatic carcinoma. 274 In this study, 0.9 mg of rhTSH was given intramuscularly every day for 2 days, followed by a minimum of 4 mCi of iodine-131 on the third day. Whole body imaging and Tg measurements were performed on the fifth day. Whole body iodine-131 images were acquired after 30 minutes of imaging or after obtaining 140,000 counts, whichever came first. A serum Tg of ≥2.0 ng/mL, obtained 72 hours after the last rhTSH injection, indicates that thyroid tissue or thyroid carcinoma is present, regardless of the whole body imaging findings. 274, 276

Treating Patients with Positive Tg and Negative Imaging

Post-treatment iodine-131 imaging may indicate the location of metastases when the serum Tg level is increased, but a tumor [or metastases] cannot be found by physical examination or other localizing techniques such as diagnostic iodine-131 imaging, neck ultrasonography, CT, MRI, or PET. Pulmonary metastases may be found only after administering therapeutic doses of iodine-131 and obtaining whole body imaging within a few days of treatment. 277 In a study of 283 patients treated with 100 mCi (3700 MBq) of iodine-131, 6.4% had lung and bone metastases detected after treatment that had been suspected based on high serum Tg concentrations alone but that had not been detected after 2-mCi (74 MBq) diagnostic imaging. 278 fortunately, most patients who are diagnostic imaging-negative and Tg positive are not rendered disease free by iodine-131 therapy; however, the tumor burden may be diminished. 279 Thus, most patients with residual or recurrent disease confined to the neck undergo reoperation rather than RAI therapy in the hopes of a cure. RAI therapy is more commonly considered for those with distant metastases or inoperable local disease.

Patients not benefiting from this therapy can be considered for clinical trials, especially those patients with progressive metastatic disease. When a large tumor is not visible on diagnostic whole body imaging, its ability to concentrate iodine-131 is very low; thus, the tumor will not respond to iodine-131 therapy.

Thyroid Hormone Suppression of TSH

1] [282] [283] However, the optimal serum levels of TSH have not been defined because of a lack of specific data; therefore, the NCCN Panel recommends tailoring the degree of TSH suppression to the risk of recurrence and death from thyroid cancer for each individual patient. For patients with known residual carcinoma or those at high risk for recurrence, the recommended TSH level is < 0.1 mU/L. For patients who are disease free and at low risk for recurrence, TSH levels should be maintained at the normal range. For patients at low risk of recurrence with imaging negative but Tg levels concerning for disease, TSH levels should be maintained at 0.1-0.5 mU/L. The risks and benefits of TSH-suppressive therapy must be balanced for each individual patient because of the potential toxicities associated with TSH-suppressive doses of levothyroxine, including cardiac tachyarrhythmias (especially in patients who are older), bone demineralization (particularly in post-menopausal patients), and frank symptoms of thyrotoxicosis. 3, 284, 285 An adequate daily intake of elemental calcium (1200 mg/day) and vitamin D (1000 units/day) is recommended for patients whose TSH levels are chronically suppressed. However, reports do not suggest that bone mineral density is altered in patients receiving levothyroxine. 286, 287 CCN Guidelines Version 5.2024 Thyroid Carcinoma

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9] [290] The optimal TSH level to be achieved is uncertain in patients who have been treated for thyroid carcinoma. Superior outcomes were associated with aggressive thyroid hormone suppression therapy in patients at high risk but were achieved with modest suppression in patients with stage II disease. 244 Excessive TSH suppression (into the undetectable, thyrotoxic range) is not required to prevent disease progression in all patients who have been treated for differentiated thyroid carcinoma.

Adjuvant External Beam RT

2] [293] One retrospective study reported a benefit of adjuvant EBRT after RAI in patients > 40 years with invasive papillary carcinoma (T4) and lymph node involvement (N1). 294 Local recurrence and locoregional and distant failure were significantly decreased. A second study reported increased causespecific survival and local relapse-free rate in select patients treated with adjuvant EBRT (in addition to total thyroidectomy and TSH-suppressive therapy with thyroid hormone) for papillary carcinoma with microscopic residuum. Not all patients received RAI therapy. 247 Benefit was not shown in patients with follicular thyroid carcinoma or other subgroups of papillary carcinoma. Similarly, patients with microscopic residual papillary carcinoma postoperatively are more commonly rendered disease free after receiving EBRT (90%) than those who do not receive it (26%). 295 A third study showed that postoperative EBRT was associated with reduced risk of locoregional failure in thyroid cancer that is pT3-4, pN+, or with R1 or R2 resection (N = 254; HR, 0.17; 95% CI, 0.10-0.29; P < .001), although no impact was observed on OS (P = .600). 296 Another retrospective study suggested that postoperative EBRT may improve survival in patients with macroscopic extrathyroidal extension following surgery. 297 Finally, another study found that recurrences did not occur in patients at high risk who received EBRT, but recurrences did occur in those who did not receive EBRT. However, the study was not powered to detect a statistical significance. 298 [301] Studies suggest that intensity-modulated radiation therapy (IMRT) is safe, effective, and less morbid in patients with thyroid cancer. 296, 299, 302 A prospective nonrandomized phase 2 study in which 27 patients with gross residual or unresectable thyroid cancer received IMRT with or without concurrent doxorubicin showed locoregional progression-free survival (PFS) and OS rates of 79.7% and 77.3%, respectively. 303 A post hoc analysis showed that use of concurrent doxorubicin was associated with significantly less locoregional failure at 2 years.

There is little evidence regarding appropriate treatment volumes for use of radiation therapy (RT) for thyroid carcinoma, but 60 to 66 Gy for the postoperative setting (≤70 Gy for incomplete resection) is supported by a 2011 review of studies in this area. 293 Additional guidance on EBRT dose and fractionation in the adjuvant setting can be found in the Principles of Radiation and Radioactive Iodine Therapy: External Beam Radiation Therapy in the NCCN Guidelines for Thyroid Carcinoma.

External Beam RT and Surgical Excision of Metastases

Surgical excision, EBRT, stereotactic body RT (SBRT), or other local therapies can be considered for symptomatic isolated skeletal metastases or those that are asymptomatic in weight-bearing sites. 304, 305 Brain metastases pose a special problem, because iodine-131 therapy may induce cerebral edema. Neurosurgical resection can be considered for brain metastases. For solitary brain lesions, either neurosurgical resection or stereotactic radiosurgery (SRS) is preferred over whole brain radiation. 306, 307 Once brain metastases are diagnosed, disease-specific mortality is very high (67%), with a reported median survival of 12.4

Systemic therapy can be considered for tumors that are not surgically resectable; are not responsive to iodine-131; are not amenable to RT or other local therapies; and have clinically significant structural disease progression during the last 6 to 12 months. Enrollment in neoadjuvant clinical trials should be encouraged. Overall, traditional cytotoxic systemic chemotherapy, such as doxorubicin, has minimal efficacy in patients with metastatic differentiated thyroid disease. 311 ] [314] [315] [316] [317] [318] [319] Agents include multitargeted kinase inhibitors, such as lenvatinib, 312,315,320- 327 sorafenib, [328] [329] [330] [331] [332] [333] [334] [335] sunitinib, 333, 336, 337 axitinib, [338] [339] [340] everolimus, 341, 342 vandetanib, 343 cabozantinib, 313, 344 and pazopanib 345 ; BRAF V600E mutant inhibitors, such as dabrafenib/trametinib 346 ; TRK inhibitors, such as larotrectinib, entrectinib, and repotrectinib [347] [348] [349] ; RET inhibitors such as selpercatinib or pralsetinib 350, 351 ; and anti-programmed cell death protein 1 (PD-1) antibodies such as pembrolizumab. 352, 353 9] [360] Lenvatinib is the preferred systemic therapy option for the treatment of patients with RAI-refractory differentiated thyroid cancer (see Papillary Thyroid Carcinoma in this Discussion and the NCCN Guidelines for Papillary [Thyroid] Carcinoma).

Vandetanib and cabozantinib, oral kinase inhibitors, are preferred systemic therapy options for the treatment of medullary carcinoma in patients with unresectable locally advanced or metastatic disease, and RET inhibitors (selpercatinib and pralsetinib) are preferred options for RET mutation-positive disease (see Medullary Thyroid Carcinoma in this Discussion and the NCCN Guidelines for Medullary [Thyroid] Carcinoma).

Cabozantinib is also an option for RAI-refractory differentiated thyroid carcinoma that has progressed on VEGFR-targeted therapies such as lenvatinib and sorafenib. 361 3] [364] [365] [366] [367] Dose modifications of kinase inhibitors may be required. Pazopanib has been reported to cause reversible hypopigmentation. 368

Papillary Thyroid Carcinoma Surgical Therapy

Imaging is performed before surgery to ascertain the extent of disease and to aid in the surgical decision-making process. A cervical ultrasound, including the thyroid and the central and lateral compartments, is the recommended principal imaging modality. 369 In one report, cervical ultrasound performed before primary surgery for newly diagnosed thyroid cancer identified metastatic sites not appreciated on physical examination in 20% of patients, and surgical strategy was altered in 39% of patients. 370 urgeon-performed preoperative ultrasound identified nonpalpable metastatic lymph nodes in 24% of patients. 371 In more than 700 patients with PTC, preoperative ultrasound detected nonpalpable nodal metastases in 33% of subjects. 372 Preoperative ultrasound findings altered the operation in > 40% of cases. In another report, 373 operative management was altered in 23% of the total group due to findings on the preoperative ultrasound. These studies indicate that preoperative ultrasound has a high sensitivity for nodal disease and will detect NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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nonpalpable nodal metastases in 20% to 33% of patients, and ultrasound should alter the index operation in a similar percentage of patients. In most cases, lesions suspicious for locoregional recurrence, which are amenable to needle biopsy, should be interrogated with FNA biopsy before surgery. Tg washout assay is a useful adjunct to FNA biopsy in these cases, particularly if cytology is negative. Cross-sectional imaging (CT or MRI) should be performed when suspicious nodes in the neck are detected by ultrasound and/or for vocal cord paresis. Iodinated contrast is required for optimal cervical imaging with CT, although iodinated contrast will delay treatment with RAI; delaying RAI treatment is not harmful. Assessment of vocal cord mobility is recommended for patients with abnormal voice, a surgical history involving the recurrent laryngeal or vagus nerves, invasive disease, or bulky disease of the central neck. Evaluation is essential in patients with voice changes. Vocal cord mobility may be evaluated by ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy. 374 e NCCN Panel agreed on the characteristics of patients at higher risk who require total thyroidectomy as the primary treatment (see Preoperative or Intraoperative Decision-Making Criteria in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). with cN0 PTC randomized to receive either total thyroidectomy alone or total thyroidectomy plus central neck dissection showed no difference in outcomes between the two groups. 377, 378 A third RCT also did not show a significant difference between study arms for structural recurrence but showed that patients with cN0 PTC who received prophylactic central neck dissection with total thyroidectomy were more likely to be upstaged to pN1a than patients who did not receive prophylactic central neck dissection with total thyroidectomy (P < .05). 379 Central neck dissection is required ipsilateral to a modified radical neck dissection done for clinically involved lateral neck lymph nodes in most cases. Selective dissection of individual nodal metastases (ie, cherry picking) is not considered adequate surgery for nodal disease in a previously undissected field.

Lobectomy is preferred for patients with lower risk PTC, while total thyroidectomy is a category 2B option (see Ipsilateral Lobectomy Versus Total Thyroidectomy in this Discussion). Lobectomy plus isthmusectomy is recommended for patients who cannot (or refuse to) take thyroid hormone replacement therapy for the remainder of their lives. 225 Note that some patients prefer to have total thyroidectomy to avoid having a second surgery (ie, completion thyroidectomy). Other patients prefer to have a lobectomy in an attempt to avoid thyroid hormone replacement therapy. Most guidelines (eg, NCCN, ATA 3 ) do not recommend active surveillance for patients with PTC. [382] [383] [384] A study of > 5000 patients found that patient survival after partial thyroidectomy was similar to survival after total thyroidectomy for patients at low and high risk. 385 An observational study (SEER database) in > 35,000 patients with PTC limited to the thyroid gland suggests that survival is similar whether (or not) patients are treated in the first year after NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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diagnosis and whether they undergo lobectomy or total thyroidectomy. 386 nother study of 2784 patients with differentiated thyroid carcinoma (86% with PTC) found that total thyroidectomy was associated with increased survival in patients at high risk. 244 A study in 52,173 patients found that total thyroidectomy reduces recurrence rates and improves survival in patients with PTC of ≥1 cm when compared with lobectomy. 387 r patients at lower risk who undergo lobectomy plus isthmusectomy, completion of thyroidectomy is recommended for any one of the following risk factors: large tumor ( > 4 cm), gross positive resection margins, gross extrathyroidal extension, confirmed contralateral disease, vascular invasion, or confirmed nodal metastases. While a retrospective study using the NCDB has shown that a sizable percentage of patients with differentiated thyroid cancer receive RAI therapy following lobectomy, 388 the Panel does not support this practice due to a lack of data showing benefit. Therefore, RAI is not recommended following lobectomy for differentiated thyroid cancer.

PTC with lymphatic invasion, poorly differentiated and differentiated highgrade disease (≤1 cm without other high-risk features), or macroscopic multifocal disease ( > 1 cm) may warrant a completion thyroidectomy (see Primary Treatment in the NCCN Guidelines for Papillary [Thyroid] Carcinoma); disease monitoring (category 2B) is another option for these patients. Measurement of Tg and anti-Tg antibodies may be useful for obtaining a postoperative baseline, but data to interpret these antibodies in the setting of an intact thyroid lobe are lacking. 389 Levothyroxine therapy can be considered for these patients to maintain low or normal TSH levels (see Principles of TSH Suppression in the NCCN Guidelines for Thyroid Carcinoma). Disease monitoring is sufficient for tumors resected with lobectomy with all of the following: negative resection margins, no contralateral lesion, no suspicious lymph node(s), and small (≤4 cm) PTCs. Levothyroxine therapy to reduce serum TSH to normal concentrations can be considered for these patients (see Principles of TSH Suppression in the NCCN Guidelines for Thyroid Carcinoma).

Radioactive Iodine Therapy

Postoperative RAI administration is recommended when a number of clinical factors predict a significant risk of recurrence, distant metastases, or disease-specific mortality. Clinicopathologic factors can be used to guide decisions about whether to use postoperative RAI (see Clinicopathologic Factors in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Algorithms can assist in decision-making about use of RAI in different settings: 1) postoperative RAI is typically not indicated for patients classified as having a low risk of recurrence/disease-specific mortality; 2) adjuvant therapy with RAI may be considered for patients with intermediate-or high-risk disease without gross residual disease, and 3) RAI treatment is often used for patients with postoperative residual disease or inoperable distant metastasis based on whether the persistent tumor is shown to be iodine-131-avid. However, some patients may have metastatic disease that may not be amenable to RAI therapy, which is also known as iodine-refractory disease (see Treatment of Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Even in the absence of thyroid bed uptake, postoperative RAI treatment may be considered.

Redifferentiation therapy to re-establish RAI uptake in patients who become RAI-refractory is a strategy that is under investigation. A prospective non-randomized phase II trial including 24 patients with metastatic BRAF V600E-mutated differentiated thyroid cancer showed that dabrafenib/trametinib restored RAI uptake in 95.2% of patients. 390 Partial response was observed in 38%, with stable disease observed in 52% of patients. PFS rates (12-and 24-month) were 82% and 68%, respectively, with median PFS not reached. 93] 394 Dose should also be modified if higher than expected uptake, such as in the event of residual thyroid uptake or distant metastasis.

] [397] Enrollment in a neoadjuvant clinical trial should be considered. Patients with bulky, locoregional, viscerally invasive disease or rapid progression should be referred to a high-volume multidisciplinary institution, including referral to a radiation oncologist. Patients with unresectable gross residual disease who received upfront EBRT and with absent RAI should be monitored, or systemic therapy treatment may be considered.

Surveillance and Maintenance

The recommendations for surveillance and maintenance are described in the algorithm (see Disease Monitoring in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). About 85% of patients are considered to be low risk after surgery for PTC. 281 Standard follow-up includes neck ultrasound and measurement of TSH, Tg, and Tg ab. Concerning results (ie, rising or new Tg ab or abnormal imaging) should result in escalated follow-up. If abnormal imaging, then biopsy of suspicious areas is recommended. 9] [400] Therefore, patients considered to be at low risk for recurrence may not require long-term ultrasound follow-up. Patients with clinically significant residual disease can typically be identified by the trend in Tg levels over time. 3 Tg should be measured using the same laboratory and the same assay, because Tg levels vary widely between laboratories. 3 patients who have had total (or near total) thyroidectomy and RAI using iodine-131, the ATA Guidelines define the absence of persistent tumor (also known as no evidence of disease [NED]) as: 1) absence of clinical evidence of tumor; 2) absence of imaging evidence of tumor; and 3) undetectable Tg levels (during either TSH suppression or TSH stimulation) and absence of anti-Tg antibodies. 3 Patients treated with total thyroidectomy should be followed with physical examination and measurement of TSH, Tg, and Tg ab. RAI imaging can be considered in patients at high risk for persistent or recurrent disease, distant metastases, or disease-specific mortality; patients with previous RAI-avid metastases; or patients with abnormal Tg levels, stable or increasing Tg ab, or abnormal ultrasound results. Iodine-avid disease that has been treated with a radioisotope and is no longer evident, has a significant biochemical response, or is dramatically reduced in prominence on follow-up imaging beyond 6 months post-therapy may be considered as having responded to treatment. Favorable response to iodine-131 treatment is also assessed through change in volume of known iodine-concentrated lesions by CT or NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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MRI, as well as by decreasing unstimulated or stimulated Tg levels. 3 nterpretation of new or rising Tg ab is assay dependent and best performed as a radioimmunoassay and with a consistent assay for interpretation of trends. Tg levels remain low and stable in patients who did not receive postoperative RAI treatment, and risk of recurrence is low in these patients. 266

Recurrent Disease

The NCCN Panel agrees that surgery is the preferred therapy for locoregional recurrent disease if the tumor is resectable (see Recurrent Disease in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). Cervical ultrasound, including the central and lateral compartments, is the principal imaging modality when locoregional recurrence is suspected. 3 ross-sectional imaging with CT or MRI may also be valuable for evaluation and surgical planning, especially when reliable high-resolution diagnostic ultrasound is unavailable and/or there is suspicion of invasion into the aerodigestive tract. In most cases, lesions suspicious for locoregional recurrence, which are amenable to needle biopsy, should be interrogated with FNA biopsy before surgery. Tg washout assay may be a useful adjunct to FNA biopsy in these cases, particularly if cytology is negative. Iodine whole body scan can be used to guide subsequent use of RAI or other follow-up approach.

Clinically significant nodal recurrence in a previously undissected nodal basin should be treated with a formal compartmental resection. 3 In the central neck, this is usually achieved through a unilateral level VI dissection and, occasionally, a level VII dissection. In the lateral compartment, a formal modified radical neck dissection-including levels II, III, IV, and Vb-should be performed. Extending the dissection field into levels I or Va may be necessary when these levels are clinically involved.

Selective dissection of individual nodal metastases (cherry picking) is not considered adequate surgery for nodal disease in a previously undissected field, and is not recommended in the NCCN Guidelines for Thyroid Carcinoma. Clinically significant nodal recurrence detected in a previously dissected nodal basin may be treated with a more focused dissection of the region containing the metastatic disease. For example, a level II recurrence detected in a patient who underwent a modified radical neck dissection as part of the primary treatment may only require selective dissection of level II. Likewise, a central neck recurrence detected in a patient who underwent a central neck dissection as part of the primary treatment may only require a focused resection of the region of recurrence.

For unresectable locoregional recurrence, RAI treatment is recommended if the iodine-131 imaging is positive. 401 Local therapies, such as ethanol ablation or RFA, are also an option if available. 402 RT alone is another option in the absence of iodine-131 uptake for select patients not responsive to other therapies. 300, 403 EBRT improves local control in patients with gross residual non-RAI-avid disease following surgery. 293 hen recurrent disease is suspected based on progressively rising Tg values (basal or stimulated) and negative imaging studies (including PET scans), RAI therapy can be considered using an empirically determined In a long-term follow-up study, no survival advantage was associated with empiric high-dose RAI in patients with negative imaging. 404 Further, potential long-term side effects (ie, xerostomia, nasolacrimal duct stenosis, bone marrow and gonadal compromise, the risk of hematologic and other malignancies) may negate any benefit. 405, 406 Active surveillance may be considered for patients with low-volume disease that is stable and distant from critical structures.

Metastatic Disease

RAI therapy may be used to treat metastatic disease that is iodine-avid, or local therapies such as ethanol ablation, cryoablation, or RFA may be used for these patients, if available. For metastatic disease not amenable to RAI therapy, several therapeutic approaches are recommended, depending on the site and number of tumor foci (see Treatment of Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma). 2] [413] Embolization (or other interventional procedures) of metastases can also be considered either prior to resection or as an alternative to resection. 408, 414 RAI is not likely to be curative, but improved survival has been observed in these patients. 188, 415 r solitary or limited CNS lesions, either neurosurgical resection or SRS is preferred. 306, 307 For multiple CNS lesions, RT can be considered, 293 as well as surgical resection for select cases such as for acute decompression (see Treatment of Metastatic Disease Not Amenable to RAI Therapy in the NCCN Guidelines for Papillary [Thyroid] Carcinoma).

For multiple or extensive CNS lesions, radiotherapy (SRS or whole brain RT) is recommended, with resection in select cases. For dosing schedules for CNS metastases, see the NCCN Guidelines for Central Nervous System Cancers (available at www.NCCN.org).

For clinically progressive or symptomatic disease, systemic therapy should be considered. 11 Recommended systemic therapy options include: 1) lenvatinib (preferred) or sorafenib; 322, 328 2) clinical trials; 3) other smallmolecule kinase inhibitors if a clinical trial is not available; or 4) resection of distant metastases and/or EBRT or IMRT. 416, 417 Lenvatinib and sorafenib are category 1 options in this setting based on phase 3 randomized trials. 322, 328 The NCCN Panel feels that lenvatinib is the preferred agent in this setting based on a response rate of 65% for lenvatinib when compared with 12% for sorafenib, although these agents have not been directly compared. 320, 322, 328 The decision to use lenvatinib or sorafenib should be individualized for each patient based on likelihood of response and comorbidities. The efficacy of lenvatinib or sorafenib for patients with brain metastases has not been established; therefore, consultation with neurosurgeons and radiation oncologists is recommended. Kinase inhibitors have been used as second-line therapy for thyroid cancer. 323, 418 nvatinib was compared with placebo in patients with metastatic differentiated thyroid cancer that was refractory to RAI in a phase 3

NCCN Guidelines Version 5.2024 Thyroid Carcinoma MS-27 randomized trial. 322 Patients receiving lenvatinib had a PFS of 18.3 months compared with 3.6 months for those receiving placebo (HR, 0.21; 99% CI, 0.14-0.31; P < .001). Six treatment-related deaths occurred in the lenvatinib group. A prespecified subset analysis of this trial found that the PFS benefit of lenvatinib compared to placebo was maintained regardless of age (using a cut-off of 65 years). Furthermore, a longer median OS was observed in older patients treated with lenvatinib compared to placebo (HR, 0.27; 95% CI, 0.31-0.91; P = .20), although patients > 65 years also had higher rates of grade 3 and greater adverse effects from treatment. A retrospective analysis of a phase 3 trial demonstrated that patients receiving lenvatinib with ECOG performance status (PS) 0 at baseline had improved PFS (HR, 0.52; 95% CI, 0.35-0.77; P = .001), OS (HR, 0.42; 95% CI, 0.26-0.69; P = .0004), and response rate (overall response rate [ORR], 3.51; 95% CI, 2.02-6.10; P < .0001) compared with patients with a baseline ECOG PS 1. 419 Any-grade treatment-emergent adverse events (TEAEs) occurred in nearly all patients who received lenvatinib, irrespective of ECOG PS at baseline (ECOG PS 0, TEAEs in 100%; ECOG PS 1, TEAEs in 99%). Taken together, these results suggest that lenvatinib is an appropriate treatment option for patients of any age with RAI-refractory differentiated thyroid cancer. 420 other phase 3 randomized trial compared sorafenib with placebo in patients with RAI-refractory metastatic differentiated thyroid cancer. 328 atients receiving sorafenib had a PFS of 10.8 months compared with 5.8 months for those receiving placebo (HR, 0.59; 95% CI, 0.45-0.76; P < .0001). One treatment-related death occurred in the sorafenib group.

Hand-foot syndrome is common with sorafenib and may require dose adjustments.

A phase 3 randomized trial compared cabozantinib to placebo in patients with RAI-refractory differentiated thyroid cancer that progressed during or after treatment with one or two VEGFR TKIs (including lenvatinib and sorafenib). 361 Interim analyses of the intention-to-treat (ITT) population (n = 187) showed that the median PFS was not reached in patients receiving cabozantinib, compared with 1.9 months for those receiving placebo (HR, 0.22; 99% CI, 0.13-0.36; P < .0001). Serious treatment-related adverse events occurred in 16% of patients in the cabozantinib arm, compared with 2% in the placebo arm, though no treatment-related deaths occurred. At time of extended follow-up, median PFS continued to favor the cabozantinib arm over the placebo arm (11.0 months vs. 1.9 months, respectively; HR, 0.22; 95% CI, 0.15-0.32; P < .0001). 421 ORR was 11.0% for the cabozantinib arm, compared to 0% for the placebo arm (P = .0003). Subgroup analyses showed that cabozantinib was associated with improved PFS compared to placebo regardless of histology (ie, papillary, follicular, oncocytic, poorly differentiated) and previous VEGFR TKI treatment used (lenvatinib or sorafenib). 422 Cabozantinib is a category 1 option for patients with disease progression after lenvatinib and/or sorafenib.

Other commercially available small-molecule kinase inhibitors may also be considered for progressive and/or symptomatic disease if a clinical trial is not available-including dabrafenib/trametinib (for BRAF-positive disease), larotrectinib, entrectinib, or repotrectinib (for NTRK gene fusion-positive disease), selpercatinib or pralsetinib (for RET fusion-positive disease), axitinib, everolimus, pazopanib, sunitinib, vandetanib, or cabozantinibalthough some of these have not been approved by the FDA for differentiated thyroid cancer (see Principles of Kinase Inhibitor Therapy in Advanced Thyroid Carcinoma in the NCCN Guidelines for Thyroid Carcinoma). Note that kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease, 322, 328, 363, 423, 424 and caution should be used in patients with untreated CNS metastases due to the associated bleeding risk. 425 The anti-PD-1 antibody pembrolizumab is also an option for patients with TMB-high (TMB-H) (≥10 mutations/megabase [mut/Mb]) disease 353 and for MSI-H or dMMR tumors NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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that have progressed following prior treatment with no satisfactory treatment options. 352 Active surveillance is often appropriate for asymptomatic patients with indolent disease and no brain metastasis. 323, 363 alliative care is recommended as indicated for patients with advanced and progressive disease (see the NCCN Guidelines for Palliative Care, available at www.NCCN.org).

Follicular Thyroid Carcinoma

The diagnosis and treatment of papillary and follicular thyroid carcinoma are similar; therefore, only the important differences in the management of follicular carcinoma are highlighted. The diagnosis of follicular thyroid carcinoma requires evidence of invasion through the capsule of the nodule or the presence of vascular invasion. 49, 426 Unlike PTC, FNA is not specific for follicular thyroid carcinoma and accounts for the main differences in management of the two tumor types. 57, 64, 101, 427 The FNA cytologic diagnosis of "[suspicious for] follicular neoplasm" will prove to be a benign follicular adenoma in 80% of cases. However, 20% of patients with follicular neoplasia on FNA are ultimately diagnosed with follicular thyroid carcinoma when the final pathology is assessed. Follicular neoplasms generally do not spread to the lymph nodes, though could spread to soft tissue within the neck. If cervical lymph node metastases are present, then this may indicate misdiagnosis of follicular variant of PTC or a mixed tumor. Molecular diagnostic testing may be useful to determine the status of follicular lesions or lesions of indeterminate significance (including follicular neoplasms or AUS) as more or less likely to be malignant based on the genetic profile.

Because most patients with follicular neoplasms on FNA actually have benign disease, total thyroidectomy is recommended only if radiographic evidence or interoperative findings of extrathyroidal extension are apparent at the time of surgery, or if the patient opts for total thyroidectomy to avoid a second surgery (ie, completion thyroidectomy) if higher risk cancer is found at pathologic review. 426, 428 Otherwise, lobectomy plus isthmusectomy is advised as the initial surgery for follicular neoplasia on FNA. If invasive follicular thyroid carcinoma (widely invasive or encapsulated angioinvasive with four or more vessels) is found on the final histologic sections after lobectomy plus isthmusectomy, prompt completion of thyroidectomy is recommended (see Primary Treatment in the NCCN Guidelines for Follicular [Thyroid] Carcinoma).

Minimally invasive cancer is characterized as an encapsulated tumor with microscopic capsular invasion and without vascular invasion. 3 Lobectomy is preferred for minimally invasive cancers, as well as NIFTP tumors, followed by surveillance, because minimally invasive follicular carcinomas and NIFTP usually have an excellent prognosis. Minimally invasive follicular carcinoma is associated with low mortality, and the Panel feels that the benefit of completion thyroidectomy for small minimally invasive follicular cancers may not justify the additional morbidity.

Oncocytic Thyroid Carcinoma

Compared to other types of differentiated thyroid cancer, oncocytic thyroid carcinoma tends to be found at a later stage and is associated with worse prognosis. 165, 166 Similar to follicular thyroid carcinoma, oncocytic thyroid carcinoma cannot be diagnosed on FNA. A cytologic result of oncocytic neoplasm has a differential diagnosis of oncocytic thyroid carcinoma as well as several common benign conditions such as adenomas and Hashimoto's thyroiditis. Historically, studies have shown that molecular diagnostics do not perform well for oncocytic neoplasms. 86, 90, 91 However, with the advent of newer genomic tests, the validity for oncocytic carcinoma is improving (see FNA and Molecular Diagnostic Results in this Discussion, above), 91, 92 and molecular diagnostics should be considered for oncocytic carcinoma.

The surgical management of oncocytic carcinoma is almost identical to follicular thyroid carcinoma, except that 1) locoregional nodal metastases are more common, and therefore therapeutic lymph node dissections of the affected compartment are needed for clinically apparent biopsy-proven disease; and 2) oncocytic carcinoma is less likely to concentrate iodine-

Medullary Thyroid Carcinoma

1] [432] [433] Sporadic MTC accounts for about 80% of all cases of the disease. The remaining cases consist of inherited tumor syndromes, such as: 1) MEN type 2A (MEN2A), which is the most common type; and 2) MEN2B. 434, 435 Familial MTC is now viewed as a variant of MEN2A. 430, 431, 436 Sporadic disease typically presents in the fifth or sixth decade of life. Inherited forms of the disease tend to present at earlier ages. 430, 431 The 5-year relative survival for stages I to III is about 93%, whereas 5-year survival for stage IV is about 28%. 2] [443] However, routine measurement of the basal serum calcitonin concentration is not recommended by the NCCN Panel for evaluating a patient with nodular thyroid disease because of: 1) the expense of screening all thyroid nodules and only finding a few cases of MTC; 2) the lack of confirmatory pentagastrin stimulation testing; and 3) the resulting need for thyroidectomy in some patients who have benign thyroid disease. 444, 445 The ATA is equivocal about routine calcitonin measurement. 3

Inherited MTC

All familial forms of MTC and MEN2 are inherited in an autosomal-dominant fashion. Mutations in the RET proto-oncogene are found in at least 95% of kindreds with MEN2A. 432, 433, 446 The RET pathogenic variant (PV) codes for a cell membrane-associated tyrosine kinase receptor whose ligand is glial cell line-derived neurotrophic factor. Mutations associated with MEN2A have been primarily identified in several codons of the cysteine-rich extracellular domains of exons 10, 11, and 13;

nearly all patients with MEN2B harbor the RET M918T mutation found within the intracellular exon 16. 430, 431 Somatic mutations in exons 11, 13, and 16 have also been found in at least 25% of sporadic MTC tumorsparticularly the codon 918 mutation that activates the tyrosine kinase function of the receptor-and are associated with poorer prognosis of the patient.

Compared with sporadic disease, the typical age of presentation for MEN2A is the third or fourth decade of life, without gender preference. In patients with MEN2A, signs or symptoms of hyperparathyroidism or pheochromocytoma rarely present before those of MTC, even in the absence of screening. Controlling for the effect of age at diagnosis, the prognosis of patients with inherited disease (who typically are diagnosed at an earlier age) is probably similar to those with sporadic disease. 447, 448 espite an even younger typical age at diagnosis, however, patients with MEN2B who have MTC are more likely than those with MEN2A (or familial MTC) to have locally aggressive disease. 448 r patients with known kindreds with inherited MTC, prospective family screening with testing for RET PV can identify disease carriers long before clinical symptoms or signs are noted. 432, 433 About 6% of patients with clinically sporadic MTC carry a germline RET PV, leading to identification of new kindreds with multiple (previously undiagnosed) affected individuals. 449, 450 Germline testing for RET PV with genetic counseling by a physician or genetic counselor is recommended for all patients with newly diagnosed MTC or clinically suspected sporadic MTC. 451 1 in the NCCN Guidelines for Thyroid Carcinoma). 10 The 8 th edition of the AJCC Cancer Staging Manual separated MTC into its own stand-alone chapter. 10 Many of the studies cited in this Discussion reporting on AJCC-TNM staging have referred to the 5 th edition of the AJCC-TNM staging 191 and not to the 6 th , 7 th , or 8 th editions. 10, 192, 193 However, the TNM staging classification lacks other important prognostic factors. 454 Notably absent is the age at diagnosis. Patients < 40 years at diagnosis have 5-and 10-year DSS rates of about 95% and 75%, respectively, compared with 65% and 50% for those > 40 years. 438, 454 her factors that may be important for predicting a worse prognosis include: 1) the heterogeneity and paucity of calcitonin immunostaining of the tumor 455 ; 2) a rapidly increasing CEA level, particularly in the setting of a stable calcitonin level 456 ; and 3) postoperative residual hypercalcitoninemia. 457 A study comparing different staging systems found that a system incorporating age, gender, and distant metastases (EORTC) had the greatest predictive value; however, the AJCC staging system was deemed to be the most appropriate. 111, 454 Codon analysis is useful for predicting prognosis. 430, 431, 458 Presence of an exon 16 mutation, either within a sporadic tumor or associated with MEN2B, is associated with more aggressive disease. 459 More than 95% of patients with MEN2B have a mutation in exon 16 (codon 918), whereas 2% to 3% have a mutation in exon 15 (codon 883). 460

Surgical Management

Surgery is the main treatment for MTC. MTC cells do not concentrate iodine. Therefore, there is no role for iodine-131 in MTC. Postoperative levothyroxine is indicated for all patients; however, TSH suppression is not appropriate because C cells lack TSH receptors. Thus, TSH should be kept in the normal range by adjusting the levothyroxine dose. 430, 431 tients should be assessed for hyperparathyroidism and pheochromocytoma preoperatively, even in patients who have apparently sporadic disease. Testing for a germline RET PV is indicated for all patients with MTC.

Total thyroidectomy and bilateral central neck dissection (level VI) are indicated in all patients with MTC whose tumor is ≥1 cm or who have bilateral thyroid disease; total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is < 1 cm and for unilateral thyroid disease (see Primary Treatment in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). 375, 438 a patient with MEN2A is diagnosed early enough, the recommendation is to perform a prophylactic total thyroidectomy, especially in patients with codon 609, 611, 618, 620, 630, or 634 RET PV. 430, 431, 461 Appropriate age of thyroidectomy in children is an evolving field. If the mutation is identified during childhood, then thyroidectomy may be considered. However, for patients with codon 768, 790, 791, 804, and 891 RET (risk level A) PVs, the lethality of MTC may be lower than with other RET PVs. 430, 431, 462, 463 In patients with these less high-risk (ie, lower-risk level A) RET PVs and no structural evidence of disease, annual basal calcitonin testing and annual ultrasound are recommended; total thyroidectomy and central node dissection may be deferred if these tests are normal, there is no family history of aggressive MTC, and the family agrees to defer surgery (see Additional Workup in the NCCN Guidelines for Medullary

[Thyroid] Carcinoma). 430, 431, 464, 465 Delaying thyroidectomy may also be appropriate for children with lower-risk mutations (ie, level A) because of the late onset of MTC development. 430, 431, 463, 464, 466 A study found no evidence of persistent or recurrent MTC ≥5 years after prophylactic total thyroidectomy in young patients with RET PVs for MEN2A; longer follow-up is necessary to determine if these patients are cured. 467 riations in surgical strategy for MTC depend on the risk for locoregional node metastases and on whether simultaneous parathyroid resection for hyperparathyroidism is necessary.

Adjuvant RT

EBRT has not been adequately studied as adjuvant therapy in MTC. 301, 430, 468 Slight improvements in local DFS have been reported after EBRT for selected patients, such as those with extrathyroidal invasion or extensive locoregional node involvement. 469 However, most centers do not have extensive experience with adjuvant EBRT for this disease. While therapeutic EBRT may be considered for grossly incomplete resection when additional attempts at surgical resection have been ruled out, adjuvant EBRT is rarely recommended (see Primary Treatment in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). 430, 431 EBRT can also be given to palliate painful or progressing bone metastases. 304, 305, 410, 430, 431 The prognosis for patients with postoperative hypercalcitoninemia depends primarily on the extent of disease at the time of initial surgery. In a study of 31 patients (10 patients with apparently sporadic disease, 15 patients with MEN2A, and 6 patients with MEN2B), the 5-and 10-year survival rates were 90% and 86%, respectively. 470 Two studies have reported higher mortality rates for patients with high postoperative serum calcitonin values, with > 50% of patients having a recurrence during a mean follow-up of 10 years. 457, 471 Routine lymphadenectomy or excision of palpable tumor generally do not normalize the serum calcitonin concentrations in such patients; therefore, some have focused on detection and eradication of microscopic tumor deposits with a curative intent in patients without distant metastases. Extensive dissection to remove all nodal and perinodal tissue from the neck and upper mediastinum was first reported to normalize the serum calcitonin levels in 4 of 11 patients at least 2 years postoperatively. 472 In subsequent larger studies, 20% to 40% of patients undergoing microdissection of the central and bilateral neck compartments were biochemically cured, with minimal perioperative morbidity. 473, 474 When repeat surgery is planned for curative intent, preoperative assessment should include locoregional imaging (ie, ultrasonography of the neck and upper mediastinum) and attempts to exclude patients with distant metastases, which may include contrast-enhanced CT or MRI of the neck, chest, and abdomen. 474

Postoperative Management and Surveillance

Calcitonin is very useful for surveillance, because this hormone is only produced in the parafollicular cells. Thus, measurements of serum calcitonin and CEA levels are the cornerstone of postoperative assessment for residual disease (see Management 2-3 Months Postoperative in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).

For patients with a detectable basal calcitonin or elevated CEA level, neck ultrasound is recommended. Patients with undetectable calcitonin levels and normal CEA levels can subsequently be followed with annual measurements of serum markers. Additional studies or more frequent testing can be done for those with significantly rising calcitonin or CEA. Nonetheless, the likelihood of significant residual disease is very low in patients with an undetectable basal calcitonin level in a sensitive assay. If the patient has MEN, annual screening for pheochromocytoma (MEN2B or MEN2A) and hyperparathyroidism (MEN2A) should also be performed.

For some low-risk RET PVs (eg, codons 768, 790, 804, or 891), less frequent screening may be appropriate.

Patients with calcitonin ≥150 pg/mL should have CT or MRI of the neck, chest, and liver. Bone scan and whole-body MRI should be considered in select patients such as those with elevated calcitonin levels. 430, 431 The NCCN Panel recognizes that many different imaging modalities may be used to examine for residual or metastatic tumor, but there is insufficient evidence to recommend any particular choice or combination of tests. 430, 431 r patients with asymptomatic disease and detectable markers in whom imaging does not identify foci of disease, the NCCN Panel recommends conservative surveillance with repeat measurement of the serum markers every 6 to 12 months. Additional imaging studies (eg, FDG-PET/CT, Ga-68 DOTATATE, or MRI with contrast of the neck, chest, and abdomen with liver protocol) may be indicated depending on calcitonin/CEA doubling time. For patients who are asymptomatic with abnormal markers and repeated negative imaging, continued disease monitoring or consideration of cervical reoperation is recommended if primary surgery was incomplete.

For the patient with increasing serum markers, more frequent imaging may be considered. Outside of clinical trials, no therapeutic intervention is recommended on the basis of abnormal markers alone.

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Recurrent or Persistent Disease

Kinase inhibitors may be appropriate for select patients with recurrent or persistent MTC that is not resectable (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Although kinase inhibitors may be recommended for patients with MTC, it is important to note that kinase inhibitors may not be appropriate for patients with stable or slowly progressing indolent disease. 323, 475, 476 8] [479] [480] [481] RET-specific inhibitors that are options for RET-mutated MTC include selpercatinib and pralsetinib. 350, 351 ndetanib is a multitargeted kinase inhibitor; it inhibits RET, VEGFR, and EGFR. 481 In a phase III randomized ZETA trial in patients with unresectable, locally advanced, or metastatic MTC (n = 331), vandetanib improved PFS when compared with placebo (HR, 0.46; 95% CI, 0.31-0.69; P < .001); OS data are not yet available. 481 A post-hoc subgroup analysis including 184 patients with symptomatic and progressive disease at baseline also showed improved PFS (HR, 0.43; 95% CI, 0.28-0.64; P < .001) in patients who received vandetanib, compared to placebo, although time to worsening pain was not significantly different between the two groups (HR, 0.67; 95% CI, 0.43-1.04; P = .07). 482 In this subgroup, the ORR was 37% in patients who received vandetanib and 2% in patients who received placebo (P < .001). The FDA approved the use of vandetanib for patients with locally advanced or metastatic MTC who are not eligible for surgery and whose disease is causing symptoms or growing. 483 However, access is restricted through a vandetanib Risk Evaluation and Mitigation Strategy (REMS) program because of potential cardiac toxicity involving prolongation of the QTc interval. 484 The NCCN Panel recommends vandetanib (category 1) as a preferred option for patients with recurrent or persistent MTC (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).

Cabozantinib is a multitargeted kinase inhibitor that inhibits RET, VEGFR2, and MET. In a phase 3 randomized trial (EXAM) in patients with locally advanced or metastatic MTC (n = 330), cabozantinib improved median PFS when compared with placebo (11.2 vs. 4.0 months; HR, 0.28; 95% CI, 0.19-0.40; P < .001). 477 The median OS for patients treated with cabozantinib was 26.6 months compared to 21.1 months for placebo, although this difference was not statistically significant (stratified HR, 0.85; 95% CI, 0.64-1.12, P = .24). 485 Exploratory analyses have suggested that cabozantinib may have a greater clinical benefit for medullary thyroid cancers harboring RET M918T or RAS mutations, although prospective trials are needed to confirm these findings. 485, 486 In 2012, the FDA approved the use of cabozantinib for patients with progressive, metastatic MTC. 487 The NCCN Panel also recommends cabozantinib (category 1) as a preferred option based on the phase III randomized trial and FDA approval (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). Rare adverse events with cabozantinib include severe bleeding and gastrointestinal perforations or fistulas; severe hemorrhage is a contraindication for cabozantinib.

RET mutations account for a significant percentage of MTC cases, [488] [489] [490] supporting investigation into the impact of RET-specific inhibitors on RETmutated MTC. Efficacy of the RET-specific inhibitor selpercatinib for patients with RET-mutant MTC was first evaluated in the phase I-II LIBRETTO-001 study (N = 143), which showed ORR and 1-year PFS rates of 69% (95% CI, 55%-81%) and 82% (95% CI, 69%-90%), respectively, for patients previously treated with vandetanib and/or cabozantinib; and 73% (95% CI, 62%-82%) and 92% (95% CI, 82%-97%), respectively, for patients with no previous vandetanib or cabozantinib treatment. 350 In the phase 3 randomized LIBRETTO-531 trial, selpercatinib was compared to cabozantinib or vandetanib for first-line treatment of progressive RET-mutant medullary thyroid cancer (N = 291). 491 ) for the control arm. Selpercatinib was also evaluated for the pediatric and adolescent population in the multicenter phase I-II LIBRETTO-121 trial, which included 14 patients with RET-mutant medullary thyroid cancer. 492 The ORR for these patients was 83.3%, and the safety profile was comparable to that for adults. Study results are currently only available in abstract form.

Pralsetinib, another RET-specific inhibitor, was evaluated in the phase I-II ARROW study, which included 92 patients with RET-mutant MTC. 493 The ORR was 60% (95% CI, 46%-74%) in patients previously treated with vandetanib and/or cabozantinib (n = 61) and 74% (95% CI, 49%-91%) in patients with no previous vandetanib or cabozantinib treatment (n = 22). Pralsetinib was generally well-tolerated, with the most commonly reported grade 3-4 treatment-related adverse events being hypertension (11%) and neutropenia (10%). These results are currently reported in abstract form, and the ARROW study is ongoing and continuing to enroll patients.

In 2020, the FDA approved both of these RET inhibitors for RET-mutated MTC requiring systemic therapy. However, the indication of advanced or metastatic RET-mutated MTC for pralsetinib was voluntarily withdrawn by the manufacturer in 2023 due to feasibility of performing confirmatory trials. In 2024, the FDA expanded the approval for selpercatinib to include pediatric and adolescent patients ≥2 years of age. Based on the available data, the NCCN Panel recommends both selpercatinib and pralsetinib as preferred options for patients with RET-mutant disease, with selpercatinib being a category 1 option and pralsetinib being a category 2B option (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). RET somatic testing should be done in patients who are germline wild-type or if germline status is unknown.

When locoregional disease is identified in the absence of distant metastases, surgical resection is recommended. For unresectable locoregional disease that is symptomatic or progressing by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, 494 the following options can be considered: 1) EBRT; or 2) systemic therapy. Treatment can be considered for symptomatic distant metastases (eg, those in bone); recommended options include palliative resection, ablation (eg, radiofrequency, embolization) or other regional treatment, and systemic therapy (see Recurrent or Persistent Disease in the NCCN Guidelines for Medullary [Thyroid] Carcinoma). These interventions may be considered for asymptomatic distant metastases (especially for progressive disease), but disease monitoring is acceptable given the lack of data regarding alteration in outcome. If systemic therapy is indicated, then vandetanib and cabozantinib are category 1 preferred options. Selpercatinib (category 1) or pralsetinib (category 2B) are preferred options for patients with RETmutation positive disease. Pembrolizumab is also an option for patients with TMB-H (≥10 mut/Mb) disease, based on results of the phase II KEYNOTE-158 trial, which included two patients with thyroid cancer. 495 MB is rarely high in MTC. Pembrolizumab is also recommended for MSI-H or dMMR tumors that have progressed following prior treatment with no satisfactory treatment options, based on the KEYNOTE-158 trial. 352 The NCCN Panel does not recommend treatment with systemic therapy for increasing calcitonin or CEA alone in the absence of radiographically evident structural disease.

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In the setting of symptomatic disease or progression, the NCCN Panel recommends systemic therapy or enrollment in a clinical trial. As stated above for locoregional disease, preferred systemic therapy options include vandetanib (category 1), cabozantinib (category 1), and selpercatinib (category 1) or pralsetinib (category 2B) for patients with RET-mutation positive disease. 3] [504] Pembrolizumab is also an option for patients with TMB-H (≥10 mut/Mb) disease and for MSI-H or dMMR tumors that have progressed following prior treatment with no satisfactory treatment options (useful in certain circumstances). 352, 495 BRT can be used for local symptoms. 2] [413] Best supportive care is also recommended.

Results from clinical trials have shown the effectiveness of novel multitargeted therapies including sunitinib, 336, 337 sorafenib, 423, 497 lenvatinib, 500 and pazopanib 499 in MTC. Severe or fatal side effects from kinase inhibitors include bleeding, hypertension, and liver toxicity; however, many side effects can be managed. 363, 366, 416, 424 Because some patients may have indolent and asymptomatic disease, potentially toxic therapy may not be appropriate. 363 6] [507] [508] Of interest, calcitonin levels decreased dramatically after vandetanib therapy, which did not directly correlate with changes in tumor volume; thus, calcitonin may not be a reliable marker of tumor response in patients receiving RET inhibitor therapy. 509 A phase 2 trial in patients with progressive metastatic MTC assessed treatment using pretargeted anti-CEA radioimmunotherapy with iodine-131. 510 OS was improved in the subset of patients with increased calcitonin doubling times. 511

Anaplastic Thyroid Carcinoma

ATCs are aggressive undifferentiated tumors, with a disease-specific mortality approaching 100%. 512 Patients with anaplastic carcinoma are older than those with differentiated carcinomas, with a mean age at diagnosis of approximately 71 years. 513 Fewer than 10% of patients are < 50 years, and 60% to 70% of patients are AFAB. 513, 514 The incidence of ATC is decreasing because of better management of differentiated thyroid cancer and because of increased iodine in the diet. 512, 515 As previously mentioned, anaplastic carcinoma is the least common type of thyroid carcinoma. An average of 63,229 patients/year were diagnosed with thyroid carcinoma between 2010 to 2014. Of these 63,229 patients, only 514 patients (0.8%) had anaplastic carcinoma. 32 proximately 50% of patients with ATC have either a prior or coexistent differentiated carcinoma. Anaplastic carcinoma develops from more differentiated tumors as a result of one or more dedifferentiating steps, particularly loss of the p53 tumor suppressor protein. 516 No precipitating events have been identified, and the mechanisms leading to anaplastic transformation of differentiated carcinomas are uncertain. Differentiated thyroid carcinomas can concentrate iodine, express TSH receptor, and produce Tg, whereas undifferentiated carcinomas typically do not. Therefore, iodine-131 imaging and therapy cannot be used.

Patients with ATC may present with symptoms such as rapidly enlarging neck mass, dyspnea, dysphagia, neck pain, Horner syndrome, stroke, and hoarseness due to vocal cord paralysis. 517 Patients with ATC present with extensive local invasion, and distant metastases are found at initial disease presentation in 15% to 50% of patients. 518, 519 The lungs and NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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pleura are the most common sites of distant metastases (≤90% of patients with distant disease). About 5% to 15% of patients have bone metastases; 5% have brain metastases; and a few have metastases to the skin, liver, kidneys, pancreas, heart, and adrenal glands.

Diagnosis

The appearance of ATCs varies widely; many ATCs have mixed morphologies. The most common morphology is biphasic spindle and giant cell tumor. Sometimes it is difficult to discriminate between ATC and other primary thyroid malignancies (ie, MTC, thyroid lymphoma) or poorly differentiated cancer metastatic to the thyroid on FNA, and thus, core or surgical biopsy is preferred when the diagnosis of ATC is suspected. 99, 520 agnostic procedures include a complete blood count (CBC) with differential, comprehensive metabolic panel, TSH level, direct exam of larynx with evaluation of vocal cord mobility, and imaging studies. Neck ultrasound can rapidly assess tumor extension and invasion. 517 CT scans of the head, neck, chest, abdomen, and pelvis can accurately determine the extent of the thyroid tumor and identify tumor invasion of the great vessels and upper aerodigestive tract structures. 521 PET/CT or MRI scans are recommended to accurately stage the patient. Bone metastases are usually lytic. All ATCs are considered stage IV (A, B, or C) (see Table 1 in the NCCN Guidelines for Thyroid Carcinoma). 10 Clinically apparent anaplastic tumors are often unresectable. Given the increasing number of therapeutic targets for ATC, tumor testing for actionable mutations (BRAF, NTRK, ALK, RET, MSI, dMMR, and TMB) is recommended (see below in the Discussion under Treatment: Systemic Therapy). 520 BRAF IHC testing is recommended due to faster turnaround compared to genetic testing.

Prognosis

No curative therapy exists for ATC; it is almost uniformly fatal. 522, 523 The median survival from diagnosis is about 5 months. 515, 524 The 1-year survival rate is about 20%. 519, 524 Death is attributable to upper airway obstruction and suffocation (often despite tracheostomy) in 50% of these patients; in the remaining patients, death is attributable to complications of local and distant disease and/or therapy. 525 Patients with disease confined to the neck at diagnosis have a mean survival of 8 months compared with 3 months if the disease extends beyond the neck. 526 8] [529] A retrospective cohort study conducted at an NCCN Member Institution, including 479 patients diagnosed with ATC between 2000 and 2019, showed that survival rates for this disease are increasing. 530 Treatment factors associated with increased survival in this sample included use of targeted therapy with or without immunotherapy, and neoadjuvant BRAF-targeted therapy followed by surgery.

Treatment

ATC has a very poor prognosis and responds poorly to conventional therapy. RAI treatment is not effective in these patients. 520 The role of palliative and supportive care is paramount and should be initiated early in the disease. 520 At the outset of the diagnosis, it is critical that conversations about end-of-life care be initiated so that a clear understanding of how to manage the airway is undertaken, which is clear to the family and all providers. Tracheostomy is often a morbid and temporary treatment of the airway associated with reduced quality of life and may not be the option a patient would choose. 525, 531

Surgery

Once the diagnosis of ATC is confirmed, it is essential to rapidly determine whether local resection is an option. 512 Before resection is attempted, the extent of disease-particularly with disease potentially involving the larynx, trachea, esophagus, pharynx, carotid artery, and other neck structuresshould be accurately assessed by an experienced surgeon who is capable NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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of complex neck surgery, if necessary. However, most patients with ATC have unresectable or metastatic disease. The patency of the airway should be assessed throughout the patient's course of treatment. 525 If the patient appears to have resectable disease (potentially curable with surgery), an attempt at total thyroidectomy with complete gross tumor resection should be made, with resection of all involved local or regional structures and nodes. 520 Total thyroidectomy with attempted complete tumor resection has not been shown to prolong survival except for the few patients whose tumors are small and confined entirely to the thyroid or readily excised structures. 524, 526, 532, 533 Patients need to receive levothyroxine if total thyroidectomy is done. Tracheostomy may be considered in patients with stage IVc disease if strongly indicated. Prophylactic tracheostomy should be avoided.

Radiation Therapy

5] [536] [537] [538] Adjuvant RT, especially when combined with concurrent chemotherapy, is associated with improved survival. 539 igher RT dose is associated with OS in patients with unresected ATC. 540 or solitary brain lesions, either neurosurgical resection or RT is recommended. Once brain metastases are diagnosed, disease-specific mortality is very high, with a reported median survival of 1.3 months. For unresected or incompletely resected disease, RT, usually with concurrent chemotherapy, should commence as quickly as possible. For R0 or R1 resection, adjuvant RT, usually with concurrent chemotherapy, should begin as soon as the patient has sufficiently recovered from surgery, ideally 2 to 3 weeks postoperatively. IMRT technique is encouraged. Enteral nutrition may be useful for some patients who have difficulty swallowing (see Principles of Nutrition: Management and Supportive Care in the NCCN Guidelines for Head and Neck Cancer, available at www.NCCN.org). If enteral feeding is considered, a careful conversation should occur with the patient about their wishes. For guidance regarding appropriate treatment volumes for use of RT for ATC, see the Principles of Radiation and Radioactive Iodine Therapy: External Beam Radiation Therapy in the NCCN Guidelines for Thyroid Carcinoma.

Systemic Therapy

Systemic therapy recommendations are described in the algorithm (see Systemic Therapy for Anaplastic Thyroid Carcinoma in the NCCN Guidelines for Anaplastic [Thyroid] Carcinoma). When systemic therapy is indicated, targeted therapy options are preferred. 51 Other recommended regimens include paclitaxel and doxorubicin monotherapies. 520 Doxorubicin combined with cisplatin is an option based on a small randomized trial. 543 Paclitaxel combined with carboplatin and docetaxel combined with doxorubicin are also systemic therapy options for patients with metastatic ATC, but these are category 2B options based on lowquality evidence 520 and less Panel consensus. Systemic therapy options for metastatic ATC that are useful in certain circumstances include pembrolizumab, 495 pembrolizumab combined with lenvatinib, 544 and nivolumab. 545, 546 The NCCN Panel recommends molecular testing to help inform decisions regarding systemic therapy and to determine eligibility for clinical trials.

The dosage and frequency of administration of all the recommended systemic therapy agents are provided in the algorithm. Either concurrent chemoradiation or chemotherapy alone regimens may be used depending on the clinical setting; however, chemoradiation is generally more toxic. If using chemoradiation, the ATA Guidelines recommend using weekly chemotherapy regimens. 520

MS-40

A phase 2, open-label trial of 16 patients with BRAF V600E-mutated ATC evaluated the efficacy and safety of dabrafenib 150 mg, twice daily, in combination with trametinib 2 mg, once daily. 541 The confirmed ORR was 69% (95% CI, 41%-89%), with seven responses ongoing. An updated analysis including 36 patients showed an ORR of 56% (95% CI, 38.1%-72.1%), including 3 complete responses, and 12-month duration of response was 50%. 547, 548 Median PFS and OS were 6.7 months and 14.5 months, respectively. 547, 548 Twelve-month OS and PFS rates were 43.2% and 51.7%, respectively. 547, 548 The combination was found to be welltolerated as evaluated in 100 patients across seven rare tumor types; common adverse events included fatigue (38%), pyrexia (37%), and nausea (35%). 541 Based on these data, the FDA approved dabrafenib/trametinib for ATC with BRAF V600E mutation in 2018.

Since 2018, three TRK inhibitors have been approved by the FDA for treatment of all patients with NTRK gene fusion-positive solid tumors. A pooled analysis of three studies (a phase 1 including adults, a phase 1/2 involving children, and a phase 2 involving adolescents and adults) studied the safety and efficacy of larotrectinib in patients with NTRK gene fusion-positive tumors, including seven patients with thyroid cancer of which one patient had ATC. 347, 549 For the whole population, the ORR was 75% (95% CI, 61%-85%) by independent review and 80% (95% CI, 67%-90%) by investigator assessment. 347, 549 One hundred percent of the thyroid cancers in this study responded to larotrectinib, with one complete response and four partial responses. 549 Larotrectinib was found to be welltolerated, as the majority (93%) of adverse events were grades 1 or 2 and no treatment-related adverse events of grades 3 or 4 occurred in more than 5% of patients. 347 A pooled analysis from a phase II trial and two phase I trials including 54 patients with NTRK gene fusion-positive cancer (9% having thyroid cancer) showed an objective response rate of 57.4% for entrectinib, another TRK inhibitor. 348 Finally, repotrectinib was evaluated in a phase I/II study including 88 patients with NTRK gene fusion-positive advanced solid tumors (48 previously treated with a TRK TKI, and 40 who were TRK TKI-naive). 349 The analysis showed an objective response rate of 58% for those who were TRK TKI-naïve, and 50% in those who were previously treated with a TRK TKI. The Panel recommends NTRK therapy options such as larotrectinib, entrectinib, and repotrectinib for patients with NTRK gene fusion-positive metastatic ATC.

The phase I-II LIBRETTO-001 study evaluated the efficacy of the RET inhibitor selpercatinib in 19 patients with previously treated RET fusionpositive thyroid cancer (2 patients with anaplastic disease). 350 The ORR was 79% (95% CI, 54%-94%), and 1-year PFS was 64% (95% CI, 37%-82%). In the ongoing phase I-II ARROW study, pralsetinib, another RET inhibitor, is being evaluated in patients with RET fusion-positive disease (NCT03037385). In an analysis including 9 patients with RET fusionpositive thyroid cancer, the ORR was 89% (95% CI, 52%-100%) with durable responses (100% disease control rate [DCR]). 351 In updated analyses including 22 patients with RET fusion-positive thyroid cancer (all papillary except for one patient with anaplastic disease), the ORR was 90.9% (95% CI, 70.8%-98.9%), median DOR was 23.6 months, and median PFS was 25.4 months. 550 In 2020, the FDA approved both of these RET inhibitors for RAI-refractory RET fusion-positive thyroid cancer requiring systemic therapy. In 2024, the FDA expanded the approval for selpercatinib to include pediatric and adolescent patients ≥2 years of age.

The FDA approved the anti-PD-1 antibody pembrolizumab for treatment of previously treated TMB-H (≥10 mut/Mb) solid tumors in 2020 based on results of the phase II KEYNOTE-158 trial, which included two patients with thyroid cancer. 495 For the whole sample, the ORR was 29% (95% CI, 21%-39%). Grade 3-5 treatment-related adverse events were reported in 15% of the patients. A phase II study evaluated another anti-PD-1 antibody, spartalizumab, in 42 patients with locally advanced or metastatic ATC. 551 The ORR was 19% (95% CI, 8.6%-34.1%), but was higher for NCCN Guidelines Version 5.2024 Thyroid Carcinoma

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patients with PD-L1-positive disease (29%; 95% CI, 13.2%-48.7%) and highest in patients with PD-L1 > 50% (35%; 95% CI, 14.2%-61.7%).

Based on extrapolation from this trial, patients with metastatic ATC may be treated with other PD-1 inhibitors such as pembrolizumab and nivolumab regardless of TMB or combined positive score (CPS). Pembrolizumab combined with lenvatinib for patients with metastatic ATC is also an option supported by a retrospective study including six patients, in which complete response was observed in 66%, with a median PFS of 16.5 months. 544 All patients with a complete response had increased TMB or PD-L1 tumor proportion score (TPS) > 50%.

Treatment with anthracyclines and taxanes is generally not very effective for advanced anaplastic disease, although some patients may show disease response or have stable disease. 520, 538 Single-agent doxorubicin is approved by the FDA for ATC. A randomized trial including 84 patients with advanced thyroid cancer (not limited to ATC) showed an 11.6% complete response rate in patients who received doxorubicin combined with cisplatin, compared to a complete response in 0 patients who received single-agent doxorubicin. 543 ORR did not differ significantly between the study arms (26% vs. 17%, respectively). 3] [554] If weekly paclitaxel is used, the ATA Guidelines 520 recommend using paclitaxel at 60 to 90 mg/m 2 IV weekly and not the dose previously reported in the study by Ain et al. 554 Given the poor outcome with current standard therapy, all patientsregardless of surgical resection-should be considered for clinical trials. 6] [557] [558] [559] [560] [561] [562] [563] A trial in 80 patients (FACT) reported that the addition of fosbretabulin-to a carboplatin/paclitaxel regimen-resulted in a nonsignificant increase in median survival (5.2 vs. 4.0 months). 555, 564 [356] [357] Hyperfractionated EBRT, combined with radiosensitizing doses of doxorubicin, may increase the local response rate to about 80%, with a subsequent median survival of 1 year. 565 Distant metastases then become the leading cause of death. 566 1] [572] [573] [574] However, the addition of larger doses of other chemotherapeutic drugs has not been associated with improved control of distant disease or with improved survival. Other radiosensitizing agents that may be considered include docetaxel and paclitaxel with or without carboplatin. 552, 554, 571, 575 Although optimal results have been reported with hyperfractionated EBRT combined with chemotherapy, the NCCN Panel acknowledges that considerable toxicity is associated with such treatment and that prolonged remission is uncommonly reported. 576 3] [584] In a case series, complete surgical resection without tracheostomy or radical re-resection was achieved in six patients with initially unresectable BRAF

|RAI BEING CONSIDERED BASED ON CLINICOPATHOLOGIC FEATURES Clinicopathologic findings prompting consideration for RAI, without gross residual disease or known distant metastasis (PAP-4) Consider pretreatment neck imaging r,s,z 6-12 weeks post-thyroidectomy RAI therapy indicated based on pathology on pathology indicated based RAI therapy not|Resect clinically significant structural disease if possible|Nodule surveillance g,j or Consider lobectomy in select situations for definitive diagnosis/ treatment Discussion or Table of Contents • Disease Monitoring and Maintenance (PAP-7) • Levothyroxine to appropriate TSH target (THYR-A) • RAI therapy for remnant ablation or adjuvant therapy q • Post-treatment iodine-131 imaging (whole body RAI scan) q| |---|---|---|

|||PAP-5|

||||Table of Contents| |---|---|---|---|

||||Discussion|

|RAI-avid disease present on post-therapy scan|• Physical examination • Neck ultrasound at 6-12 months • TSH • Tg measurement and Tg ab ee • Consider TSH-stimulated RAI whole body scan||Consider additional imaging (CT neck/ chest), PET, or RAI imaging • Physical examination • TSH l •|

|Total thyroidectomy with RAI||||

|RAI-avid disease absent on post-therapy scan|• Physical examination • Neck ultrasound at 6-12 months • TSH • Recurrent Disease (PAP-9) or Metastatic Disease (PAP-10)|||

|persistent/recurrent locoregional or distant metastatic disease not amenable to RAI therapy|Bone metastases (PAP-11) Soft tissue metastases (eg, lung, liver, muscle) excluding central nervous system (CNS) metastases (see below) instability (MSI)Preferred Regimens • Continue to suppress TSH with levothyroxine l • For advanced, progressive, or threatening disease, somatic testing to identify actionable mutations (including ALK, NTRK, BRAF, and RET gene fusions), mismatch repair deficiency (dMMR), microsatellite ◊ Lenvatinib (category 1) kk Other Recommended Regimens ◊ Sorafenib (category 1) kk Useful in Certain Circumstances ◊ Cabozantinib (| |---|---|

|NCCN Guidelines Index| |---|

|Table of Contents|

|Discussion|

|PAP-11|

|Preferred Regimens ◊ Lenvatinib (category 1) kk,rr,ss Other Recommended Regimens ◊ Sorafenib (| |---|

ory 1) kk,rr,ss Other Recommended Regimens ◊ Sorafenib (| |---|

||||NCCN Guidelines Index|

||||Table of Contents|

|FNA RESULTS|DIAGNOSTIC PROCEDURES|PRIMARY TREATMENT||

|Follicular neoplasm a (Bethesda IV) (THYR-1)|• Thyroid and neck ultrasound (including central and lateral compartments), if not previously done • CT/MRI with contrast for locally advanced disease or vocal cord paresis b • Consider assessment of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy) c • Screen for personal and/or family history suggestive of inherited cancer risk i|• Total thyroidectomy if radiographic evidence or intraoperative findings of extrathyroidal extension or patient preference • Perform therapeutic neck dissection of involved compartments for clinically apparent/ biopsy-proven disease or Lobectomy/ isthmusectomy|Benign or NIFTP e Papillary Carcinoma (PAP-3) Levothyroxine therapy to keep TSH normal f Follicular carcinoma Invasive cancer (widely invasive or encapsulated Completion of thyroidectomy Postsurgical Evaluation (FOLL-2) angioinvasive h with ≥4 vessels) Encapsulated angioinvasive h with < 4 vessels or Minimally invasive follicular thyroid carcinoma (FTC) d Disease monitoring or Completion of thyroidectomy g • Consider Monitoring and Management (FOLL-6) or NIFTP e monitoring Disease Benign • Disease normal f TSH low or therapy to keep levothyroxine|

||||Papillary Carcinoma (PAP-3)|

||||Footnotes on FOLL-1A|

||||FOLL-1|

|||||NCCN Guidelines Index| |---|---|---|---|---|

|||||Table of Contents|

|||||Discussion|

|POSTSURGICAL EVALUATION|||||

|No gross residual disease in neck|No gross residual disease|Consideration for Initial Postoperative RAI Therapy After Total Thyroidectomy (FOLL-3)|Consideration for Initial Postoperative RAI Therapy After Total Thyroidectomy (FOLL-3)|Consideration for Initial Postoperative RAI Therapy After Total Thyroidectomy (FOLL-3)|

|Gross residual disease in neck|Resectable Unresectable j|Resect, if possible • TSH + Tg measurement Gross residual disease + Tg ab (6-12 wks postoperatively) rhTSH) (category 2B) hormone withdrawal or stimulation (thyroid imaging with TSH total body radioiodine • Iodine-123 or iodine-131 l|RAI uptake absent m,n|Monitoring of residual disease or Consider EBRT if disease is threatening vital structures k or Consider RAI therapy k|

||||m If higher than expected uptake (residual thyroid uptake or distant metastasis), change|m If higher than expected uptake (residual thyroid uptake or distant metastasis), change|

||||dose accordingly.||

|||||FOLL-2|

||• Suppress TSH with levothyroxine f • Disease Monitoring and Management (FOLL-6)| |---|---|

|RAI uptake present m or No RAI imaging|• Post-treatment iodine-131 whole body imaging • TSH-stimulated Tg|

|CLINICOPATHOLOGIC FACTORS|

|RAI not typically recommended (if all present):|

|• Largest primary tumor ≤2 cm|

|• Intrathyroidal|

|• No vascular invasion|

|• Clinical N0|

|• No detectable Tg ab|

|• Postoperative unstimulated Tg < 1 ng/mL or stimulated Tg < 2 ng/mL o|

|•|

|FOLL-3|

|o Tg values obtained 6-12 weeks after total thyroidectomy. p If preoperative imaging incomplete, postoperative imaging should evaluate central and lateral neck. q Minimal extrathyroidal extension alone likely does not warrant RAI. r Additional cross-sectional imaging (| |---|

|||||||NCCN Guidelines Index|

|||||||Table of Contents|

|||||||Discussion|

|RAI BEING CONSIDERED BASED ON CLINICOPATHOLOGIC FEATURES|||||||

|6-12 weeks post-thyroidectomy|Clinicopathologic findings prompting consideration for RAI, without gross residual disease or known distant metastasis (FOLL-3)|on pathology indicated based RAI therapy not RAI therapy indicated based on pathology|Consider pretreatment neck imaging m,n,u|Resect clinically significant structural disease if possible|• RAI therapy for remnant ablation or adjuvant therapy k • Post-treatment iodine-131 RAI scan) k (whole body imaging|Disease Monitoring and Management (FOLL-6) Levothyroxine TSH target (THYR-A) to appropriate|

|k Principles of Radiation and RAI Therapy (THYR-C). m If higher than expected uptake (residual thyroid uptake or distant metastasis) change dose accordingly. n A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated.|||||||

|||||||FOLL-4|

|KNOWN OR SUSPECTED DISTANT METASTATIC DISEASE|||||

|6-12 weeks post-thyroidectomy|Known or suspected distant metastases at presentation or elevated Tg (FOLL-3)|• Appropriate cross-sectional imaging (CT or MRI with contrast) of known metastatic foci v,y • Resect clinically significant structural disease if possible|Confirmed radioiodine-avid tumor or Thyroid remnant uptake only|• Disease Monitoring and Management (FOLL-6) • Levothyroxine to appropriate TSH target (THYR-A)|

|||||FOLL-5|

||||||NCCN Guidelines Index|NCCN Guidelines Index| |---|---|---|---|---|---|---|

|TREATMENT|DISEASE MONITORING|FINDINGS|MANAGEMENT|• RAI therapy k and|||

|Lobectomy Total without RAI thyroidectomy|• Physical examination • TSH • Neck ultrasound at 6-12 months • Physical examination • TSH • Tg||At least 4-6 weeks following CT with contrast x : • Consider pretreatment radioiodine diagnostic imaging (iodine-123 or iodine-131) with TSH stimulation k,u,w|No uptake|post-treatment imaging (whole body RAI scan) k • Consider other local therapies (EBRT, k etc) as primary therapy or postoperative for symptomatic structural metastatic disease|Postsurgical evaluation (FOLL-2) Recurrent Disease (FOLL-8) or Metastatic disease (FOLL-9) Recurrent Disease (FOLL-8)|

|||||||Recurrent Disease (FOLL-8) or Metastatic Disease (FOLL-9)|

|Total thyroidectomy with RAI (FOLL-7)|||||||

|||||||FOLL-6|

||NCCN Guidelines Index| |---|---|

||Table of Contents|

||Discussion|

|• Physical examination • Neck ultrasound at 6-12 months • TSH • Tg measurement and Tg ab aa|Recurrent Disease (FOLL-8)|

|Total thyroidectomy with RAI||

||Recurrent Disease (FOLL-8) or Metastatic Disease (FOLL-9)|

|TREATMENT|DISEASE MONITORING|FINDINGS|MANAGEMENT|| |---|---|---|---|---|

|RAI-avid disease present on post-therapy scan|||||

|RAI-avid disease absent on post-therapy scan|• Physical examination • Neck ultrasound at 6-12 months • TSH • Tg measurement and Tg||||

|f Principles of TSH Suppression (THYR-A). aa In selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated Tg and consider concomitant diagnostic RAI imaging.|||||

|||||FOLL-7|

|Recurrent Disease (FOLL-8) or Metastatic Disease (FOLL-9)| |---|

ecurrent Disease (FOLL-8) or Metastatic Disease (FOLL-9)| |---|

|FOLL-8|

|ee The administered activity of RAI therapy should be adjusted for| |---|

|pediatric patients. See Principles of Radiation and RAI Therapy|

|(THYR-C).|

|Unresectable locoregional recurrent/ persistent disease|

|CNS metastases (|

|Preferred Regimens ◊ Lenvatinib (category 1) gg Other Recommended Regimens ◊ Sorafenib (category 1) gg Useful in Certain Circumstances ◊ Cabozantinib| |---|

ory 1) gg Useful in Certain Circumstances ◊ Cabozantinib| |---|

|f Principles of TSH Suppression (THYR-A). k Principles of Radiation and RAI Therapy (THYR-C). ff Ethanol ablation, cryoablation, RFA, etc. gg Kinase inhibitor therapy may not be appropriate for patients with stable or slowly| |---|

|progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B). hh Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus,|

|pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive, category 2B], or|

|dabrafenib [BRAF positive, category 2B]) can be considered if clinical trials are not|

|available or appropriate.|

|||NCCN Guidelines Index| |---|---|---|

|||Table of Contents|

|||Discussion|

|Structurally persistent/recurrent locoregional or distant metastatic disease not amenable to RAI therapy|• Continue to suppress TSH with levothyroxine f • For advanced, progressive, or trial • Consider clinical TMB dMMR, MSI, and RET gene fusions), NTRK, BRAF, and (including ALK, mutations identify actionable somatic testing to threatening disease,|Bone metastases (FOLL-10) Soft tissue metastases (eg, lung, liver, muscle) excluding CNS metastases (see below)|

|||FOLL-10|

|Preferred Regimens ◊ Lenvatinib (category 1) gg Other Recommended Regimens ◊ Sorafenib (category 1)| |---|

) gg Other Recommended Regimens ◊ Sorafenib (category 1)| |---|

|k Principles of Radiation and RAI Therapy (THYR-C). ff Ethanol ablation, cryoablation, RFA, etc. gg Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B). hh Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus, pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive, category 2B], or|jj Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with high-risk disease who are not appropriate for VEGF inhibitors. kk Selpercatinib is also FDA approved for pediatric patients two years of age and older. ll RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. mm Denosumab and intravenous bisphosphonates can be associated with severe| |---|---|

|dabrafenib [BRAF positive, category 2B]) can be considered if clinical trials are not|hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at|

|available or appropriate. ii Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies|increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical vertebral fractures. An FDA-approved biosimilar is an appropriate substitute for|

|were small and underpowered.|denosumab.|

|k Principles of Radiation and RAI Therapy (THYR-C). gg Kinase inhibitor therapy may not be appropriate for patients with stable or slowly progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B). hh Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus,|ll RAI therapy is an option in some patients with bone metastases and RAI-sensitive disease. mm Denosumab and intravenous bisphosphonates can be associated with severe hypocalcemia; patients with hypoparathyroidism and vitamin D deficiency are at|

|pazopanib, sunitinib, vandetanib, vemurafenib [BRAF positive, category 2B], or|increased risk of hypocalcemia. Discontinuing denosumab can cause rebound atypical|

|dabrafenib [BRAF positive, category 2B]) can be considered if clinical trials are not|vertebral fractures. An FDA-approved biosimilar is an appropriate substitute for|

|available or appropriate. ii Cytotoxic chemotherapy has been shown to have minimal efficacy, although most studies|denosumab. nn After consultation with neurosurgery and radiation oncology; data on the efficacy of|

|were small and underpowered. jj Dabrafenib/trametinib could also be appropriate as a first-line therapy for patients with|lenvatinib or sorafenib for patients with brain metastases have not been established. oo TKI therapy should be used with caution in otherwise untreated CNS metastases due to|

|high-risk disease who are not appropriate for VEGF inhibitors. kk Selpercatinib is also FDA approved for pediatric patients two years of age and older.|bleeding risk.|

|FNA RESULTS|DIAGNOSTIC PROCEDURES|PRIMARY TREATMENT|

|Oncocytic follicular neoplasm a (|||

|invasive disease, or bulky disease of the central neck. Evaluation is imperative in those with voice changes. d Minimally invasive oncocytic carcinoma is characterized as an encapsulated tumor with microscopic capsular invasion and without vascular invasion. e Consider thyroidectomy if tumor > 4 cm in diameter. f Principles of TSH Suppression (THYR-A). g Disease monitoring is preferred in most circumstances. However, there are certain clinical scenarios in which completion of thyroidectomy may be appropriate. h Blood vessel invasion fewer than 4 vessels does not require completion thyroidectomy.|

|i Principles of Cancer Risk Assesment and Counseling (THYR-E)|

|f Principles of TSH Suppression (THYR-A). j For bulky, locoregional, viscerally invasive disease or rapid progression, refer to high-volume| |---|

|multidisciplinary institution, including radiation oncology referral. k If considering dosimetry, iodine-131 is the preferred agent. l Principles of Radiation and RAI Therapy (THYR-C). m If higher than expected uptake (residual thyroid uptake or distant metastasis), change dose accordingly. n A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise|

|indicated.|

|o A majority of oncocytic carcinoma are non-iodine-avid, particularly for high-risk disease that is negative on iodine-123/iodine-131 imaging. A negative post-therapy scan, especially done without single-photon emission computerized tomography (SPECT), will likely miss distant structural disease. If Tg is high and/ or pathology is high risk, FDG-PET is indicated. p Tg values obtained 6-12 weeks after total thyroidectomy. q If preoperative imaging incomplete, postoperative imaging should evaluate central and lateral neck.|r Minimal extrathyroidal extension alone likely does not warrant RAI. s Additional cross-sectional imaging (CT or MRI of the neck with contrast and chest CT [with contrast if there is concern about mediastinal lymph node metastases]) should be considered to rule out the presence of significant normal thyroid remnant or gross residual disease and to detect clinically significant distant metastases. t Differentiated high-grade carcinoma includes oncocytic carcinoma with ≥5 mitoses per 2 mm 2 and/or tumor necrosis.|

|k Principles of Radiation and RAI Therapy (THYR-C). m If higher than expected uptake (residual thyroid uptake or distant metastasis), change dose accordingly. n A false-negative pretreatment scan is possible and should not prevent the use of RAI if otherwise indicated. u While pre-ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre-ablation diagnostic| |---|

|scans based on pathology, postoperative Tg, intraoperative findings, and available imaging studies. Furthermore, dosimetry studies are considered in patients at high|

|risk of having RAI-avid distant metastasis. Empiric RAI doses may exceed maximum tolerable activity levels in patients with decreased GFR. Patients on dialysis|

|require special handling.|

|disease u While pre-ablation diagnostic scans in this setting are commonly done at NCCN Member Institutions, the panel recommends selective use of pre-ablation diagnostic k Principles of Radiation and RAI Therapy (THYR-C).| |---|

|require special handling. v To evaluate macroscopic metastatic foci for potential alterative therapies (such as surgical resection and/or EBRT) to prevent invasion/compression. w Thyrotropin alfa may be used for elderly patients for whom prolonged hypothyroidism may be risky. x Consider 24-hour urine iodine.|

|Recurrent Disease (ONC-|

|f Principles of TSH Suppression (THYR-A). z In selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated Tg and consider concomitant diagnostic RAI imaging. aa Interpretation of rising or new Tg ab is assay dependent and best performed as a radioimmunoassay and with a consistent assay for interpretation of trends.|

||bb Generally, a tumor is considered iodine-responsive if follow-up iodine-123 or| |---|---|

||low-dose iodine-131 (1-3 mCi) whole body diagnostic imaging done 6-12|

||months after iodine-131 treatment is negative or shows decreasing uptake|

||compared to pre-treatment scans. It is recommended to use the same|

||preparation and imaging method used for the pre-treatment scan and therapy.|

||Favorable response to iodine-131 treatment is additionally assessed through|

||change in volume of known iodine-concentrated lesions by CT/MRI, and by|

||decreasing unstimulated or stimulated Tg levels. cc The administered activity of RAI therapy should be adjusted for pediatric|

|f Principles of TSH Suppression (THYR-A). k Principles of Radiation and RAI Therapy (THYR-C).|patients. See Principles of Radiation and RAI Therapy (THYR-C). dd Preoperative vocal cord assessment, if central neck recurrence. ee Ethanol ablation, cryoablation, RFA, etc.|

|Structurally persistent/ recurrent locoregional or distant metastatic disease not amenable to RAI therapy|• Continue to suppress TSH with levothyroxine f • For advanced, progressive, or threatening disease, somatic testing to identify actionable mutations (including ALK, NTRK, BRAF|(ONC-10) Bone metastases| |---|---|---|

|f Principles of TSH Suppression (THYR-A). k Principles of Radiation and RAI Therapy (THYR-C). ee Ethanol ablation, cryoablation, RFA, etc. ff Kinase inhibitor therapy may not be appropriate for patients with stable or slowly|f Principles of TSH Suppression (THYR-A). k Principles of Radiation and RAI Therapy (THYR-C). ee Ethanol ablation, cryoablation, RFA, etc. ff Kinase inhibitor therapy may not be appropriate for patients with stable or slowly||

|progressive indolent disease. See Principles of Kinase Inhibitor Therapy (THYR-B).\ gg Commercially available small-molecule kinase inhibitors (such as axitinib, everolimus,|||

|CLINICAL PRESENTATION|PRIMARY TREATMENT|

|Medullary thyroid carcinoma on FNA by cytology or molecular diagnostics||

||MEDU-1|

|≥1.0 cm in diameter or bilateral thyroid disease|(MEDU-5) Postoperative 2-3 Months Management| |---|---|

|< 1.0 cm in diameter and unilateral thyroid disease|Total thyroidectomy and consider neck dissection (level VI)|

|CLINICAL PRESENTATION|ADDITIONAL WORKUP|MANAGEMENT|

|Medullary thyroid surgery h after initial thyroid carcinoma diagnosed|• Basal serum calcitonin level • CEA •||

|||MEDU-2|

|Additional Workup and Primary Treatment (MEDU-3)| |---|

|Management 2-3 Months Postoperative (MEDU-5)|

||||NCCN Guidelines Index| |---|---|---|---|

|CLINICAL PRESENTATION|ADDITIONAL WORKUP|PRIMARY TREATMENT||

|RET PV a,c Germline|Multiple endocrine neoplasia (MEN2B) (RET PV) j|• Basal serum calcitonin level k • CEA • Pheochromocytoma screening b,l • Central and lateral neck compartments ultrasound, m if not previously done •||

||MEN2A/Familial medullary thyroid carcinoma (FMTC) (RET PV) j|||

||||MEDU-3|

|Management 2-3 Months Postoperative (MEDU-5)| |---|

|MANAGEMENT 2-3 MONTHS POSTOPERATIVE|||DISEASE MONITORING p|

|Detectable basal calcitonin or Elevated CEA s|• Neck ultrasound • If calcitonin ≥150 pg/mL, CT or MRI with contrast of neck, liver, and chest patients with very elevated calcitonin levels body MRI in scan and whole • Consider bone|Imaging positive or symptomatic disease asymptomatic negative and Imaging|• Serum calcitonin, CEA every 6-|

|• Basal calcitonin • CEA||||

|Basal calcitonin undetectable and range o reference CEA within|Disease monitoring|||

||||MEDU-5|

|Recurrent or Persistent Disease (MEDU-6 and MEDU-7)| |---|

|Continue disease monitoring or Consider cervical reoperation, if primary surgery incomplete|

|Recurrent or Persistent Disease (MEDU-6 and MEDU-7)|

|RECURRENT OR PERSISTENT LOCOREGIONAL DISEASE||

|Locoregional|Recurrent or Persistent Disease; Distant Metastases (MEDU-7)|

||MEDU-6|

|RECURRENT OR PERSISTENT DISEASE DISTANT METASTASES|

|Asymptomatic disease|

|Symptomatic disease or Progression t|

|MEDU-7|

||NCCN Guidelines Version 5.2024 Thyroid Carcinoma -Anaplastic Carcinoma|NCCN Guidelines Index Table of Contents Discussion|

|FNA OR CORE BIOPSY FINDING a|• Disease monitoring • Systemic therapy t if not resectable and progressing by RECIST criteria u,v • Consider resection (if possible), ablation (eg, RFA, embolization, other regional therapy) DIAGNOSTIC PROCEDURES ESTABLISH GOALS OF THERAPY c||

|Anaplastic thyroid carcinoma (ATC)|Preferred Regimens ◊ Vandetanib w (category 1) ◊ Cabozantinib (category 1) ◊ Selpercatinib (positive for RET PV) x,y (category 1) • CBC with differential Somatic testing x Somatic testing x • Comprehensive chemistry • TSH • Neck ultrasound • CT with contrast of head, neck, chest, abdomen, pelvis • Laryngoscopy, including evaluation of vocal cord mobility • Fluorodeoxyglucose (FDG)-PET/CT or MRI • In case of airway invasion, bronchoscopy testing b • BRAF immunohistochemistry (IHC) mutations b • Molecular testing for actionable • Expedient consultation with multidisciplinary management team • Discuss prognosis • Discuss risks/benefits of treatment options • Discuss palliative care options including airway management||

||NCCN Guidelines Version 5.2024 Thyroid Carcinoma -Anaplastic Carcinoma|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion| |---|---|---|---|---|---|

|STAGE d||TREATMENT||DISEASE MONITORING AND MANAGEMENT||

|Stage IVA or IVB a,c (locoregional disease)|Resectable (potentially curable with surgery)|Neoadjuvant dabrafenib/ trametinib for BRAF V600E-mutated disease may be considered (category 2B)|Total thyroidectomy with therapeutic lymph node dissection|R0/R1 resection e achieved (usually as incidentally discovered, very small ATC) Incomplete (R2 resection) • Cross-sectional imaging Adjuvant EBRT f with radiosensitizing chemotherapy g when clinically appropriate EBRT f with chemotherapy g when clinically appropriate (CT or MRI with contrast) of brain, neck, chest, abdomen, and pelvis at frequent intervals as months after initial therapy • Consider FDG-PET/CT 3-6 clinically indicated • Continued disease Disease Monitoring and Management (ANAP-3) monitoring if no evidence of disease (NED) • Palliative locoregional RT • Local||

||Unresectable e or borderline resectable|Consider molecularly targeted neoadjuvant therapy h for borderline resectable disease when safe to do so or EBRT f with chemotherapy g when clinically appropriate|Surgery can be reconsidered after neoadjuvant therapy depending on response|||

||||||ANAP-2 ANAP-3|

|• Total thyroidectomy with therapeutic lymph node dissection if resectable (R0/R1) • Tracheostomy only if strongly indicated ± steroid (avoid prophylactic tracheostomy) • Locoregional RT • Systemic therapy ± RT (ANAP-A [1 of 3])| |---|

|Palliative care|

|NCCN Guidelines Version 5.2024 Thyroid Carcinoma -Anaplastic Carcinoma NCCN Guidelines Version 5.2024 Thyroid Carcinoma -Anaplastic Carcinoma|NCCN Guidelines Index Table of Contents Discussion NCCN Guidelines Index Table of Contents Discussion| |---|---|

|SYSTEMIC THERAPY||

|Systemic Therapies for Metastatic Disease ANAP-A (2 of 4)||

||References and Footnotes on ANAP 4 of 4|

||ANAP-A 1 OF 4 ANAP-A 2 OF 4|

|NCCN Guidelines Version 5.2024 Thyroid Carcinoma -Anaplastic Carcinoma|NCCN Guidelines Index Table of Contents Discussion|| |---|---|---|

|Preferred Regimens|||

|Dabrafenib/trametinib 2 (BRAF V600E mutation positive)|Dabrafenib 150 mg PO and Trametinib 2 mg PO|Twice daily Once daily|

|Larotrectinib 3 (NTRK gene fusion positive)|100 mg PO|Twice daily|

|Entrectinib 4 (NTRK gene fusion positive)|600 mg PO|Once daily|

|Repotrectinib 12 (NTRK gene fusion positive)|160 mg PO|Once daily for 14 days, then twice daily|

|Pralsetinib 5 (RET gene fusion-positive)|400 mg PO|Once daily|

|Selpercatinib 6,b (RET gene fusion-positive)|120 mg PO ( < 50 kg) or 160 mg PO (≥50 kg)|Twice daily|

|Other Recommended Regimens|||

|||References and Footnotes on ANAP 4 of 4|

|NCCN Guidelines Version 5.2024 Thyroid Carcinoma -Anaplastic Carcinoma|NCCN Guidelines Index Table of Contents Discussion| |---|---|

|SYSTEMIC THERAPY REFERENCES||

|FOOTNOTES||

||References and Footnotes on ANAP 4 of 4 ANAP-A 3 OF 4 ANAP-A 4 OF 4|

|PRINCIPLES OF RADIATION AND RADIOACTIVE IODINE THERAPY IODINE-131 ADMINISTRATION|

|Administered Activity|

|See special circumstances below for pediatric dose adjustment.|

|• Remnant ablation:|

|30 mCi|

|◊ If RAI|

|THYR-C 2 OF 5|

||for T, N, M||| |---|---|---|---|

|T|Primary Tumor|Primary Tumor|N|

|TX|Primary tumor cannot be assessed|NX|Regional lymph nodes cannot be assessed|

|T0|No evidence of primary tumor|N0|No evidence of locoregional lymph node metastasis|

|T1|Tumor ≤2 cm or less in greatest dimension limited to the thyroid|N0a One or more cytologically or histologically confirmed benign lymph nodes||

|T1a Tumor ≤1 cm in greatest dimension limited to the thyroid T1b Tumor > 1 cm but ≤2 cm in greatest dimension limited to the thyroid|N0b No radiologic or clinical evidence of locoregional lymph node metastasis N1 Metastasis to regional nodes|||

|T2 T3 T3a Tumor > 4 cm limited to the thyroid Tumor > 2 cm but ≤4 cm in greatest dimension limited to the thyroid Tumor > 4 cm limited to the thyroid, or gross extrathyroidal extension invading only strap muscles T3b Gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles) from a tumor of any size T4 Includes gross extrathyroidal extension beyond the strap muscle|N1a Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease N1b Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes Distant Metastasis M0 No distant metastasis M|||

|nerve from a tumor of any size tissues, larynx, trachea, esophagus, or recurrent laryngeal T4a Gross extrathyroidal extension invading subcutaneous soft|M1 Distant metastasis|||

|T4b Gross extrathyroidal extension invading prevertebral fascia or encasing the carotid artery or mediastinal vessels from a tumor of any size||||

|Note: All categories may be subdivided: (s) solitary tumor and (m) multifocal tumor (the largest determines the classification).||||

|Histopathologic Type|

|• Papillary thyroid carcinoma (PTC)|

|Papillary microcarcinoma|

|Follicular variant of PTC|

|Encapsulated variant of PTC|

|Columnar cell variant of PTC|

|Oncocytic variant of PTC|

|• Follicular thyroid carcinoma (FTC), NOS|

|FTC, minimally invasive|

|FTC, encapsulated angioinvasive|

|FTC, widely invasive|

|• Oncocytic carcinoma • Poorly differentiated thyroid carcinoma (used for insular|

|carcinoma as a subtype of poorly differentiated)|

|• Anaplastic thyroid carcinoma|

|Continued|

|ST-1|

||||NCCN Guidelines Version 5.2024 Thyroid Carcinoma|NCCN Guidelines Index Table of Contents Discussion| |---|---|---|---|---|

|American Joint Committee on Cancer (AJCC) TNM Staging For Thyroid-Medullary Carcinoma (8th ed., 2017)|American Joint Committee on Cancer (AJCC) TNM Staging For Thyroid-Medullary Carcinoma (8th ed., 2017)|American Joint Committee on Cancer (AJCC) TNM Staging For Thyroid-Medullary Carcinoma (8th ed., 2017)|American Joint Committee on Cancer (AJCC) TNM Staging For Thyroid-Medullary Carcinoma (8th ed., 2017)||

|Differentiated Under 55 years|||||

||T|N|M||

|Stage I|Any T Any N M0||||

|Stage II|Any T Any N M1||||

|Differentiated 55 Years and Older|||||

||T2|N0/NX M0|N0/NX M0|N0/NX M0|

|Stage II|T1|N1|M0||

||T2|N1|M0||

||T3a/T3b Any N M0|T3a/T3b Any N M0|T3a/T3b Any N M0|T3a/T3b Any N M0|

|Anaplastic|||||

||T|N||M|

|Stage IVA T1-T3a|N0/NX|M0|||

|Stage IVB T1-T3a|N1||M0||

||T3b|Any N|M0||

||T4|Any N|M0||

|Stage IVC Any T|Any N|M1|Continued||

|||||ST-2|

||for T, N, M| |---|---|

|T|Primary Tumor|

|TX|Primary tumor cannot be assessed|

|T0||

|N||Regional Lymph Nodes||| |---|---|---|---|---|

|NX||Regional lymph nodes cannot be assessed|||

|N0||No evidence of locoregional lymph node metastasis|||

||N0a One or more cytologically or histologically confirmed benign lymph nodes||||

||N0b No radiologic or clinical evidence of locoregional lymph node metastasis||||

|N1||Metastasis to regional nodes|||

||N1a Metastasis to level VI or VII (pretracheal, paratracheal, or prelaryngeal/Delphian, or upper mediastinal) lymph nodes. This can be unilateral or bilateral disease||||

||N1b Metastasis to unilateral, bilateral, or contralateral lateral neck lymph nodes (levels I, II, III, IV, or V) or retropharyngeal lymph nodes||||

|M0 No distant metastasis|||||

|M1 Distant metastasis|||||

|||T|N|M|

|Stage I|T1|N0|M0||

|Stage II|T2|N0|M0||

|||T3|N0|M0|

|Stage III|T1-T3 N1a|M0|||

|Stage IVA|T4a|Any N M0|||

|||T1-T3 N1b|M0||

|Stage IVB|T4b|Any N M0|||

|Stage IVC|Any T Any N M1||||

|||MSI-H|microsatellite instability-high| |---|---|---|---|

|||MTC|medullary thyroid cancer|

|||NED|no evidence of disease|

|||NIFTP|noninvasive follicular thyroid neoplasm with papillary-like nuclear features|

|||PHTS|PTEN hamartoma tumor|

||||syndrome|

|||PTC|papillary thyroid carcinoma|

|||PTV|planning target volume|

|||PV|pathogenetic variant|

|||RAI|radioactive iodine|

|||RFA|radiofrequency ablation|

|||rhTSH|recombinant human TSH|

|||SIB|simultaneous integrated boost|

|||SPECT|single-|

|||Tg ab|antithyroglobulin antibodies|

|||TMB|tumor mutational burden|

|||TMB-H|tumor mutational burden-high|

|GTV|gross tumor volume|TSH|thyroid-stimulating hormone|

|IMRT|intensity-modulated radiation||factor|

||therapy|WBRT|whole brain radiation therapy|

|MEN2A|multiple endocrine neoplasia type 2A|||

|MEN2B|multiple endocrine neoplasia type|||

||2B|||

|MSI|microsatellite instability|||

|Prognosis| |---|

|Age, Stage, and Sex at Diagnosis|

|Although many factors influence the outcome for patients with papillary|

|and follicular carcinomas, patient age at the time of initial therapy and|

|127,128 PHTS should be suspected if the patient| |---|

|also has a personal or family history of breast cancer, endometrial cancer,|

|colorectal cancer/colorectal hamartomas, multiple mucocutaneous lesions,|

|macrocephaly, and/or a wide range of other features as detailed in the|

|NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast,|

|Ovarian, and Pancreatic (available at www.NCCN.org). All patients who|

|3,375,376 A total thyroidectomy| |---|

|is recommended for patients with any one of the following factors,|

|including: known distant metastases, extrathyroidal extension, lateral|

|cervical lymph node metastases or gross central neck lymph node|

|metastases, or poorly differentiated and differentiated high-grade|

|histology. Total thyroidectomy may be considered for patients with bilateral|

|nodularity, tumor > 4 cm in diameter, or a prior exposure to radiation|

|(category 2B for radiation exposure). Clinically positive and/or biopsy-|

|proven nodal metastases should be treated with a formal compartmental|

|resection.|

|The other features of management and follow-up for follicular thyroid| |---|

|carcinoma are similar to those of PTC. Clinicopathologic factors can be|

|used to guide decisions about whether to administer initial postoperative|

|RAI (see Clinicopathologic Factors in the NCCN Guidelines for Follicular|

|[Thyroid] Carcinoma). The NCCN Guidelines provide algorithms to assist|

|in decision-making about use of RAI in different settings: 1) postoperative|

|RAI is not typically indicated for patients classified as having a low risk of|

|recurrence/disease-specific mortality; 2) adjuvant RAI may be|

|recommended for patients with intermediate and high risk for recurrence|

|with the goal of decreasing recurrence risk, and 3) RAI may be used to|

|treat known or suspected distant metastatic disease (see Clinicopathologic|

|Factors in the NCCN Guidelines for Follicular [Thyroid] Carcinoma).|

|Clinicopathologic factors can be used to guide decisions about whether to| |---|

|use initial postoperative RAI (see Clinicopathologic Factors in the NCCN|

|Guidelines for Oncocytic [Thyroid] Carcinoma). The NCCN Guidelines|

|provide algorithms to assist in decision-making about use of RAI in|

|different settings: 1) postoperative RAI is not typically indicated for patients|

|classified as having a low risk of recurrence/disease-specific mortality; 2)|

|adjuvant RAI may be recommended for patients with intermediate and|

|high risk for recurrence with the goal of decreasing recurrence risk; and 3)|

|RAI may be used to treat known or suspected distant metastatic disease|

|(see Clinicopathologic Factors in the NCCN Guidelines for Oncocytic|

|[Thyroid] Carcinoma).|

|Data to support RAI therapy for unresectable disease with positive iodine-|

|131 imaging for oncocytic carcinoma are limited and inconsistent. Iodine-|

|131 therapy (100-150 mCi) may be considered after thyroidectomy for|

|patients with rising or newly elevated Tg levels who have negative scans|

|(including FDG-PET) (see Recurrent Disease in the NCCN Guidelines for|

|Oncocytic [Thyroid] Carcinoma). 429 Pretreatment radioiodine diagnostic|

|imaging (iodine-123 or iodine-131) with adequate TSH stimulation (thyroid|

|withdrawal or thyrotropin alfa) may be considered in patients with known|

|Metastatic cervical adenopathy appears in about 50% of patients at initial| |---|

|presentation. Symptoms of upper aerodigestive tract compression or|

|invasion are reported by up to 15% of patients with sporadic disease. 438|

|Distant metastases in the lungs or bones cause symptoms in 5% to 10%|

|of patients at initial presentation. Many patients with advanced MTC have|

|diarrhea and flushing, because the tumor can secrete calcitonin and|

|sometimes other hormonally active peptides (ie, adrenocorticotropic|

|hormone [ACTH], calcitonin gene-related peptide [CGRP] ). Rarely,|

|Cushing syndrome occurs due to tumor ACTH production. Treatment with|

|somatostatin analogs (eg, octreotide, lanreotide) may be useful in patients|

|with these symptoms.|

|Before surgery for MTC, it is necessary to diagnose coexisting| |---|

|pheochromocytoma. When present, pheochromocytoma should be|

|resected before the MTC to avoid hypertensive crisis during surgery (see|

|Pheochromocytoma/Paraganglioma in the NCCN Guidelines for|

|Neuroendocrine and Adrenal Tumors, available at www.NCCN.org).|

|Pheochromocytoma should be removed using laparoscopic|

|adrenalectomy. 430,431,453|

|Staging|

|As previously mentioned, the NCCN Guidelines for Thyroid Carcinoma do|

|not use TNM staging to guide therapy. Instead, many characteristics of the|

|With a concurrent diagnosis of hyperparathyroidism in MEN2A, the| |---|

|surgeon should leave or autotransplant the equivalent mass of one normal|

|parathyroid gland if multiglandular hyperplasia is present.|

|Cryopreservation of resected parathyroid tissue should be considered to|

|allow future implantation in the event of iatrogenic hypoparathyroidism.|

|Disfiguring radical node dissections do not improve prognosis and are not|

|indicated. In the presence of grossly invasive disease, more extended|

|procedures with resection of involved neck structures may be appropriate.|

|Function-preserving approaches are preferred. In some patients, MTC is|

|diagnosed after thyroid surgery. In these patients, additional workup is|

|recommended to ascertain whether they have RET PV (eg, exons 10, 11,|

|13-16), which will determine whether they need additional surgery (eg,|

|completion thyroidectomy and/or neck dissection) (see Additional Workup|

|in the NCCN Guidelines for Medullary [Thyroid] Carcinoma).|

|Persistently Increased Calcitonin| |---|

|Basal serum concentrations of calcitonin and CEA should be measured 2|

|or 3 months postoperatively. About 80% of patients with palpable MTC|

|and 50% of those with nonpalpable but macroscopic MTC who undergo|

|supposedly curative resection have serum calcitonin values indicative of|

|residual disease. Those patients with residual disease may benefit from|

|further evaluation to detect either residual resectable disease in the neck|

|or the presence of distant metastases. Patients with detectable basal|

|calcitonin or elevated CEA who have negative imaging and who are|

|asymptomatic may be followed (see Surveillance in the NCCN Guidelines|

References

引用 / 出处

NCCN临床实践指南：甲状腺癌（2024.V5）. 2024.