Thyroid Cancer: Clinical Guidelines

List of Abbreviations

ALT – alanine aminotransferase

AST – aspartate aminotransferase

ATC – anaplastic thyroid cancer

anti-TPO – anti-thyroperoxidase antibodies

anti-Tg – anti-thyroglobulin antibodies

Bethesda – Bethesda System for Reporting Thyroid Cytology 

HTE – hemithyroidectomy

HI – histological examination

EBRT – external beam radiotherapy

DTC – differentiated thyroid cancer

Russian Ministry of Health – Ministry of Health of the Russian Federation

MRI – magnetic resonance imaging

MTC – medullary thyroid cancer (C-cell carcinoma)

MEN – multiple endocrine neoplasia syndrome

MEN2A – multiple endocrine neoplasia type 2A syndrome

MEN2B – multiple endocrine neoplasia type 2B syndrome

LNs – lymph nodes

RT – radiotherapy

PTC – papillary thyroid cancer

PET – positron emission tomography

PET/CT – positron emission tomography + computed tomography

TC – thyroid cancer

RIT – radioiodine therapy

CEA – carcinoembryonic antigen

TFD – total focal dose

WBS – whole body scintigraphy

ST – suppressive hormone therapy

FNA – fine-needle aspiration biopsy

FNAB – fine-needle aspiration biopsy

T₄ – thyroxine

T₃ – triiodothyronine

Tg – thyroglobulin

TSH – thyroid-stimulating hormone

TE – thyroidectomy

TI-RADS – thyroid image reporting data system

US (UT) – ultrasound examination

FTC – follicular thyroid cancer

¹⁸FDG – fludeoxyglucose [18F]

CI – cytological examination

TG – thyroid gland

ALP – alkaline phosphatase

Terms and Definitions

Survival analysis is a class of statistical models used to estimate the probability of an event occurring.

Medical intervention – a range of medical examinations and/or medical procedures performed by a medical worker or other employee authorized to carry out medical activities, affecting the physical or mental state of a person and having a preventive, diagnostic, therapeutic, rehabilitative, or research orientation, as well as artificial termination of pregnancy.

Syndrome – a set of symptoms sharing a common etiology and pathogenesis.

Surgical intervention – an invasive procedure that may be used for diagnostic purposes and/or as a method of treating diseases.

Surgical treatment – a method of treating diseases by dividing and uniting tissues during a surgical operation.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Thyroid cancer is a malignant tumor developing from the glandular epithelium elements of the thyroid gland.

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

In pediatric patients, thyroid cancer is less common than in adults and has a more aggressive clinical course, especially in prepubertal children. Thyroid cancer is more prevalent in females; the girl-to-boy ratio in children ranges from 2:1 to 6:1. Thyroid cancer in children is more frequently diagnosed at later stages compared to adults.

In adolescents, the incidence of thyroid cancer is 10 times higher than in younger children [1].

Papillary thyroid cancer (PTC) is the most common form in children and adolescents, accounting for 70–99%, with an average of 80% of all cancer forms [2–5]. This variant of thyroid cancer is characterized by a high percentage of regional metastasis to the cervical lymph nodes (80–90%), a high frequency of intraglandular dissemination ranging from 30 to 81%, and the presence of "occult" forms, where metastases are sometimes the only manifestation of the disease. Compared to adult patients, children have a significantly higher percentage of non-encapsulated carcinomas; a capsule is identified in 13% of observations in children under 10 years of age, and in 21% of children aged 11–15 years. Distant metastases develop in 30–35% of children and adolescents, typically in the lungs. Bone metastases in children are very rare. Involvement of the central nervous system and other organs is observed in isolated cases. Differentiated thyroid cancer in children differs between prepubertal and pubertal age groups. The younger the child, the more aggressive the disease course, and extrathyroidal extension, regional metastasis, and lung metastases are more frequently observed.

Follicular thyroid cancer (FTC) is the second most common type in children, accounting for 5% to 12% of cases. Unlike in adults, FTC in children has a benign and slow clinical course.

Medullary thyroid cancer (MTC) in children occurs both sporadically and as part of hereditary endocrine syndromes, accounting for 2% to 25% (most commonly 2% to 5%) of all thyroid cancer cases; 30% are sporadic cases and 70% are familial variants.

Familial forms of MTC may present in combination with multiple endocrine neoplasia (MEN) syndromes or as isolated MTC:

• MEN 2A (Sipple syndrome) – combination of MTC with pheochromocytoma (in 10–60%), parathyroid gland pathology (20–23%), and cutaneous lichen amyloidosis (less than 5%).

• MEN 2B (Gorlin syndrome) – combination of MTC with pheochromocytoma (50–60%), multiple neuromas of the oral mucosa, lips, and eyelids (100%), and a "marfanoid" body habitus (100%).

• Familial MTC (without MEN).

The etiological factor of thyroid cancer associated with the development of MEN2 syndrome is a heritable missense mutation in the RET proto-oncogene located on the long arm of chromosome 10 (10q11.2). Cases of differentiated thyroid cancer have also been described in Beckwith-Wiedemann syndrome [6], Li-Fraumeni syndrome [7], McCune-Albright syndrome [8], and Peutz-Jeghers syndrome [9].

Undifferentiated thyroid cancer in children has been described only in isolated case reports. In adults, it is also a rare tumor, accounting for 0.5–2% of all thyroid cancer cases according to various authors.

Several risk factors are associated with the development of thyroid nodules in children: iodine deficiency, prior radiation exposure (low-dose radiation is particularly dangerous), a family history of thyroid disease, and the presence of a genetic syndrome in patients [10].

The thyroid gland in children and adolescents is the most sensitive to iodine deficiency and radiation exposure. The prevalence of endemic goiter in children in the central region of Russia reaches up to 40% in some areas. Growth factors activated by a decrease in iodolactones play a major role in hyperplastic processes driven by iodine deficiency. The Chornobyl nuclear power plant accident, which resulted in the release of radioactive substances, led to a catastrophic surge in thyroid pathology in children [11]. According to many researchers, the incidence of thyroid cancer in Belarusian children increased more than 70-fold, indicating a direct effect of radiation.

One of the high-risk groups includes patients who previously received radiation therapy to the neck region for a malignant tumor (Hodgkin lymphoma, CNS tumors, leukemia, neuroblastoma, craniospinal irradiation for CNS tumors, soft tissue tumors of the face and neck) [12,13]. The disease risk is high among patients who received radiation therapy in early childhood, particularly under the age of 1 year and at doses up to 20–29 Gy [14,15].

1.3 Epidemiology of the Disease or Condition

The proportion of thyroid cancer in the structure of all malignant tumors under the age of 18 is 1–1.5% [2–5]. The annual increase in thyroid cancer incidence worldwide ranges from 2 to 12%. Thyroid cancer in children accounts for 2 to 6% of all tumors and 8 to 22% of malignant solid head and neck tumors. Thyroid cancer predominates in females; the girl-to-boy ratio in children ranges from 2:1 to 6:1, with an average ratio of 3.6:1. The main age of patients at disease onset is 8–14 years. Children under 6 years of age account for 15–20% of all cases, and rare cases of thyroid cancer in children under 3 years of age have been documented (about 3% of cases). The largest number of children (61%) develop the disease at the age of 11–14 years, i.e., during puberty, with a girl-to-boy ratio of 4.6:1. At age 15–19, differentiated thyroid cancer is the eighth most common cancer in males and the second most common in females, in whom it is diagnosed 5 times more frequently than in males of the same age.

1.4 Features of Coding the Disease or Condition

C73 – Malignant neoplasm of thyroid gland

1.5 Classification of the disease or condition

Malignant tumors of the thyroid gland (according to the WHO Classification of Thyroid Tumors, 5th edition, 2022)

Follicular cell-derived carcinomas

Papillary carcinoma 8260/3

– Follicular histotype, including diffuse follicular 8340/3

– Encapsulated variant 8343/3

– Columnar cell variant 8344/3

– Oncocytic variant 8342/3

– Tall cell variant

- Diffuse sclerosing variant

- Papillary carcinoma with fibromatous (fasciitis-like) stroma

- Solid/trabecular variant

- Spindle cell variant

- Clear cell variant

- Warthin-like variant

- Hobnail variant

Follicular carcinoma, NOS 8330/3

1.1.1 Minimally invasive follicular carcinoma 8335/3

1.1.2 Encapsulated angioinvasive follicular carcinoma 8339/3

1.1.3 Widely invasive follicular carcinoma 8330/3

1.1.4 Oncocytic carcinoma of the thyroid 8290/3

High-grade non-anaplastic follicular cell-derived carcinoma

1.1.5 Poorly differentiated carcinoma 8337/3

1.1.6 Poorly differentiated oncocytic carcinoma 8290/3

1.1.7 High-grade well-differentiated carcinoma

1.1.8 Anaplastic carcinoma 8020/3

Salivary-type carcinomas of the thyroid gland:

Mucoepidermoid carcinoma 8430/3

Secretory carcinoma 8502/3

Thyroid carcinomas of uncertain histogenesis:

Sclerosing mucoepidermoid carcinoma with eosinophilia 8430/3

Cribriform-morular carcinoma 8201/3

Medullary carcinoma 8345/3

Medullary carcinoma

Medullary carcinoma, high grade

Mixed medullary and follicular tumors:

Mixed medullary and follicular carcinoma 8346/3

Mixed medullary and papillary carcinoma 8347/3

Group of other tumors: encapsulated follicular-patterned thyroid tumors

1. Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) 8349/1

2. Thyroid tumors of uncertain malignant potential: incl.

a) Follicular tumor of uncertain malignant potential 8335/1

б) Well-differentiated tumor of uncertain malignant potential 8348/1

1.1.9 3. Hyalinizing trabecular tumor 8336/1

1.1.10 Thymic tumors within the thyroid gland:

1.1.11 Thymoma 8580/3

1.1.12 Spindle epithelial tumor with thymus-like elements 8588/3

1.1.13 Intrathyroidal thymic carcinoma 8589/3

1.1.14 Embryonic neoplasms of the thyroid gland

1.1.15 Thyroblastoma

WHO Classification of Tumours of Endocrine Organs (4th edition, 2017)

Papillary carcinoma 8260/3

– Follicular variant of papillary carcinoma 8340/3

– Encapsulated variant of papillary carcinoma 8343/3

– Papillary microcarcinoma 8341/3

– Columnar cell variant of papillary carcinoma 8344/3

– Oncocytic variant of papillary carcinoma 8342/3

– Diffuse-sclerosing variant of papillary carcinoma

Tall cell papillary carcinoma

Cribriform-morular variant of papillary carcinoma

Hobnail variant of papillary carcinoma

Papillary carcinoma with fibromatous (fasciitis-like) stroma

Solid/trabecular variant

Spindle cell variant of papillary carcinoma

Clear cell variant of papillary carcinoma

Warthin-like variant of papillary carcinoma

Follicular carcinoma, NOS 8330/3

– Minimally invasive follicular carcinoma 8335/3

– Encapsulated follicular carcinoma with vascular invasion 8339/3

– Widely invasive follicular carcinoma 8330/3

– Hürthle cell carcinoma 8290/3

– Poorly differentiated carcinoma 8337/3

– Anaplastic carcinoma 8020/3

– Squamous cell carcinoma 8070/3

Medullary carcinoma 8345/3

Mixed medullary and follicular carcinoma 8346/3

Mucoepidermoid carcinoma 8430/3

Sclerosing mucoepidermoid carcinoma with eosinophilia 8430/3

Mucinous carcinoma 8480/3

Group of other tumors: encapsulated follicular-patterned thyroid tumors

– Follicular tumor of uncertain malignant potential 8335/1

– Well-differentiated tumor of uncertain malignant potential 8348/1

– Noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) 8349/1

TNM staging system for thyroid cancer

The TNM system describes the extent of the tumor within the thyroid gland itself, its size, the extension of the tumor process to surrounding organs and tissues (T category), the presence of tumor cells in regional lymph nodes of the neck (N category), and the presence of metastases in distant organs (M category).

There are two classifications of the "T" indicator – clinical and pathological.

The clinical classification is based on examination data, ultrasound findings, and fine-needle aspiration biopsy. It determines the treatment strategy and, in particular, the extent of surgery.

In the preoperative stage, it is not always possible to determine the true extent of the tumor process; the stage is more accurately determined after surgical removal of the tumor based on the results of histological examination (pathological stage). Postoperative staging allows for individual risk stratification for each patient, which will ultimately determine the type and frequency of subsequent follow-up examinations. It should be noted that if the patient did not undergo regional lymph node dissection, the N stage must be classified as Nx and cannot be precisely determined.

Primary tumor (T).

Tx – insufficient data to assess the primary tumor

T0 – no tumor found in the thyroid gland

T1 – tumor 2 cm or less in greatest dimension, limited to the thyroid gland tissue:

T1a – tumor up to 1 cm inclusive

T1b – tumor greater than 1 cm and up to 2 cm inclusive

T2 – tumor greater than 2 cm, but not exceeding 4 cm in greatest dimension, limited to the thyroid gland tissue

T3a – tumor greater than 4 cm in greatest dimension, limited to the thyroid gland tissue

T3b – tumor of any size with gross extension into the sternothyroid or sternohyoid muscles

T4a – tumor of any size extending beyond the thyroid capsule, involving subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve

T4b – tumor invading the prevertebral fascia, or encasing the carotid artery or mediastinal vessels

Regional lymph nodes (N).

Regional lymph nodes of the central compartments, lateral, cervical, and upper mediastinal.

Nx – insufficient data to assess regional lymph nodes

N0 – no cancer cells in regional lymph nodes

N1 – regional lymph node metastases are present.

In this case, two subgroups are distinguished depending on the location of the affected lymph nodes:

N1a – metastases to level VI lymph nodes (paratracheal, pretracheal, prelaryngeal [Delphian]), or upper mediastinal lymph nodes (level VII).

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

IA – submental lymph node group

IB – submandibular lymph node group (located anterior and posterior to the submandibular salivary gland).

II – upper jugular, jugulodigastric, and upper spinal accessory lymph nodes,

III – mid jugular lymph nodes,

IV – lower jugular and omohyoid lymph nodes,

V – lower spinal accessory and transverse cervical lymph nodes,

VI – anterior compartment lymph nodes – pre- and paratracheal lymph nodes, prelaryngeal (Delphian) and parathyroid lymph nodes, including lymph nodes along the recurrent laryngeal nerve.

VII – upper mediastinal lymph nodes

Distant metastases (M).

Mx – distant metastases cannot be assessed

M0 – no distant metastases

M1 – distant metastases are present

Staging in groups of patients with papillary and follicular thyroid cancer (differentiated cancer), medullary, and anaplastic thyroid cancer is performed separately.

For patients with differentiated thyroid cancer under the age of 45 years, there are only two stages – stage I and stage II. The distinction between stage I and stage II is solely the presence of distant thyroid cancer metastases (in the lungs, bones).

Patients under 45 years of age:

Stage I – tumor of any T and N value, no distant metastases – M0.

Stage II – tumor of any T and N value, presence of distant metastases – M1.

Note: Thyroid cancer metastases in regional lymph nodes detected within the first three months after initial surgical treatment are regarded as primarily diagnosed.

Distant thyroid cancer metastases detected within the first six months after surgery are equated to primarily established ones. All other cases of tumor process detection after the specified periods are regarded as disease relapse.

For medullary thyroid carcinoma (all age groups)

Stage I – T1N0M0

Stage II – T2N0M0, T3N0M0

Stage III – T1, T2, T3, N1aM0

Stage IVA – T1, T2, T3, N1b, M0

Stage IVB – T4, any N, no distant metastases (M0)

Stage IVC – any T and N stages, in the presence of distant metastases

For anaplastic (undifferentiated) thyroid carcinoma

Any case of anaplastic carcinoma is assessed as stage IV of the disease.

Stage IVA – T4a, any N stage, M0

Stage IVB – T4b, any N stage, M0

Stage IVC – any T stage, any N, M1

T4a – tumor is resectable; T4b – tumor is unresectable.

Using the TNM classification system, patients are divided into three risk groups for disease recurrence or the appearance of distant metastases.

1. Low-risk group.

Tumor is confined to the thyroid gland (T1-T2), no lymph node involvement (N0), or presence of micrometastases (replacement of no more than 15% of the lymph node cross-section by tumor cells) in no more than 3 level VI lymph nodes (N1a).

2. Intermediate-risk group.

Primary tumor T3. Lymph node tumor involvement N1a, or a minimal number (no more than 3) of involved N1b nodes.

3. High-risk group.

Primary tumor T4. Lymph node tumor involvement N1b. Presence of M1 or without metastases.

Table 2 Prognostic factors for follicular carcinoma

Table 3 Prognostic factors for PTC

MTC is characterized by an aggressive clinical course, manifested by a high percentage of metastasis to the neck lymph nodes (from 60% in sporadic to 90% in hereditary forms), and is represented by two clinical variants of the disease – sporadic and hereditary. The hereditary variant is characterized by multifocality and bilateral involvement.

Undifferentiated carcinoma in children is extremely rare and the prognosis of the disease is very unfavorable.

1.6 Clinical presentation of the disease or condition

The clinical presentation of thyroid cancer in pediatric patients is generally very scant. The only clinical manifestations of the disease are deformations and asymmetries in the neck region (identified or visually detectable thyroid nodule or enlarged neck lymph nodes). The presence of enlarged regional lymph nodes (LNs) is the second most frequent symptom of thyroid cancer. Cervical LNs located along the neurovascular bundle are most frequently affected. In some cases, with a prolonged course of the disease, children develop breathing difficulties caused by tumor invasion into the trachea. In other observations, metastatic involvement of the lung tissue during dissemination of the process can lead to the development of respiratory failure. Invasion of the recurrent nerve by the tumor can cause voice changes ranging from hoarseness to aphonia (an extremely rare manifestation of the disease). Metastatic involvement of regional neck LNs is noted in 84% of observations; in 54% of them, regional metastases are visually determined earlier than changes in the thyroid gland.

Diagnostic and treatment tactics for thyroid cancer are similar to those in adults, but thyroid cancer in children has a number of significant differences. Children and adolescents do not have clinically latent thyroid carcinomas, since at this age a malignant thyroid tumor, even of a very small size, is potentially dangerous and can give regional and distant metastases. The term "thyroid microcarcinoma" as a tumor with low aggressiveness potential is not used in pediatric patients. It should be noted that childhood age as a factor activating the potential of tumor aggressiveness manifests itself in any histological type of thyroid cancer, and the risk is higher the younger the child is. In childhood and adolescence, proliferative changes in tissues have a much higher intensity compared to adults. These processes reach their highest activity during puberty in the endocrine system organs. At the same time, the immune system of the growing organism is actively forming and improving, including anti-carcinogenic immunity. This reactive physiological state probably explains the high rates of frequency and extent of tumor dissemination, and as a consequence, the rapid and aggressive course of thyroid cancer in childhood and adolescence. Lung metastases in children are usually determined as small-focal dissemination, and therefore they are rarely detected radiologically, and in the overwhelming percentage of cases are diagnosed during examination with ¹³¹I (occult metastases). Metastases in children are functionally more active than in adults, which ensures a higher efficacy of radioiodine therapy in pediatric and adolescent patients. The functional activity of PTC cells is not uniform in tumors of various structures. It is higher in PTC of follicular structure and lower in cells of the solid variant. These clinical and anatomical features should be taken into account when planning treatment tactics.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The definitive diagnosis and extent of thyroid cancer are established after routine pathomorphological examination of the surgical material and whole-body scintigraphy. Assessment of the tumor process extent is carried out in accordance with the TNM and pTNM classification systems.

It is necessary to carry out differential diagnosis of thyroid cancer, primarily with benign neoplasms such as adenoma and nodular goiter, and with acute and chronic thyroiditis. Much less frequently, specific strumitis such as tuberculosis, actinomycosis, and echinococcosis develops in the thyroid gland in children. Regional metastases of thyroid cancer are most often mistaken for banal lymphadenopathies, tuberculosis, median and lateral neck cysts, Hodgkin's disease, etc. Cytological examination of the node punctate is of decisive importance in differential diagnosis. An auxiliary diagnostic method in Hashimoto's autoimmune thyroiditis can be immunochemiluminescent, as well as tandem mass-spectrometric hormone testing of the thyroid gland.

Examination methods for pediatric patients with suspected thyroid cancer:

1. Assessment of the patient's subjective sensations and collection of medical history.

2. Evaluation of visual data.

3. Performing physical examination methods.

4. Performing ultrasound diagnostics of the thyroid gland and cervical lymph nodes.

5. Determination of thyroid hormone profile, TSH determination, calcitonin level determination in case of suspected medullary thyroid carcinoma (MTC).

6. Performing FNAB (puncture of thyroid tumor nodules and altered lymph nodes under ultrasound guidance).

7. Assessing thyroglobulin and calcitonin levels in washout from fine-needle aspiration biopsy of altered lymph nodes in suspected medullary carcinoma

8. Performing computed tomography of the thoracic cavity.

9. Positron emission tomography in generalized forms of medullary or undifferentiated thyroid cancer

10. .

The main objectives of the examination are:

1) confirmation (verification) of the diagnosis of "thyroid cancer", preferably determining the form and variant of thyroid cancer;

2) detection and determination of the degree of local tumor spread and detection of regional metastases;

3) detection and determination of the degree of distant tumor spread (distant metastases).

2.1 Complaints and Anamnesis

In the initial period of the disease, the patient has no complaints. As the nodular formation in the thyroid gland grows, the patient develops discomfort in the neck during swallowing, voice changes, cough, a palpable nodular formation in the projection of the thyroid gland, and enlarged cervical lymph nodes. In adolescent patients, complaints of malaise, headache, menstrual irregularities in girls, and overweight often come to the foreground, which prompts patients to see a doctor.

In the early stages, thyroid cancer may present as a single nodular formation of dense-elastic consistency, movable upon swallowing. As the tumor grows and extends beyond the organ capsule, the tumor formation becomes fixed, does not move upon swallowing, and is fused with surrounding soft tissues. Thyroid cancer arising against the background of autoimmune thyroiditis (AIT) is particularly difficult to diagnose because the thyroid gland and lymph nodes are enlarged, which complicates the diagnosis of the disease.

There are clinical variants where the tumor exhibits rapid and aggressive growth extending beyond the thyroid capsule, with infiltration and invasion of surrounding tissues and extensive regional or distant metastasis. The younger the child, the more aggressive the disease course (spread beyond the thyroid gland, distant metastasis). The deep jugular lymph nodes located along the neurovascular bundle of the neck are most frequently involved in the process; lesions of this lymph node group are detected in 98% of patients with metastases, and distant metastases are detected in 20–22% of children (in the lungs for differentiated cancers, and in the lungs, liver, bones, and brain for medullary cancer, mostly in the lungs and very rarely in bones). Of particular interest are pediatric patients with occult thyroid cancer, where there is a small-sized tumor lesion of the thyroid gland not detected by available diagnostic methods, and the first clinical sign serves as "chronic cervical lymphadenopathy", and the cause of such "lymphadenopathies" may be thyroid cancer.

Anamnesis of differentiated thyroid cancer (DTC).

Often, a child is treated by pediatricians or pediatric surgeons for suspected cervical lymphadenitis of various etiologies, and only after a long period of time, sometimes two years or more, is the diagnosis of primary thyroid cancer and metastatic cervical lymph node involvement established.

Anamnesis of medullary thyroid carcinoma (MTC).

Taking the anamnesis in suspected MTC is carried out according to the scheme for DTC with additional examinations. Additionally, anamnestic data are collected regarding the presence of MTC in close relatives, parathyroid pathology (frequent bone fractures, kidney stones, etc.), pheochromocytoma (cases of hypertensive crises and strokes at a young age); and whether diarrhea accompanied the thyroid pathology.

Anamnesis taking: interviewing parents and the patient (if age permits); taking into account the child's complaints, place of residence before the onset of disease signs, cases of cancer among relatives, harmful exposures to the mother's body during pregnancy and to the child, prior anti-cancer therapy, and indications of a congenital nature of the disease.

Comments: when taking the anamnesis, attention should be paid to cases of thyroid cancer in the family and close relatives, and cases of sudden death. During the examination and interview with the patient, attention must be paid to the presence of concomitant endocrinological pathology and unusual appearance. When questioning the parents and the patient, attention should be paid to the time of onset of neck deformation, the rate of external changes, and the presence of complaints [4,5,10,16].

2.2 Physical Examination

Comments: these signs may indicate the tumor of the thyroid gland extending beyond its borders, as well as pulmonary tissue involvement.

2.3 Laboratory Diagnostics

At the stage of establishing a diagnosis of thyroid cancer:

Comments: comprehensive laboratory diagnostics provides information on the state of internal organs. For the diagnosis of tumor diseases and the assessment of the functional state of the thyroid gland, immunochemiluminescent and tandem mass spectrometric determination of markers and thyroid hormone levels (TSH, free T₄, anti-TPO, anti-Tg, Tg) are used. After thyroidectomy for papillary or follicular cancer, normalization of the thyroglobulin level is observed; with the appearance of relapse and metastases, it rises again.

Comments: stimulated calcitonin is determined 2 minutes and 5 minutes after the administration of #calcium gluconate** at a rate of 0.27 mg/kg of the patient's body weight [18]. An elevated calcitonin level serves as a marker for medullary carcinoma.

2.4 Instrumental Diagnostics

Diagnostics of DTC:

• For all patients with suspected malignant neoplasm of the thyroid gland, as well as before radioiodine therapy, it is recommended to perform ultrasound of the thyroid and parathyroid glands, ultrasound of the cervical lymph nodes (one anatomical zone), comprehensive abdominal ultrasound, and retroperitoneal ultrasound [5,10,19].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment: Ultrasound is the primary method for quantitative and qualitative assessment of changes in the thyroid gland. The method makes it possible to evaluate the localization, dimensions, structure, number of foci (nodules) in the thyroid gland, the nature of the nodule's blood supply, and the presence of calcifications. The integrity of the nodule capsule and the thyroid gland itself is assessed, as well as the relationship of the tumor with the larynx and trachea. When examining the cervical lymphatic drainage system, a detailed analysis of all groups of cervical lymph nodes is performed, assessing the lymph node structure, the presence or absence of inclusions, and the relationship with blood vessels and surrounding tissues. Real-time ultrasound elastography is performed to assess the density of the thyroid tumor formation.

To classify thyroid nodules and stratify malignancy risk, Horvath et al. (2011) proposed a specially developed program called TI-RADS (Thyroid Imaging Reporting and Data System). This classification reflects the malignancy risk of a thyroid nodule expressed as a percentage (Table 4).

Classification TI-RADS

EU-TIRADS Classification

The use of TI-RADS facilitates a clear determination of the risk of thyroid cancer in detected nodules and the indications for fine-needle aspiration biopsy to assess the necessity of surgical intervention [27]. Nodular lesions with TI-RADS 3 to TI-RADS 5 diagnostic categories are subject to puncture biopsy.

TI-RADS 3 nodular lesions are subject to puncture if the nodular lesion is 1 cm or larger. For nodular lesions less than 1 cm in the absence of: altered lymph nodes, vocal fold paresis not of traumatic or iatrogenic origin, the child belonging to a high-risk group for thyroid cancer development (history of radiation therapy to the head/neck or I-131-MIBG administration, hereditary syndromes predisposing to thyroid neoplasms, history of radiation exposure).

Abdominal and retroperitoneal ultrasound must evaluate the liver, pancreas, adrenal glands (to rule out pheochromocytoma), ovaries in girls, and, if necessary, testicular examination in boys. When diagnosing medullary thyroid carcinoma, an adrenal ultrasound must be performed.

Comments: MRI provides an accurate assessment of the local and regional extent of the tumor process. Contrast-enhanced MRI can identify a thyroid mass measuring 1–2 mm or larger, assess its margins, presence of a capsule, and determine tumor invasion into surrounding organs (larynx, trachea, esophagus, and the relationship of the tumor to the great vessels of the neck and upper mediastinum). MRI allows for the detection of metastatic involvement of retrotracheal and upper mediastinal lymph nodes.

Comments: the scintigraphy method is based on differences in radionuclide uptake between tumor and healthy thyroid tissue, allowing for the determination of the extent of the tumor process. In the vast majority of cases, thyroid cancer is visualized as a "cold" nodule. Scintigraphy is indicated in determining the causes of thyrotoxicosis with a thyroid nodule to rule out autonomy, which is also encountered in thyroid cancer.

Scintigraphy with #sodium iodide [131I] (V09FX03 according to the ATC classification) and #sodium iodide [123I] (V09FX02 according to the ATC classification) is used to assess the radicality of performed surgical treatment and in case of suspected disease recurrence.

Comments: in case of phonation disorders or breathing difficulties, laryngoscopy is mandatory, revealing in some cases the involvement of the recurrent nerve, its damage during previous surgeries, or tumor invasion into the tracheal wall. If tumor invasion into the tracheal or esophageal wall is suspected, tracheoscopy and esophagoscopy are indicated.

Comments: the main indication for PET is a progressive rise in thyroglobulin or calcitonin levels in the absence of uptake on 131I scintigraphy [2¹³¹].

• In patients whose medullary thyroid carcinoma presents in combination with MEN 2B syndrome (see section 1.2 of these guidelines), it is recommended to perform esophagogastroduodenoscopy and colonoscopy to rule out mucosal neuromas [31].

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

2.5 Other Procedures

Comments: molecular genetic testing must be performed if a hereditary nature of the disease is suspected. This is especially important when a familial form of MTC is suspected; in this case, genetic diagnostics are performed not only for the patient, but also for all family members (siblings and parents). Rare familial variants of papillary thyroid cancer, Gardner syndrome, and Cowden syndrome must be kept in mind [4,5,16]. Screening of relatives of patients with MTC using clinical methods alone only detects already manifested cases of the disease. Screening using molecular biological testing allows the identification of RET mutation carriers [32].

Comments: A mandatory diagnostic method is the confirmation of malignancy via FNAB followed by cytological examination of the aspirate from the thyroid nodule(s) and enlarged cervical lymph nodes.

The clinical diagnosis is based on cytological examination.

The results of the cytological examination are classified in accordance with the 2023 Bethesda System for Reporting Thyroid Cytology [35–38].

The latest version of the classification distinguishes 6 diagnostic categories (Table 3).

In case of an indeterminate cytologic conclusion that does not correspond to clinical data, repeat FNA is necessary. Indications for repeat cytological examination include changes in the nodule structure during follow-up, which should be performed at least once every 3 months [36].

Comments: analysis of the lymph node aspirate for thyroglobulin and calcitonin will allow a conclusion to be made regarding metastatic lymph node involvement.

Comments: the routine histological report must include: a) macroscopic description of the specimen (dimensions of the removed gland, consistency, color, presence of a capsule; areas of stellate retraction and other features of the gland must be noted); b) microscopic examination of all nodular formations: description of the histological type of structure (papillary, follicular, trabecular, alveolar, solid, a combination of different types (note the presence of psammoma bodies), calcifications, foci of necrosis, sclerosis, squamous cell metaplasia, lymphoplasmacytic infiltration); description of proliferating cells (size, shape, tinctorial properties of the cytoplasm: clear, "empty", oxyphilic, granular. Characteristics of nuclei with a description of their size, shape, contours, chromatin state. Presence of intranuclear cytoplasmic inclusions, nucleolus, longitudinal nuclear grooves, mitotic activity); description of the node capsule, foci of peripheral sclerosis. It is necessary to note the severity of capsule invasion from microinvasion to tumor breakthrough beyond the capsule of the node or gland, pay attention to vascular invasion, considering vessels inside and/or outside the node capsule; when examining the thyroid tissue surrounding the node, pay attention to the presence of foci of tumor growth, lymphoplasmacytic infiltration; description of the state of lymph nodes (metastasis, lymphoid tissue hyperplasia) [2,4,5,16].

When performing a biopsy and/or surgical intervention in a non-specialized medical organization, it is advisable to have the biopsy (surgical) material re-evaluated by a pathologist in a specialized medical organization.

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

Methods of thyroid cancer treatment in pediatric patients include: surgical, radiation (radioiodine therapy and external beam radiotherapy), medical, and their combination.

Goal of treatment: complete recovery.

Indications for hospitalization: surgical treatment, radioiodine therapy

The main method of treatment for thyroid cancer in pediatric patients is surgery.

3.1. Surgical treatment

Surgical intervention in pediatric patients with thyroid cancer should be radical, yet maximally organ-preserving with respect to other vital anatomical structures.

• All pediatric patients with thyroid cancer undergoing surgical treatment are recommended to use intraoperative neuromonitoring [78-80].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comments: Surgical treatment of children with thyroid cancer should be performed in specialized centers with the greatest experience in thyroid and regional neck lymph node surgery in children, the lowest rate of postoperative complications, and a multidisciplinary team of specialists.

Before performing surgical treatment, it is recommended to obtain:

1. Consent for surgical treatment from the parents (legal guardians) or from the patient themselves if the child has reached the age of 15.

2. Conclusion from a pediatric oncologist and/or pediatric endocrinologist regarding the diagnosis of "thyroid cancer" or "suspected thyroid cancer".

3. Absence of chronic diseases in the decompensated stage, severe organ dysfunctions.

4. Absence of signs of a severe active infection.

5. Negative pregnancy test in girls older than 12 years.

6. Absence of allergic reactions to local anesthetics and general anesthesia medications.

Indications for surgical treatment in pediatric thyroid cancer are:

1. Patients in Bethesda diagnostic category III with node size greater than 1 cm, tendency to grow, presence of altered lymph nodes, vocal cord paresis not of traumatic or iatrogenic origin, belonging of the child to a high-risk group for thyroid cancer (history of head/neck radiation therapy or I-131-MIBG therapy, hereditary syndromes predisposing to thyroid neoplasms, history of radiation exposure) undergo diagnostic hemithyroidectomy. If the node size is less than 1 cm, repeat FNA is performed (in 3-6 months).

2. Categories IV, V, and VI of the cytological conclusion according to the international cytological classification (follicular neoplasm or suspicion of a follicular neoplasm, suspicion of malignancy, malignant neoplasm (Bethesda System for Reporting Thyroid Cytopathology, 2023);

3. presence of metastatic lesion in a neck lymph node on diagnostic puncture,

4. presence of distant metastases of thyroid cancer

The approach to deciding the scope of surgery on the thyroid gland depends on the morphological structure of the tumor (form and variant of thyroid cancer), disease stage, localization and number of nodes in the thyroid gland, and the child's age. All thyroid surgeries are performed extracapsularly.

• Hemithyroidectomy (HT) with isthmusectomy is recommended as the minimum volume of intervention [3–5,13,29,32,36,39].

Level CLevel 5Level of recommendation evidence C (reliability level of evidence – 5).

Comment: The scope of surgery for papillary carcinoma in pre-pubertal children is total thyroidectomy, except for T1aN0M0.

Hemithyroidectomy with isthmusectomy and central neck lymph node dissection is performed in patients with a malignant neoplasm size up to 1 cm, in the absence of tumor involvement of lymph nodes or the presence of no more than 3 micrometastases in the lymph nodes of the paratracheal and pretracheal region on the affected side, with indication of the total number of removed lymph nodes (St. T1aN(0-1a)M0).

Hemithyroidectomy with isthmusectomy and central neck dissection is acceptable in stage T1bN(0-1a-micrometastases in no more than 3 lymph nodes, provided the total number of removed lymph nodes is specified)M0, provided the tumor has an intrathyroid location with an intact thyroid capsule, a favorable morphological variant, ultrasound-proven unilateral thyroid involvement, absence of abnormal lymph nodes, and no hereditary history or history of radiation exposure.

In children with a time interval of more than 10 years after radiation exposure, stage T1aN(0)M0 indicates hemithyroidectomy with isthmusectomy.

For stages above T1bN(0-1a)M0, thyroidectomy with central neck dissection is indicated.

If the primary tumor diameter in differentiated thyroid cancer does not exceed 1.0 cm, but multifocal disease is detected or metastases are found preoperatively, thyroidectomy should be performed immediately.

Following thyroidectomy, secondary lesions can easily be detected by measuring thyroglobulin levels; this approach yields a low recurrence risk that rarely exceeds 3–4%. Furthermore, radioiodine therapy becomes feasible, as does monitoring for recurrence or tumor metastases during suppressive hormone therapy. The risk of death from thyroid cancer with this strategy can be reduced to 1–2%, and the rate of major complications to 1–2%. Follow-up studies have shown a 100% 15-year survival rate after thyroidectomy in patients with invasive differentiated thyroid cancer, compared to 74.2% with a lesser extent of surgery. Another argument in favor of thyroidectomy is the possibility of ¹³¹I treatment.

Underestimating regional metastatic dissemination in thyroid cancer leads to non-radical surgical treatment, a high recurrence rate, and disease progression. The extent of surgery on the cervical lymphatic drainage system depends on the tumor morphology and the extent of the metastatic process. For instance, in pediatric patients with differentiated thyroid cancer, regional metastasis occurs very frequently; therefore, prophylactic removal of the central neck adipose tissue (paratracheal, pretracheal, and prelaryngeal) along with lymph nodes is mandatory for all patients. Removal of other lymph node groups should be based on preoperative imaging results and surgical exploration of the neck lymphatics, potentially supported by morphological examination (cytological and histological). The extent of surgery is determined intraoperatively—ranging from central neck dissection (level VI) to lateral neck dissection (removal of levels II–VI) and/or removal of other lymph node levels (I, VII) unilaterally or bilaterally.

• Considering that pediatric follicular thyroid cancer is predominantly minimally invasive—characterized by a favorable course without regional or distant metastasis—hemithyroidectomy with isthmusectomy and central neck dissection is recommended for T1–T3N0M0 tumors [42].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

• In the presence of metastatic cervical lymph nodes (N1), it is recommended to perform thyroidectomy with central neck dissection and lateral neck dissection depending on the level of involvement [42].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

• In pediatric follicular thyroid cancer, removal of cervical lymph nodes and adipose tissue is recommended only in cases of proven metastatic involvement [42].

GPP CLOE 4Grade of Recommendation C (Level of Evidence – 4).

Comment: Prophylactic removal of the central neck adipose tissue and lymph nodes is not performed due to the extremely rare occurrence of cervical lymph node metastasis.

In sporadic medullary thyroid cancer, the approach to regional lymph node surgery is similar to that for differentiated thyroid cancer.

In hereditary forms of medullary thyroid carcinoma, especially those associated with MEN syndrome, thyroidectomy with central lymph node dissection is recommended; if metastases are suspected – lateral lymph node dissection on the affected side.

• During the intraoperative phase, in the absence of preoperative histological verification, the operating surgeon is recommended to clarify the type of thyroid cancer by:

- examining the removed gross specimen to determine the presence or absence of a true capsule around the tumor node, invasion through the tumor capsule, thyroid capsule, or surrounding tissues, as well as the presence or absence of additional tumor foci within the thyroid parenchyma and cervical lymph nodes;

- labeling the tumors: noting their number, size, and topography;

- for Bethesda diagnostic categories III, IV, and V, if lymph nodes suspicious for tumor involvement are found in the central compartment of the neck, frozen section analysis is indicated to determine the extent of surgery [3,4,19,29,40].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: at the first stage, hemithyroidectomy with resection of the isthmus is performed on the affected side, along with lymph node biopsy if metastatic involvement is suspected; the tissue sample is sent for frozen section biopsy. In case of metastatic lymph node involvement (when the pathological formation size is >1 cm), the scope of surgery is extended to total thyroidectomy with central neck dissection (level VI). Indications for intraoperative histological examination may include: suspicion of thyroid cancer based on cytological examination data (Bethesda category V), or detection during intraoperative revision of central neck lymph nodes suspicious for tumor involvement (for Bethesda categories III and IV). The sensitivity of the method ranges from 32 to 92%, specificity – from 97 to 100%, and accuracy from 87 to 97%. The effectiveness of the examination largely depends on the experience of morphologists in interpreting the results. In addition, the effectiveness of the examination varies significantly in the diagnosis of different histological variants of cancer. The sensitivity of frozen section biopsy (FSB) in detecting the classical variant of papillary thyroid cancer reaches 94–98%, while the encapsulated form of the follicular variant of papillary thyroid cancer and follicular thyroid cancer can be detected in 26–55% [3,5]. FSB makes it possible to perform radical surgery at the first stage and reduce the number of reoperations.

Comment: patients with solitary papillary carcinoma (stage T1a–T1b N0–N1a with micrometastases in no more than 3 lymph nodes, provided the total number of removed lymph nodes is specified, M0) require extrafascial hemithyroidectomy with isthmusectomy and removal of the paratracheal, pretracheal, and prelaryngeal lymph node groups on the affected side (level VI)

Patients with papillary carcinoma ranging from stage T1a to T3aN1aM0 are indicated for extrafascial thyroidectomy with level VI lymph node dissection. For stages T1a through T4 with category N1b, extrafascial thyroidectomy with removal of lymph node levels I through VI (lateral neck dissection) unilaterally or bilaterally is required depending on the extent of disease [44].

For follicular carcinoma without signs of invasion on preoperative ultrasound (stage T1–T3a, N0, M0, TNM 2017), extrafascial hemithyroidectomy with isthmusectomy is indicated.

For follicular thyroid cancer at stage T1–T3a with micrometastases in no more than 3 lymph nodes (provided the total number of removed lymph nodes is specified), extrafascial hemithyroidectomy with isthmusectomy and ipsilateral central neck dissection is indicated. In cases of N1a–N1b lymph node involvement, extrafascial thyroidectomy with level VI lymph node dissection and lateral neck dissection is indicated depending on the level of involvement [44–51].

In the absence of clinical or sonographic signs of metastatic lymph node involvement, lymphatic surgery is limited to level VI on the affected side. For any other extent of differentiated thyroid cancer, thyroidectomy is performed with removal of central neck lymph nodes (level VI: prelaryngeal, pretracheal, and paratracheal lymph nodes, and level VII: anterosuperior mediastinal lymph nodes if involved). This enables postoperative ¹³¹I ablation and subsequent adequate disease monitoring.

If metastases are detected in the lateral cervical lymph nodes, lateral neck dissection is additionally performed with mandatory removal of lymph nodes from levels II to VI on the affected side or bilaterally (as clinically indicated). Special care should be taken to identify and preserve the accessory nerve [30,50,51].

During thyroid surgery, special attention is paid to preserving the integrity of the laryngeal nerves, which is monitored by a neuromonitor during thyroid mobilization and excision of metastases, and their integrity and functionality are also documented at the end of the operation [92, 93, 94]. Control and preservation of the parathyroid glands are mandatory. After thyroidectomy, a thorough inspection of its posterior-lateral surfaces is performed. If excised parathyroid glands are identified, they are minced and implanted into the neck muscles.

Invasion of the trachea and esophagus by the tumor is rare in pediatric patients. However, given the potential for life-threatening complications and the limited efficacy of non-surgical treatment methods, surgical resection must be performed in such situations in the absence of distant metastases. The indication for surgery must take into account not only the technical feasibility of tumor removal, but also the patient's general condition. Depending on the extent of invasion, the surgical strategy can range from "window" tracheal resection to complex laryngotracheal and esophageal resections. In pediatric patients, it is more advisable to perform superficial tumor debulking of the larynx and trachea, leaving a minimal amount of tumor on the surface ("shaving" resection), in the presence of distant metastases, taking into account the possibility of subsequent radioiodine therapy [16,28,37,52–55].

Non-radical surgical treatment is considered to be operations performed without regard to the local and regional extent of the tumor process or without observing the principles of ablative surgery. If a non-radical operation is performed, the patient should undergo a second-stage reoperation for the complete removal of the remaining thyroid tissue, regional, and distant metastases. Factors such as a tumor size greater than 1 cm, multifocal thyroid involvement, extrathyroidal tumor extension and/or vascular invasion, the presence of local or distant metastases, a history of neck radiation therapy in patients with a second primary tumor, and unfavorable histological variants of carcinoma should be taken into account. In cases where the primary tumor exceeds 10 mm in diameter, with invasion of the tumor node capsule and/or the presence of affected lymph nodes diagnosed by postoperative histological examination, a decision must be made to perform completion thyroidectomy.

Repeat neck surgeries may be performed in the following cases:

• if thyroid cancer is diagnosed on routine histological examination after surgery for presumed benign thyroid neoplasms, and the scope of the performed surgical treatment did not meet the criteria specified above;

• in case of thyroid cancer recurrence in the remaining thyroid tissue (total thyroidectomy with removal of level VI lymph nodes is indicated);

• for recurrence of metastases in neck lymph nodes (removal of affected lymph nodes along with fibrofatty tissue and remaining thyroid tissue is indicated) [3,4,43,48,53].

Reoperation for highly differentiated thyroid cancer is not performed: if the tumor size did not exceed 20 mm and, according to morphological examination data, it was represented by a single focus, surrounded by a capsule throughout, without signs of capsular and vascular invasion, as well as in the absence of data for regional metastases, or in the presence of micrometastases in no more than 3 lymph nodes of the central neck compartment, provided the total number of removed lymph nodes is indicated; in WDTC with minimally expressed invasive properties (stages T1a-T3aN0M0)

• In patients with WDTC after total thyroidectomy with central neck dissection, it is recommended to determine parathyroid hormone and calcium levels in the postoperative period. If pathological levels are detected, for the prevention of hypocalcemic tetany, prescribe alfacalcidol** 25–50 ng/kg/day orally under the control of blood calcium levels (vitamin D3 analogue), vitamin D and its analogues (according to the ATC classification) along with calcium preparations (A12A according to the ATC classification) (see section 7.1 – complications of surgical treatment) [57,81].

GCR BLoE 3Level of Evidence B (Level of Confidence of Evidence – 3)

3.2. Conservative treatment

• For patients with radioactive iodine-refractory differentiated thyroid cancer (DTC), it is recommended to obtain an oncology board (tumor board) conclusion to resolve the issue of prescribing targeted therapy [58,59,82].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comment: according to statistics, approximately 10–15% of DTC patients receiving ¹³¹I therapy develop resistance to this type of treatment, which subsequently leads to a worse survival prognosis. Resistance may be initially present or develop during the course of treatment. Today, the mandatory use of targeted therapy—gene- and molecular-targeted—is discussed, which blocks oncogenic proliferation and progression pathways and, moreover, can restore the ability of the cell to accumulate #sodium iodide [131I]. In order to prescribe targeted therapy, a conclusion by a multidisciplinary medical committee is required.

When radioiodine refractoriness develops, progression is a mandatory condition for initiating targeted therapy.

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

• absence of #sodium iodide [131I] uptake in all lesion sites on scintigraphy;

• absence of #sodium iodide [131I] accumulation in at least 1 of all existing tumor lesions, but not in all of them;

• tumor progression during radioactive iodine therapy despite #sodium iodide [131I] uptake;

• reaching the maximum recommended activity.

• In recurrent unresectable or metastatic differentiated thyroid cancer when radioactive iodine therapy is ineffective, in case of disease progression and/or the presence of a life-threatening, tumor-associated condition, it is recommended to prescribe #lenvatinib** at a dose of 14 mg/day orally until progression or unacceptable toxicity to increase patient survival [82].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comment: The use of #lenvatinib** is preferred in pediatric patients due to a more significant clinical response, based on clinical trials conducted.

• In recurrent unresectable or metastatic radioiodine-refractory differentiated thyroid cancer progressing on standard targeted therapy regimens, it is recommended to perform comprehensive genomic profiling using tumor tissue samples in order to identify specific molecular targets and prescribe a specific targeted therapy acting against them [68,79].

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

Comment: Promising mutations to determine include mutations in the RET proto-oncogene and fusions in the NTRK gene.

• For patients with medullary thyroid cancer with distant metastases who are not candidates for surgical treatment, it is recommended to administer conservative treatment with #vandetanib** 100-300 mg/m²/day orally continuously for palliative purposes [60].

LeRR CLoE 4Level of recommendation confidence C (level of evidence – 4)

Comment: #vandetanib** is another protein kinase inhibitor (L01XE according to the ATC classification) with activity against VEGFR (primarily VEGFR-2) and EGFR, as well as the Ret proto-oncogene.

3.3. Treatment of medullary thyroid cancer

• For children and adolescents with medullary thyroid cancer, surgical treatment is recommended [61–63]

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

Comment: the standard operation for medullary thyroid cancer in children and adolescents, regardless of tumor size, is solely total thyroidectomy, supplemented by central lymph node dissection or lateral neck lymph node dissection with mandatory removal of lymph nodes from levels II to VI on the affected side or bilaterally (as indicated). In familial forms of medullary thyroid cancer, total thyroidectomy with central neck compartment dissection and lateral neck lymph node dissection with mandatory removal of lymph nodes from levels II to VI on the affected side or bilaterally is performed in all cases. During the surgery, the parathyroid glands are inspected, and if adenomas are detected, they are removed. If concomitant pheochromocytoma is diagnosed, its removal is performed at the first stage, and surgical treatment of medullary thyroid cancer is performed at the second stage.

• For patients with medullary thyroid cancer following total thyroidectomy with central lymph node dissection, it is recommended to determine parathyroid hormone and calcium levels in the postoperative period. If abnormal levels are detected, for the prevention of hypocalcemic seizures, prescribe alfacalcidol** (vitamin D and its analogues (according to the ATC classification)) together with calcium preparations (A12A according to the ATC classification) (see section 7.1 – complications of surgical treatment) [57].

GCR BLEL 3Grade of Recommendation B (Level of Evidence – 3)

• For children and adolescents with unresectable medullary thyroid cancer, radiation therapy with a cumulative absorbed dose of 60 Gy to the primary lesion area and 40 Gy to the regional metastasis zones is recommended [62–64]

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

• Children and adolescents with MTC following treatment are recommended lifelong replacement therapy with levothyroxine sodium** [65].

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

• All children identified with a RET gene mutation at the preclinical stage of the disease are recommended to undergo prophylactic thyroidectomy based on detailed medical and genetic counseling for families at risk for MEN syndrome [51,62].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comment:

Table 5 – Clinical risk groups for the aggressiveness of clinical course and recommended timing for preventive treatment of hereditary MTC [66]

In 2009, the American Thyroid Association (ATA) published new guidelines for prophylactic thyroidectomy in carriers of germline RET mutations [63]. The ATA proposed dividing all mutation types into 4 levels (A, B, C, and D), supplemented newly identified mutations, and placed mutations in codon 634 into a separate category deserving special attention due to the aggressiveness of MTC and the high frequency of MTC combined with pheochromocytoma and hyperparathyroidism (Table 6).

Table 6 – Recommendations on the timing of prophylactic thyroidectomy [63]

* under the following conditions: normal basal and stimulated calcitonin levels, no structural changes in the thyroid gland on ultrasound, low penetrance, and non-aggressive course of MTC in other family members

According to ATA guidelines, prophylactic thyroidectomy was proposed for all carriers of germline RET mutations, except for certain cases belonging to ATA level A with low penetrance, a non-aggressive MTC course, and no family history of MTC-related mortality. In general, the question was not whether to perform prophylactic thyroidectomy, but when to perform it. The strategy for choosing the optimal timing of thyroidectomy is based on analyzing the following factors: the minimum age of metastatic MTC onset for a given mutation type (according to literature data), the most expected age of MTC manifestation, basal and stimulated calcitonin levels, neck ultrasound data, familial features of MTC, and a combination of these factors. An argument in favor of early thyroidectomy (prior to expected metastatic involvement) should be the possibility of radical treatment in a lesser extent, without lymph node dissection, which increases the rate of surgical complications. The advantage of delayed thyroidectomy is treatment in older children and adults, which is technically less challenging. Lymph node dissection is recommended if neck lymph node metastases are detected, as well as when the primary tumor size exceeds 5 mm and calcitonin levels are above 40 pg/ml. Later, many countries, including Russia, developed their own guidelines for managing carriers of germline RET mutations. Most of them align with the ATA guidelines (2009), varying slightly and detailing certain aspects regarding lymph node dissections, threshold calcitonin levels for decision-making, and the age for thyroidectomy (BTA, ESES) [51,67]. A special position is held by the European Thyroid Association (ETA, 2012), which suggests determining calcitonin levels (basal and/or stimulated depending on the ATA risk level) in all patients with a detected mutation, and performing thyroidectomy only if levels are elevated. Exceptions include certain cases of MEN 2B syndrome with normal calcitonin levels, where thyroidectomy is performed earlier. When calcitonin levels exceed 30–60 pg/ml, thyroidectomy is recommended to be supplemented with central lymph node dissection [68]. The guidelines of the Russian Association of Endocrinologists (2013) also align with the ATA regarding the timing of prophylactic thyroidectomy and lymph node dissection [62].

Table 7 – Summary table. Recommendations for prophylactic thyroidectomy, lymph node dissection, and calcitonin testing

In 2015, the ATA presented updated recommendations for mutation level stratification and timing of thyroidectomy [69]. The new edition again proposes 3 levels of MTC aggressiveness (highest – HST=Highest, high – H=High, and moderate – MOD=Moderate). The position of certain mutations in the classification and recommendations for the management of moderate-risk MTC have changed (Table 8). Lymph node dissection at the ATA-HST level in the absence of overt metastases is indicated only if parathyroid gland preservation is feasible; at the ATA-H level, when CCT is above 40 pg/mL.

Table 8 – New ATA recommendations for prophylactic thyroidectomy [69]

3.4. Radioiodine therapy, radioiodine ablation

Radioiodine therapy (RIT) is the second stage of treatment for patients with differentiated thyroid cancer (DTC). Over 80 years of global clinical experience, the efficacy—and in many cases, the irreplaceability—of this treatment method has been proven for both adults and children with DTC [3,4,53,70]. Due to the lack of evidence base derived from well-designed retrospective and prospective studies with large pediatric cohorts, most concepts of DTC management in children are borrowed from adult practice. However, a more aggressive course of DTC in children, coupled with a good overall prognosis and long life expectancy during which adverse effects of RIT may manifest, necessitates a personalized approach to treating such patients. These arguments emphasize the need for specific guidelines for the treatment and follow-up of children with thyroid masses.

Indication for RIT: Pediatric patients with DTC after total or near-total thyroidectomy belonging only to the high and intermediate risk groups

• of progression, radioiodine therapy is recommended [3,4,70].

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

Comments: According to the European Thyroid Association (ETA) Guidelines for the Management of Children and Adolescents with Thyroid Nodules and Differentiated Thyroid Cancer, RIT is indicated for all children with DTC, and postoperative staging is based on high-sensitivity post-therapeutic whole-body scintigraphy with sodium iodide [131I] [78]. The American Thyroid Association (ATA), conversely, uses a personalized approach for prescribing RIT, based on postoperative staging using low-sensitivity distant-metastasis scintigraphy with ¹²³I [79]. In the opinion of Russian experts, in the absence of and until the results of clinical trials in a large cohort of pediatric patients become available, the indications and goals of RIT in children with DTC should be determined based on the risk of progression according to the ATA guidelines for adult DTC patients [80].

The recommended timeframe for RIT is up to 6 months after the surgical stage of treatment for the primary or recurrent tumor, taking into account the goal of RIT and the extent of the tumor process.

The activity dose for postoperative radioiodine therapy (RIT) with sodium iodide [131I] ranges from 30 to 100 mCi [22,71,85,87], depending on the patient's inclusion in the postoperative recurrence risk stratification group. For subsequent RIT sessions, a therapeutic activity of sodium iodide [131I] is indicated in the range of 100 to 200 mCi [22, 71, 85, 87], and in rare cases may reach 300 mCi.

Additional examination: post-therapy whole-body planar/SPECT-CT scintigraphy after the patient is discharged from inpatient isolation to determine foci of sodium iodide [131I] hyperfixation

Repeat RIT courses: if a large thyroid remnant and/or iodine-avid tumor foci are detected, repeat RIT courses may be indicated.

Comments: the decision to perform a repeat RIT course should be made individually depending on the response to the previous RIT course; the recommended interval is approximately one year.

The use is based on the following assumptions: treatment with sodium iodide [131I] of microscopic tumor foci that may remain after surgery can reduce the recurrence rate and, potentially, mortality; ablation with ¹³¹I of residual normal thyroid tissue facilitates early diagnosis of recurrence based on continuous serum thyroglobulin (Tg) monitoring and, where indicated, whole-body scintigraphy with sodium iodide [131I] (¹³¹I-WBS), based on TSH, Tg, and anti-Tg levels; high activity of sodium iodide [131I] allows for

high-sensitivity postoperative whole-body scintigraphy 2–5 days after its administration, as well as the detection of previously undiagnosed tumor foci.

Selection of sodium iodide [131I] activity: to calculate the most optimal activity of sodium iodide [131I], it is recommended to use an individualized approach to the patient, taking into account potential side effects of sodium iodide [131I] with increased activity. The preferred drug activity should be discussed by a multidisciplinary team.

Comments: Fixed activities of #sodium iodide [131I] are used as the treatment standard, and therapy is repeated as needed. The choice of activity may be determined by the extent of the disease and should be optimally adjusted based on the patient's body weight, at least in prepubertal children [83]. In the German treatment protocol for children with radiation-induced differentiated thyroid cancer (DTC) following the Chernobyl accident, #sodium iodide [131I] activities of 50 MBq/kg of body weight were used as adjuvant therapy for the ablation of residual thyroid tissue and to reduce the risk of recurrence, and 100 MBq/kg for the treatment of known metastases [84]. Currently, the issue of choosing the #sodium iodide [131I] activity remains "open", since there are no data in the literature on the most optimal dose-response curve for #sodium iodide [131I] with the lowest side effects, calculated based on body weight/fixed activity or dosimetry.

Levothyroxine sodium** suppressive therapy: on the 3rd day after sodium iodide [131I] administration at a dose of 2.5–3 µg/kg of body weight, in the morning at least 1 hour before a meal.

Additional examination: post-therapy whole-body scintigraphy after the patient is discharged from inpatient isolation to determine foci of sodium iodide [131I] hyperfixation.

Features of RIT in children with lung metastases:

• patients with lung metastases receive radioiodine therapy as a first-line treatment;

• pulmonary function testing must be performed prior to repeat treatment in patients with diffuse lung metastases;

• in children who have previously received agents with pulmonary toxicity, such as bleomycin, RIT should be administered with extreme caution due to the risk of pulmonary fibrosis;

• repeat RIT courses should always be prescribed with caution and after an adequate interval, as well as a thorough evaluation of the response to the previous RIT course.

Comments: Pediatric DTC lung metastases occur twice as frequently as in adults. At the same time, complete remissions are more frequently achieved with RIT in children, because in the vast majority of cases, lung metastases are miliary (micrometastatic) in nature and, being well-differentiated and iodine-avid cells, respond better to sodium iodide [131I] therapy. Structural and biochemical response to the first RIT course may be observed up to 15–18 months after therapy [83]. Given this fact, long intervals—about 12 months—should be maintained before repeat treatment. When deciding on a repeat RIT course, in addition to maintaining an adequate interval, it is important to evaluate the response to the previous RIT course. For theranostic purposes, if a Tg level indicating persistence/recurrence of the disease after thyroidectomy and RIT is detected in patients with a previous positive post-therapeutic sodium iodide [131I] scan, diagnostic scanning with ¹²³I may be useful. However, one should not forget that lung metastases may not be visualized on a ¹²³I scan [84].

Patient preparation for RIT: Prior to RIT, to improve the uptake of sodium iodide [131I], TSH stimulation (>30 mIU/L) is required, which can be achieved either by thyroid hormone withdrawal for 2–3 weeks or by using recombinant human TSH (rhTSH). The decision on how to stimulate TSH depends on the clinical experience of the treating team. A low-iodine diet for 1–2 weeks before RIT may enhance iodine uptake.

Comments: Effective radioiodine therapy (RIT) requires adequate stimulation of thyroid-stimulating hormone (TSH), which is achieved by one of two methods: withdrawal of L-thyroxine or administration of recombinant human thyroid-stimulating hormone (rhTSH). The use of rhTSH has been extensively studied in adults, whereas experience in children is limited. Currently, the drug is not approved for the pediatric population and has not undergone official safety and efficacy trials. In addition, the use of rhTSH during RIT in patients with persistent local or metastatic DTC remains an "off-label" use, which should be approached with all the caution required in such situations [26]. The second condition for RIT preparation is adhering to a low-iodine diet, the impact of which on treatment outcomes is not universally recognized. The standard duration of the diet is 1–2 weeks before RIT.

• Prior to RIT, it is recommended to perform the following examinations [3,4,53,70]:

  • determination of TSH levels (recommended TSH level >30 µIU/mL), free T₄,

  • determination of blood thyroglobulin levels, anti-thyroglobulin antibodies,

  • complete blood count (CBC),

  • general clinical blood chemistry panel,

  • routine urinalysis,

  • ultrasound of the thyroid gland, parathyroid glands, and lymph nodes (one anatomical area) (abdominal ultrasound and other areas as indicated),

  • initial ENT (otolaryngologist) examination

  • Chest computed tomography

GDR CLE 5Grade of recommendation C (level of evidence – 5)

• To prepare for RIT, it is recommended to [3,4,53,70]:

  • discontinue levothyroxine sodium** 2 weeks before the procedure;

  • adhere to a low-iodine diet for up to 2 weeks (exclude iodinated salt, iodinated bread, seafood, walnuts, as well as medications containing iodine, bromine, lithium);

  • avoid CT scans with iodine-based contrast for 2–3 months

GDR CLE 5Grade of recommendation C (level of evidence – 5)

3.5. External beam radiation therapy (EBRT) in DTC.

External beam radiation therapy (EBRT) in DTC has low efficacy.

• Radiation therapy is recommended for DTC patients only in cases of tumor invasion into adjacent organs, when radical surgical removal is impossible, or for palliative purposes when protein kinase inhibitors (ATC code L01E) are ineffective [3,4,72].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

Comments: postoperative EBRT is administered starting from 10–14 days after non-radical surgical treatment using conventional fractionation techniques to the tumor invasion area up to a total dose of 50–56 Gy. Radioiodine therapy is indicated 2–3 weeks after its completion.

3.6. The role of cytotoxic chemotherapy and experimental treatment methods.

Cytotoxic chemotherapy is not used in the routine management of adult patients with papillary or follicular thyroid cancer, and its use in pediatric patients is likewise impractical. Its use is limited to cases of disease progression where surgery, radioiodine therapy, or other treatment modalities cannot be performed. Molecularly targeted therapies and anti-angiogenic drugs are at the stage of prospective controlled trials.

3.7. Management of patients with recurrent or progressive disease.

Treatment is based on a combination of surgery and #sodium iodide [131I] therapy in patients who show uptake of the isotope. When complete surgical removal is not possible, external beam radiotherapy can be performed in cases of minimal #sodium iodide [131I] uptake within the tumor foci.

Lung metastases in pediatric patients are detected in 10% to 30% of papillary carcinoma cases, rarely in medullary carcinoma, and very rarely in follicular carcinoma.

Bone metastases in pediatric patients are a very rare finding and are more frequently detected in medullary carcinoma. Bone metastases should be treated with a combination of surgery, when feasible, #sodium iodide [131I] therapy (provided there is isotope uptake in the metastases), and external beam radiotherapy (EBRT) for both curative and pain-palliative purposes. Other local modalities, such as embolization and cement augmentation injections, may also prove effective.

Brain metastases in pediatric patients are a very rare finding, more commonly detected in medullary carcinoma. Whenever possible, they should be surgically excised; if they are unresectable and do not concentrate radioiodine, EBRT may be administered as a palliative measure. Brain metastases typically indicate an unfavorable disease prognosis.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

The problem of medical and social rehabilitation of children cured of thyroid cancer has not yet been fully resolved. Poorly compensated hormonal disorders (thyroid and parathyroid insufficiency), along with other treatment consequences (gross postoperative scars, cervical lymph and blood circulation disorders, pulmonary tissue fibrosis), can lead to a low quality of life not only for the cured former patient but also for their family.

Comments: rehabilitation is aimed at eliminating cosmetic defects resulting from thyroid surgery, correcting potential lymphatic drainage disorders (lymphedema) following extensive lymph node dissection, and restoring phonation and physiological respiration. Long-term health monitoring of former patients cured of thyroid cancer should involve not only oncologists and endocrinologists, but also geneticists, medical psychologists, and other specialists.

5. Prevention and Dispensary Observation

Comments: following surgical treatment for pediatric thyroid cancer, patients are subject to mandatory lifelong dispensary follow-up by an oncologist/pediatric oncologist and an endocrinologist. This may be carried out in a specialized medical center or another healthcare facility, depending on local infrastructure.

During the first year after surgery, patient visits to the endocrinologist should be conducted quarterly, with mandatory serum measurements of TSH, free T₄, thyroglobulin, and antithyroglobulin antibodies. Following organ-sparing surgeries in the low-risk group, measuring TSH levels alone is sufficient. The examination should include ultrasound of the residual thyroid tissue, the thyroid bed, and regional metastasis sites. Chest X-ray is performed every six months. Dispensary follow-up is carried out periodically for the purposes of: early diagnosis of disease recurrence and progression; monitoring and adjustment of replacement or suppressive hormone therapy; management of postoperative complications; and social rehabilitation.

Frequency of follow-up examinations: the first year – every three months; over five years – at least once every six months; subsequent years – at least once a year (lifelong). The scope of diagnostic procedures during follow-up examinations includes: a consultation (examination, assessment) with a pediatric oncologist; ultrasound of the thyroid gland and parathyroid glands; computed tomography of the chest organs (at least once a year); blood tests for thyroid-stimulating hormone (TSH), thyroglobulin, antithyroglobulin antibodies, as well as parathyroid hormone, total calcium, ionized calcium, and inorganic phosphorus in cases of persistent postoperative hypoparathyroidism for its management.

Whether it is advisable to monitor serum Tg stimulated by recombinant human TSH for 3–5 years requires confirmation.

Clinical physical examination has very low specificity for detecting disease persistence or recurrence in the neck. Neck ultrasound depends on the operator's experience, so professional development can improve individual diagnostic capabilities. Ultrasound is unquestionably much more sensitive than neck palpation and is routinely used to assess regional lymph node compartments and the thyroid bed. If lymph nodes larger than 5 mm in the shortest diameter are present, ultrasound-guided fine-needle aspiration biopsy (FNAB) with subsequent cytological examination must be performed [34].

Tg is a specific and extremely valuable tumor marker during the follow-up of patients with papillary and follicular thyroid cancer, but only after total thyroidectomy. Tg is synthesized by both normal and neoplastic thyroid cells, and its production is regulated by TSH. Its measurement should be performed using a sensitive immunoradiometric assay (functional sensitivity <1.0 ng/mL) standardized against the European reference standard – Certified Reference Material (CRM 457). When using such methods, the presence of anti-Tg antibodies in the blood can interfere with the assay, leading to false-negative Tg results. Anti-Tg antibodies may decrease and disappear in patients in complete disease remission, with the time interval between the disappearance of the antigen and the antibody taking 2–3 months. Therefore, an increase or appearance of circulating anti-Tg antibodies can be considered a disease "indicator." When determining Tg levels, serum TSH must always be measured. In very low-risk patients not undergoing ¹³¹I radioiodine ablation, the risk of disease recurrence is, by definition, very low; therefore, TSH stimulation via hormone withdrawal or administration of thyrotropin alfa is generally not recommended. Follow-up examinations are based on serum thyroglobulin testing while on levothyroxine sodium** therapy and performing a neck ultrasound. Following complete thyroid ablation via surgery and 131I, the Tg level should become undetectable, and any detectable level should alert the clinician.

Ablation with #sodium iodide [131I] increases the specificity of Tg determination, while TSH stimulation improves sensitivity without reducing specificity. Rare false-negative results of Tg determination during TSH stimulation are most often associated with small lymph node metastases that are clearly visible on ultrasound. The stimulated Tg level is usually lower with thyrogen (recombinant human TSH) stimulation than after thyroid hormone withdrawal. A sensitive Tg assay must be used, and any detectable level must be taken into account because the mere fact of an elevated blood Tg concentration does not distinguish between normal thyroid tissue remnants, local recurrence, or distant metastases. Serum Tg may remain undetectable for several months after surgery or #sodium iodide [131I] therapy. Therefore, it is pointless to determine serum Tg for at least three months after initial treatment. To ensure the comparability of results during monitoring, clinicians should use the same serum Tg assay method throughout the entire follow-up period [6]. The laboratory must perform both internal and external quality control for serum Tg determination.

In patients with elevated Tg levels during endogenous or exogenous TSH stimulation, or with rising blood Tg levels during subsequent measurements under similar conditions (while on levothyroxine sodium** therapy or TSH stimulation), and in the absence of other disease manifestations, administration of a high activity of #sodium iodide [131I] is indicated, followed by whole-body scintigraphy (WBS) 3–5 days later, which may reveal previously undiagnosed neoplastic foci. Identification of the source of Tg production can guide targeted treatment tactics (surgery in case of regional lymph node involvement or removal of a solitary distant metastasis). Serum Tg may remain detectable for several months after initial treatment; however, high activity of #sodium iodide [131I] should be prescribed only to those whose Tg level exceeds the permissible threshold and shows an upward trend.

In patients with a negative postoperative WBS scan, there is no need to repeat the administration of high activity of #sodium iodide [131I]. Other diagnostic imaging modalities may be used, including computed tomography (CT), magnetic resonance imaging (MRI), or [18F]fluorodeoxyglucose positron emission tomography ([18F]FDG-PET) [16,27,29].¹⁸

As mentioned earlier, in patients with high anti-Tg antibody titers, an undetectable blood Tg level cannot be interpreted as evidence of remission. These patients should be periodically evaluated using diagnostic administration of #sodium iodide [131I] followed by WBS, as well as neck ultrasound. If distant metastases are suspected, these patients should be evaluated using CT, MRI, and ¹⁸FDG-PET. The disappearance of anti-Tg antibodies during follow-up can itself be considered evidence of remission.

For diagnostic whole-body scintigraphy (WBS) with #sodium iodide [131I], TSH stimulation is achieved by prolonged thyroid hormone withdrawal or by intramuscular injections of #thyrotropin alfa (on days 1 and 2, with #sodium iodide [131I] administration on day 3) [74]. #Sodium iodide [131I] is administered in an activity of 2 to 5 mCi (74–185 MBq) [22,86,87], followed by WBS 2 or 3 days later. It is preferable to use a dual-detector gamma camera equipped with high-energy collimators and a thick crystal. Scanning should be performed at a low speed of 6–8 cm/min for at least 30 minutes (or at 140,000 counts) with targeted imaging of any suspicious area of isotope uptake. In patients with small thyroid remnants, postoperative WBS with high activity of ¹³¹I has higher sensitivity than diagnostic scanning after low-activity administration during follow-up; ablation (no visible uptake or, if present, <0.1% with an undetectable serum Tg level) is achieved in virtually all patients. Diagnostic WBS will detect uptake foci outside the thyroid bed only in patients with detectable serum Tg levels after TSH stimulation. Therefore, in the absence of signs of persistent tumor process, follow-up diagnostic WBS is generally not indicated. To date, the best evidence of successful ablation is an undetectable blood Tg level after TSH stimulation in the presence of a normal ultrasound finding.

TSH stimulation increases Tg production by thyroid cells and thus enhances the sensitivity of Tg testing for detecting disease recurrence.

Uptake of ¹³¹I is reduced or absent during TSH suppression; therefore, TSH stimulation for diagnostic or therapeutic purposes must be performed prior to the administration of #sodium iodide [131I]. TSH stimulation can be achieved in two alternative ways:

1) thyroid hormone withdrawal: levothyroxine sodium** therapy is withdrawn for a period of 3–4 weeks. Serum TSH must be measured prior to the administration of #sodium iodide [131I], and its level must exceed the empirically established threshold (>30 mIU/L). Rare cases in which patients fail to achieve sufficient endogenous TSH secretion are associated with hypothalamic or pituitary dysfunction or prolonged systemic corticosteroid therapy;

2) in children, the use of thyrotropin alfa is performed within the framework of scientific research. #Thyrotropin alfa injections: #thyrotropin alfa is administered intramuscularly for two consecutive days, and #sodium iodide [131I] is administered the day after the second injection (day 3) [66,67]. Serum Tg is determined on the third day after the second #thyrotropin alfa injection. #Thyrotropin alfa provides TSH stimulation comparable in efficacy to that of thyroid hormone withdrawal for diagnostic purposes, with the exception of a few isolated cases of thyroid cancer metastases that were not stimulated by #thyrotropin alfa but were detected after endogenous TSH elevation. Adverse effects are very rare, minor, and transient, presenting as nausea, fatigue, and headache. No serious toxicity has been reported to date, nor has the appearance of anti-TSH antibodies been noted after #thyrotropin alfa injections. The advantages of using #thyrotropin alfa are that it avoids hypothyroidism symptoms, preserves a high quality of life, and reduces the risk of disease exacerbation due to thyroid hormone withdrawal. In patients who fail to achieve an endogenous TSH elevation or for whom prolonged hormone withdrawal is contraindicated due to poor tolerance, stimulation should be performed using #thyrotropin alfa in preparation for treatment. In patients with spinal cord compression or brain metastases, a short course of high-dose systemic corticosteroids prevents the worsening of neurological symptoms [16].

Additional diagnostic methods include CT of the neck and lungs, and MRI of the bones and brain. Bone scintigraphy has low sensitivity. ¹⁸FDG-PET is rarely indicated for such patients. This study is used to identify neoplastic foci in the posterior neck or mediastinum among patients with elevated serum Tg levels who do not exhibit pathological uptake

It can also be performed prior to any aggressive treatment to ensure the absence of other neoplastic foci. The sensitivity of the method can be enhanced by TSH stimulation. Finally, high ¹⁸FDG uptake in large tumors may have an adverse prognostic significance. When ¹⁸FDG-PET is available, it reduces or eliminates the indications for scintigraphy with other diagnostic radiopharmaceuticals [28].

If WBS performed a few days after the administration of #sodium iodide [131I] reveals small thyroid remnants and no uptake outside the thyroid bed, patients are scheduled for a follow-up examination at 3 months (while on levothyroxine sodium** therapy) to assess blood thyroid-stimulating hormone (TSH) and thyroglobulin levels.

At 6–12 months, disease status is assessed by physical examination, neck ultrasound, and serum Tg level measurement performed on the 3rd day after the second #thyrotropin alfa injection. Thyroid hormone withdrawal should be used only when #thyrotropin alfa is unavailable. Low-risk patients with a normal ultrasound finding and an undetectable serum Tg level during #thyrotropin alfa stimulation are considered cured, as subsequent recurrences are extremely rare in them (<1% over 10 years).

Suspicious findings on thyroid and parathyroid ultrasound should prompt further evaluation: either a follow-up ultrasound of the thyroid and parathyroid glands in a few months if the suspicious lesion is ≤5 mm, or ultrasound-guided fine-needle aspiration biopsy (FNAB) followed by cytological examination if the lesion is >5 mm in its smallest dimension. In patients with a detectable serum Tg level of 1–2 ng/mL during #thyrotropin alfa stimulation, a repeat Tg measurement using #thyrotropin alfa should be scheduled after 12 months. If blood Tg is undetectable, the patient is considered cured. If the serum Tg level has increased compared to its previous value, disease recurrence must be ruled out using CT of the neck and chest, and high therapeutic activity of ¹³¹I should be prescribed. Very low-risk patients, who generally undergo hemithyroidectomy, are periodically evaluated using neck ultrasound and blood Tg measurements during suppressive levothyroxine sodium** therapy [6].

Follow-up care for medullary thyroid cancer. The frequency of follow-up examinations is the same as for differentiated thyroid cancer (DTC). Additionally, blood calcitonin levels are monitored. In familial forms, blood calcium and phosphorus are monitored to rule out hyperparathyroidism, and the levels of catecholamines and their metabolites are investigated if a tumor of the adrenal medulla is suspected [39].

Follow-up care in patients with anaplastic thyroid cancer. Follow-up examinations should be performed at least once a month. During follow-up examinations, clinical and ultrasound monitoring of local and regional recurrence and the appearance of distant metastases is of particular importance. The prognosis for this form of thyroid cancer is very poor.

Postoperative management of patients with thyroid cancer should be based on the blood thyroglobulin (Tg) level [75,76]. In the blood serum of patients who underwent total thyroidectomy and radioiodine ablation, the Tg level during suppressive therapy should not exceed 1 mcg/L. When tracking the Tg level, the level of antithyroid antibodies must also be taken into account. If an increase in the concentration of Tg or antibodies to it in the blood serum is detected, the patient must undergo a thorough clinical and instrumental examination, with the mandatory inclusion of sodium iodide [131I] scintigraphy (radiological activity 5-10 millicuries) in the diagnostic measures. If disease recurrence is detected, surgical treatment or radioiodine therapy is required.

If thyroid tissue remains, the diagnostic sensitivity of Tg as a marker of thyroid cancer recurrence is insignificant. If there is a tendency towards an increase in the concentration of Tg or antibodies to it in the blood serum, it is necessary to assess the degree of TSH suppression (if necessary, adjust hormone therapy), the presence of clinical signs of thyroiditis in the residual thyroid tissue, and the anti-Tg antibody level in the blood serum. In addition, a thorough clinical and instrumental study should be performed. If disease recurrence is detected, surgical treatment is indicated, which includes the complete removal of residual thyroid tissue, followed by radioiodine therapy.

Table. Follow-up examinations after achieving thyroid cancer remission

6. Organization of Medical Care

1. If a pediatrician (or other specialist) suspects nodular thyroid disease based on external examination and palpation, the child must be referred to a specialized medical organization—an endocrinology or pediatric oncology center.

2. Surgical treatment of thyroid cancer should be performed in specialized pediatric oncology institutions, specialized endocrinology institutions with the capability to perform a complete comprehensive preoperative examination of the patient, allowing for disease staging at the preoperative stage, as well as the capability to perform intraoperative histological examination. Surgical treatment should be performed only by experienced surgeons who are members of a multidisciplinary team specializing in relevant operations and performing a high annual volume of surgical interventions for thyroid cancer, including primary cases and reoperations.

Indications for hospitalization in a medical organization:

1. Need for biopsy, surgical treatment, radiation therapy, drug treatment;

2. Correction of treatment complications requiring inpatient stay;

3. Need for procedures under general anesthesia

Indications for patient discharge from a medical organization

1. End of the treatment phase, provided the patient is in a stable satisfactory somatic status

2. Completion of all treatment, achievement of remission, provided the patient is in a stable satisfactory somatic status

3. Incurability of the patient with the possibility of transfer to palliative care or hospice care

7. Additional Information

7.1. Complications of surgical treatment:

1. Recurrent laryngeal nerve palsy. Depending on the size of the primary tumor, postsurgical recurrent laryngeal nerve palsy is rare (<2% of cases), provided the patient is operated on by an experienced surgeon. Transient voice dysfunction is much more common and resolves spontaneously in most patients within 1-6 months. A higher complication rate is observed if the operation is performed by non-specialized surgeons.

After surgery, even if the voice is unchanged, all patients are recommended to be referred to a specialist for laryngoscopy [2,5,10,16].

GDR CLE 5Grade of recommendation C (level of evidence – 5)

2. Hypoparathyroidism. Following total thyroidectomy with or without central lymph node dissection or parathyroid autotransplantation, hypocalcemia occurs in one-third of cases. Attention should be paid to symptoms of hypocalcemia; blood total calcium along with ionized calcium must be assessed the day after surgery and daily thereafter until stabilization. Eight hours after surgery, total and ionized calcium in the blood should be checked. Total calcium level less than 2.1 mmol/L, ionized calcium less than 0.95 mmol/L (critical level less than 0.8 mmol/L). If total calcium is below 2.1 mmol/L, 0.5 mcg of alfacalcidol** (active vitamin D3) must be added, the first dose is given immediately; if calcium decreases at the next measurement, 0.5 mcg of alfacalcidol** must be added; if ionized calcium is less than 0.95 mmol/L, or there are symptoms of hypocalcemia, intravenous calcium preparations must be started: 10 ml of 10% calcium gluconate** IV over 10 minutes, followed by 1-2 mg/kg/h for 4-5 hours (via syringe pump). Monitoring of magnesium levels in the blood chemistry panel is mandatory! If necessary, its correction should be carried out. In parallel, alfacalcidol** 0.5-2 mcg (sometimes higher) and calcium preparations (ATC code A12AA) in tablet form are prescribed for maximum gastrointestinal (GI) absorption.

Dynamic monitoring of peripheral blood serum calcium and phosphorus levels is required. Measurement of blood serum parathyroid hormone levels can help in borderline cases and predict the possibility of normalization of blood calcium levels. In the case of permanent hypoparathyroidism, replacement therapy using vitamin D and its analogs (ATC code A11CC) is prescribed while meeting the physiological requirement for calcium according to the age norm by expanding the diet or using tablet calcium preparations (ATC code A12AA) [77]. To prevent hypercalcemia, careful monitoring of serum calcium is necessary. To prevent hypothyroidism, all patients after surgical intervention for DTC (in an extent less than total thyroidectomy) must be prescribed thyroid hormone suppressive therapy (levothyroxine sodium**), except when preparing for radioiodine diagnostics or radioiodine therapy.

7.2. Postoperative management of patients with differentiated thyroid cancer

Further management of patients with DTC is based on determining serum levels of TSH, T₄, thyroglobulin, anti-thyroglobulin antibodies using highly sensitive laboratory methods, neck ultrasound, scintigraphy, and X-ray results. Based on the examination results, the adequacy of the levothyroxine sodium** dose and the need for reoperation or radiation therapy are determined.

Levothyroxine sodium** suppressive therapy (LST) for DTC

The use of hormone suppressive therapy (HST) is indicated for papillary and follicular thyroid cancer in patients in the intermediate and high-risk groups. In the low recurrence risk group after surgery, levothyroxine sodium** is not prescribed in patients who have reached puberty. 4-6 weeks after surgery, it is necessary to check the TSH level and, depending on the result, decide on the need for replacement therapy.

Rationale:

a) the role of TSH-suppressive therapy after surgery has two goals: the first goal is to correct hypothyroidism by prescribing a specific dosage of levothyroxine sodium** to achieve normal blood thyroid hormone levels. The second goal is to suppress TSH-dependent growth of residual cancer cells by suppressing TSH secretion to a level of ≤0.1 mIU/L. In patients in complete remission during long-term follow-up (at least 3 years), there is no need for further suppression of endogenous TSH secretion, so the treatment regimen can be switched from suppressive to replacement;

b) levothyroxine sodium** is the drug of choice. Initially, the dose of levothyroxine sodium** must be sufficient to reduce serum TSH to ≤0.1 mIU/L. There is no evidence that greater TSH suppression (0.05 or lower) improves prognosis. TSH levels are monitored at least 1 month after starting treatment. The dose of levothyroxine sodium** is subsequently adjusted by decreasing or increasing it by 25 mcg/day with re-monitoring of serum TSH in 3 months. Once the optimal dosage of levothyroxine sodium** is achieved, FT4 and TSH levels are monitored every 6-12 months.

c) TSH-suppressive therapy (serum TSH level ≤0.1 mIU/L) must be performed in patients with signs of disease persistence (including cases of detectable blood Tg levels in the absence of other tumor manifestations);

d) in high-risk patients who have achieved definite remission during treatment, suppressive therapy is recommended for 3-5 years;

e) in low-risk patients after adequately administered treatment, the risk of recurrence is very low (<1%), therefore the dose of levothyroxine sodium** can be reduced immediately provided that serum TSH is maintained within the lower range of normal values (between 0.5 and 1 ≤0.1 mIU/L);

f) ideally, treatment with levothyroxine sodium** should be managed by endocrinologists or other members of the multidisciplinary team. The dose of levothyroxine sodium** is taken once a day, in the morning on an empty stomach 20-30 minutes before breakfast;

g) side effects in the form of subclinical thyrotoxicosis due to secondary TSH suppression most commonly manifest as cardiac symptoms and bone demineralization. Retrospective studies have shown that these effects are minimal if an appropriate dose of levothyroxine sodium** is selected and carefully monitored to avoid exceeding blood levels of FT₄ and FT₃; (TSH less than 0.1 mIU/L with normal free T4)

h) in case of pregnancy, the dose of levothyroxine sodium** may require adjustment based on TSH measurement results. In documented stable remission, the optimal TSH level should be within the lower range of normal values, whereas in cases of disease persistence or high risk of recurrence, the TSH suppression level should be below 0.1 mIU/L. In any case, the duration of TSH suppression therapy should be at least: 5 years for microcarcinoma T1N0-1M0 in the absence of recurrence and/or metastases; 10 years for stage T2-3N0-1M0 if there has been no recurrence and metastases during this period.

The dosage of levothyroxine sodium** is calculated based on:

a) when performing hemithyroidectomy (HTE) in individuals under 20 years of age – 2.5-3 mcg/kg body weight/day;

b) when performing total thyroidectomy (TT) in individuals under 20 years of age – 3-3.3 mcg/kg body weight/day; c) when performing HTE in individuals over 20 years of age – 2.5 mcg/kg body weight/day;

d) when performing TT in individuals over 20 years of age – 2.0-2.2 mcg/kg body weight/day.

Adjustment of the levothyroxine sodium** dose can be carried out 1 month after drug administration based on the results of hormone testing (TSH, free T₄). The dose is considered adequately selected if, given the patient's euthyroid clinical state, the serum TSH level does not exceed the lower limit of normal (less than 0.2-0.5 mIU/L), thyroid hormone values are normal, or the level of free or total triiodothyronine (FT₃ or TT₃) may be within the normal range, and the level of free or total thyroxine (FT₄ or TT₄) slightly exceeds the upper limit of normal values. It is important to discontinue thyroid hormones before radioiodine therapy or radioiodine diagnostics (withdrawal 3-4 weeks prior if taking levothyroxine sodium**).

In the postoperative period during suppressive therapy with levothyroxine sodium**, the serum tumor marker Tg (thyroglobulin) is measured, the diagnostic value of which is very high [3,5,6].

Levothyroxine sodium** therapy regimens:

Suppressive therapy – recommended target TSH value <0.1 and >0.05 mIU/L, free T4 does not exceed the upper limit of normal (postoperative high-risk group of differentiated thyroid cancer, during follow-up – group with structural tumor recurrence or absence of biochemical remission)

Moderate suppressive therapy – recommended target TSH value 0.1-0.5 mIU/L (postoperative assessment – moderate-risk group of differentiated thyroid cancer)

Replacement therapy – recommended target TSH value 0.5-2 mIU/L (postoperative low-risk group of differentiated thyroid cancer, patients with medullary thyroid cancer, anaplastic thyroid cancer, during follow-up – biochemical remission group)

7.3. Adverse effects of #sodium iodide [131I]

Potential early adverse effects of #sodium iodide [131I]

Radiation thyroiditis with local edema and neck discomfort is most common in patients with large remnants of thyroid tissue, and its manifestation can be minimized by administering systemic corticosteroids for several days. Taste and smell disturbances occur quite frequently, but they are temporary. Nausea and vomiting can be managed by prescribing antiemetics (ATC code A04A). The development of sialadenitis can be prevented by generous hydration and lemon juice taken 24 hours after receiving #sodium iodide [131I] Dry eyes are also rare.

Bladder (or gonadal) irradiation can be reduced by prescribing hyperhydration, and rectal irradiation by prescribing laxatives.

Hypospermia in adolescents and adults is noted after treatment with #sodium iodide [131I], but it is transient.

Potential late adverse effects of #sodium iodide [131I]

A significant increase in the risk of leukemia and secondary cancers was found in patients with high cumulative activity of ¹³¹I (>22 GBq; 600 mCi). For this reason, #sodium iodide [131I] should be prescribed only in cases where positive effects are expected, and in these patients it is recommended to administer the minimum activity. Radiation fibrosis may develop in patients with diffuse lung metastases who have repeatedly received activities of #sodium iodide [131I] at short time intervals.

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Vladimir G. Polyakov, D.Sc. (Med.), Professor, Academician of the RAS, Advisor to the Director of the Durnov Research Institute of Pediatric Oncology and Hematology, Head of the Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors) at the Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Head of the Durnov Department of Pediatric Oncology, Russian Medical Academy of Continuous Professional Education (RMAPO) of the Russian Ministry of Health

2. Natalia V. Ivanova, Ph.D. (Med.), Pediatric Surgeon, Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors), Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

3. Vladimir A. Korolev, Ph.D. (Med.), Otorhinolaryngologist, Pediatric Oncology Department of Surgical Treatment Methods with Chemotherapy No. 1 (Head and Neck Tumors), Durnov Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

4. Elena V. Mikhailova, Ph.D. (Med.), Head of Department – Radiologist, Pediatric X-ray Diagnostics Department, Consultative and Diagnostic Center, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

5. Tamara M. Geliashvili, Ph.D. (Med.), Oncologist, Head of Department – Radiotherapist, Radionuclide Therapy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

6. Olga V. Romanova, Pathologist, Pathological Anatomy Department, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health

7. Tamara R. Panferova, Ph.D. (Med.), Senior Researcher, X-ray Diagnostics Department, Research Institute of Pediatric Oncology and Hematology, N.N. Blokhin National Medical Research Center of Oncology of the Russian Ministry of Health, Member of the Russian Society of Pediatric Oncologists (RSPO), Member of the Russian Association of Ultrasound Diagnostics Physicians (RASUDM), Member of the Russian Association of Radiologists (RAR).

8. Aleksey V. Kiyaev, D.Sc. (Med.), Professor, Department of Hospital Pediatrics, Ural State Medical University of the Russian Ministry of Health, Head of the Regional Center of Pediatric Endocrinology, Regional Children's Clinical Hospital, Yekaterinburg

9. Roman A. Chernikov, D.Sc. (Med.), Endocrine Surgeon, Oncologist, Pediatric Surgeon, Head of the Department of Endocrine Surgery, North-Western Center for Endocrinology, Saint Petersburg

10. Ilya V. Sleptsov, D.Sc. (Med.), Endocrine Surgeon, Oncologist, Pediatric Surgeon, Professor, Department of Faculty Surgery, Saint Petersburg State University (SPbSU), North-Western Center for Endocrinology on Fontanka and Pirogov Clinic of High Medical Technologies of SPbSU

11. Aleksandr V. Gostimsky, D.Sc. (Med.), Professor, Chief Medical Officer, Children's City Multidisciplinary Clinical Specialized Center for High Medical Technologies (Children's City Hospital No. 1), Saint Petersburg

12. Vladimir E. Vanushko, D.Sc. (Med.), Chief Researcher, Department of Endocrine Surgery, Endocrinology Research Centre of the Ministry of Health of the Russian Federation, Professor, Institute of Higher and Continuing Professional Education

13. Dmitry N. Brovin, Ph.D. (Med.), Head of the Pediatric Surgery Department, Endocrinology Research Centre of the Ministry of Health of the Russian Federation

14. Dmitry A. Morozov, D.Sc. (Med.), Professor, Director of the Veltischev Research and Clinical Institute of Pediatrics and Pediatric Surgery, Head of the Department of Pediatric Surgery and Urology-Andrology named after L.P. Alexandrov, I.M. Sechenov First Moscow State Medical University

15. Nikolay S. Grachev, Professor, D.Sc. (Med.), Chief Executive Officer, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Head of the Department of Pediatric Surgery with a Course of Oncology and Reconstructive-Plastic Surgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the Federation of Head and Neck Disease Specialists, Member of the Russian Society of Pediatric Oncologists (RSPO).

16. Natalia V. Babaskina, Pediatric Oncologist, Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, ENT Specialist, Oncologist. Department of Oncology and Pediatric Surgery, Dmitry Rogachev NMRCPHOI

17. Kapitolina D. Starokorova, Pediatric Surgeon, Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health

18. Igor N. Vorozhtsov, Ph.D. (Med.), Head of the Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health, Member of the Federation of Head and Neck Disease Specialists.

19. Raisa S. Oganesyan, Pediatric Surgeon, Department of Pediatric Oncology, Head and Neck Surgery, and Neurosurgery, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.

20. Pavel O. Rumyantsev, D.Sc. (Med.), Highest-Category Oncologist-Radiotherapist, Deputy Director of the Center, Director of the Institute of Oncoendocrinology, Endocrinology Research Centre of the Russian Ministry of Health

21. Sergey L. Vorobyov, Ph.D. (Med.), Deputy Head of the Leningrad Regional Pathological Anatomy Bureau (LRPAB), Leading Specialist of the Bureau – Endocrinopathologist, Head of the Morphological Research Laboratory, Saint Petersburg Clinical Complex of the Pirogov National Medical and Surgical Center, Saint Petersburg

22. Marina E. Boriskova, D.Sc. (Med.), Surgeon, Oncologist, Head of the Department of Surgical Endocrinology, Academician I.P. Pavlov First Saint Petersburg State Medical University, Professor, Department of General Surgery with Clinic, First SPbSGMU

Conflict of interest: none.

Appendix A2. Methodology for Developing Clinical Guidelines

Target audience for these clinical guidelines:

1. Practicing medical professionals in the following specialties (pediatric oncology, endocrinology, pediatric surgery, radiology, pediatrics, genetics, radiology/diagnostic imaging, ultrasound diagnostics, pathological anatomy)

2. Medical students, residents, and postgraduate students

In these clinical guidelines, all data are ranked by level of reliability (evidence) depending on the quantity and quality of studies on the issue.

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Scale for grading levels of evidence certainty (LEC) for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for grading grades of recommendation (GR) for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)

Method of guidelines validation:

• External peer review

• Internal expert review

Method for guideline validation: The preliminary version of these guidelines was peer-reviewed by independent experts.

Comments were received from primary care pediatric oncologists regarding the clarity of the presentation of the recommendations and their assessment of the importance of the recommendations as a practical tool for daily practice.

Comments received from experts were carefully systematized and discussed by the working group members. Each point was discussed, and the resulting changes made to the guidelines were documented. If no changes were made, the reasons for refusing to make changes were recorded.

Consultations and expert review: The draft guidelines were also reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the guidelines.

Working group: For final editing and quality control, the guidelines were re-analyzed by the working group members, who concluded that all comments and remarks from the experts had been taken into account, and the risk of systematic bias in guideline development was minimized.

Updates to clinical guidelines: Updating is carried out at least once every three years, taking into account new information on the diagnosis and management of patients with thyroid cancer. The decision to update is made by the Ministry of Health of the Russian Federation based on proposals submitted by medical professional non-profit organizations. The formulated proposals must take into account the results of a comprehensive assessment of medicinal products and medical devices, as well as the results of clinical approbation.

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its reliability. The result of this examination affects the level of evidence assigned to the publication, which in turn affects the strength of the recommendations derived from it.

Procedure for updating clinical guidelines.

The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on 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

No

Appendix B. Physician Action Algorithms

Management of a patient with generalized thyroid cancer

Appendix C. Patient Information

Tanning beds must be completely avoided, sunbathing on the beach during holidays is prohibited, and physiotherapy and vaccinations must be approved by a pediatric oncologist and a pediatric endocrinologist. Upon reaching the age of 18, patients are transferred to outpatient follow-up at the adult department.

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

No