Differentiated thyroid cancer: clinical guidelines

List of Abbreviations

DTC – differentiated thyroid cancer

CT – computed tomography

ICD-10 – International Classification of Diseases 10th Revision

RIT – radioiodine therapy

TC – thyroid cancer

WBS – whole body scintigraphy

FNA – fine-needle aspiration biopsy

Tg – thyroglobulin

TSH – thyroid-stimulating hormone

US – ultrasound examination

TG – thyroid gland

Terms and Definitions

Bethesda System for Reporting Thyroid Cytopathology (2009, 2017) – a standardized reporting system for thyroid fine-needle aspiration cytology.

EU-TIRADS (European Thyroid Imaging Reporting and Data System) – a standardized reporting system for thyroid ultrasound.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Differentiated thyroid cancer (DTC) – a malignant tumor arising from follicular cells of the thyroid gland that retain features of differentiation.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

To date, several major risk factors for thyroid cancer development are identified: mutations in BRAF, PTEN, APC, DICER1, MNG, NRAS, KRAS, TERT and other genes, exposure to ionizing radiation, and hereditary syndromes (Gardner, Cowden, multiple endocrine neoplasia types 2A and 2B, etc.) [1].

1.3 Epidemiology of the Disease or Condition

In 2021, thyroid cancer accounted for 2.16% of all malignant neoplasms in terms of incidence structure. The mean patient age was 54 years. The standardized incidence rate of thyroid cancer in the Russian Federation in 2021 was 6.14 per 100,000 population (2.42 in men; 9.39 in women), and the mortality rate was 0.32 per 100,000 population (0.28 in men; 0.34 in women) [1, 2].

1.4 Features of Coding the Disease or Condition

International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) code – C73 Malignant neoplasm of thyroid gland.

Despite sharing a single ICD-10 code, differentiated thyroid cancer and medullary thyroid cancer are distinct nosologies. The diffuse origin of C-cells in the thyroid gland can be considered an independent organ by origin and function, comparable, for example, to the parathyroid glands. This accounts for the somewhat different properties of C-cell tumors. Medullary thyroid cancer shares only anatomical location with A- and B-cell thyroid tumors, and that concludes their similarities. The neuroendocrine nature of medullary thyroid cancer necessitates fundamentally different approaches to diagnosis, treatment, and follow-up. Therefore, it was decided to split the clinical guidelines for thyroid cancer treatment into two separate documents: clinical guidelines for the diagnosis and treatment of differentiated thyroid cancer, and clinical guidelines for the diagnosis and treatment of medullary thyroid cancer.

International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) code – D44.0 Neoplasm of uncertain or unknown behavior of endocrine glands, Thyroid gland.

1.5 Classification of the disease or condition

World Health Organization (WHO) Histological Classification of Thyroid Tumors (2022):

1. Thyroglossal duct cyst

2. Other congenital anomalies of the thyroid gland

3. Follicular nodular disease of the thyroid gland

4. Follicular adenoma

5. Follicular adenoma with papillary architecture

6. Oncocytic adenoma of the thyroid gland

7. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features

8. Thyroid tumor of uncertain malignant potential

9. Hyalinizing trabecular tumor

10. Follicular thyroid carcinoma

11. Invasive encapsulated follicular variant of papillary carcinoma

12. Papillary thyroid carcinoma

- classic subtype of papillary thyroid carcinoma

- infiltrative follicular subtype of papillary thyroid carcinoma

-tall cell subtype of papillary thyroid carcinoma

-columnar cell subtype of papillary thyroid carcinoma

-oncocytic subtype of papillary thyroid carcinoma

-hobnail subtype of papillary thyroid carcinoma

-solid subtype of papillary thyroid carcinoma

-Warthin-like subtype of papillary thyroid carcinoma

-diffusely sclerosing subtype of papillary thyroid carcinoma

13. Oncocytic carcinoma of the thyroid gland

14. High-grade follicular carcinomas

15. High-grade differentiated thyroid carcinoma

16. Poorly differentiated thyroid carcinoma

17. Anaplastic follicular cell carcinoma of the thyroid gland

18. C-cell carcinoma of the thyroid gland

19. Medullary thyroid carcinoma

20. Mixed medullary and follicular cell-derived carcinomas

21. Mucoepidermoid carcinoma of the thyroid gland

22. Secretory carcinoma

23. Sclerosing mucoepidermoid carcinoma with eosinophilia.

24. Cribriform morular thyroid carcinoma.

25. Thymoma

26. Spindle epithelial tumor with thymus-like elements.

27. Thymic carcinoma family

28. Thyroblastoma

Stages of differentiated and anaplastic thyroid cancer (American Joint Committee on Cancer [AJCC], 8th edition, 2017).

The T category includes the following grades:

• T – primary tumor;

• Tx – primary tumor cannot be assessed;

• T0 – no evidence of primary tumor;

• T1 – tumor ≤2 cm in greatest dimension, limited to the thyroid gland;

• T1a – tumor <1 cm, limited to the thyroid gland;

• T1b – tumor >1 cm but <2 cm in diameter, limited to the thyroid gland;

• T2 – tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid gland;

• T3 – tumor >4 cm in greatest dimension, limited to the thyroid gland, or any tumor with minimal extrathyroidal extension (into the sternothyroid muscle or perithyroid soft tissues);

• T3a – tumor >4 cm, limited to the thyroid gland;

• T3b – tumor of any size with gross extrathyroidal extension invading only strap muscles (sternohyoid, sternothyroid, thyrohyoid, or omohyoid muscles);

• T4 – gross extrathyroidal extension beyond the thyroid capsule;

• T4a – tumor invades the thyroid capsule and extends to any of the following structures: subcutaneous soft tissues, larynx, trachea, esophagus, recurrent laryngeal nerve;

• T4b – tumor invades prevertebral fascia, mediastinal vessels, or carotid artery sheath.

The N category indicates the presence or absence of regional lymph node metastases:

• Nx – regional lymph nodes cannot be assessed;

• N0 – no regional lymph node metastases;

• N0a – one or more cytologically or histologically confirmed lymph nodes without evidence of tumor;

• N0b – no radiologic or clinical evidence of regional lymph node metastases;

• N1 – regional lymph node metastases present;

• N1a – metastases to level VI or VII lymph nodes (pre- and paratracheal, prelaryngeal, or upper mediastinal). Can be unilateral or bilateral;

• N1b – metastases to unilateral, bilateral, or contralateral cervical lymph nodes (levels I, II, III, IV, or V), or retropharyngeal lymph nodes.

The M category characterizes the presence or absence of metastases:

• M0 – no distant metastases;

• M1 – distant metastases present.

Stage grouping

1.6 Clinical presentation of the disease or condition

Differentiated thyroid cancer has no specific clinical presentation and usually manifests as nodular goiter. Anaplastic thyroid cancer presents as a rapidly growing tumor mass on the anterior surface of the neck. In later stages, respiratory and swallowing disorders and regional lymph node enlargement join the clinical picture [4, 5].

2. Diagnostics, medical indications and contraindications for diagnostic methods

Criteria for establishing the diagnosis/condition: at the preoperative stage – results of cytological examination of thyroid punctates; punctates of altered cervical lymph nodes and needle washings for thyroglobulin; at the postoperative stage – routine pathomorphological examination of the surgical specimen (if necessary – with immunohistochemical typing) [1, 6–9].

2.1 Complaints and Anamnesis

Introduction: The vast majority of differentiated thyroid cancer cases are detected during the examination of patients for nodular goiter. A smaller proportion of cases are diagnosed due to a burdened personal or family history, voice alteration, detection of enlarged cervical lymph nodes, or distant metastases [6].

As methods for the primary diagnosis of nodular goiter, palpation of the thyroid gland and regional lymph nodes, preliminary assessment of vocal function, and taking a history to exclude risk factors for belonging to the risk group for aggressive forms of thyroid cancer are recommended [1, 6–10].

• When collecting complaints and medical history from patients presenting for an initial appointment regarding nodular goiter, it is recommended to pay attention to the following factors in order not to miss high-risk thyroid cancer:

• family history of thyroid cancer;

• history of head and neck radiation therapy;

• dysphagia, dysphonia;

• thyroid nodules accidentally detected on [18F]fluorodeoxyglucose positron emission tomography;

• history of surgery for thyroid cancer [1, 6–10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

2.2 Physical Examination

2.3 Laboratory Diagnostics

• When a thyroid nodule is detected in a patient, it is recommended to test blood calcitonin levels to exclude or confirm medullary thyroid carcinoma [3].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• When a thyroid nodule is detected in a patient, it is recommended to test blood thyroid-stimulating hormone (TSH) levels to assess hormonal status [11].

Level of Evidence BGrade of Recommendation 3Level of Clinical Effectiveness – B (level of evidence – 3)

Comments: Assessment of basal blood calcitonin concentration significantly outperforms fine-needle aspiration biopsy (FNAB) in the diagnosis of medullary thyroid cancer. This test may influence the indications for FNAB and therefore should be performed at the primary stage of examination.

• Blood calcitonin level (concentration) is recommended to be evaluated taking into account gender differences in the upper limit of reference ranges for adequate interpretation of results [3].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comment: An increase in basal calcitonin levels >100 pg/ml is highly suspicious for medullary thyroid cancer.

• Preoperative investigation of blood thyroglobulin (Tg) levels in primary patients with thyroid nodules is not recommended, as this parameter is not a marker of thyroid cancer at this stage [12].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

2.4 Instrumental Diagnostics

Ultrasound examination

Introduction: Despite its high resolution, ultrasound examination (US) should not be used in the general population as a screening method for thyroid cancer due to low efficacy from both clinical and financial perspectives: the method detects a large number of cases of nodular colloid goiter, which, as a rule, has no clinical significance and does not require any treatment.

Early detection of papillary microcarcinomas (tumors <1 cm in size) does not affect the prognosis of overall and disease-free survival of patients.

The main role of ultrasound in thyroid cancer is to refine indications for FNAB, provide navigation during its execution, assess local tumor spread, and evaluate the state of lymph nodes to determine the optimal extent of surgical intervention [13, 14].

• Thyroid and parathyroid ultrasound, and cervical lymph node ultrasound (one anatomical zone) are recommended for patients with suspected thyroid tumors in the following cases to assess the extent of the process, the condition of lymph nodes, and to evaluate the scope of upcoming surgical treatment:

o palpable neck mass;

o enlarged cervical lymph nodes;

o family history of thyroid cancer;

o history of head and neck radiation therapy;

o vocal fold paralysis;

o symptoms of dysphagia;

o thyroid nodules accidentally detected on [18F]fluorodeoxyglucose positron emission tomography;

o history of surgery for thyroid cancer [6, 8].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: The protocol for ultrasound of the thyroid and parathyroid glands includes determining the size, localization, and ultrasound characteristics of the tumor. Suspicious signs include (evaluated only in solid nodules or solid areas of nodules) [1, 6, 8, 13]:

o hypoechoic solid structure;

o irregular, indistinct, or polycyclic margins;

o punctate hyperechogenic foci (microcalcifications);

o anteroposterior dimension of the nodule exceeding its width ("taller-than-wide").

• For ultrasound assessment of the likelihood of malignancy of a thyroid tumor and determination of indications for FNAB, it is recommended to use the EU-TIRADS (European Thyroid Imaging Reporting and Data System) classification [15].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comments:

o EU-TIRADS 1 – absence of thyroid nodules on ultrasound;

o EU-TIRADS 2 – benign lesion. Malignancy risk – 0%. Includes 2 categories of nodules: anechoic (cysts) and spongiform nodules. If cystic nodules contain a mural solid component, they are reclassified into the low-risk category. FNAB is not indicated, but may be performed for therapeutic purposes;

o EU-TIRADS 3 – low-risk malignancy lesion. Malignancy risk – 2–4%. Isoechoic or hyperechoic lesions, round or oval shape, with smooth margins, in the absence of any suspicious features. FNAB is indicated for nodules ≥ 2.0 cm in size;

o EU-TIRADS 4 – intermediate-risk malignancy lesion. Malignancy risk – 6–17%. Moderately hypoechoic lesions, round or oval shape, with smooth margins, in the absence of any suspicious features. The main difference between low and intermediate risk lies in the echogenicity of the solid areas of the nodule. In case of nodule heterogeneity, the presence of any hypoechoic area will classify the nodule into the intermediate-risk group. FNAB is indicated for nodules ≥1.5 cm in size;

o EU-TIRADS 5 – high-risk malignancy lesion. Malignancy risk – 26–87%. A lesion with at least 1 sign of malignancy: hypoechoic nodule, irregular shape, indistinct margins, microcalcifications (punctate hyperechogenic foci), anteroposterior dimension of the nodule greater than its width ("taller-than-wide"). FNAB is indicated for nodules ≥1 cm in size. If the initial benign result of FNAB is obtained, it should be repeated soon to rule out a false-negative result. If the nodule size is <1 cm and there are no changes in regional lymph nodes, dynamic surveillance with regular ultrasound every 3–6 months is recommended.

The protocol for ultrasound of cervical lymph nodes (one anatomical zone) should include the assessment of the following parameters [8, 13, 16]:

o size (it is necessary to evaluate the diameter or anteroposterior dimension, not the length. For all cervical lymph nodes except level II of the fascial-cell spaces of the neck (submandibular area), the maximum size is no more than 0.6 cm; for level II, no more than 0.8 cm);

o long-to-short axis ratio;

o presence/absence of the hilum;

o cystic changes;

o punctate hyperechogenic foci (microcalcifications);

o vascularity pattern (hilar or diffuse throughout the lymph node);

o increased echogenicity of the lymph node (resemblance to normal thyroid tissue).

The most specific signs allowing suspicion of metastatic lymph node involvement are microcalcifications, a cystic component, peripheral vascularity, resemblance of the lymph node tissue to thyroid tissue; less specific signs are enlargement, rounded contours, and absence of the hilum.

• In the presence of suspicious ultrasound features in a thyroid nodule, it is recommended to perform laryngeal ultrasound to assess vocal fold mobility in order to rule out tumor invasion into the larynx and/or vocal fold paresis due to recurrent laryngeal nerve involvement (depending on the anatomical structure of the larynx) [1, 6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• In thyroid cancer or suspected thyroid cancer, regardless of subjective voice function assessment, all patients at the preoperative stage are recommended to undergo videolaryngoscopy for an objective assessment of vocal cord mobility, if laryngeal ultrasound is not feasible [1, 6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Fine-needle aspiration biopsy followed by cytological examination of the fine-needle aspiration biopsy micropreparation

• Fine-needle aspiration biopsy of the thyroid gland followed by cytological examination of the fine-needle aspiration biopsy smear is recommended for all patients with suspected thyroid cancer as the primary method for the differential diagnosis of benign and malignant thyroid and lymph node lesions [17].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

• Fine-needle aspiration biopsy of the thyroid gland followed by cytological examination of the fine-needle aspiration biopsy smear is recommended to be performed under ultrasound guidance to increase the diagnostic accuracy of the procedure [18].

GCR BLEL 2Grade of Recommendation – B (Level of Evidence – 2)

Comments: FNAB can be performed by a physician of any specialty who is proficient in the technique (endocrinologist, endocrine surgeon, oncologist, diagnostic radiologist).

Indications for FNAB [1, 8, 17]:

⮚ thyroid nodules EU-TIRADS 2 – puncture biopsy is not indicated;

⮚ thyroid nodules EU-TIRADS 3, equal to or greater than 2.0 cm in diameter;

⮚ thyroid nodules EU-TIRADS 4, equal to or greater than 1.5 cm in diameter;

⮚ thyroid nodules EU-TIRADS 5, equal to or greater than 1.0 cm in diameter;

⮚ thyroid nodules EU-TIRADS 5 or other EU-TIRADS categories sized <1 cm in the presence of the following factors:

o basal calcitonin concentration above gender-specific reference ranges;

o presence of enlarged regional lymph nodes;

o history of head and neck radiation therapy;

o family history of medullary thyroid cancer;

o vocal fold paralysis;

o patients under 18 years of age;

o to determine the scope of surgery if a nodule is present in the contralateral lobe

For lesions sized <1 cm, if the patient is not at risk for aggressive forms of thyroid cancer, performing FNAB is impractical regardless of the ultrasound characteristics of the neoplasm [10].

• If a benign Bethesda II cytological report is obtained from a nodule with suspicious ultrasound features of EU-TIRADS 5, FNAB is recommended to be repeated in the near future to rule out a diagnostic error [10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• If abnormal regional lymph nodes at levels II–V of the neck are detected, targeted FNAB is recommended to verify potential metastatic involvement [19]. FNAB of abnormal level VI lymph nodes of the neck is performed based on individual indications.

GGR CLEL 3Grade of Recommendation – C (Level of Evidence – 3)

Comment: The diagnostic accuracy of lymph node FNAB increases when washout fluid from the needle is tested for thyroglobulin or calcitonin, depending on the suspected morphological form of thyroid cancer

• When a solid hypoechoic thyroid nodule is detected that rapidly increases in size (an increase in the maximum size of the nodule by more than 1 cm per month) and is not accompanied by pain syndrome or cystic transformation, especially in the presence of symptoms (difficulty breathing, voice alteration, difficulty swallowing), the patient is recommended to be referred to a specialized center for a nodule biopsy as soon as possible [8, 13].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: The fastest-growing thyroid neoplasms are anaplastic thyroid cancer and lymphoma. Both tumors have a high growth rate, frequently cause regional lymphadenopathy, are hypoechoic on ultrasound, and most commonly lack areas of cystic transformation within their structure. During growth, these tumors do not cause pain syndrome. Left untreated, they can cause airway compression symptoms and laryngeal dysfunction due to invasion into the recurrent laryngeal nerve. Both tumors require prompt initiation of treatment, and determining the treatment strategy requires genetic testing or immunohistochemistry (IHC) on material obtained via fine-needle aspiration or core-needle biopsy. Given that treatment outcomes for these tumors directly depend on the time of initiation, primary care physicians should make maximum efforts for the rapid routing of patients to specialized centers with appropriate diagnostic capabilities.

• When performing a cytological examination of a fine-needle aspiration biopsy smear from thyroid nodules to increase the diagnostic accuracy of the procedure, it is recommended to use the 6 standard report categories of the modern international cytological classification (Bethesda Thyroid Classification, 2009, 2017) when evaluating punctates from thyroid nodules to increase the diagnostic accuracy of the study [20].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: The international cytological classification of thyroid nodule punctates includes 6 categories:

o Category I – non-diagnostic puncture;

o Category II – benign lesion (colloid and adenomatous nodules, chronic autoimmune thyroiditis, subacute thyroiditis);

o Category III – atypia of undetermined significance (a difficult-to-interpret puncture with suspected neoplastic involvement);

o Category IV – follicular neoplasm or suspicion of a follicular neoplasm;

o Category V – suspicious for malignancy (suspicious for papillary carcinoma, medullary carcinoma, metastatic carcinoma, lymphoma);

o Category VI – malignant tumor (papillary, poorly differentiated, medullary, anaplastic carcinoma).

Reports containing only a descriptive part, as well as reports without a specific cytological diagnosis, are non-diagnostic. In these situations, it is necessary to have the prepared cytological slides reviewed by an experienced morphologist or to repeat FNAB in a specialized medical institution

Computed tomography

• Spiral computed tomography (CT) of the neck and computed tomography of the chest organs with intravenous bolus contrast enhancement is recommended for tumor size T3-4, suspicion of extrathyroidal extension, or the presence of abnormal regional lymph nodes according to ultrasound, in order to clarify the extent of tumor spread [1, 8, 10].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Magnetic resonance imaging and whole-body positron emission tomography with tumor-tropic radiopharmaceuticals are used for metastasis diagnostics based on individual indications.

2.5 Other Procedures

Molecular genetic testing

Modern methods of molecular genetic testing (detection of point mutations, chromosomal rearrangements, various types of microRNAs) for the differential diagnosis of thyroid tumors within the framework of cytological reports of groups III, IV, and V according to the Bethesda Thyroid Classification (2009, 2017) do not allow omitting surgical treatment, as they do not reliably rule out thyroid cancer (low negative predictive value) and, as a rule, do not affect the scope of surgery. To date, the capabilities of these methods are limited and require further accumulation of data [21].

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

Given the various morphological variants of thyroid cancer, which have individual tumor biology features, clinical courses, and prognoses, the treatment of differentiated forms and anaplastic carcinoma is discussed separately in these clinical guidelines. At the same time, poorly differentiated thyroid cancer is an aggressive variant of malignant neoplasms of the thyroid gland originating from follicular cells. Given that this histological variant shares a common origin with differentiated forms of thyroid cancer, the treatment strategy for patients with this variant of malignant neoplasms should follow the recommendations regarding differentiated thyroid cancer.

3.1 Surgical Treatment

Introduction: Treatment and follow-up of patients with well-differentiated thyroid cancer (WDTC) must be carried out in specialized medical institutions possessing a full arsenal of diagnostic tools and experience in treating WDTC [1, 6, 8].

Patient management at all stages of treatment depends on recurrence risk stratification, which can be conventionally divided into three main stages.

1. Preoperative risk stratification to determine indications and optimal scope of surgery.

2. Postoperative risk stratification to determine the adequacy of the scope of surgery, indications for radioiodine therapy / radioiodine ablation,

3. and levothyroxine sodium suppressive therapy**.

4. Dynamic risk stratification to assess the response to treatment and determine optimal patient management tactics.

• For categories IV, V, and VI of the cytological report according to the international cytological classification (Bethesda Thyroid Classification, 2009), surgical treatment is recommended [21, 65].

GGR CLEL 4Grade of Recommendation – C (Level of Evidence – 4)

• For category III (atypia of undetermined significance), a repeat puncture is recommended to clarify the degree of malignancy risk of the nodule and the indication for surgical treatment [21, 66].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• For intrathyroidal tumors of Bethesda Thyroid Classification categories IV, V, and VI measuring less than 1.0 cm, it is recommended to perform surgical treatment in the scope of hemithyroidectomy. For this group of patients, if preferred by the patient, active surveillance (with expert ultrasound every 6 months) is a possible alternative to hemithyroidectomy. Surgical treatment is most appropriate in cases where the tumor is localized in the area of the recurrent laryngeal nerve, with close contact with the trachea (Stages of differentiated and anaplastic thyroid cancer (American Joint Committee on Cancer 9th AJCC edition, 2017; NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 3.2018)). If any of the three linear dimensions of the microcarcinoma increases by 0.3 cm, or if one of the dimensions exceeds 1 cm, or if the volume of the tumor node increases by more than 50%, as well as in the event of changed regional lymph nodes or distant metastases, signs of invasion into the recurrent nerve, trachea, or esophagus, or signs of extrathyroidal invasion, such patients are indicated for surgical treatment depending on the nature of progression. Large prospective studies have established that typically no more than 7–8% of patients in the surveillance group progress [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• For tumors of Bethesda Thyroid Classification categories V and VI measuring from 1 to 4 cm without extrathyroidal invasion (determined clinically or by ultrasound) and/or metastatic lymph nodes (cN0), it is recommended to perform surgical treatment (hemithyroidectomy or thyroidectomy) to improve patient survival [22, 23].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

Comments: Hemithyroidectomy is an adequate scope of surgery in low-risk patients. A potential choice of thyroidectomy may be associated with a decision regarding postoperative RAI therapy and simplified follow-up, or patient preference.

• For tumors of Bethesda Thyroid Classification categories V and VI measuring >4 cm, or for tumors with pronounced extrathyroidal invasion (clinically T3), clinically evident metastases (cN1), or distant metastases (M1), thyroidectomy with maximal surgical ablation of the tumor tissue is recommended as primary treatment for the purpose of subsequent RAI therapy and improving patient survival [10, 20, 21].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Surgical intervention on neck lymph nodes

• Removal of central compartment lymph nodes (level VI) is recommended if preoperative or intraoperative examination suspects the presence of metastases in this zone (cN1) for the purpose of adequate pathomorphological staging of the disease and determining indications for RAI therapy [6].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• In nodes of Bethesda Thyroid Classification categories V and VI, T1–T2, and in the presence of enlarged level 6 lymph nodes on the affected side, it is possible to perform prophylactic ipsilateral level 6 lymph node dissection in addition to hemithyroidectomy for the purpose of adequate pathomorphological staging of the disease and making decisions on further patient management tactics [21].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: performing ipsilateral level 6 lymph node dissection practically does not affect the complication rate of hemithyroidectomy (the probability of hypoparathyroidism and recurrent laryngeal nerve injury practically does not differ from hemithyroidectomy), but it allows staging the disease and reducing the likelihood of recurrence if metastatic involvement of this fascial space is detected. The presence of micrometastases does not increase the risk of recurrence; the presence of metastases from 0.3 to 1 cm slightly increases the risk of recurrence and does not require an immediate decision to expand the scope of surgery for the purpose of RAI therapy (the decision can be made based on serial ultrasound).

• Prophylactic central lymphadenectomy (level VI neck lymphadenectomy, ipsi- or bilateral) is recommended in advanced primary tumor forms (T3–4) or preoperatively verified metastases in the lateral neck lymph nodes (cN1b) to increase treatment efficacy [6, 8]:

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: prophylactic central lymphadenectomy in primary T1–2 tumors increases the complication rate without affecting mortality, despite the high rate of micrometastasis (25–30%). Micrometastases of papillary carcinoma are the result of migration of primary tumor cells that are incapable of proliferation and undergo apoptosis.

• Removal of levels II–V neck adipose-fascial tissue (neck lymphadenectomy) is recommended only with proven metastatic involvement of these zones based on FNA results to improve patient survival [8].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: Selective removal of metastatic lymph nodes outside the fascial-sheath block is inadequate.

3.2 Postoperative risk stratification for recurrence and persistence of differentiated thyroid cancer

Modern principles of postoperative risk staging and determining indications for [131I] sodium iodide therapy are based on the 2015 American Thyroid Association (ATA) guidelines [10, 24, 25, 26]. There are 3 groups: high, intermediate, and low risk.

Low-risk group – radioiodine therapy is generally not indicated, but radioiodine ablation may be performed if iodine-avid tissue is present in the thyroid bed:

⮚ Differentiated thyroid cancer (DTC) with all of the following features:

o without locoregional or distant metastases;

o all macroscopic tumor tissue removed;

o absence of extrathyroidal invasion;

o absence of vascular invasion;

o non-aggressive histological variant;

⮚ cN0 or pN1 with involvement of no more than 5 lymph nodes, micrometastases (<0.2 cm in greatest dimension);

⮚ intrathyroidal DTC with or without capsular invasion and minimal vascular invasion (<4 foci);

⮚ intrathyroidal papillary carcinoma <4 cm in size

⮚ intrathyroidal unifocal or multifocal papillary microcarcinoma

⮚ undetectable thyroglobulin antibody levels

⮚ unstimulated Tg level $\le$1 ng/mL at 6–12 weeks post-thyroidectomy

Intermediate-risk group – radioactive iodine therapy is prescribed on an individual basis: 

⮚ aggressive histological variant;

⮚ cN1 or pN1 with >5 metastatic lymph nodes, macrometastases (<3 cm in greatest dimension);

⮚ differentiated thyroid cancer with vascular invasion;

⮚ positive resection margin

⮚ unstimulated Tg level up to 10 ng/mL at 6–12 weeks post-thyroidectomy

High-risk group – absolute indications for radioactive iodine therapy 

⮚ residual tumor;

⮚ pN1 with any metastatic lymph node >3 cm in greatest dimension;

⮚ macroscopic extrathyroidal extension;

⮚ widely invasive follicular carcinoma (>4 foci);

⮚ suspected distant metastases and their management;

⮚ unstimulated Tg level >10 ng/mL at 6–12 weeks post-thyroidectomy

3.3 Radioiodine therapy / radioiodine ablation

Indicated for patients with verified papillary, follicular, or Hürthle cell thyroid carcinoma according to the risk stratification for disease recurrence and persistence [21, 27, 28, 29, 30].

• In preparation for radioactive iodine therapy (RAI) without recombinant human TSH (thyrotropin alfa), all patients are recommended to discontinue levothyroxine sodium** 3–4 weeks prior to the procedure to achieve the proper therapeutic effect of RAI [21, 27, 28, 29, 30, 67, 68, 69].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Radioactive iodine therapy is performed following a 2-week low-iodine diet. Following radiocontrast imaging, administration of sodium iodide [131I] should be withheld for 2 months. RAI requires a high blood TSH concentration (>30 mIU/L). The latter can be achieved via endogenous stimulation by discontinuing levothyroxine sodium** for 3–4 weeks or by administration of thyrotropin alfa. In low-risk patients, radioiodine ablation may be performed at a TSH level >10 mIU/L

• Radioiodine ablation in the low-risk group is recommended when unstimulated serum Tg levels are >0.2 but <1 ng/mL to destroy remnant thyroid tissue, which is necessary for subsequent accurate interpretation of serum Tg levels during follow-up and for increasing the diagnostic yield of post-treatment sodium iodide [131I] whole-body scans [21, 27, 28, 29, 30].

Level of Evidence CGrade of Recommendation 4Level of Evidence – C (Grade of Recommendation – 4).

• The recommended therapeutic activity interval for sodium iodide [131I] is 30–80 mCi [21, 27, 28, 29, 30].

GCP CLEL 3Grade of Recommendation – C (Level of Evidence – 3).

• Adjuvant radioactive iodine therapy is recommended to reduce the risk of disease recurrence, increase overall and recurrence-free survival in patients with intermediate and high risk, including those with biochemical persistence of the disease [21, 27, 28, 30].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• A therapeutic interval of sodium iodide [131I] activity of 30–150 mCi is recommended for patients in the moderate- and high-risk groups, including those with biochemical persistence of the disease [21, 27, 28, 29, 30].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• A therapeutic interval of sodium iodide [131I] activity of 100–200 mCi is recommended in the presence of distant metastatic lesions or unresectable locoregional recurrence [21, 27, 28, 29, 30].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5).

• For sodium iodide activities exceeding 120 mCi, it is recommended to perform biodosimetry to prevent and control excessive radiation exposure to the blood and bone marrow [28, 30, 70].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• When the cumulative therapeutic activity of sodium iodide exceeds 1000 mCi, it is recommended to assess the risk of long-term adverse events and myelosuppression [28, 30, 70].

GoR CLoE 5Grade of Recommendation - C (Level of Evidence - 5)

• Upon detection of iodine-avid foci, repeated courses of radioiodine therapy are recommended at 3–6 month intervals until iodine uptake in metastatic lesions completely disappears and stimulated thyroglobulin levels are < 1 ng/L [28, 30, 70].

GSI CLoE 5Grade of Recommendation — C (Level of Evidence — 5)

3.4 Levothyroxine sodium therapy**

Levothyroxine sodium** replacement therapy is aimed at correcting postoperative hypothyroidism, whereas suppressive therapy aims to suppress TSH-dependent growth of residual tumor cells.

• In low-risk patients with biochemical remission, suppressive therapy with levothyroxine sodium** is not recommended due to the lack of improved survival and quality of life; replacement therapy is recommended instead [32].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• In patients with intermediate risk, biochemical recurrence, and indeterminate tumor status, suppressive hormone therapy with levothyroxine sodium** is recommended to improve patient survival rates [32].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: mild suppression is appropriate in the presence of tachycardia and menopause; replacement therapy is indicated for patients over 60 years of age, or with atrial fibrillation or osteoporosis.

• In high-risk patients and those with structural recurrence, suppressive hormone therapy with levothyroxine sodium** is recommended to improve survival rates, except for patients with atrial fibrillation, who should receive mild suppression [32].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comments: Target TSH ranges under various regimens [1, 6, 8]:

o suppressive therapy: TSH level <0.1 mIU/L, free thyroxine level does not exceed the upper limit of normal;

o mild suppression: TSH level 0.1–0.5 mIU/L;

o replacement therapy: TSH level 0.4–4.0 mIU/L

3.5 Targeted therapy

• Upon the development of radioiodine-refractiveness—i.e., failure of radioiodine therapy and documented tumor progression over the past 12 months according to RECIST 1.1 criteria—systemic targeted therapy with drugs approved in the Russian Federation for the corresponding medical indications (lenvatinib**, sorafenib**, cabozantinib**) is recommended to increase overall patient survival [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: When radioiodine-refractiveness develops, progression according to RECIST 1.1 criteria is a mandatory prerequisite for initiating targeted therapy. Elevated thyroglobulin and antithyroglobulin antibody levels alone, without structural progression per RECIST, do not constitute an indication for starting targeted therapy.

A patient is considered radioiodine-refractory if at least one of the following criteria is met:

o absence of 131I uptake in at least one of all existing tumor lesions following administration of a therapeutic activity of 131I of at least 100 mCi;

o tumor progression during radioiodine therapy over the past 12 months;

o absence of a positive therapeutic effect from radioiodine therapy at a cumulative therapeutic activity >600 mCi

• In primary unresectable life-threatening or symptomatic DTC, systemic targeted therapy with drugs registered in the Russian Federation for these medical indications (lenvatinib**, sorafenib**, cabozantinib**) is recommended to increase overall patient survival [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: Cabozantinib** is used exclusively as a second-line or subsequent targeted therapy.

• Regardless of the chosen drug, it is recommended to initiate treatment at the starting dose specified in the package leaflet, followed by dose reduction upon the development of grade 3 or higher adverse events to achieve optimal therapeutic efficacy and treatment tolerability [34].

GRL ALEL 2Grade of Recommendation – A (Level of Evidence – 2).

• In recurrent, unresectable, or metastatic differentiated thyroid cancer with radioiodine therapy failure, disease progression, and/or the presence of a life-threatening tumor-associated condition, lenvatinib** is recommended at a dose of 24 mg orally once daily until disease progression or unacceptable toxicity, to improve patient survival [35].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

Comment: The use of lenvatinib** is preferred over sorafenib** due to a more significant clinical response, manifesting as an extended time to progression with a median progression-free survival of 18.3 months, and an objective response rate of up to 64.8% versus 12.2%.

• In recurrent, unresectable, or metastatic differentiated thyroid cancer with radioiodine therapy failure, disease progression, and/or the presence of a life-threatening tumor-associated condition, sorafenib** is recommended at a dose of 400 mg orally twice daily until disease progression or unacceptable toxicity, to improve patient survival [36].

GSI ALoE 2Grade of Recommendation — A (Level of Evidence — 2)

• In recurrent, unresectable, or metastatic radioiodine-refractory differentiated thyroid cancer progressing during lenvatinib** and/or sorafenib** therapy, cabozantinib** is recommended at 60 mg orally once daily until disease progression or unacceptable toxicity, to improve patient survival [37].

GCR ALEL 2Grade of Recommendation – A (Level of Evidence – 2)

• In recurrent, unresectable, or metastatic radioiodine-refractory differentiated thyroid cancer progressing on standard targeted therapy regimens, comprehensive genomic profiling based on next-generation sequencing using tumor tissue samples or liquid biopsy is recommended to identify specific molecular targets and prescribe corresponding targeted therapy [38].

GSI CLoE 5Grade of Recommendation – C (Level of Evidence — 5)

Comment: target mutations to test for include RET proto-oncogene mutations and NTRK gene fusions.

• In recurrent, unresectable, or metastatic radioiodine-refractory differentiated thyroid cancer progressing on standard targeted therapy regimens, in the presence of a confirmed NTRK gene fusion, larotrectinib is recommended at 100 mg orally twice daily to improve survival [39].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• In recurrent, unresectable, or metastatic radioiodine-refractory differentiated thyroid cancer progressing on standard targeted therapy regimens, in the presence of a confirmed NTRK gene fusion, entrectinib is recommended at 600 mg orally once daily to improve survival [40].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• In recurrent, unresectable, or metastatic radioiodine-refractory differentiated thyroid cancer progressing on standard targeted therapy regimens, in the presence of a confirmed RET gene fusion, selpercatinib is recommended at a dose of 120 mg orally twice daily (for body weight under 50 kg) and 160 mg orally twice daily (for body weight of 50 kg or more) to improve survival [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• In the event of tumor progression or life-threatening toxicity during treatment with one targeted agent, switching the patient to another agent is recommended [21].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

3.6 External beam radiation therapy

• External beam radiotherapy in selected cases is recommended for patients with solitary, non-sodium iodide [131I]-avid, surgically unresectable thyroid cancer metastases, as well as for palliative treatment of pain or compression syndromes (e.g., tracheal or spinal cord compression) [41, 42, 74, 75, 76, 77].

Level of Recommendations – CLevel of Evidence – 4Level of Recommendations – C (Level of Evidence – 4)

Comment: The use of external beam radiotherapy is limited due to the low sensitivity of differentiated thyroid cancer to this treatment modality.

3.7 Systemic radionuclide therapy with samarium-153 Sm-oxabifor

• Systemic radionuclide therapy with Samarium-153 Sm oxabifor, taking into account the theranostic approach, is recommended in the presence of osteotropic radiopharmaceutical uptake based on SPECT (SPECT/CT) results and confirmation of metastatic skeletal lesions based on X-ray and/or magnetic resonance imaging to improve the quality of life of patients with differentiated thyroid cancer [43, 44, 45, 46, 47].

GCP CLOE 5Grade of Recommendation – C (Level of Evidence – 5)

• Systemic radionuclide therapy with Samarium-153 Sm oxabifor is recommended for patients with confirmed metastatic skeletal lesions (number of foci ≥3) for pain relief, in the absence of symptoms of spinal cord compression, at intervals of 3–6 months, with a therapeutic activity of 0.5–1.0 mCi/kg [43, 44, 45, 46, 47].

GCP CLOE 5Grade of Recommendation – C (Level of Evidence – 5)

3.8 Bone-modifying agent therapy

• In case of metastatic skeletal bone lesions, all patients are indicated for therapy with an osteomodifying agent: zoledronic acid** 4 mg IV every 28 days or denosumab** 120 mg subcutaneously every 28 days [71, 72, 73].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

3.9 Treatment of anaplastic thyroid cancer

Ultrasound-guided fine-needle aspiration biopsy is recommended for the initial diagnosis of anaplastic thyroid cancer.

• In case of an non-informative biopsy result with clinical suspicion of anaplastic thyroid cancer, it is recommended to perform an ultrasound-guided core needle biopsy of the lesion [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Upon establishing the diagnosis of anaplastic thyroid cancer, it is recommended to urgently refer the patient to a specialized center equipped to perform genetic testing and targeted therapy and experienced in the surgical treatment of patients with anaplastic thyroid cancer. Treatment attempts in general oncology facilities are not recommended [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Upon establishing the cytological diagnosis of anaplastic thyroid cancer, it is recommended to determine the presence of the BRAF ^V600E mutation in the cytological material or core biopsy material as soon as possible [21].

GCP CLOE 5Level of Evidence Assurance – C (Level of Evidence – 5)

Comment: In anaplastic thyroid cancer containing areas of differentiated thyroid cancer, BRAF^V600E mutations were detected in both anaplastic and differentiated thyroid cancer, suggesting that BRAF mutations play a role in the progression of anaplastic thyroid cancer from differentiated thyroid cancer. Thus, the dedifferentiation process is likely driven by the progressive accumulation of somatic mutations in cancer-related genes, particularly TP53 and genes encoding proteins involved in the phosphatidylinositol 3-kinase (PI3K)-AKT pathway.

Among anaplastic thyroid cancers, the BRAF^V600E mutation is the most frequent mutation, observed in 50–70% of cases. If differentiated thyroid cancer coexists with anaplastic thyroid cancer in the thyroid tissue, more than 90% of tumors may harbor the BRAF^V600E mutation.

It has also been described that MAPK/MEK kinases enhance antitumor activity compared to single-agent B-raf (BRAF) serine-threonine kinase inhibitors, suggesting that dual inhibition of the MAPK signaling pathway improves treatment response and delays or prevents MAPK pathway reactivation, a known mechanism of resistance.

This strategy has proved successful in the treatment of BRAF V600-mutant melanoma and lung cancer, with combined BRAF and MEK inhibition increasing the overall response rate, response duration, progression-free survival, and overall survival compared to B-raf (BRAF) serine-threonine kinase inhibitor monotherapy.

Comment: The PCR method provides the maximum speed of obtaining results; in the case of a positive reaction, the reliability of the conclusion is very high, which allows for the rapid initiation of targeted therapy, although false-negative results do occur. The sequencing method requires more time to perform, but has higher sensitivity, making its use justified in the event of a negative PCR result.

• When performing molecular genetic testing for the BRAF V600 mutation by PCR or sequencing, it is recommended to simultaneously analyze other mutations that could potentially influence the choice of drug therapy (molecular genetic testing for mutations in the ALK, NTRK, RET, TSC2, PI3K/mTOR/AKT, ROS1 genes). Determination of PD-L1 protein expression by immunohistochemistry [21].

GCP CLOE 5Level of Evidence Assurance – C (Level of Evidence – 5)

• In anaplastic thyroid cancer, it is recommended to perform comprehensive genomic profiling based on next-generation sequencing using tumor tissue samples or liquid biopsy to identify molecular targets and the subsequent benefit of specific targeted therapy [48].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

Comment: In the presence of genetic targets for targeted drugs, every effort should be made to enroll the patient in relevant clinical trials or administer targeted drugs by decision of the medical commission. Thus, if the patient has mutations in the RET proto-oncogene, therapy with selpercatinib may be used (orally, at a weight of less than 50 kg, 120 mg once daily; at a weight of 50 kg or more, 160 mg once daily) [21]; in the presence of NTRK gene fusions, therapy with larotrectinib or entrectinib is recommended (including for ROS1 gene mutations/fusions) [21].

• All patients with a confirmed diagnosis of anaplastic thyroid cancer are recommended to undergo positron emission tomography combined with computed tomography using tumorotropic radiopharmaceuticals and brain MRI to rule out distant tumor metastases that significantly affect prognosis and treatment tactics [21].

GCP CLOE 5Level of Evidence Assurance – C (Level of Evidence – 5)

Comment: If PET/CT is unavailable or there is a need for a long wait for the study, it is advisable to perform CT of the chest, abdominal, and pelvic organs with intravenous bolus contrast enhancement.

• In case of detecting the BRAF ^V600E mutation in recurrent, unresectable, and/or metastatic anaplastic thyroid cancer, it is recommended to use #dabrafenib** (orally 150 mg twice daily) in combination with #trametinib** (orally 2 mg daily) or #vemurafenib** 960 mg twice daily orally + #cobimetinib** 60 mg once daily orally, course duration 21 days, interval between courses 7 days) until progression or unacceptable toxicity [21, 49, 50, 54, 63].

For #dabrafenib** in combination with #trametinib** Grade of Recommendation – C (Level of Evidence – 5)

For #vemurafenib** with #cobimetinib** Grade of Recommendation – C (Level of Evidence – 4)

Comments: Combination therapy with BRAF and MEK signaling pathway inhibitors is more effective than monotherapy with L01EC: B-raf serine-threonine kinase (BRAF) inhibitors. The detection of distant tumor metastases should not be a reason to refuse targeted therapy or delay its initiation, since the tumor response to treatment is currently unpredictable, and there are cases of complete response to targeted therapy. In case of a pronounced clinical response and compliance of the tumor process with resectability criteria, surgical treatment may be considered.

• Assessment of the resectability of a tumor harboring the BRAF ^V600E mutation is recommended to be carried out after targeted therapy with BRAF (ATC L01EC)/MEK (ATC L01EE) inhibitors [49, 50].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• In recurrent, inoperable, or metastatic anaplastic thyroid cancer with confirmed NTRK gene fusion, it is recommended to use larotrectinib 100 mg twice daily orally to improve progression-free survival or until unacceptable toxicity [51].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• In recurrent, inoperable, or metastatic anaplastic thyroid cancer with confirmed NTRK gene fusion, it is recommended to use entrectinib 600 mg once daily orally to improve survival [52].

GIB CLOE 4Grade of Recommendation – C (Level of Evidence – 4)

• In recurrent, inoperable, or metastatic anaplastic thyroid cancer with confirmed RET gene mutation, it is recommended to use selpercatinib at a dose of 120 mg twice daily (for body weight less than 50 kg) and 160 mg twice daily (for body weight of 50 kg or more) orally to improve survival [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• If R0/R1 tumor resection is feasible, it is recommended to perform radical tumor removal in the scope of thyroidectomy with selective resection of all affected local or regional structures and lymph nodes to increase patient survival rates [53, 54].

GCP CLOE 5Level of Evidence Assurance – C (Level of Evidence – 5)

• To assess the feasibility of radical tumor resection, it is recommended to perform esophagogastroduodenoscopy and laryngobronchoscopy [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Postoperative histological diagnosis of anaplastic thyroid cancer requires mandatory confirmation by immunohistochemistry [21].

GCP CLOE 5Level of Evidence Assurance – C (Level of Evidence – 5)

• Following surgical treatment, it is recommended to use radiation therapy to the neck region (preferably IMRT) in combination with chemotherapy [21].

GCP CLOE 5Level of Evidence Assurance – C (Level of Evidence – 5)

Comments: The initiation of chemotherapy is recommended within the first week after surgery, followed by the start of radiation therapy.

• chemotherapy is recommended in cases where there are no genetic targets for targeted therapy. The following chemotherapy regimens are recommended [21]: #paclitaxel** 60–100 mg/m² + carboplatin** AUC 2 IV weekly or #paclitaxel** 60–90 mg/m² IV inf., weekly or #paclitaxel** 135–175 mg/m² + carboplatin** AUC 5–6 IV once every 3 weeks or #docetaxel** 60 mg/m² + doxorubicin** 60 mg/m² IV once every 3–4 weeks until unacceptable toxicity or #docetaxel** 20 mg/m² + doxorubicin** 20 mg/m² IV weekly or doxorubicin** 60–75 mg/m² IV once every 3 weeks or doxorubicin** 20 mg/m² IV weekly [21, 55–64].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

4. Analgesia

The procedure and recommendations for pain management in differentiated thyroid cancer comply with the guidelines "Chronic Pain Syndrome in Adult Patients Requiring Palliative Care", presented in the rubricator of clinical guidelines of the Russian Ministry of Health.

Medical Nutrition Therapy

Not applicable.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

General principles of rehabilitation for patients after surgery, RAI therapy, radiation therapy, and/or chemotherapy correspond to those for head and neck malignancies presented in the clinical guidelines "Malignant Neoplasms of the Oral Cavity".

5. Prevention and Dispensary Observation

5.1 Dynamic risk stratification and follow-up of patients

A patient's risk category is not static and must be dynamically reassessed depending on the response to treatment. This allows for individualized follow-up, reduced financial costs, and timely detection of structural disease recurrence, thereby positively influencing the prognosis of the disease.

Dynamic risk stratification allows patients to be divided into the following 4 main groups based on treatment outcomes [6].

1. Biochemical remission (recurrence probability is 1–4%):

• negative ultrasound findings;

• unstimulated Tg concentration <0.2 ng/mL with low anti-Tg antibody levels;

• stimulated Tg concentration <1 ng/mL if the patient has been reclassified from another group.

2. Biochemical recurrence:

• negative ultrasound, WBS, CT findings;

• unstimulated Tg concentration >1 ng/mL;

• stimulated Tg concentration >10 ng/mL;

• rise in anti-Tg antibodies (persistent increase in antibody levels on follow-up).

In this group, approximately 30% of patients experience a spontaneous decrease in biochemical markers, 20% achieve remission after additional treatment (RAI therapy), and 20% develop a structural recurrence. Thyroid cancer-related mortality is <1%.

If Tg concentration remains stable or decreases, active surveillance is performed in most cases; TSH suppression is preferred in the absence of specific contraindications. If Tg levels rise or anti-Tg antibodies show an upward trend, active evaluation and additional therapeutic options (RAI therapy) are recommended.

Patients with indeterminate tumor status are identified as an intermediate group between those with biochemical remission and biochemical recurrence.

3. Indeterminate tumor status:

• negative or nonspecific ultrasound, WBS, CT findings;

• unstimulated Tg concentration is >0.2 but <1 ng/mL;

• Tg concentration after stimulation is more than 1, but less than 10 ng/mL;

• anti-Tg antibody levels are stable or decreasing.

Nonspecific changes may be stable or resolve, the probability of structural recurrence is estimated to be somewhat lower than in the biochemical recurrence group (15–20%), and cause-specific mortality is <1%. In most cases, continued follow-up is necessary (imaging, Tg level determination). If suspicious changes are detected, additional imaging and biopsy should be performed.

4. Structural recurrence: structural or functional signs of the tumor at any concentration of Tg and/or anti-Tg antibodies.

Prognosis: about 50–60% of patients remain with persistent disease despite additional treatment. Thyroid cancer-related mortality is 11% for cervical metastases and 50% for distant metastases. The choice of treatment strategy depends on the size, location, extent of involvement, growth rate, uptake of sodium iodide [131I] or fludeoxyglucose [18F], and histological variant of the tumor.

5.2 Determination of thyroglobulin and anti-thyroglobulin antibodies

The most highly sensitive method of dynamic follow-up is the determination of Tg, a specific highly sensitive marker of thyrocytes as well as cells of papillary and follicular thyroid cancer.

The presence of anti-Tg antibodies in the blood can cause a false-negative result in Tg level determination. Tg determination should be performed using a sensitive immunoradiometric assay (functional sensitivity of 0.2 ng/mL).

Following primary treatment, Tg may be detected in the blood of patients for several months; therefore, its determination is advisable no earlier than 3 months after the last treatment stage [1, 6, 8].

• Postoperative blood thyroglobulin testing and serum anti-thyroglobulin antibody determination during levothyroxine sodium therapy** are recommended for all patients every 6–12 months to rule out disease recurrence [21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• In the biochemical remission group, the interval for blood thyroglobulin testing and serum anti-thyroglobulin antibody determination during levothyroxine sodium therapy** is recommended to be extended to 12–24 months to improve patients' quality of life and reduce economic costs [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• The blood TSH testing interval is recommended to be no more than 12 months for all patients receiving levothyroxine sodium therapy** for the timely detection of disease recurrence [6].

GCP CLoE 5Grading of Recommendations Assessment, Development and Evaluation (GRADE) – C (Level of Evidence – 5)

• Dynamic blood Tg testing at least every 6–12 months is recommended in patient groups with high risk, structural recurrence, biochemical recurrence, or indeterminate tumor status to improve patient survival [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: Re-determination of stimulated Tg is recommended in the following patient groups [51]:

o high risk;

o structural recurrence;

o biochemical or indeterminate recurrence status;

• Re-evaluation of the stimulated blood Tg level is not recommended in low-risk patients and those with biochemical remission due to low diagnostic efficacy [6]/

GCR CLEL 5Grade of Recommendation — C (Level of Evidence — 5)

5.3 Postoperative ultrasound examination

• Following surgical treatment, ultrasound of the thyroid and parathyroid glands, and neck lymph node ultrasound (one anatomical zone) are recommended in 6–12 months, depending on the risk group and Tg concentration dynamics, to detect structural recurrence [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• If suspicious lymph nodes with a maximum size of >0.8–1.0 cm are detected on ultrasound, targeted FNAB is recommended, supplemented by Tg assay in the needle washout fluid for morphological or biochemical verification of disease recurrence [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: For smaller lymph node sizes, active surveillance is possible (if node dimensions remain stable and there is no threat of invasion into vital structures).

5.4 Whole-body bone scintigraphy

• In patients with biochemical remission after RAI therapy, routine whole-body bone scintigraphy is not recommended due to low diagnostic value [6, 21,78].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Whole-body bone scintigraphy is recommended 6–12 months after RAI therapy in high- and intermediate-risk patients without achieved biochemical remission and with persistent disease to assess disease progression [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

5.5 Computed, Magnetic Resonance, and Positron Emission Tomography

• Spiral computed tomography of the neck and computed tomography of the chest organs are recommended when there are doubts regarding the adequate assessment of disease spread on ultrasound, suspicion of trachea, larynx, pharynx, or esophagus invasion, detection of lung metastases and mediastinal lymph nodes in high-risk patients with elevated Tg concentration (typically >10 ng/mL) or with a rise in anti-Tg antibodies regardless of whole-body scintigraphy results, in order to adequately assess the extent of the disease [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Magnetic resonance imaging of the brain, bone tissue (one region), and abdominal organs is recommended for high-risk patients with elevated Tg concentration (typically >10 ng/mL) in the absence of metastases to the lungs, neck and mediastinal lymph nodes, or in the presence of characteristic symptoms of metastatic lesions in the above locations, in order to adequately assess disease dissemination and detect structural recurrence [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Whole-body positron emission tomography with tumorotropic radiopharmaceuticals is recommended for high-risk patients with a high Tg concentration (>10 ng/mL) and negative whole-body bone scintigraphy findings to rule out structural disease progression, for initial staging in poorly differentiated or widely invasive follicular thyroid cancer, or to evaluate treatment outcomes in radioiodine-refractory forms of differentiated thyroid cancer [6].

GCR CLEL 5Grade of Recommendation — C (Level of Evidence — 5)

5.6 Thyroid cancer and pregnancy

Differentiated thyroid cancer is in most cases a tumor with latent progression, and its detection during pregnancy is not an indication for pregnancy termination. Pregnancy is not a factor contributing to the progression of differentiated thyroid cancer. Most studies indicate that the long-term prognosis of differentiated thyroid cancer diagnosed during pregnancy is no different from that of thyroid cancer detected in other settings. There are no differences in mortality and persistence rates of differentiated thyroid cancer in pregnant women who underwent surgery in the 2nd trimester up to 24 weeks and in women who underwent surgery after delivery. Moreover, according to retrospective studies, the prognosis does not worsen even when surgical treatment is performed a year after the initial diagnosis of differentiated thyroid cancer during pregnancy.

If fine-needle aspiration biopsy and cytological examination diagnose differentiated thyroid cancer in a pregnant woman, she is indicated for surgical treatment, but the decision on the timing of surgery should be individualized.

There are studies reporting a higher rate of specific and nonspecific complications in women who underwent surgery during pregnancy compared to non-pregnant women, which necessitated a longer hospital stay and increased treatment costs. The scope of complex treatment for patients with differentiated thyroid cancer can be individualized based on the fact of pregnancy planning (sodium iodide [131I] therapy may be delayed in some cases) [6].

• Artificial termination of pregnancy (abortion) is not recommended upon detection of differentiated thyroid cancer [6, 21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• The detection of differentiated thyroid cancer is an indication for surgical treatment, the timing of which is determined individually, while in most cases it can be delayed until the postpartum period [6, 21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comment: For differentiated thyroid cancer diagnosed cytologically in early pregnancy, dynamic ultrasound is indicated at a frequency of once a month.

• With progressive tumor enlargement or the appearance of altered regional lymph nodes, surgical treatment is recommended in the 2nd trimester of pregnancy up to 24 weeks gestation [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• The issue of pregnancy planning by women who have received treatment for differentiated thyroid cancer is decided individually: it may be recommended immediately after surgical treatment or 6 months after radioactive iodine therapy [6, 21].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• Men who have undergone radioiodine therapy/radioiodine ablation are not recommended to participate in pregnancy planning for 120 days (the lifespan of a spermatozoon) [6].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

• When planning pregnancy after thyroid surgery, it is recommended to maintain stable euthyroidism in order to reduce the risk of recurrence and ensure normal fetal development [10, 79, 80].

GCP CLEL 5Grade of Recommendation – C (Level of Evidence – 5)

Comments: It is advisable to prescribe levothyroxine sodium** replacement therapy (at a dose of about 2 mcg/kg of body weight) with a target TSH concentration of 0.1–2.5 mIU/L. Monitoring blood TSH levels during pregnancy is necessary every 6–8 weeks. Women who have received treatment for differentiated thyroid cancer are not contraindicated for breastfeeding [6], during which potassium iodide** is required at a dosage of 200 mcg per day due to the ongoing iodine deficiency in the country.

6. Organization of Medical Care

Medical care, with the exception of medical care provided as part of clinical trials, in accordance with Federal Law No. 323-FZ dated November 21, 2011, "On the Basics of Protecting the Health of Citizens in the Russian Federation," is organized and provided:

1) in accordance with the regulations on the organization of medical care by types of medical care, approved by the authorized Federal Executive Authority;

2) in accordance with the procedure for the provision of medical care in the profile "oncology", mandatory for implementation throughout the Russian Federation by all medical organizations;

3) based on these clinical guidelines;

4) taking into account the standards of medical care approved by the authorized Federal Executive Authority.

Primary specialized health care is provided by an oncologist and other specialist physicians at an outpatient oncological care center or in a primary oncological office, or in the outpatient department of an oncological dispensary (oncological hospital).

If an oncological disease is suspected or detected in a patient, general practitioners, district general practitioners, general practice physicians (family physicians), specialist physicians, and mid-level medical personnel shall refer the patient in the established manner for consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) for the provision of primary specialized health care.

Consultation at an outpatient oncological care center, a primary oncological office, or the outpatient department of an oncological dispensary (oncological hospital) must be performed no later than 5 working days from the date of issuance of the referral for consultation. The oncologist of the outpatient oncological care center (in the absence of an outpatient oncological care center, the oncologist of the primary oncological office or the outpatient department of the oncological dispensary (oncological hospital)) shall arrange for the acquisition of biopsy (surgical) material, as well as other diagnostic tests necessary to establish the diagnosis, including the extent of the oncological process and the stage of the disease.

In the event of the impossibility of acquiring biopsy (surgical) material or performing other diagnostic tests within the medical organization that incorporates the outpatient oncological care center (primary oncological office), the attending physician shall refer the patient to an oncological dispensary (oncological hospital) or to a medical organization providing medical care to patients with oncological diseases.

The timeframe for performing pathological examinations necessary for the histological verification of malignant neoplasms shall not exceed 15 working days from the date of receipt of the biopsy (surgical) material by the pathoanatomical bureau (department).

The timeframes for diagnostic instrumental and laboratory examinations in case of suspected oncological disease shall not exceed the timeframes established in the state guarantee program for the free provision of medical care to citizens, approved by the Government of the Russian Federation.

The diagnosis of an oncological disease is established by an oncologist, and in the case of malignant neoplasms of lymphoid, hematopoietic, and related tissues included in ICD-10 categories C81–C96, also by a hematologist.

An oncologist from an outpatient oncological care center (primary oncology office) refers the patient to an oncological dispensary (oncology hospital) or another medical organization providing medical care to cancer patients, including one subordinate to a federal executive body (hereinafter referred to as a federal medical organization), to clarify the diagnosis (if establishing the diagnosis is impossible, including the extent of the oncological process and disease stage), determine treatment tactics, and in the presence of medical indications for specialized, including high-tech, medical care.

For oncological diseases included in ICD-10 categories C37, C38, C40–C41, C45–C49, C58, D39, C62, C69–C70, C72, C74, as well as those corresponding to the codes of the International Classification of Diseases for Oncology (ICD-O), 3rd Edition 8936, 906-909, 8247/3, 8013/3, 8240/3, 8244/3, 8246/3, 8249/3, an oncologist at an oncological dispensary (oncological hospital) or other medical organization providing medical care to patients with oncological diseases shall organize a consultation or a medical board (consilium), including via telemedicine technologies, at federal state budgetary institutions subordinate to the Russian Ministry of Health that provide medical care (hereinafter referred to as national medical research centers for the purposes of this Procedure), in order to determine the treatment tactics.

In complex clinical cases, to clarify the diagnosis (in the event of the impossibility of establishing the diagnosis, including the extent of the oncological process and the stage of the disease) for the purpose of evaluation, interpretation, and description of the results, the oncologist shall arrange for the referral of:

digital images obtained from pathomorphological studies to the pathoanatomical bureau (department) of the fourth group (reference center) [1] via information interaction, including the use of telemedicine technologies during remote interaction between medical workers;

of digital images obtained from diagnostic imaging methods to the remote diagnostic imaging consultation center via information interaction, including the use of telemedicine technologies for remote interaction between medical workers;

biopsy (surgical) material for repeated pathomorphological, immunohistochemical, and molecular genetic studies: to the pathoanatomical bureau (department) of the fourth group (reference center), as well as to molecular genetic laboratories for molecular genetic testing.

Treatment tactics are established by a medical board (consilium) comprising oncologists, a radiation therapist, and a neurosurgeon (in cases of nervous system tumors) of the medical organization that includes departments of surgical methods for treating malignant neoplasms, antineoplastic drug therapy, and radiotherapy (hereinafter referred to as the oncological consilium), including an oncological consilium conducted using telemedicine technologies, with the involvement of other specialist physicians when necessary.

Dispensary follow-up by an oncologist for a patient with a diagnosed oncological disease is established and carried out in accordance with the procedure for dispensary observation of adults with oncological diseases.

For record-keeping purposes, information about a newly diagnosed case of an oncological disease shall be sent within 3 working days by the oncologist of the medical organization where the respective diagnosis was established to the oncological dispensary or the organization of the subject of the Russian Federation performing the function of registering patients with newly diagnosed malignant neoplasms, including via the Unified State Health Information System.

Specialized, including high-tech, medical care in medical organizations providing medical care to the adult population for oncological diseases is provided based on medical indications stipulated by the regulations on organizing the provision of specialized, including high-tech, medical care.

Specialized medical care, excluding high-tech care, in medical organizations subordinate to federal executive authorities is provided based on medical indications stipulated by paragraph 5 of the procedure for referring patients to medical organizations and other organizations subordinate to federal executive authorities for the provision of specialized (excluding high-tech) medical care, as provided in the appendix to the regulations on organizing the provision of specialized, including high-tech, medical care.

Waiting times for the provision of specialized (excluding high-tech) medical care shall not exceed the timeframes established in the program of state guarantees of free medical care to citizens, approved by the Government of the Russian Federation.

If a patient with an oncological disease has medical indications for medical rehabilitation, the oncologist arranges for it to be provided in accordance with the procedure for organizing adult medical rehabilitation.

If a patient with an oncological disease has medical indications for sanatorium-resort treatment, the oncologist arranges for it in accordance with the procedure for organizing sanatorium-resort treatment.

Palliative medical care for a patient with oncological diseases is provided in accordance with the regulations on organizing the provision of palliative medical care, including the procedure for interaction between medical organizations, social service organizations, and public associations and other non-profit organizations operating in the field of health protection.

If an oncological disease is suspected and/or detected in a patient during the provision of emergency medical care, the patient is transferred or referred to medical organizations providing medical care to patients with oncological diseases to determine management tactics and the need for additional other methods of specialized antitumor treatment.

Indications for hospitalization in a medical organization in an emergency or urgent form are:

1) the presence of complications of the oncological disease requiring the provision of specialized medical care in an emergency and urgent form;

2) presence of complications of treatment (surgical intervention, RT, drug therapy, etc.) of the oncological disease.

Indications for hospitalization in a medical organization in a planned form are:

1) the need to perform complex interventional diagnostic medical procedures requiring subsequent monitoring in an inpatient or day-hospital setting;

2) the presence of indications for specialized antitumor treatment (surgical intervention, RT, including contact, EBRD and other types of RT, drug therapy, etc.) requiring monitoring in an inpatient or day hospital setting.

Indications for discharging a patient from a medical organization are:

1) completion of a course of treatment or one of the stages of providing specialized, including high-tech, medical care in an inpatient or day hospital setting, provided there are no treatment complications requiring drug correction and/or medical interventions in an inpatient setting;

2) refusal of the patient or their legal representative from specialized, including high-tech, medical care in an inpatient or day hospital setting established by the multidisciplinary team of the medical organization providing cancer care, provided there are no complications of the underlying disease and/or treatment requiring drug correction and/or medical interventions in an inpatient setting;

3) in cases of non-compliance by the patient with prescriptions or the internal regulations of the medical and prophylactic institution, provided this does not threaten the patient's life and the health of others;

4) the need to transfer the patient to another medical organization according to the relevant medical specialty profile.

The conclusion on the advisability of transferring a patient to a specialized medical organization is made after a preliminary consultation on the provided medical documents and/or a preliminary examination of the patient by specialist physicians of the medical organization to which the transfer is planned.

7. Additional Information

Factors influencing thyroid cancer outcomes:

• extent of the tumor process;

• localization of metastatic foci;

• ability of the tumor and metastases to take up radioactive iodine;

• development of adverse events from targeted therapy drugs.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Polyakov Andrey Pavlovich, MD, PhD, Associate Professor, Head of the Microsurgery Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists

2. Polkin Vyacheslav Viktorovich, PhD, Head of the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, ORCID: 0000-0003-0857-321X; eLibrary SPIN: 5604-2012; e-mail: polkin83@mail.ru.

3. Agababyan Tatev Artakovna, PhD, Head of the Diagnostic Radiology Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Email: tatevik.05@mail.ru, SPIN code: 5752-3393, AuthorID: 622660, https://orcid.org/0000-0002-9971-3451

4. Alymov Yury Vladimirovich, PhD, Oncologist at the Department of Surgical Treatment No. 5 (Endocrine Oncology), Clinical Oncology Research Institute named after N.N. Blokhin of the National Medical Research Center of Oncology of the Russian Ministry of Health, Executive Director of the National Association of Head and Neck Oncologists; ORCID: https://orcid.org/0000-0002-6851-9867, e-mail: allmedperevod@gmail.com.

5. Beltsevich Dmitry Germanovich, MD, PhD, Professor, Head of Surgical Department 1 of the Department of Surgery, National Medical Research Center for Endocrinology of the Russian Ministry of Health; ORCID: http://orcid.org/0000-0001-7098-4584, eLibrary SPIN: 4475-6327, e-mail: belts67@gmail.com.

6. Borodavina Ekaterina Vladimirovna, PhD, Senior Researcher, Radiologist at the Department of Radiosurgical Treatment with Unsealed Radionuclides, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists.

7. Vanushko Vladimir Eduardovich, MD, PhD, Professor, Head of Surgical Department 2 of the Department of Endocrine Surgery, National Medical Research Center for Endocrinology of the Russian Ministry of Health; ORCID: http://orcid.org/0000-0001-6338-7490, eLibrary SPIN: 6097-8990, e-mail: vanushko@gmail.com.

8. Vladimirova Lyubov Yuryevna, MD, PhD, Professor, Head of the Department of Drug Treatment of Tumors, National Medical Research Center of Oncology of the Russian Ministry of Health

9. Gevorkov Artem Rubenovich, PhD, Senior Researcher, Radiation Oncologist at the Department of Radiation Therapy with Modification, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists

10. Guz Alexander Olegovich, PhD, Head of the Head and Neck Tumors Department, Chelyabinsk Regional Clinical Center of Oncology and Nuclear Medicine, member of the National Association of Head and Neck Oncologists.

11. Gulidov Igor Alexandrovich, MD, PhD, Professor, Head of the Radiation Therapy Department, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

12. Ignatova Anastasia Valeryevna, PhD, Oncologist at the Department of Surgical Treatment No. 5 (Endocrine Oncology), Clinical Oncology Research Institute named after N.N. Blokhin of the National Medical Research Center of Oncology of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists, Assistant at the Department of General and Clinical Dentistry, Peoples' Friendship University of Russia (RUDN University). ORCID: https://orcid.org/0000-0002-6796-0968

13. Ilyin Alexey Amurovich, MD, PhD, Leading Researcher at the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

14. Isaev Pavel Anatolyevich, MD, PhD, Leading Researcher at the Department of Radiation and Surgical Treatment of Head and Neck Diseases, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health

15. Kostromina Ekaterina Viktorovna, PhD, Senior Researcher at the Scientific Department of Diagnostic and Interventional Radiology, N.P. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, Associate Professor of the Department of Academic and Methodological Work, Associate Professor of the Department of Radiology and Biomedical Imaging, Faculty of Postgraduate Education, North-State Medical University, Radiologist at the Diagnostic Radiology Department, N.P. Petrov National Medical Research Center of Oncology.

16. Kropotov Mikhail Alekseevich, MD, PhD, Head of the Head and Neck Tumors Department, National Medical Research Center of Oncology of the Russian Ministry of Health

17. Krylov Valery Vasilyevich, MD, PhD, Head of the Department of Radiosurgical Treatment with Unsealed Nuclides, A.F. Tsyb Medical Radiological Research Center – branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

18. Kulbakin Denis Evgenyevich, MD, PhD, Senior Researcher, Highest Category Physician at the Head and Neck Tumors Department, Cancer Research Institute of the Tomsk National Research Medical Center.

19. Kutukova Svetlana Igorevna, MD, PhD, Associate Professor at the Department of Dentistry and Maxillofacial Surgery, Associate Professor at the Department of Oncology of the Faculty of Postgraduate Education, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Health of the Russian Federation, Oncologist at Department No. 10 (Antineoplastic Drug Therapy), City Clinical Oncology Dispensary of Saint Petersburg

20. Melnichenko Galina Afanasyevna, MD, PhD, Professor, Academician of the Russian Academy of Sciences, Deputy Director, National Medical Research Center for Endocrinology of the Russian Ministry of Health; ORCID: http://orcid.org/0000-0002-5634-7877, eLibrary SPIN: 8615-0038, e-mail: teofrast2000@mail.ru.

21. Mudunov Ali Muradovich, MD, PhD, Professor of the Russian Academy of Sciences, Head of the Head and Neck Tumors Department, Lapino Medical Center, President of the National Association of Head and Neck Oncologists.

22. Musin Shamil Ismagilovich, PhD, Head of the Head and Neck Tumors Department, Republican Clinical Oncology Dispensary of the Ministry of Health of the Republic of Bashkortostan

23. Nikiforovich Petr Alekseevich, PhD, Oncologist, Deputy Chief Physician for Oncological Service Coordination, National Medical Research Center for Endocrinology of the Russian Ministry of Health.

24. Podvyaznikov Sergey Olegovich, MD, PhD, Professor, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Vice President of the National Association of Head and Neck Oncologists.

25. Radzhabova Zamira Akhmedovna, PhD, Head of the Head and Neck Surgical Department, N.P. Petrov National Medical Research Center of Oncology of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists

26. Reshetov Igor Vladimirovich, MD, PhD, Academician of the Russian Academy of Sciences, Head of the Department of Oncology, Radiotherapy and Reconstructive Surgery, I.M. Sechenov First Moscow State Medical University, President of the Federation of Specialists in the Treatment of Head and Neck Diseases

27. Romanov Ilya Stanislavovich, MD, PhD, Senior Researcher at the Department of Surgical Treatment No. 5 (Endocrine Oncology), Clinical Oncology Research Institute named after N.N. Blokhin of the National Medical Research Center of Oncology of the Russian Ministry of Health, member of the National Association of Head and Neck Oncologists. ORCID: https://orcid.org/0000-0002-5421-5985

28. Romashchenko Pavel Nikolaevich, MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Department and Clinic of Faculty Surgery named after S.P. Fedorov, S.M. Kirov Military Medical Academy of the Ministry of Defense of the Russian Federation.

29. Rubtsova Natalia Aleftinovna, MD, PhD, Head of the Diagnostic Radiology Department, P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Center of the Russian Ministry of Health. Chief Freelance Specialist in Diagnostic Radiology and Instrumental Diagnostics of the Russian Ministry of Health in the Central Federal District of the Russian Federation.

30. Rudyk Andrey Nikolaevich, PhD, Assistant at the Department of Oncology, Radiology and Palliative Medicine, Kazan State Medical Academy, Oncologist at the Head and Neck Tumors Department, Prof. M.Z. Sigal Republican Clinical Oncology Dispensary of the Republic of Tatarstan

31. Rumyantsev Pavel Olegovich, MD, PhD, Deputy Chief Physician, Chief Oncologist-Radiologist, SOGAZ International Medical Center, member of the National Association of Head and Neck Oncologists; ORCID: http://orcid.org/0000-0002-7721-634X, eLibrary SPIN: 7085-7976, e-mail: pavelrum@gmail.com.

32. Severskaya, Natalia V., Cand. of Sci. (Med.), Head of the Clinical Laboratory Diagnostics Department, Endocrinologist at the A.F. Tsyb MRRC, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health, ORCID: 0000-0002-9426-8459, eLibrary SPIN: 3999-8816, e-mail: severskn@mrrc.obninsk.ru

33. Semiglazova, Tatiana Yu., Dr. of Sci. (Med.), Associate Professor, Head of the Scientific Department of Innovative Methods of Therapeutic Oncology and Rehabilitation at the N.N. Petrov National Medical Research Center of Oncology

34. Sleptsov, Ilya V., Dr. of Sci. (Med.), Professor at the Department of Surgery with a Course of Surgical Endocrinology at the Institute of Medical Education, Deputy Director for Medical Affairs; ORCID: 0000-0002-1903-5081; eLibrary SPIN: 2481-4331; e-mail: newsurgery@yandex.ru.

35. Stepanova, Alexandra M., Head of the Rehabilitation Department at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health

36. Falaleeva, Natalia A., Dr. of Sci. (Med.), Head of the Department of Drug Treatment of Malignant Neoplasms at the A.F. Tsyb MRRC, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health

37. Khmelevsky, Evgeny V., Dr. of Sci. (Med.), Professor, Head of the Radiotherapy Department at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health, Radiation Oncologist at the P.A. Herzen Moscow Oncology Research Institute, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health

38. Chernikov, Roman A., Dr. of Sci. (Med.), Head of the Department of Endocrinology and Endocrine Surgery at the Pirogov Clinic of High Medical Technologies, Saint Petersburg State University; ORCID: 0000-0002-3001-664X; eLibrary SPIN code: 7093-1088; e-mail: yaddd@yandex.ru.

39. Choynzonov, Evgeny L., Dr. of Sci. (Med.), Academician of the Russian Academy of Sciences, Director of the Cancer Research Institute of the Tomsk National Research Medical Center, Head of the Head and Neck Tumors Department at the Cancer Research Institute of the Tomsk National Research Medical Center, Head of the Department of Oncology at the Siberian State Medical University of the Russian Ministry of Health, Member of the All-Russian Public Organization "Russian Society of Head and Neck Cancer Specialists"

40. Shurinov, Andrey Yu., Cand. of Sci. (Med.), Senior Researcher at the Department of Radiosurgical Treatment with Open Radionuclides at the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

    Healthcare Delivery Organization Section

41. Gevorkyan, Tigran G., Deputy Director at the N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

42. Ivanov, Sergey A., Dr. of Sci. (Med.), Professor of the Russian Academy of Sciences, Director of the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health

43. Nevolskikh, Alexey A., Dr. of Sci. (Med.), Deputy Director for Clinical Work at the A.F. Tsyb MRRC – a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

44. Khaylova, Zhanna V., Cand. of Sci. (Med.), Deputy Director for Organizational and Methodological Work at the A.F. Tsyb MRRC, a branch of the National Medical Research Radiological Center of the Russian Ministry of Health.

Conflict of interest. The authors declare no conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Oncologist;

2. Surgeon;

3. Endocrinologist;

4. Radiologist;

5. Radiation oncologist;

6. General Practitioner (Family Doctor)

7. Pathologist.

Methods used for evidence collection/selection: searching electronic databases using keywords related to thyroid cancer and relevant sections of clinical guidelines, evaluating the quality and relevance of the retrieved sources.

Databases used for evidence collection/selection. The evidence base for the guidelines includes publications from the Cochrane Library, Embase, and MedLine databases. The search depth was up to 40 years.

Methods used to determine the quality and strength of evidence:

• expert consensus;

• assessment of significance in accordance with levels of evidence (Tables 1–3).

Table 1. Scale for assessing levels of evidence certainty for diagnostic methods (diagnostic interventions)

Table 2. Scale for assessing levels of evidence certainty for preventive, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitation interventions)

Table 3. Scale for assessing recommendation grades for preventive, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitation interventions)

Procedure for updating clinical guidelines. The mechanism for updating clinical guidelines provides for their systematic revision at least once every 3 years, as well as upon the emergence of new data from the perspective of evidence-based medicine regarding the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.

Appendix A3. Reference Materials

1. Beltsevich, D.G., Vanushko, V.E., Melnichenko, G.A., et al. Clinical guidelines of the Russian Association of Endocrinologists for the diagnosis and treatment of (multi)nodular goiter in adults (2015). Endocrine Surgery 2016;(1):5–12.

2. Beltsevich, D.G., Vanushko, V.E., Rumyantsev, P.O., et al. Russian clinical guidelines for the diagnosis and treatment of well-differentiated thyroid cancer in adults, 2017. Endocrine Surgery 2017;11(1):6–27. DOI: 10.14341/serg201716-27.

Appendix B. Physician Action Algorithms

Appendix C. Patient Information

1. Postoperative use of sodium levothyroxine** as replacement therapy does not adversely affect quality of life.

2. Pregnancy does not lead to the progression of thyroid cancer.

3. Thyroid cancer is not an indication for pregnancy termination.

4. After radioactive iodine treatment, planning a pregnancy is not recommended for 6 months.

5. Men are not recommended to participate in pregnancy planning for 120 days after radioactive iodine treatment.

6. Breastfeeding is not contraindicated for female patients who have received complex treatment for thyroid cancer.

Preparation for diagnostics or postoperative radioactive iodine therapy can be performed either by 3–4 weeks of sodium levothyroxine** withdrawal or by recombinant human TSH injections.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.