1. The creation of authors’ group

In view of the 2016 publication of the American Thyroid Association (ATA) guidelines on adult patients with thyroid nodules and differentiated thyroid carcinoma, there was a need to compare the existing Polish recommendations with them and to harmonize them in case of identified discrepancies.

Therefore, the Chair of the Scientific Committee of the Thyroid Cancer 2022 Conference has issued an invitation to the Presidents and Boards of Thyroid Cancer Scientific Societies to send three representatives of their respective Society to the Scientific Committee that will prepare new, up-to-date Recommendations. Presidents of the following Societies: Polish Society of Endocrinology, Society of Polish Surgeons, Polish Society of Pediatric Surgeons, Polish Society of Pathologists, Polish Society of Oncological Endocrinology, Polish Thyroid Association, Polish Society of Oncology, Polish Society of Radiation Oncology, Polish Society of Nuclear Medicine, Polish Society of Clinical Oncology, Polish Society of Ultrasound, Polish Society of Pediatric Endocrinology and Diabetology, Polish Society of Human Genetics selected delegates and on May 19, 2021, the Scientific Committee was constituted, which undertook the task of preparing Polish Recommendations update. At the same time, it was decided that this work will be done jointly with the Expert Panel of the National Oncological Strategy, chaired by Professor Marek Dedecjus, particularly since most members of this Panel were members of the Scientific Committee of the Thyroid Cancer 2022 Conference. It was also decided that following the update of the adult recommendations, an update of the guidelines for children and adolescents would be undertaken, with authors drawn from the current group.

2. Who are the recommendations addressed to?

The guidelines are addressed to physicians of all specialties who are involved in the differentiation of benign and malignant goiter in adult patients and the diagnosis and treatment of thyroid cancer, as well as to other physicians who want to learn what are the current recommendations, i.e., to endocrinologists, surgeons, including endocrine surgeons and oncologic surgeons, nuclear medicine specialists and internists, general practitioners, family medicine physicians and nurses cooperating with physicians in this field. The recommendations may also serve interested patients and their families and constitute the basis for determining the policy of financing medical services.

3. What scientific evidence are Polish recommendations based on?

In view of the careful analysis of scientific evidence conducted by the authors of the ATA guidelines, prepared in 2015, and in view of the analysis of scientific evidence conducted by the National Comprehensive Cancer Center Network (NCCN) in 2021, the authors of the Polish recommendations decided that it is necessary to update Polish recommendations for the diagnosis and treatment of adult patients and to evaluate the evidence presented and to respond to it taking into account the specific Polish conditions – both epidemiological and legal. We felt that recommendations issued by other scientific societies, including the European Thyroid Association (ETA), European Society for Medical Oncology (ESMO), European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB), National Comprehensive Cancer Network (NCCN), Society of Radiologists, American Society of Hematology, and American Association of Clinical Endocrinologists (AACE), should also be analyzed. Simultaneously, we reviewed new data published between 2015 and 2021 as needed, relying on the PubMed database and including English-language literature. Members of the team were asked to submit Polish publications relating to the diagnosis and treatment of thyroid cancer, which we also considered in preparing the recommendations.

4. The adopted method for updating the Polish recommendations

It was agreed that we followed the AGREE II protocol in preparing evidence-based recommendations, and we based on the existing 2018 Polish recommendations. An Initiative Group was also established. It presented a number of inconsistencies between the Polish recommendations and the ATA 2015 guidelines, as well as the NCCN guidelines. It was decided that the ADAPTE protocol would be used for adaptation to Polish conditions. We believed that in some cases by transferring the universally accepted findings of international bodies on the issue of classification, we would limit ourselves to assessing the strength of recommendation (SoR) but not the quality of evidence (QoE).

It was agreed that the selected experts would draw up and present to the whole Team scientific arguments for changing the Polish recommendations towards the direction proposed by ATA and NCCN, and the discussions would be held by teleconference. As of December 1, 2021, 12 teleconferences have been organized. After discussing a given topic and presenting a proposal for a new recommendation by the Expert, each time, a survey was conducted among the Team members, in which they could express their opinion on the new recommendation. After the acceptance of the most important recommendations by the majority of team members, thematic subgroups were formed, which in parallel proceeded to work on a given part of the manuscript and on the assessment of the strength and quality of scientific evidence on which the recommendation was based.

The agreement was received from all authors on the content of the recommendation and acceptance of the prepared manuscript.

5. Evaluation of the strength of recommendation and the quality of evidence

In selecting the method of assessing the strength of recommendations and quality of scientific evidence, we analyzed the methods used by NCCN and ATA. The method used by NCCN was adopted, as recommended by AOTMiT (Agency for Health Technology Assessment and Tarif System) (Tab. 1–2). However, since recommendations on diagnosis and treatment of thyroid cancer mainly refer to diagnostic procedures — including their applied classifications of results, as well as therapeutic interventions (including diagnostic interventions), which consist of surgical, cytologic, and nuclear-medical procedures, the Team decided to make an additional choice of assessing the strength of recommendation and quality of evidence according to ATA, which was used in previous Polish recommendations. A detailed description of the criteria used by ATA is presented in Tables 3–6. The Team of Authors of Polish recommendations has also decided to limit itself to providing only the strength of recommendation in relation to diagnostic tests and their classification proposed by recognized international bodies, as it does not require our assessment of the quality of scientific evidence.

Part I

Thyroid cancer diagnostics

1. Ultrasound (US) is the primary imaging test for diagnosing cancer and other thyroid diseases. Indications for thyroid ultrasound [1–4]:

1.1. Nodular goiter or palpable thyroid nodule.

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R6

1.2. Enlargement of the thyroid gland without a palpable nodule.

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R6

1.3. Focal thyroid lesion detected by ultrasound performed for other indications or by another imaging study.

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R6

1.4. Suspected other thyroid disease.

SoR 2A QoE: IV

SoR: 1 QoE: +

1.5. Carrying a RET mutation and/or calcitonin levels above normal [5].

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL MTC

1.6. History of neck exposure to ionizing radiation [6–8].

SoR 2A QoE: III

SoR: 1 QoE: +++

1.7. Cervical lymph node enlargement not associated with infection.

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R6 [1]

2. Other useful diagnostic tests for nodular goiter include:

2.1. In all cases of nodular goiter, the assessment of thyroid stimulating hormone (TSH). If the TSH result is abnormal, evaluation of serum free thyroxine (fT4) or fT4 and free triiodothyronine (fT3).

SoR 2A QoE: IV

SoR: 1 QoE: +++

2.2. Anti-thyroid peroxidase antibody level (anti-TPO) and/or other anti-thyroid antibodies according to the center’s experience.

SoR 2B QoE: IV

SoR: 2 QoE: +

2.3. Serum calcitonin measurement is not recommended in all cases of nodular goiter [5].

SoR 2A QoE: III

SoR: 2 QoE: +

However, serum calcitonin measurement is helpful in:

2.3.1. In clinically suspected medullary thyroid carcinoma (MTC) and in RET mutation carriers.

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL MTC [5]

2.3.2. To rule out MTC before planned thyroid surgery (see section 3.3.1).

SoR 2B QoE: IV

SoR: 2 QoE: + ATA GL MTC [5]

2.4. 99mTc thyroid scintigraphy is useful if TSH levels are near the lower limit or below normal in a patient with nodular goiter [9].

SoR 2A QoE: III

SoR: 1 QoE: ++

2.5. Elastography is not required for routine US evaluation of focal thyroid lesions. If elastography is available, it may be helpful in qualification for fine-needle aspiration biopsy (FNAB) and monitoring after FNAB (Tab. 7–9) [1–3, 10].

SoR 2A QoE: IV

SoR: 1 QoE: ++

Table 8. Asteria score [376]

Score (Figure)	Characteristics
1 (A)	The entire nodule shows even elasticity
2 (B)	Elasticity in large portion of the nodule
3 (C)	No elasticity in large portion of the nodule
4 (D)	No elasticity in the entire nodule

Green, red colors describe deformable (“soft”) parts. The blue color represents non-deformable elements (“hard”). Score 2* — so-called BGR (blue-green-red) — a typical pattern for the liquid component of a nodule (E)

2.6. Nuclear Magnetic resonance (MRI), computed tomography (CT), and positron emission tomography (PET) with 18fluorodeoxyglucose (18FDG) are not recommended for the differential diagnosis of focal thyroid lesions.

SoR 2A QoE: IV

SoR: 2 QoE: ++ ATA GL R18 [1]

3. The malignancy risk in a focal thyroid lesion is evaluated based on clinical and sonographic features:

3.1. The clinical features of increased risk of malignancy are as follows:

3.1.1. Presence of lymph node metastases or distant metastases [9, 11].

SoR 2A QoE: III

SoR: 1 QoE: +++

3.1.2. History of head and neck exposure to ionizing radiation [6–8].

SoR 2A QoE: IV

SoR: 1 QoE: +++

3.1.3. History of familial MTC [5].

SoR 2A QoE: III

SoR: 1 QoE: +++

3.1.4. Enlargement of a focal lesion is not synonymous with its malignant nature, but its rapid growth (within a few weeks) points to significant suspicion of anaplastic thyroid carcinoma and requires urgent endocrine-oncologic consultation [12].

SoR 2A QoE: III

SoR: 1 QoE: +++

3.1.5. Presence of a hard, immobile, fixed nodule.

SoR 2A QoE: V

SoR: 1 QoE: ++

3.1.6. Nodule diameter > 4 cm.

SoR 2A QoE: V

SoR: 1 QoE: ++

3.1.7. The appearance of a thyroid nodule before the age of 14.

SoR 2A QoE: V

SoR: 1 QoE: ++

3.1.8. The appearance of a thyroid nodule after the age of 70.

SoR 2A QoE: V

SoR: 1 QoE: ++

3.1.9. Recurrent laryngeal nerve palsy, especially unilateral one.

SoR 2A QoE: V

SoR: 1 QoE: ++

3.2. Sonographic risk features – any focal lesion found on US should be subjected to ultrasound-based malignancy risk stratification [2, 3].

SoR 2A QoE: III

SoR: 1 QoE: +++

The authors recommend using for this purpose EU-TIRADS-PL score, a modified EU-TIRADS score (Tab. 7, 10–12) [13].

SoR 2A QoE: IV

SoR: 2 QoE: +

4. Thyroid fine-needle aspiration biopsy (FNAB):

4.1. Focal thyroid lesions are eligible for FNAB based on the EU-TIRADS-PL score [14].

SoR 2A QoE: IV

SoR: 2 QoE: +

4.2. The risk of thyroid cancer is similar in patients with multiple thyroid lesions and patients with a single focal thyroid lesion [15,16].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.3. FNAB is required in a thyroid lesion regardless of its diameter if thyroid cancer lymph node or distant metastases are diagnosed, serum calcitonin is elevated, or carrying of a germline RET mutation predisposing to MTC is confirmed [5, 17].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.4. FNAB of multiple thyroid lesions [18, 19]:

4.4.1. If the foci are multiple, each one should be subjected to ultrasound risk assessment according to the EU-TIRADS-PL score [9, 20].

SoR 2A QoE: IV

SoR: 1 QoE: ++

4.4.2. Optimal management involves selecting lesions for FNAB in order of highest to lowest ultrasound malignancy risk according to the EU-TIRADS-PL score [9].

SoR 2A QoE: IV

SoR: 1 QoE: +

4.4.3. It is advisable to puncture the focal lesion with the highest risk of malignancy according to the EU-TIRADS-PL score and all foci requiring FNAB. Obtaining a “benign lesion” result from all such selected nodules can be considered as excluding a significant risk of malignancy with a reasonable probability [1, 9, 18–20].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.5. If the foci are multiple with a similar sonographic appearance and do not show high-risk sonographic features of malignancy (EU-TIRADS-PL 3 or 4), FNAB of only the largest lesion is acceptable [9, 21].

SoR 2A QoE: V

SoR: 1 QoE: ++

4.6. In the diffuse echostructural lesions, indications for FNAB are relative, and FNAB may be limited to a single lesion [9].

SoR 2A QoE: IV

SoR: 2 QoE: +

4.7. Indications for FNAB following the detection of a nodule on other imaging studies:

4.7.1. Nodules detected in the thyroid gland on ultrasound, CT, or MRI for other indications should be eligible for FNAB according to the rules outlined in sections 3 and 4 [9].

SoR 2B QoE: III

SoR: 1 QoE: +++

4.7.2. Areas of increased glucose uptake detected by 18F-FDG PET/CT and hot spot(s) by 99mTcMIBI scintigraphy (e.g., cardiac SPECT) should undergo ultrasound evaluation and, if a focal thyroid lesion is confirmed, FNAB is recommended [22]. However, the clinical context should be considered.

SoR 2B QoE: IV

SoR: 2 QoE: +

5. FNAB of a focal thyroid lesion may be abandoned if no clinical risk factors are identified [9, 13] and:

5.1. The nodule is anechoic or presents a spongiform appearance (EU-TIRADS-PL 2).

SoR 2A QoE: IV

SoR: 1 QoE: +++

5.2. EU-TIRADS-PL 3 nodule is < 20 mm in diameter.

SoR 2A QoE: IV

SoR: 1 QoE: +++

5.3. EU-TIRADS-PL 4 nodule is < 15 mm in diameter.

SoR 2A QoE: IV

SoR: 1 QoE: +++

5.4. EU-TIRADS-PL 5 nodule is < 5 mm in diameter.

SoR 2B QoE: IV

SoR: 2 QoE: +

5.5. Focal lesion demonstrates autonomic function on thyroid scintigraphy (so-called hot nodule).

SoR 2A QoE: IV

SoR: 1 QoE: ++

6. Cytological classification of lesions subjected to FNAB should be based on the National Cancer Institute (NCI) guidelines, referred to The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) called “Bethesda classification” in these recommendations (Tab. 13) [1, 23].

SoR 2A QoE: IV

SoR: 1 QoE: +++ ATA GL R9

7. FNAB — execution and technique:

7.1. FNAB always requires ultrasound-guidance.

SoR 2A QoE: III

SoR: 1 QoE: ++ ATA GL R8, R10 [1]

7.2. Written informed consent is required for FNAB.

7.3. FNAB technique:

7.3.1. FNAB should be performed using a needle with a diameter between 0.4–0.6 mm. In exceptional cases, a needle with a larger external diameter may be used (cyst drainage) [24–26].

SoR 2A QoE: III

SoR: 1 QoE: +++

7.3.2. A nodule > 20 mm should be biopsied in a manner that allows the collection of material from different areas of the lesion [1].

SoR 2A QoE: III

SoR: 1 QoE: +++

7.3.3. The purpose of FNAB is to collect cellular material. After FNAB is performed, the presence of the material should be checked on the slide. Cellular material is visible as granules. Caution: do not allow to dry out the smear used for subsequent hematoxylin and eosin (H-E) staining.

7.3.4. If a repeat FNAB is performed because of a previous non-diagnostic biopsy, a rapid on-site examination (ROSE) is recommended, and the quantity and quality of the collected material should be checked [27].

SoR 2A QoE: IV

SoR: 1 QoE: +++ ATA GL R10 [1]

7.3.5. If the ROSE method is not available, a minimum of three separate punctures of the same nodule are indicated [28].

SoR 2A QoE: IV

SoR: 1 QoE: ++

7.3.6. In case of H-E staining it is recommended to fix the preparation in alcohol (96% ethanol). It is permissible to use fixatives in atomizer or spray, keeping in mind the risk of aggregation and dispersion of material on the edges of the slide.

8. Information, which should be provided in the FNAB referral form (Dz.U. 2017, poz. 2435):

8.1. Name, first name, professional license number and signature of the physician referring for FNAB.

8.2. The name of the health care provider whose physician orders and refers for FNAB.

8.3. Patient’s first and last name and address.

8.4. Patient’s personal identification number (PESEL).

8.5. Patient’s sex and age.

8.6. Initial clinical diagnosis.

8.7. Lesion location and diameter.

8.8. Data related to patient history (any primary cancer, exposure to neck irradiation, concomitant thyroid disorders).

8.9. Information related to administered treatment, if relevant to interpretation of cytological results.

8.10. Data on any previous FNAB (date, lesion location, diagnosis).

9. FNAB of suspected lymph nodes:

9.1. If a thyroid nodule is accompanied by a suspicious lymph node on US examination, its FNAB has to be performed [9, 29].

SoR 2A QoE: III

SoR: 1 QoE: +++

9.2. Features raising suspicion of lymph node metastasis: microcalcifications, increased echogenicity of the cortex of a lymph node, litho-cystic appearance, round shape, absence of fatty hilum, peripheral or diffusely increased vascularization with irregular pattern, reduced elasticity of the node (in case of multiple abnormal nodes) [10, 29, 30].

SoR 2A QoE: IV

SoR: 1 QoE: +++

9.3. Determination of thyroglobulin and/or calcitonin in the needle washout is helpful in the cytologic diagnosis of sonographically suspicious lymph nodes [9, 31].

SoR 2A QoE: IV

SoR: 1 QoE: ++

10. FNAB is subjected to qualitative and quantitative assessment. Quantitative evaluation of FNAB shall be performed only on material of satisfactory quality. The following grades of quantitative assessment should be used:

10.1. Diagnostic material: at least six groups of cells containing at least ten well-preserved follicular cells. It is necessary to consider the clinical context when preparing this assessment [23].

10.2. Diagnostic material, in spite of its poor cellularity, (ex. cyst liquid, thyroid inflammation) [23].

10.3. Non-diagnostic material due to lack of or a small number of follicular cells (< 60) [23].

11. Clinical and radiological context:

11.1. Solid thyroid nodules:

11.1.1. Diagnosis of cellular features indicating suspicion of malignancy in a cytological smear must be given in the final FNAB report, even if the number of cells is small [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

11.1.2. A lesion with a large colloid amount — the presence of a large colloid amount is reliable proof of a tumor being benign, so FNAB may be diagnostic despite its poor cellularity [23].

SoR 2A QoE: V

SoR: 1 QoE: ++

11.2. If FNAB of the cyst has been performed, a sparse or absent number of follicular cells is the expected cytologic picture. In combination with a clear ultrasound image, the diagnosis of thyroid cyst can be made in this case [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12. Recommended diagnostic terminology — it is recommended that six classes of cytological diagnosis be used, according to the Bethesda Classification (Tab. 13) [23]:

SoR: 1

12.1. Nondiagnostic biopsy, Bethesda category I:

12.1.1. The FNAB result is defined as non-diagnostic if it does not fulfil representativeness criteria (section 10) considering the clinical-radiological context (section 11) [23].

12.1.2. Non-diagnostic FNAB may be related to three causes [23]:

12.1.2.1. Inadequate cellularity.

12.1.2.2. Lack of follicular cells.

12.1.2.3. Incorrect sample fixation and storage.

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.2. Benign nodule, Bethesda category II — this term represents the final diagnosis of nodular goiter, thyroiditis (acute, subacute, and autoimmune), a single hyperplastic, or a colloid nodule. The risk of malignancy is minimal [32].

SoR 2A QoE: IV

SoR: 1 QoE: +++

12.3. Follicular lesion of undetermined significance, Bethesda category III:

12.3.1. Follicular lesion of undetermined significance is an equivocal diagnosis requiring correlation with clinical data and sonographic appearance during subsequent FNAB. This diagnosis should be stated as rarely as possible [23].

12.3.2. It is an exclusion category that encompasses those cytologic images that do not meet the eligibility criteria for “suspicious for a follicular neoplasm” or “suspicious for malignancy” [23].

12.3.3. Classification in this category may also result from sample limitations (low cellularity, blood admixture, fixation errors) when cell characteristics do not clearly indicate benign nature or even raise concerns about the malignant risk of the nodule [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.3.4. A diagnosis of the Bethesda III category should be completed with one of the subcategories: AUS (atypia of undetermined significance), FLUS (follicular lesion of undetermined significance), AUS/FLUS, Hurthle cell atypia (AUS and/or FLUS), atypia unspecified:

12.3.4.1. The subcategory “cellular atypia” (AUS) describes smears with cell structure abnormalities and is characterized by strong nuclear polymorphism, cellular polymorphism, nuclear heterochromasia, single nuclear grooves and clearances, and macronucleosis (in previously untreated lesions). This subcategory refers primarily to smears with cellular features suggestive of papillary thyroid carcinoma [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.3.4.2. The subcategory “atypia of cellular arrangements” (FLUS) is characterized by poor cellularity of an aspirate, variable acidophilicity of the cytoplasm, the presence of numerous rosettes, and a scant colloid background [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.3.4.3. Features of the above two subcategories may appear together, in which case we refer to them as “atypia of cells and their arrangements” (AUS/FLUS) [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.3.4.4. The subcategories described above may involve Hurthle cells, in which case they should be referred to as “Hurthle-cell atypia” and/or “Hurthle-cell arrangements” (atypia of Hurthle cells and/or their arrangements — AUS and/or FLUS) [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.3.4.5. In addition, the subcategory “indeterminate atypia” was distinguished to describe atypia of an unspecified nature [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.4. Suspicious for a follicular neoplasm, Bethesda category IV:

12.4.1. The diagnostic criteria are summarized in Table 14.

12.4.2. This diagnosis may correspond to the final histopathological diagnoses of follicular adenoma, high cellularity nodular hyperplasia, noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP), or lymphocytic thyroiditis (in which features of disrupted cell structure are often found). On the other hand, category IV on FNAB may correspond to the histopathological diagnosis of follicular carcinoma, Hurthle-cell carcinoma, follicular and oxyphilic variant of papillary thyroid carcinoma [23].

SoR 2A QoE: IV

SoR: 1 QoE: +++

12.4.3. It is recommended to use the term “Bethesda category IV” due to the difficulty in appropriate Polish translation.

SoR 2A QoE: V

SoR: 1 QoE: +

12.4.4. The Category IV diagnosis should be completed by cell type, as this category includes both lesions defined as “suspicious for a follicular neoplasm” and “suspicious for a Hurthle-cell follicular neoplasm” [33].

SoR 2A QoE: IV

SoR: 1 QoE: +

12.4.5. In cases where NIFTP is suspected due to the atypia of cell nuclei and the presence of follicular arrangements, and the lack of papillary structures and pseudoinclusions, the diagnosis should be completed with the comment “NIFTP cannot be excluded” [32].

SoR 2A QoE: IV

SoR: 1 QoE: +

12.4.6. A category IV diagnosis should be made in cases where the pathologist anticipates the need for surgical procedures to obtain material and make a final histopathological diagnosis [23].

SoR 2A QoE: IV

SoR: 1 QoE: +

12.4.7. Considering this diagnosis, the risk of cancer should be evaluated individually together with clinical-epidemiological factors [23].

SoR 2A QoE: V

SoR: 1 QoE: +

12.4.8. If category IV on FNAB is an indication for surgery, confirmation of the diagnosis by a second pathologist is useful.

SoR 2A QoE: V

SoR: 1 QoE: +

12.5. Suspicious for malignancy, Bethesda category V:

12.5.1. Such a statement means that some features of malignant tumors are present but not all that would allow a diagnosis of malignancy [33].

SoR 2A QoE: V

SoR: 1 QoE: +

12.5.2. Suspicious for papillary carcinoma most commonly corresponds to its follicular variant and, in rare cases, to NIFTP [23].

SoR 2A QoE: IV

SoR: 1 QoE: ++

12.5.3. Suspicion for MTC should be accompanied by serum calcitonin assessment or immunocytochemical testing for calcitonin in the cells of the smear. Basal Ct > 100 ng/L allows MTC to be diagnosed with a high probability [33, 34].

SoR 2A QoE: IV

SoR: 1 QoE: +++

12.5.4. Suspicion for lymphoma or metastasis of another cancer to the thyroid gland should lead to more detailed cyto and/or histologic diagnostics. Repeating FNAB using flow cytometry, FNAB with cytoblock evaluation, core or surgical biopsy should be considered [23].

SoR 2A QoE: IV

SoR: 1 QoE: +++

12.6. Malignant tumor, Bethesda category VI:

12.6.1. This category involves the diagnosis of papillary thyroid cancer, anaplastic thyroid cancer, or metastatic carcinoma [33].

SoR 2A QoE: III

SoR: 1 QoE: +++

12.6.2. MTC diagnosis and localization of primary focus of metastasis from other cancer and lymphoma require more detailed diagnostics [33].

SoR 2A QoE: IV

SoR: 1 QoE: +++

13. FNAB report should contain:

13.1. Information related to the nodule location and its features enabling its identification and/or a photo.

13.2. Information concerning FNAB representativeness, both qualitative and quantitative [23].

13.3. Description of cytological examination of each nodule assessed.

13.4. A diagnostic conclusion that classifies FNAB findings to one of six Bethesda categories (Tab. 13, see section 12) [33].

13.5. It is recommended that a comment be attached to the FNAB report [23].

14. FNAB reliability and limitations:

14.1. Differentiation between follicular carcinoma and adenoma based on cytological examination is not possible [33].

SoR 2A QoE: III

SoR: 1 QoE: +++

14.2. Because there is always a risk of a false negative result of FNAB, clinicians should evaluate the presence of clinical features of malignancy indicating surgical treatment [35].

SoR 2B QoE: IV

SoR: 1 QoE: ++ ATA GL R23 [1]

14.3. The risk of a false positive result is 1% [36].

SoR 2A QoE: IV

SoR: 1 QoE: ++

14.4. Complementing FNAB with immunocytochemical staining is recommended in selected cases in centers with adequate facilities (Tab. 15).

SoR 2A QoE: V

SoR: 1 QoE: +

15. Contraindications to FNAB:

15.1. Absolute [32]:

15.1.1. Serious hemorrhagic diathesis.

15.1.2. Purulent skin lesions.

15.1.3. Lack of patient cooperation.

SoR 2A QoE: V

SoR: 1 QoE: +

15.2. Relative:

15.2.1. The use of anticoagulants (Tab. 16). According to the published data, thyroid FNAB is considered a low-risk bleeding procedure, generally not requiring discontinuation of anticoagulant therapy [29, 37–42].

SoR 2A QoE: IV

SoR: 1 QoE: ++

15.2.1.1. Vitamin K antagonists K (VKA): acenocoumarol, warfarin — the use of acenocoumarol and warfarin is not a contraindication to FNAB [29, 38, 39], especially if a 0.4–0.6 mm needle is used and the INR is within the therapeutic range. Current anticoagulant treatment guidelines recommend continuing VKA therapy and optimizing local hemostasis [43]. Switching to low-molecular-weight heparin may be considered when there are additional factors that increase the risk of bleeding, e.g., thrombocytopenia with coexisting high thromboembolic risk (e.g., during the first three months after ischemic stroke or pulmonary embolism, artificial mitral valve, superior vena cava syndrome in the course of cancer, severe thrombophilia [44].

SoR 2A QoE: IV

SoR: 1 QoE: ++

15.2.1.2. Low molecular weight heparin (enoxaparin, dalteparin, nadroparin) — the use of low molecular weight heparin is not a contraindication to FNAB. At least an 8–12-hour break after administration of heparin is necessary.

SoR 2A QoE: IV

SoR: 1 QoE: ++

15.2.1.3. Oral anticoagulants that are not vitamin K antagonists (novel oral anticoagulants — NOAC; direct oral anticoagulants — DOAC; target specific oral anticoagulants — TSOAC).

SoR 2A QoE: IV

SoR: 1 QoE: ++

15.2.1.3.1. Direct inhibitor of coagulation factor IIa (thrombin) — dabigatran. Dabigatran use requires discontinuation prior to FNAB. The duration of dabigatran discontinuation depends on creatinine clearance: with the normal renal function, it should be 24 hours, with reduced renal filtration capacity, a longer (≥ 36–48 hours) discontinuation may be necessary (Tab. 16) [45, 46].

SoR 2A QoE: IV

SoR: 1 QoE: +

15.2.1.3.2. Direct Factor Xa inhibitors — fondaparinux, rivaroxaban, apixaban, edoxaban. It is recommended to discontinue these medications 24 hours prior to FNAB [45, 46].

SoR 2A QoE: IV

SoR: 1 QoE: +

15.2.1.4. Anti-platelet and anti-inflammatory drugs — there are no contraindications to FNAB if acetylsalicylic acid in doses up to 0.3 g or other non-steroidal anti-inflammatory drugs are taken.

SoR 2A QoE: IV

SoR: 1 QoE: +

15.2.1.5. Other antiplatelet drugs: ticlopidine, clopidogrel, ticagrelor, prasugrel, cilostazol. If drug discontinuation is contraindicated for cardiovascular reasons, thyroid FNAB is allowed in a patient on antiplatelet drugs if absolutely indicated. Switching to low-molecular-weight heparin is not justified because of the different mechanisms of action.

SoR 2A QoE: V

SoR: 1 QoE: +

15.2.1.6. Currently, there are no published data to determine the risk of bleeding in patients on dual antiplatelet therapy. Because of the potentially higher thromboembolic risk, if treatment is discontinued, these patients should be advised by their treating physician regarding possible treatment modification before FNAB.

SoR 2A QoE: V

SoR: 1 QoE: +

16. FNAB complications:

16.1. Transient:

16.1.1. Hematoma (prevention — compression of FNAB site following biopsy. If deeply located lesions are aspirated, 30-minute observation is recommended).

SoR 2A QoE: IV

SoR: 1 QoE: ++

16.1.2. Pain and edema (prevention — ice compress, paracetamol).

SoR 2A QoE: IV

SoR: 1 QoE: ++

16.1.3. Syncope.

SoR 2A QoE: IV

SoR: 1 QoE: ++

16.2. Serious complications — extremely rare:

16.2.1. Recurrent laryngeal nerve palsy (the absolute risk is 0.036%) — dysphonia and dysphasia typically develop on the second day after FNAB, and recovery takes up to four months.

SoR 2A QoE: IV

SoR: 1 QoE: ++

16.2.2. Hemorrhage or hematoma requiring surgery.

SoR 2A QoE: IV

SoR: 1 QoE: ++

16.2.3. Infection (rare even in patients with immune deficiency), increased risk in patients infected with HIV or with diagnosis of diabetes mellitus, tuberculosis, atopic dermatitis.

SoR 2A QoE: IV

SoR: 1 QoE: +

16.2.3.1. Staphylococcal infection. If skin hygiene is poor, the skin should be thoroughly disinfected.

SoR 2A QoE: IV

SoR: 1 QoE: +

17. Further follow-up after non-diagnostic FNAB:

17.1. Solid nodule or solid nodule with cystic degeneration (EU-TIRADS-PL 3) — a clinically benign lesion with non-diagnostic FNAB results requires ultrasound monitoring and subsequent FNAB depending on clinical and/or sonographic risk [6, 9, 11, 47].

SoR 2A QoE: III

SoR: 1 QoE: ++

17.2. Solid nodule or solid nodule with cystic degeneration (EU-TIRADS-PL 4 lub 5) — if diagnostic material was not obtained during the first FNAB, repeat FNAB is indicated. During FNAB of a solid-cystic lesion, the solid part should be biopsied [9, 48].

SoR 2A QoE: III

SoR: 1 QoE: ++ ATA GL R10 [1]

17.3. The interval between non-diagnostic and second FNAB:

17.3.1. This interval could be shorter than three months if clinical or sonographic features suggest an increased risk of malignancy (EU-TIRADS-PL 5) or an incorrect FNAB procedure is highly probable [6, 9, 11, 47].

SoR 2A QoE: IV

SoR: 1 QoE: +++

17.3.2. In the vast majority of cases, where the clinical risk is not high (EU-TIRADS-PL 3/4), repeated FNAB may be performed after 6–12 months [49].

SoR 2A QoE: III

SoR: 1 QoE: ++

18. Two non-diagnostic FNABs in a solid nodule (EU-TIRADS-PL ≥ 3) [48]:

18.1. Surgery depending on clinical and ultrasound risk features should be considered [9, 11].

SoR: 2B QoE: III

SoR: 2 QoE: ++

18.2. A repeated FNAB at another center should be considered if conservative management is chosen.

SoR: 2B QoE: III

SoR: 2 QoE: ++

18.3. In the case of two non-diagnostic FNABs with clinical suspicion of poorly differentiated cancer or undifferentiated (anaplastic) carcinoma, core biopsy should be considered at a center adequately prepared to perform such a biopsy.

SoR 2B QoE: III

SoR: 2 QoE: ++

18.4. If a maximum nodule diameter is < 1 cm and no increase in clinical and sonographic risk features is observed during follow-up, further monitoring is recommended.

SoR 2A QoE: IV

SoR: 1 QoE: +++

19. Further follow-up after the diagnosis of a benign nodule on FNAB (category II).

19.1. Benign FNAB result does not unequivocally negate surgery.

SoR 2A QoE: IV

SoR: 1 QoE: ++

19.2. Follow-up of EU-TIRADS-PL 3-5 solid and solid-cystic nodule benign on FNAB [23, 50].

19.3. A solid focal lesion diagnosed as benign on FNAB requires clinical and ultrasound monitoring every 6–18 months [50].

SoR 2A QoE: V

SoR: 1 QoE: +

19.3.1. Repeated FNAB during follow-up is not required unless there are no clinical or ultrasound doubts [50].

SoR 2A QoE: V

SoR: 1 QoE: +

19.3.2. If there is no correlation between the cytologic and sonographic findings, repeated FNAB can help ensure the diagnosis [51].

SoR 2A QoE: IV

SoR: 1 QoE: ++

19.3.3. Conservative management is acceptable, even if a significant nodule growth is observed if the repeated FNAB gives a benign result [52].

SoR 2A QoE: IV

SoR: 1 QoE: +

20. Further management after the diagnosis of follicular lesion of undetermined significance (Bethesda category III) on FNAB [23, 50, 53]:

20.1. Conservative management — Bethesda III focal lesion requires clinical and sonographic monitoring every six months. Repeated FNAB to be considered after 6–12 months.

SoR 2A QoE: V

SoR: 2 QoE: +

20.1.1. Accelerated repeated FNAB at an interval of 3–6 months could be indicated if the lesion shows sonographic malignancy risk features (see section 3.2) or the FNAB result provides the information about abnormal cellular structure raising suspicion of malignancy. In case of a similar result of repeated FNAB (category III), surgical management should be considered.

SoR 2A QoE: V

SoR: 2 QoE: ++

20.2. Surgery is an optimal management recommended in nodules > 4 cm, as well as in smaller focal lesions, if they grow significantly or if there are other clinical or sonographic risk features [54].

SoR 2A QoE: IV

SoR: 1 QoE: ++

21. Further management after the diagnosis of “suspicious for a follicular neoplasm” (Bethesda category IV) in FNAB [23, 53]:

21.1. Conservative management [23]:

21.1.1. If clinical and sonographic risk features are absent in small lesions (up to 1 cm), further clinical and ultrasound monitoring should be considered.

SoR: 2B QoE: V

SoR: 2 QoE: +

21.1.2. If a Bethesda category IV focal lesion is qualified for conservative management, clinical and ultrasound monitoring is indicated every 6 months. If there is an increase in sonographic and/or clinical risk features, subsequent FNAB is indicated.

SoR 2B QoE: V

SoR: 2 QoE: +

21.2. Surgery [23]:

21.2.1. Confirmation of a Bethesda category IV diagnosis by a second pathologist is useful before surgical treatment is undertaken. If such confirmation is obtained, repeat FNAB will not add anything to the diagnosis, especially if performed after a short time.

SoR 2B QoE: V

SoR: 2 QoE: +

21.2.2. Surgical treatment is intended to resolve diagnostic uncertainties, particularly when clinical or ultrasound risk features coexist. It is the optimal route to establish the final diagnosis (diagnostic-therapeutic surgery).

SoR 2A QoE: II

SoR: 1 QoE: +++ ATA GL R19, R20 [1]

21.2.3. If the FNAB result is “suspicious of a Hurthle-cell neoplasm”, surgical treatment is recommended [55]. This recommendation does not refer to nodules < 1 cm, in which optimal management has not been established.

SoR 2B QoE: IV

SoR: 2 QoE: +

21.3. Radioiodine (RAI) — if a Bethesda category IV focal lesion proves to be an autonomic nodule on scintigraphy, RAI treatment may be recommended [9].

SoR 2A QoE: IV

SoR: 2 QoE: ++

22. Further management after the diagnosis „suspicious for malignancy (Bethesda category V) on FNAB:

22.1. Surgery is recommended, regardless of the presence of sonographic risk features. In some cases, so-called “active surveillance” of the lesion is acceptable (see Part III) [1, 56, 57].

SoR 2B QoE: II

SoR: 2 QoE: +++

22.2. Confirmation of FNAB diagnosis by a second pathologist before surgery is undertaken is necessary.

SoR 2B QoE: V

SoR: 2 QoE: +

23. Malignant neoplasm (Bethesda category VI):

23.1. Surgery is recommended, regardless of the presence of sonographic risk features. In some cases, so-called “active surveillance” of the lesion is acceptable (see Part III) [1, 56, 57].

SoR 2A QoE: V

SoR: 1 QoE: +

23.2. Confirmation of FNAB diagnosis by a second pathologist before surgery is undertaken is necessary.

SoR 2B QoE: V

SoR: 2 QoE: +

24. Core needle biopsy:

24.1. Core needle biopsy is not a routine procedure for the diagnosis of thyroid cancer and should be reserved for centers with immediate treatment options in case of complications.

SoR 2A QoE: V

SoR: 1 QoE: +

24.2. Core needle biopsy of the thyroid gland yields histological material for a wide immunohistochemistry (Tab. 15).

SoR 2A QoE: IV

SoR: 1 QoE: +

24.3. Core needle biopsy may be an alternative to surgical biopsy in the diagnosis of anaplastic carcinoma and lymphoma, differentiation of inflammatory tumors and metastases to the thyroid gland [58].

SoR 2B QoE: IV

SoR: 2 QoE: +

25. Recommendations for preoperative molecular diagnosis of focal thyroid lesions are given in Part V.

Part II

General principles adopted in the treatment and follow-up of thyroid cancer

1. Therapeutic decisions in thyroid cancer should be made within a multidisciplinary tumor board (MTB). The treatment of thyroid cancer should optimally be carried out within the dedicated Thyroid Cancer Unit/Endocrine Cancer Unit of the reference center. The treatment of difficult, clinically complex cases must take place in such a unit.

SoR 2A QoE: V

SoR: 1 QoE: +

2. Postoperative staging of thyroid cancer is done according to the TNM classification of the most recent update. Currently, it is based on the 8th Edition of the UICC TNM Classification of Malignant Tumors published in 2017 (Tab. 17 and 18).

SoR 2A

SoR: 1

3. The authors adopt the 2015 ATA risk stratification system [1] for differentiated thyroid cancer (papillary or follicular) (Tab. 19).

SoR 2A QoE: IV

SoR: 1 ATA GL R48

4. Similarly, a response to treatment should be classified according to the principles proposed by the 2015 ATA GL [1, 59] (Tab. 20).

SoR 2A QoE: V

SoR: 1 QoE: +

Part III

Management of papillary thyroid microcarcinoma

1. For the preoperative diagnosis of stage cT1aN0M0 papillary carcinoma in a single focal lesion ≤ 1 cm in the largest dimension, surgery may be waived if it is a low-risk lesion [60–68] (Tab. 21), and the patient agrees to such a management.

SoR 1 QoE: III

SoR: 1 QoE: +++

2. The rules to be followed for eligibility are shown in the Table 21 and Figure 1.

SoR 2A QoE: IV

SoR: 2 QoE: +

Figure 1. Surgical management scheme in patients with a diagnosis or suspicion of thyroid cancer, depending on the preoperative assessment of the risk of cancer recurrence, according to the European Society of Medical Oncology (ESMO) guidelines [56], modified. *Aggesive features on cytology, encompass each suspicion towards advers PTC variants or poorly differentiated, medullary; **ETE — extra thyroidal extension; TT — total thyreoidectomy; CND — central node dissection; MIT — minimally invasive techniques; EBRT — external beam radiotherapy

If the patient, along with the physician, decided to have surgical treatment for a papillary thyroid microcarcinoma, the recommended extent of surgery treatment is loboisthmectomy.

SoR 2A QoE: III

SoR: 1 QoE: +++

3. In case of progression (an increase of the nodule size by ≥ 3mm or occurrence of lymph node metastases), it is necessary to refer the patient for surgical treatment, which extent depends on the advancement of the disease [63, 69–71].

SoR 2A QoE: III

SoR: 1 QoE: +++

4. Active surveillance should be carried out in a center with appropriate facilities for at least one year. After that time, the patient may be referred for further follow-up by an endocrinologist in the place of residence or remain at the reference center.

SoR 2A QoE: III

SoR: 1 QoE: +++

5. The protocol of active surveillance includes ultrasound examinations every six months for the first two years then once a year [63, 69–71].

SoR 2A QoE: III

SoR: 1 QoE: +

6. Once a papillary thyroid microcarcinoma is identified, the patient has to be informed of alternative management options:

6.1. Surgery — hemithyroidectomy (see Part IV, section 2.5.2).

6.2. Active surveillance (see sections 1–6 above).

6.3. The use of minimally invasive techniques (see Part IV, section 2.5.3).

6.4. The decision on the choice of management should be made together with the patient.

SoR 2A QoE: III

SoR: 1 QoE: +++

Part IV

Surgical treatment of thyroid carcinoma

1. Preoperative diagnostics [1]:

1.1. The examinations necessary to prepare the patient for surgical treatment in case of diagnosis or suspicion of malignancy:

1.1.1. History and physical examination.

SoR 2A QoE: III

SoR: 1 QoE: +++

1.1.2. Neck ultrasound of:

— the thyroid

— lymph nodes

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R32

1.1.3. Ultrasound-guided FNAB of:

— focal thyroid lesions

— suspicious lymph nodes (see Part I, section 9.2)

SoR 2A QoE: III

SoR: 1 QoE: +++

1.1.4. Serum TSH evaluation to exclude functional thyroid disturbances.

NOTE: In patients treated with levothyroxine for suppressive purposes, low TSH is only an effect of ongoing treatment and requires a reduction in the dose of L-thyroxine. Surgery is possible without a delay and treatment required in patients with overt hyperthyroidism

SoR 2B QoE: V

SoR: 2 QoE: +

1.1.5. The assessment of serum total calcium concentration.

SoR 2A QoE: III

SoR: 2 QoE: +++

1.1.6. The assessment of serum calcitonin concentration (see Part I, section 2.3).

SoR 2B QoE: III

SoR: 2 QoE: +

1.1.7. Chest X-ray (posterior and lateral).

SoR 2A QoE: III

SoR: 2 QoE: +++

1.1.8. Laryngological examination to assess vocal cord function.

SoR 2A QoE: II

SoR: 2 QoE: +++

1.2. Tests useful in the differential diagnosis and staging of thyroid malignancies [1, 72, 73]:

1.2.1. CT scan of the neck and upper mediastinum if there is doubt about the resectability of thyroid cancer (e.g., stage cT4).

NOTE: For differentiated carcinomas, a non-contrast CT scan is indicated if scintigraphy or RAI treatment will be performed within the next 6 weeks

SoR 2B QoE: V

SoR: 2 QoE: + ATA GL R33

1.2.2. CT scan is not a routine preoperative examination indicated in all cases of thyroid cancer.

SoR 2A QoE: IV

SoR: 1 QoE: +++

1.2.3. Evaluation of the presence of distant metastases on other imaging studies only if indicated.

SoR 2A QoE: IV

SoR: 1 QoE: +++

1.2.4. For MTC, preoperative clinical exclusion of adrenal pheochromocytoma.

SoR 2A QoE: IV

SoR: 1 QoE: +++

1.3. The role of serum calcitonin evaluation (see Part I) [5, 74]:

1.3.1. Calcitonin testing is required for suspected MTC if the patient meets at least one criterion:

— positive family history;

— nodular goiter in a patient with pheochromocytoma;

— history of persistent nondiagnosed diarrhea;

— MTC suspicion in cytology;

— suspicious for a follicular neoplasm in cytology (Bethesda category IV), particularly oxyphilic one.

SoR 2A QoE: IV

SoR: 1 QoE: ++

1.3.2. Calcitonin testing in a patient scheduled for thyroid surgery minimizes the risk of undiagnosed MTC [74].

SoR 2A QoE: IV

SoR: 1 QoE: +++

1.3.3. The authors of these guidelines propose this recommendation as a compromise solution in the face of conflicting views: the ETA position recommending calcitonin determination in all cases of nodular goiter [75] and the ATA position treating indication for this test as an unevidenced one [1].

SoR 2A QoE: IV

SoR: 1 QoE: ++

1.3.4. If calcitonin level exceeds 100 ng/l, this result is almost unequivocally indicative of MTC. However, differentiation with rare cases of calcitonin-secreting neuroendocrine carcinoma, especially lung cancer, is necessary [75, 76].

SoR 2A QoE: IV

SoR: 1 QoE: ++

1.3.5. For calcitonin levels between 10–100 ng/L, the risk of a false positive should be considered in the context of MTC diagnosis [75–77].

SoR 2A QoE: V

SoR: 1 QoE: +

2. Thyroid surgery in patients diagnosed with thyroid carcinoma or suspicion of thyroid carcinoma:

2.1. General principles (Fig. 1) [1, 56, 57, 78, 79]:

2.1.1. The most important part of the surgical strategy is careful preoperative cancer diagnostics in every case of thyroid surgery (see Part I).

SoR 2A QoE: IV

SoR: 1 QoE: +++ ATA GL R33

2.1.2. Surgery of the thyroid gland without prior FNAB may be undertaken only in exceptional cases.

SoR 2A QoE: IV

SoR: 2 QoE: +

2.1.3. If FNAB prior to surgery was negative for cancer and the suspicion of malignancy persists, diagnostic surgery should be considered. Intraoperative examination of identified focal lesions or thyroid nodules may be helpful but is not mandatory.

SoR 2A QoE: V

SoR: 2 QoE: +

2.1.4. Surgical management should be guided by the principle of the increasing extent of surgery with increased risk of malignant neoplasm and increasing clinical stage of malignant neoplasm.

SoR 2A QoE: II

SoR: 1 QoE: +++ ATA GL R35

2.1.4.1. The surgeon who prepares for thyroid surgery, during which the risk of malignancy cannot be excluded, must be guided by the principle of avoiding complications, particularly hypoparathyroidism.

SoR 2A QoE: II

SoR: 1 QoE: +++

2.1.4.2. Thyroid resection due to cancer has to be performed by an experienced surgeon in specialized centers with adequate surgical experience and diagnostic facilities, optimally within a separate Thyroid Unit.

SoR 2A QoE: V

SoR: 1 QoE: +

2.1.5. Visualization of the recurrent laryngeal nerve during surgery is recommended. It is also important to preserve the external branch of the superior laryngeal nerve during tissue preparation near the superior pole of the thyroid gland.

SoR 2A QoE: II

SoR: 1 QoE: +++

2.1.6. Intraoperative electrostimulation of the nerve (with or without neuromonitoring) may be used to help identify the nerve and assess its function.

SoR 2A QoE: II

SoR: 1 QoE: +++

2.1.7. During surgery, efforts should be made to preserve properly vascularized parathyroid glands.

SoR 2A QoE: III

SoR: 1 QoE: +++

2.1.8. Modern infrared parathyroid detection methods can be used to facilitate intraoperative parathyroid identification and preservation in situ.

SoR 2A QoE: IV

SoR: 2 QoE: +

2.2. Surgical management in cases suspicious for a follicular neoplasm on FNAB (Bethesda category IV) [80,81]:

2.2.1. If there is a suspicion for a follicular neoplasm on cytologic examination (including an oxyphilic neoplasm), further preoperative cytologic differentiation between benign and malignant tumors is not possible. If possible, preoperative molecular testing of the lesion (called a molecular biopsy) may be considered for a broader assessment of malignancy risk.

SoR 2A QoE: III

SoR: 1 QoE: +++

2.2.2. The principle of operating on all nodules/focal lesions with a cytologic diagnosis “suspicious for a follicular neoplasm”, proposed by the American guidelines, cannot be literally implemented in Poland because of its epidemiologic situation: the past period of iodine deficiency in the 1980s–1990s has now resulted in an increased incidence of benign thyroid nodules previously defined in FNAB as follicular nodules, which according to the currently proposed nomenclature corresponds to the diagnosis of “suspicion for a follicular neoplasm”. The published Polish data indicated that the risk of cancer in Bethesda category IV ranged from 8.2% to 19% [82, 83].

SoR 2B QoE: IV

SoR: 2 QoE: +

2.2.3. In focal lesions with a cytologic diagnosis of “follicular lesion of undetermined significance” or “suspicious for a follicular neoplasm” that are autonomous nodules on RAI or 99mTc scintigraphy, the risk of malignancy is low, and therefore there is no absolute indication for surgery.

SoR 2A QoE: III

SoR: 1 QoE: ++

2.2.4. In small nodules/focal lesions (< 2 cm in diameter) with a cytologic diagnosis of “suspicious for a follicular neoplasm” that are well controlled by continuous follow-up and, if necessary, by subsequent biopsy, it is acceptable to waive surgical treatment because of the low clinical risk, as far as calcitonin levels are not indicative of MTC.

SoR 2B QoE: V

SoR: 2 QoE: +

2.2.5. Surgical treatment is necessary for oxyphilic nodules (recommended diagnosis: suspicious for a Hurthle-cell neoplasm) because the risk of malignancy is higher in these nodules, especially if they are > 1 cm in diameter.

SoR 2B QoE: V

SoR: 2 QoE: +

2.2.6. For the diagnosis “suspicious of a follicular neoplasm”, the minimal extent of surgery includes, in a single nodule, complete excision of one lobe with the isthmus. Its extension to the second lobe (near-total or total excision) depends on the individual assessment of the risk of malignancy and the presence of focal lesions in the second lobe.

SoR 2A QoE: V

SoR: 2 QoE: +

2.2.6.1 If the diagnosis “suspicious for follicular neoplasm” is made in a case of nodular goiter located in only one lobe of the thyroid where only a single focal lesion is suspected, loboisthmectomy may be considered. Alternatively, complete excision of the involved thyroid lobe with the isthmus and subtotal excision of the other thyroid lobe is acceptable.

SoR 2A QoE: V

SoR: 1 QoE: +

2.3. If “suspicious for a follicular neoplasm” is diagnosed in one nodule of multinodular goiter, complete resection of the involved lobe should be performed, whereas on the other side, the extent depends on the indication. If focal lesions are also found, efforts should be made to minimize the residual thyroid gland left so that if thyroid cancer is diagnosed postoperatively, postoperative RAI treatment can be undertaken.

SoR 2B QoE: V

SoR: 2 QoE: +

2.4. For a cytologic diagnosis of a “follicular lesion of undetermined significance” (see Part I), surgical treatment is not mandatory but may be clinically indicated.

SoR 2B QoE: V

SoR: 2 QoE: +

2.4.1. As mentioned above, it is necessary to assess serum calcitonin level if follicular lesions are diagnosed (both “follicular lesion of undetermined significance” and “suspicious for a follicular neoplasm” and especially “suspicious for a Hurthle-cell neoplasm”), particularly if surgery is planned to be abandoned (because some of these lesions could be MTC).

SoR 2A QoE: V

SoR: 2 QoE: +

2.5. Thyroid surgery in patients with cytologic diagnosis/suspicion of cancer:

2.5.1. Total/near-total thyroidectomy is a standard surgical treatment [1, 56, 57, 78, 79].

SoR 2A QoE: III

SoR: 1 QoE: +++

2.5.2. Unilateral lobectomy with isthmectomy is an acceptable surgical procedure in patients who are preoperatively diagnosed with papillary carcinoma in a single focal lesion measuring ≤ 2.0 cm, stage cN0, if there is no obvious indication for bilateral surgery, and the treatment team has obtained the patient’s consent for such procedure [84–96].

SoR 2A QoE: III

SoR: 2 QoE: +++

2.5.3. The development of modern technologies — minimally invasive ablative techniques (MIT) using laser light (LA), radiofrequency ablation (RFA), microwave ablation (MWA), or high-frequency ultrasound ablation (HIFU) — makes it possible to apply them to ablate appropriately selected benign and malignant focal thyroid lesions. In selected cases of both primary thyroid carcinomas (papillary carcinoma cT1aN0M0), structural local and/or nodal recurrences, and single distant metastases, the use of LA or RFA may be considered [97–104].

SoR 2B QoE: IV

SoR: 2 QoE: +

2.5.4. In patients with thyroid carcinoma, minimally invasive techniques may be considered in cases with significant comorbidities, at increased surgical risk, older age, after multiple surgical procedures, or if the patient refuses surgery or active surveillance. The decision should be made by a multidisciplinary team together with the patient after the careful presentation of the advantages and limitations of the method.

SoR 2A QoE: IV

SoR: 1 QoE: +

2.6. Completion thyroidectomy [105–108]:

2.6.1. Completion thyroidectomy should be considered for thyroid cancer diagnosed after surgery of lesser extent than total or near-total thyroid resection (with exceptions given below). The decision should be made by a multidisciplinary tumor board.

SoR 2A QoE: IV

SoR: 1 QoE: + ATA GL R38, R39 [1]

2.6.2. The principle of completion thyroidectomy may be omitted if low-risk cancer was diagnosed in patients in whom total unilateral lobectomy with isthmectomy or total unilateral lobectomy with isthmectomy and subtotal resection of contralateral lobe or subtotal bilateral resection were performed in the following cases:

2.6.2.1. Unifocal papillary thyroid carcinoma ≤ 2 cm in diameter (pT1), if neither lymph node metastases nor distant metastases are diagnosed.

SoR 2A QoE: III

SoR: 1 QoE: +++

2.6.2.2. Well-differentiated carcinoma with a higher T feature (pT2) if the residuals of both thyroid lobes assessed by ultrasound are no larger than 1 mL on each side and the available data indicate full radicalness of the surgery and low-risk carcinoma.

SoR 2B QoE: IV

SoR: 2 QoE: ++

2.6.2.3. Higher cancer stage if available clinical data indicate that radical surgery is not feasible or will not benefit the patient (particularly in poorly differentiated and undifferentiated carcinomas).

SoR 2A QoE: V

SoR: 1 QoE: +

2.6.3. Exception from total thyroidectomy may refer to minimally invasive follicular cancer < 1 cm in diameter (pT1a), diagnosed after lobectomy or subtotal thyroidectomy if distant or lymph node metastases are not found. The beneficial impact of completion thyroidectomy on long-term outcomes has not been unequivocally proved in such cases. The extent of necessary surgery should be defined individually by a multidisciplinary tumor board. The decision should be shared with the patient.

SoR 2A QoE: IV

SoR: 1 QoE: +

2.7. The assessment of the completeness of surgery:

2.7.1. If the extent of surgery is not unequivocal, the assessment of its completeness is based on joint interpretation of postsurgical histopathology, ultrasound, postsurgical neck RAI), and Tg level. All examinations should be performed no earlier than 1–2 months after surgery. TSH stimulation is necessary for neck scan and Tg level assessment [109].

SoR 2B QoE: V

SoR: 2 QoE: +

2.7.2. Surgery may be considered as near-total thyroidectomy if the volume of remnant tissue in neck sonography does not exceed 1 mL at each side. The evaluation of the completeness of surgery by the use of neck ultrasound should include neck lymph nodes.

SoR 2A QoE: V

SoR: 1 QoE: +++

2.7.3. The assessment of RAI uptake and postsurgical thyroid scan, performed after TSH stimulation, are useful in defining the extent of thyroid surgery. However, it is not an absolute criterion of its completeness. In a patient in whom total thyroidectomy was performed, RAI uptake after rhTSH stimulation is usually less than 1%. For endogenous TSH stimulation (3–4-week break in L-thyroxine treatment), the expected RAI uptake is < 5%, whereas RAI uptake < 2% is reliable proof of total thyroid resection. Nevertheless, a higher RAI uptake with a small volume of thyroid remnants on ultrasound is not an indication for reoperation. Completion thyroidectomy may be considered in cases given in section 4.5. Such a decision should be made by the multidisciplinary tumor board.

SoR 2A QoE: V

SoR: 1 QoE: + ATA GL R38

3. Lymph node surgery in primary thyroid cancer:

3.1. Central neck lymph node dissection [1]:

3.1.1. The evaluation of central cervical neck lymph nodes should involve group VI lymph nodes (central neck compartment) — prelaryngeal, pretracheal, paratracheal, and parathyroidal ones. Central lymph node dissection diminishes the risk of cancer relapse and significantly reduces postoperative serum Tg level. The 2015 ATA GL does not recommend such a procedure in low-risk thyroid cancer. With a view to reducing the risk of postoperative complications, the authors of the guidelines accept this position.

SoR 2A QoE: III

SoR: 1 QoE: ++

3.2. Whenever involvement of this compartment or lateral neck lymph nodes occurs, surgery is a therapeutic procedure and is definitely indicated at each stage of primary tumor. If there are no features of nodal involvement in the central neck compartment, surgery is a prophylactic one [110, 111].

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R36 [1]

4. Prophylactic surgery may be limited to central ipsilateral lymph node dissection (performed on the side of the confirmed cancer lesion) [112–115].

SoR 2B QoE: V

SoR: 2 QoE: +

4.1. 2015 ATA GL accept resignation from a routine prophylactic (elective) central neck dissection [110, 111, 116]:

4.1.1. In low-risk papillary thyroid carcinoma, staged cT1b (particularly if primary tumor diameter is ≤ 1 cm), if there are no features of nodal involvement on preoperative neck ultrasound and during intraoperative evaluation [105–111].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.1.2. In minimally invasive follicular thyroid carcinoma, if a diagnosis is known preoperatively (presence of distant metastases) and intraoperative assessment of central lymph node gives no suspicion of metastases [1].

SoR 2A QoE: IV

SoR: 1 QoE: ++

4.1.3. The relationship between prophylactic central neck dissection and the frequency of permanent postsurgical side-effects speaks for the limitation of the number of indications [1, 110, 124, 125].

SoR 2A QoE: III

SoR: 1 QoE: +++

4.2. Lateral cervical lymph node dissection in differentiated thyroid cancers:

4.2.1. Uni- or bilateral lateral neck lymph node dissection as a modified procedure (without dissection of the jugular vein, sternocleidomastoid muscle, and XI nerve) is indicated if lymph node metastases are confirmed by a positive FNAB (with or without Tg assessment) or intraoperative biopsy) [1, 126–132].

SoR 2A QoE: III

SoR: 1 QoE: +++ ATA GL R37 [1]

4.2.2. Selective resection of metastatic lymph nodes (“berry picking”) instead of modified lateral lymph node dissection in differentiated thyroid cancer is not optimal management and should not be performed [1, 126–132].

SoR 2A QoE: III

SoR: 1 QoE: ++

4.2.3. Intraoperative biopsy of lateral lymph nodes is indicated for exclusion of lymph node metastases. If positive, modified lateral lymph node dissection is indicated [126, 129, 131–136].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.2.4. Postoperative histopathological diagnosis of lymph node micrometastases in ≤ 5 neck lymph nodes (< 2 mm in the greatest dimension) is not an indication for secondary lymph node dissection in differentiated thyroid cancers if there are no other clinically overt metastases and postoperative RAI treatment is available [1, 123, 137].

SoR 2A QoE: IV

SoR: 1 QoE: ++

4.2.5. The presence of central neck lymph node involvement does not require a lateral neck lymph node dissection if there are no lateral lymph node metastases [1, 123, 137].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.3. The extent of cervical lymph node dissection in medullary thyroid carcinoma:

4.3.1. The extent of lymph node dissection in hereditary MTC depends on the primary tumor diameter, serum calcitonin concentration, and the type of RET mutation — its detailed description is given elsewhere in these recommendations (see Part XIV) [138].

SoR 2A QoE: IV

SoR: 1 QoE: +++

4.3.2. Central neck lymph node dissection as a general rule is routine treatment in MTC except for patients in whom surgery is carried out at a very early stage of the disease. Unilateral lymph node dissection on the primary tumor side is always recommended if there is an enlargement of lymph nodes suggesting metastases or if they are found on FNAB. Elective surgery is also considered if the primary focus exceeds 1 cm in diameter and calcitonin level is high. In advanced MTC with a high calcitonin level, bilateral neck lymph node dissection should be considered.

SoR 2A QoE: IV

SoR: 1 QoE: ++

4.3.3. In a case of prophylactic thyroidectomy, performed in proto-oncogene RET mutation carriers, indications for elective lymphadenectomy depend on the type of germinal RET mutation (i.e., type of hereditary cancer) and age when the surgery is performed as well as on the current calcitonin level [138].

SoR 2A QoE: IV

SoR: 1 QoE: ++

4.4. The extent of lymph node dissection in poorly differentiated and undifferentiated thyroid carcinoma:

4.4.1. Elective lymph node dissection is recommended in poorly differentiated and undifferentiated (anaplastic) thyroid carcinoma. However, usually, the advancement of disease unequivocally suggests lymph node involvement, and the extent of surgery depends on whether these tumors are resectable or not. In undifferentiated (anaplastic) thyroid cancer, a Jawdynski-Crile lateral neck dissection may be necessary.

SoR 2A QoE: IV

SoR: 1 QoE: ++

4.5. Surgery of mediastinal lymph nodes in differentiated thyroid carcinoma:

4.5.1. Mediastinal lymph nodes are operated on in the case of confirmed metastases or if suspected lymph nodes are present. There is no indication for elective mediastinal lymph node dissection and a preoperative CT scan.

SoR 2A QoE: IV

SoR: 1 QoE: ++

5. Multiple organ surgery:

5.1. Multiple organ surgery may be carried out in differentiated thyroid cancers if there is infiltration of adjacent structures (larynx, esophagus, blood vessels) and if complete resection (so-called R0 resection) is possible. In undifferentiated cancer confirmed in histopathology, the infiltration of adjacent organs requires a combined therapy.

SoR 2A QoE: IV

SoR: 1 QoE: ++

6. Complications after surgery of thyroid carcinoma:

6.1. The most common complications after surgery are recurrent laryngeal nerve palsy and hypoparathyroidism [139–143].

SoR 2A QoE: III

SoR: 1 QoE: +++

6.1.1. Both complications may be transient or permanent. The frequency of permanent complications is an important measure of a particular center’s experience. However, it is also related to the stage of the disease [141, 142, 144–146].

SoR 2A QoE: III

SoR: 1 QoE: +++

6.1.2. A center’s experience with frequent central and lateral neck lymphadenectomy rather than total thyroid resection is more critical to reduce the overall incidence of complications [110, 124, 125].

SoR 2A QoE: V

SoR: 1 QoE: +

6.2. Recurrent laryngeal nerve palsy [143, 147]:

6.2.1. The laryngological examination should be performed before and after each operation to assess vocal fold function and indications for treatment of possible complications (vocal fold palsy/impairment).

SoR 2A QoE: III

SoR: 1 QoE: +++

6.2.2. If vocal cord paralysis is diagnosed, phoniatric rehabilitation is necessary, and if this complication is permanent, remedial surgery may be considered.

SoR 2A QoE: III

SoR: 1 QoE: +++

6.2.3. Bilateral vocal fold palsy may require tracheostomy immediately after surgery.

SoR 2A QoE: III

SoR: 1 QoE: +++

6.3. Hypoparathyroidism [139, 148–150]:

6.3.1. The rules referring to the treatment of hypoparathyroidism follow the guidelines of the European Society of Endocrinology (ESE) [151].

6.3.2. In the immediate postoperative period, monitoring of serum ionized (or corrected) calcium is necessary to assess parathyroid function.

SoR 2A QoE: III

SoR: 1 QoE: +++

6.3.3. Parathormone (PTH) determination in the immediate postoperative period is necessary to predict the risk of hypoparathyroidism [139].

SoR 2A QoE: IV

SoR: 1 QoE: ++

6.3.4. If hypoparathyroidism persists for more than a few days after surgery, its severity should be assessed by more detailed tests — in addition to calcium levels, PTH and phosphate levels should be reevaluated.

SoR 2A QoE: IV

SoR: 1 QoE: +++

6.3.5. Transient hypoparathyroidism usually recovers in 1–6 months; however, it may disappear even later, after 1–2 years. For this reason, assessment of indications for treatment continuation should be repeated six months, a year, and two years after the operation [139, 150, 152].

SoR 2A QoE: IV

SoR: 1 QoE: ++

6.3.6. Efforts should be made to maintain ionized (or corrected) calcium concentrations at or slightly below the lower range of normal so that clinical signs of calcium deficiency are not present. Calciuria should be maintained within the normal range for gender. Serum phosphate and magnesium concentrations should also be within the normal range, and the calcium-phosphate index should remain below 4.4 mmol2/L2 (55 mg2/dL2).

SoR 2A QoE: IV

SoR: 1 QoE: ++

6.3.7. The treatment of hypoparathyroidism involves the use of calcium supplementation and active vitamin D analogs. Simultaneously, vitamin D supplementation in a daily dose 400–800 IU is recommended [151, 153].

SoR 2A QoE: IV

SoR: 1 QoE: +++

6.3.8. Hypoparathyroidism’s biochemical monitoring should consist of assessing ionized (or corrected) calcium, phosphorus, magnesium, and creatinine every few months (e.g., every 3–6 months). Biochemical control should be performed for up to 2 weeks if therapy is changed. Calcium level in a daily urine collection may be determined less frequently (e.g., every 1–2 years).

SoR 2A QoE: IV

SoR: 1 QoE: +++

6.3.9. For hyperphosphatemia and/or elevated calcium-phosphate index, a low-phosphate diet and/or adjustment of calcium and vitamin D supplementation may be considered. For hypercalciuria, a sodium-restricted diet, reduction in calcium supplementation, and/or addition of a thiazide diuretic has to be considered.

SoR 2A QoE: IV

SoR: 1 QoE: ++

6.3.10. Because the use of active vitamin D analogs does not provide adequate 25-OH-D3 concentrations at the tissue level, efforts should be made to equalize 25-OH-D3 above a serum concentration of 30 ng/mL using vitamin D supplementation.

SoR 2A QoE: IV

SoR: 1 QoE: ++

6.3.11. PTH evaluation allows distinguishing between hypoparathyroidism and other reasons for hypocalcemia. Normal PTH level is an indication to decrease substitution doses gradually.

SoR 2A QoE: IV

SoR: 1 QoE: ++

Part V

Histopathological examination of postoperative thyroid material

1. Guidelines for the preparation of histopathological examination after thyroid surgery [154]:

1.1. Management:

1.1.1. Measure and weigh the surgical specimen.

1.1.2. Mark the surface and cut line of the slide with ink if possible before fixation of the surgical specimen.

1.1.3. Orient the surgical specimens topographically and cut parallel slice 5 mm each.

1.1.4. Check for parathyroid glands in the surrounding tissues.

1.2. Description of the gross surgical specimen:

1.2.1. Type of surgery (lobectomy, isthmectomy, subtotal thyroid resection, total thyroidectomy, etc.).

1.2.2. Weight, shape, color, and consistency of the specimen.

1.2.3. Mark in ink the margins of the surgical incision.

1.2.4. Describe the appearance of the cut surface of the surgical specimen (smooth/nodular, number of nodules and their characteristics: diameter, appearance, color, solid/cystic, presence of calcifications, hemorrhages, necrosis, lobulation, demarcation from surrounding parenchyma, distance from the surgical incision line).

1.2.5. Photographic documentation may be considered.

1.3. Collection of sections for microscopic examination:

1.3.1. For diffuse lesions: three sections from each lobe and one from the isthmus.

1.3.2. For a solitary encapsulated nodule up to 5 cm in diameter: take sections that cover the entire circumference of the nodule; for larger nodules, take one additional section for each additional 1 cm of the lesion; most sections should include the tumor margin and surrounding parenchyma.

1.3.3. For nodular goiter: one slice from each nodule (up to a maximum of 5 nodules per lobe), containing its slice with adjacent thyroid parenchyma.

1.3.4. For suspected papillary carcinoma: take the whole thyroid, including carefully marking the surgical incision lines.

1.3.5. For suspicion of cancer other than papillary carcinoma: three sections from the tumor, three from the tumor-free thyroid tissue, and one section from the surgical incision line closest to the tumor.

1.3.6. Take a parathyroid sample if parathyroid glands are present in the specimen.

1.3.7. Count and collect whole lymph nodes, describing their location.

1.3.8. Identify other anatomical structures present (ex. thymus) and take them whole for histopathological evaluation.

2. Intraoperative histopathological examination [155, 156]:

2.1. The decision on whether or not to perform an intraoperative examination should be made on an individual basis.

2.2. If the pathology department is able to evaluate fresh specimens, the pathologist should perform grossing of the surgical specimen. If suspicious lesions are found, a microscopic examination of frozen sections (using cryostat) should be performed.

2.3. The intraoperative histopathological examination allows for distinction between non-neoplastic goiter and papillary, medullary, and undifferentiated thyroid carcinoma.

2.4. The intraoperative histopathological examination of the lymph nodes allows for the diagnosis of lymph node metastases and appropriate qualification for lymphadenectomy [157, 158].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.5. Intraoperative examination at the suspicion of cancer allows assessment of diagnostic usefulness of surgical specimen and may serve to verify surgical margins [159].

SoR: 2B QoE: IV

SoR: 2 QoE: +

2.6. If the surgeon suspects an anaplastic component during surgery for a previously diagnosed differentiated cancer, intraoperative verification of the diagnosis should be considered [160].

SoR: 2A QoE: V

SoR: 1 QoE: +

2.7. For intraoperative diagnosis of the follicular variant of papillary thyroid carcinoma, it is necessary to perform imprint cytology of the cross-sectional surface of the tumor, as it enables the identification of very characteristic nuclear features of the cells (grooves and intranuclear inclusions). In the differential diagnosis of well-demarcated tumors, it is necessary to consider NIFTP [161].

SoR: 2B QoE: V

SoR: 2 QoE: +

3. Histopathological examination should involve:

3.1. A precise assessment of thyroid cancer type and subtype, tumor diameter, and TNM staging (Tab. 17 and 18).

3.2. Detailed description of the lymph nodes (see section 3.5.4).

3.3. The diagnosis should fulfill the World Health Organization’s (WHO 2017) accepted histopathological classification of thyroid tumors (Tab. 22) [162].

SoR: 1 QoE: IV

SoR: 1 QoE: ++

3.4. The conclusion of the histopathological report should include Tumor–Node–Metastasis (TNM) classification according to the Eighth Edition of Union for International Cancer and American Joint Committee on Cancer criteria (AJCC/UICC) (Tab. 17 and 18) [163].

SoR: 2A QoE: III

SoR: 1 QoE: +++

3.5. The following issues should be involved in the histopathological report [163, 164]:

SoR: 2A QoE: III

SoR: 1 QoE: +++

3.5.1. Type of surgical specimen (consistent with the extent of the procedure performed) with the information referred to its fixation, condition (any damage, intended or not), and topography.

3.5.2. Histopathological diagnosis with a microscopic subtype of and the following data on:

— tumor location, tumor size (three dimensions necessary), and grossing;

— the appearance of the parenchyma outside the tumor;

— presence and condition of the tumor capsule;

— presence and extent of angioinvasion (number of involved vessels: up to four and more than four vessels) [165–168];

SoR: 2A QoE: III

SoR: 1 QoE: +

— extrathyroid extension divided into a minimal invasion, i.e., surrounding soft tissues and sternothyroid, sternohyoid and omohyoid muscles, and gross invasion — i.e., when cancer infiltrates subcutaneous fatty tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve [169–174];

SoR: 2A QoE: IV

SoR: 1 QoE: ++

— the radicalness of surgery, including surgical margins, marked with ink with unequivocal information on whether they are infiltrated or not [175–177];

SoR: 2A QoE: IV

SoR: 1 QoE: ++

— multifocality;

— pathological lesions in the thyroid, outside the tumor.

3.5.3. Parathyroid glands: if present, the number of parathyroid glands and information about any abnormalities.

3.5.4. The number of all lymph nodes, the number of involved nodes, the diameter of lymph node metastases. Lesions < 2 mm in diameter should be defined as micrometastases. The information on whether cancer cells exceed the nodal capsule should be provided [178–185].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

3.5.5. Description of extrathyroidal tissues.

3.6. In addition, the report should include the data on:

3.6.1. Mitotic and/or proliferative activity as determined with Ki-67 antibody [164].

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.6.2. The presence and extent of necrosis in the tumor expressed as a percentage [164].

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.6.3. The presence of squamous metaplasia and clear cell changes [186].

SoR: 2A QoE: V

SoR: 1 QoE: +

3.6.4. The presence and type of tumor calcification, stromal changes (such as diffuse fibrosis) [186–188].

SoR: 2A QoE: V

SoR: 1 QoE: +

3.6.5. Immunohistochemical findings.

3.7. Immunohistochemistry plays an important role in the diagnosis of thyroid neoplasms. It should be assumed that in some types of tumors, it is indispensable [189, 190]:

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.7.1. If MTC is suspected, immunohistochemical tests for calcitonin, chromogranin, and Tg are mandatory. MTC stratification into low-risk and high-risk prognostic groups requires Ki-67 proliferative activity additionally and/or mitotic index/2 mm2 and evaluation of the tumor for the presence of necrotic foci [191–193].

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.7.2. Tg and Ki-67 immunostaining should be performed if poorly differentiated thyroid cancer is suspected [162, 194].

SoR: 2A QoE: III

SoR: 1 QoE: +

3.7.3. Vascular invasion in doubtful cases should be verified by immunostaining for endothelial cell markers (e.g., CD 34, CD31) [162].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

3.8. Whenever anaplastic carcinoma and differentiated carcinoma coexist, the percentage of each component should be determined. For this purpose, it is advisable to perform Tg, TTF-1, and PAX8 immunostaining (Tab. 23) [160, 162, 195–197].

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.9. In view of the recent 2017 WHO classification of Thyroid Tumors, Fourth edition (Tab. 22) and the recognition of NIFTP as a neoplasm that metastasizes only in extremely rare cases (practically benign), we recommend making this postoperative diagnosis according to the criteria proposed by the WHO [162, 198–200].

SoR 2A QoE: V

SoR: 1 QoE: +

3.9.1. NIFTP diagnosis is not possible on the basis of preoperative FNAB.

3.9.2. The criteria excluding the diagnosis of NIFTP, i.e., the presence of papillae and/or nucleolar inclusions, should be strictly followed.

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.9.3. The diagnosis of NIFTP should be confirmed by a negative result of immunohistochemistry or molecular analysis of the BRAF mutation.

SoR: 2A QoE: IV

SoR: 1 QoE: +

3.9.4. NIFTP diagnosis has to be confirmed by another pathologist.

SoR: 2B QoE: IV

SoR: 2 QoE: +

3.10. Difficult cases in which there is disagreement about the diagnosis of cancer or its microscopic type routinely evaluated by pathologists working under the Polish Group for Endocrine Tumors, a scientific section of the Polish Society of Endocrinology.

4. Genetic testing is a valuable addition to cytologic, histologic, and clinical diagnosis. Genetic testing in thyroid cancer may refer to:

4.1. The evaluation of germline changes in peripheral blood for hereditary cancers:

SoR: 1 QoE: I

SoR: 1 QoE: +++

4.1.1. All confirmed MTC cases in whom the presence of germline RET gene mutations should be evaluated to exclude hereditary cancer [5].

SoR: 1 QoE: I

SoR: 1 QoE: +++

4.2. The assessments of prognostic somatic alteration in histological specimens:

SoR: 1 QoE: II

SoR: 1 QoE: ++

4.2.1. The evaluation of the BRAF gene status, useful in differentiating borderline tumors (including NIFTP) [201].

SoR: 2B QoE: IV

SoR: 2 QoE: ++

4.2.2. In differentiated thyroid carcinomas, the presence of mutant BRAF protein can be assessed by immunohistochemistry, but a positive or equivocal test result needs to be verified by molecular methods that can confirm the presence of activating alternations (mutations) at codon 600 of the BRAF gene [58].

SoR: 2B QoE: IV

SoR: 2 QoE: +

4.3. The evaluation of somatic prognostic changes in cytological and histopathological specimens [202, 203]:

SoR: 1 QoE: III

SoR: 1 QoE: +++

4.3.1. Genetic testing of cytologic samples (molecular biopsy) improves the diagnostic performance of FNAB in Bethesda Class III, IV, and V thyroid lesions, reducing the rate of unnecessary diagnostic surgery.

SoR: 1 QoE: III

SoR: 1 QoE: +++

4.3.2. Such a study is highly recommended in centers with adequate facilities and experience in molecular testing.

4.3.3. The principle must be followed that the patient has to be fully informed of the relevance of the results of such tests, and their interpretation has to be carried out by the physician.

4.4. The evaluation of somatic genetic variants in the tumor to identify molecularly targeted treatment options:

4.4.1. In advanced thyroid carcinomas originating from the follicular cell, it is reasonable to evaluate the following molecular markers in the tumor cells [56, 58, 204, 205]:

4.4.1.1. Subtype and prognosis markers, including BRAF, pTERT, RAS family genes (NRAS, KRAS, HRAS).

SoR: 2B QoE: IV

SoR: 2 QoE: ++

4.4.1.2. Predictive markers for selecting a drug that aims at a molecular target, including:

4.4.1.2.1. Mutations of fusions of the RET gene.

SoR: 2A QoE: II

SoR: 1 QoE: +++

4.4.1.2.2. NTRK and ALK gene rearrangements.

SoR: 2A QoE: II

SoR: 1 QoE: +++

4.4.1.2.3. BRAF mutations in anaplastic thyroid cancer. Pathogenic alterations of the BRAF gene are evaluated in histological and cytological specimens. They can also be assessed in liquid biopsy at the ctDNA level. Molecular biology techniques are recommended to perform such tests.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

4.4.2. For advanced sporadic MTC, it is necessary to evaluate somatic pathogenic variants in the RET gene in the tumor tissue [206, 207].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

Part VI

Postoperative risk stratification

1. Postoperative risk stratification is based on TNM and 2015 ATA classification [1] (see Part II, sections 2 and 3, and Tab. 17–19).

SoR: 1

Part VII

Postoperative radioiodine (RAI) treatment of differentiated thyroid carcinomas

The general rule applies in RAI treatment: the patient should receive comprehensive information on the purpose of therapy, its course, including rules of radiological protection, possible consequences, and contraindications. The patient’s consent to this treatment is necessary [208].

SoR: 2A QoE: III

SoR: 1 QoE+++

1. The aims of RAI treatment [1]:

1.1. To destroy thyroid remnants after surgery (ablation of thyroid remnants).

1.2. Sterilization of the remaining cancer microfoci in the thyroid bed and lymph nodes (adjuvant therapy).

1.3. Sterilization of distant micrometastases.

1.4. Treatment of distant metastases.

SoR: 1 QoE: III

SoR: 1 QoE: +++ ATA GL R5

2. Indications for RAI treatment (Fig. 2) [1, 209]:

2.1. Indications for RAI treatment may be considered only in DTC patients.

SoR: 1 QoE:III

SoR: 1 QoE:+++

Figure 2. Eligibility scheme for postoperative radioiodine (RAI) treatment

2.2. Types of postoperative RAI treatments — due to differences in the interpretation of individual types of radioactive iodine treatment, presented below in sections 2.2.1–2, the consensus of international scientific societies decided not to distinguish these types and to use only the term “postoperative treatment” with radioactive iodine (131I). The authors of these guidelines have adopted this principle; nevertheless, it was decided to retain the definitions of the different types of treatment presented below for clarification:

2.2.1. Adjuvant RAI therapy concerns the patients showing no signs of persistent disease after radical surgery; however, possible cancer micrometastases are assumed. By definition, it does not apply to patients with overt distant metastases or inoperable locoregional disease [210].

SoR: 2A QoE:IV

SoR: 1 QoE:+++

2.2.2. Adjuvant therapy is considered as both a type of oncologic treatment and ablation of the residual thyroid gland. These treatments differ in their goal of therapy:

2.2.2.1. Ablation of thyroid remnants after surgical treatment might be considered in low-risk cancer. An essential consequence of this treatment is that it allows accurate monitoring of the further course of the disease based on Tg levels [1, 211] and anti-thyroglobulin (anti-Tg) antibodies, but the decision should be made on an individual basis, after discussion with the patient and presenting him with all the advantages and disadvantages.

SoR: 2A QoE:IV

SoR: 1 QoE: +++ ATA GL R51

2.2.2.2. Adjuvant treatment aims at the sterilization of possible cancer micrometastases that are not detected by other examinations [109].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3. Indications for RAI postoperative treatment in low-risk DTC patients — in this group of patients, RAI treatment may be abandoned [212, 213], unless postoperative diagnosis reveals an increased risk of tumor recurrence [214].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

4. The assessment of the effect of surgical treatment includes: ultrasound, the measurement of stimulated Tg levels (Tg levels < 10 ng/mL are considered optimal [109]) and diagnostic RAI whole-body scan (WBS) (no uptake outside the thyroid lobe is expected):

SoR: 2A QoE: IV

SoR: 1 QoE: +++

4.1. One should add that in low-risk cancer, the use of diagnostic scintigraphy should be individualized.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

4.2. In stage pT1amN0-x, ultrasound and Tg assessment on thyroxine (LT4) treatment is sufficient for postoperative evaluation.

SoR: 2B QoE: IV

SoR: 1 QoE: +++

5. In low-risk cancer, postoperative RAI treatment may be considered: (1) in patients with lymph node micrometastases [215, 216], (2) in patients above 55 years of age [217], (3) in multifocal tumors > 1 cm or BRAF-mutated cancers (if mutation status is known) [218], (4) in tumors > 4 cm.

SoR: 2B QoE: IV

SoR: 2 QoE: ++

6. Indications for postoperative RAI therapy in intermediate-risk patients:

6.1. In this group, postoperative RAI treatment is indicated in the majority of patients.

SoR: 2B QoE: V

SoR: 2 QoE: ++

6.2. Postoperative RAI therapy may be abandoned in young patients (younger than 55 years of age) whose only indication for RAI therapy is minimal extrathyroidal extension [217].

SoR: 2B QoE: V

SoR: 2 QoE: +

7. In high-risk patients, postoperative RAI treatment is indicated in all cases unless contraindicated.

SoR: 2A QoE: III

SoR: 1 QoE: ++

8. RAI treatment may also be an adjunct to incomplete thyroid resection if a patient who has previously undergone non-radical surgery has contraindications to or does not consent to completion thyroidectomy.

SoR: 2B QoE: V

SoR: 2 QoE: +

9. RAI activities used in postoperative treatment:

9.1. The range of RAI activity used in postoperative treatment is most commonly between 1.1–3.7 GBq (30–100 mCi).

SoR: 2A QoE: III

SoR: 1 QoE: +++

9.1.1. Lower RAI activities should be used in low-risk patients, following the rule that activity administered once should not be lower than 1.1 GBq (30 mCi) [219].

SoR: 2A QoE: III

SoR: 1 QoE: +++

9.1.2. If the risk of DTC micrometastases is high, the use of higher RAI activities, i.e., 3.7–5.5 GBq (100–150 mCi), may be justified, particularly in high-risk patients.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

10. Indications for RAI treatment of distant metastases in DTC [220]:

10.1. Treatment of metastatic DTC may be carried out with radical or palliative intent.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

10.2. Radical treatment is possible in those DTC patients who are found to have metastases that accumulate RAI to a sufficient degree for the dose of absorbed ionizing energy to have a sterilizing effect; this includes micrometastases and metastases non-exceeding 1 cm in diameter, all of which show RAI avidity.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

10.3. Palliative treatment may be considered in DTC patients with the inoperable primary tumor, inoperable local recurrence, or presence of distant metastases with RAI uptake insufficient to allow a sterilizing effect of ionizing energy. RAI treatment may then reduce the tumor size and slow cancer progression as well as alleviate disease symptoms (ex. pain).

SoR: 1 QoE: III

SoR: 1 QoE: +++

10.4. If a patient is diagnosed with distant metastases that do not show RAI uptake on post-therapeutic WBS, but significant iodine uptake is found in the thyroid bed, it is necessary to destroy the thyroid remnants before definitive assessment of RAI uptake of the metastases; the recommended RAI activity is ≥ 3.7 GBq.

SoR: 2A QoE: V

SoR: 2 QoE: ++

11. Qualification for RAI therapy:

11.1. The patient should be informed about the aim of treatment, its course, including the principles of radiological protection, possible consequences, and contraindications.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

11.2. Before RAI treatment for DTC, its goal should be defined, and the following qualifying examinations should be performed:

— neck ultrasound;

— serum Tg and anti-Tg measurement;

— hematology;

— diagnostic WBS is not necessary prior to RAI treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

11.3. Imaging studies performed if metastases are suspected [221]:

11.3.1. CT or MRI imaging of selected areas. Please note that the interval between iodine contrast studies and RAI treatment should not be shorter than 6–8 weeks [222, 223].

11.3.2. Bone scan if bone metastases are suspected (most often 99mTc-MDP bone scintigraphy or 18F-NaF PET/CT).

11.3.3. FDG-PET/CT in selected cases [224].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

12. Guidelines for stable iodine prior to RAI treatment:

12.1. There is no indication for routine urinary iodine concentration measurement before RAI treatment.

SoR: 2B QoE: V

SoR: 2 QoE: +

12.2. Urinary iodine excretion testing may be necessary if stable iodine contamination is suspected.

SoR: 2B QoE: V

SoR: 2 QoE: +

12.3. Data on the impact of a low-iodine diet on RAI treatment outcomes — currently, there is no iodine deficiency in Poland (according to studies in school children), the application of restrictions on iodine intake/exposure to iodine (algae, seafood, vitamin preparations, and iodine-containing disinfectants) for about one week should be sufficient

SoR: 2B QoE: V

SoR: 2 QoE: +

13. Contraindications to RAI treatment — absolute contraindications include pregnancy (in fertile females, pregnancy has to be excluded by a pregnancy test) and breastfeeding (the interval between completion of breastfeeding and RAI treatment should be at least six weeks). The patient should not return to breastfeeding after RAI treatment [225].

SoR: 1 QoE:IV

SoR: 1 QoE: +++

14. Course of RAI treatment:

14.1. RAI treatment is conducted in licensed centers.

SoR :1 QoE: IV

SoR: 1 QoE: ++

14.2. Administration of recombinant human TSH (rhTSH) is the preferred method of TSH stimulation during postoperative RAI treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

14.3. Treatment after L-thyroxine withdrawal is a second choice option used if rhTSH stimulation is not feasible [1, 226–229]. Admission to treatment is conditional on achieving TSH levels ≥ 30 mIU/L.

SoR: 2A QoE: V

SoR: 1 QoE: + ATA GL R54

15. When to carry out postoperative RAI treatment?

15.1. The optimal time to perform it is a minimum of 4 weeks after completion of surgical treatment (optimally up to 3 months after surgery) when the wound has healed, postoperative edema has subsided, Tg levels have decreased, and early postoperative complications have resolved.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

15.2. However, treatment between 3–12 months after surgery is also sufficient [230].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

15.3. If more than 12 months have passed since surgical treatment and the patient shows no evidence of persistent disease (biochemically or structurally) despite not receiving RAI after surgery, the indication for follow-up treatment becomes questionable.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

16. Post-treatment WBS — the administered RAI treatment must be completed with WBS (the so-called post-treatment WBS) to determine the presence of RAI-avid foci in the patient’s body.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

17. Patient information after the completion of RAI treatment:

17.1. After the completion of RAI treatment, the patient should receive full information resulting from the conducted examinations, answering the following questions:

— whether the studies performed indicate the persistence of residual disease;

— how to interpret neck RAI uptake, if present;

— if no persistent disease is found, what risk category for recurrence does the patient qualify for;

— when and where follow-up examinations are to be done.

SoR: 2A QoE: V

SoR: 1 QoE: ++

17.2. After RAI treatment, the patient should receive full information on how to behave at home to avoid contamination and whether and for how long to avoid contact with other people, especially children, and pregnant women. On average, a period of 1–2 weeks is sufficient for postoperative treatment.

SoR: 2A QoE: V

SoR: 1 QoE: ++

18. Dosimetry of RAI treatment — currently, there are no established principles for dosimetry planning of RAI treatment, and there is no developed, universally accepted method for individual selection of treatment activity ensuring an optimal dose of ionizing energy capable of sterilizing cancer foci without excessive side effects on healthy body organs. Therefore, pre-therapeutic dosimetry is not obligatory

SoR: 2A QoE: V

SoR: 2 QoE: +

19. Complications after RAI treatment and how to avoid them:

19.1. When the cumulative activity of 18.5 GBq (500 mCi) is exceeded, the rationale for further treatment should be considered, taking into account the increased risk of secondary cancer induction.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

19.2. Contraception is recommended for 6–12 months in women and 4–6 months in men after RAI therapy.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

Part VIII

L-thyroxine treatment in thyroid cancer

1. L-thyroxine treatment in DTC patients [1]:

1.1. Hormonal treatment with L-thyroxine is an important part of combined DTC treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.2. The goal of L-thyroxine therapy in DTC patients is:

1.2.1. Supplementation of existing hormonal deficiencies (replacement therapy — achieving TSH levels 0.5–2.0 mU/L).

SoR: 2A QoE: III

SoR: 1 QoE: +++

1.2.2. Reduction of the risk of relapse due to TSH being a growth factor for cancer cells. Suppressive treatment (complete suppression — achieving TSH levels < 0.1 mU/L; mild suppression — achieving TSH levels 0.1–0.5 mU/L) is currently indicated only in high-risk patients or in patients who do not demonstrate excellent treatment response.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.3. L-thyroxine treatment is also used in patients with low-risk thyroid cancer who have undergone lobectomy [231–234]:

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.3.1. In patients with risk factors for hypothyroidism, such as high TSH before surgery, the presence of anti-thyroid antibodies (especially anti-TPO), and features of chronic thyroiditis on histopathological examination, appropriately higher doses of l-thyroxine should be used [232, 233].

SoR: 2A QoE: IV

SoR: 2 QoE: +

2. Indications for TSH suppression:

2.1. Complete TSH suppression (< 0.1 mU/L) is necessary [235–238]:

2.1.1. In patients with persistent, clinically apparent DTC symptoms.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.1.2. In patients with incomplete biochemical response according to ATA – i.e., patients with no structural disease, but elevated stimulated Tg levels (> 10 ng/ml) and/or elevated Tg levels on thyroxine suppression (> 1 ng/mL), or increased level of anti-Tg antibodies.

SoR: 2A QoE:IV

SoR: 1 QoE: ++

2.1.3. Complete TSH suppression is indicated in patients who are at high risk of recurrence and have no contraindications to suppressive therapy, or the benefits of therapy outweigh the risks of suppressive therapy [239].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

2.2. Evidence for the safety of abandoning suppressive therapy has been published in low-risk patients [235, 237, 240, 241]. The resignation from suppressive therapy is acceptable:

2.2.1. In pT1aN0M0 patients.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.2.2. In patients staged pT1b-T2N0M0, radically treated with excellent response to treatment, L-thyroxine replacement doses should be given. Mild suppression (TSH 0.1–0.5 mIU/L) is also acceptable, but the decision should be personalized.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.2.3. In these patients, in whom an excellent treatment response has been confirmed by all possible methods, including a low stimulated serum Tg level in the absence of anti-Tg antibodies, and whose remission has been maintained for at least five years, substitution therapy may be used.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.3. In all patients who have undergone DTC treatment, increases in TSH levels above 2.0 mIU/L should be avoided except for short periods when TSH stimulation is necessary for follow-up.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.4. In patients receiving complete suppressive therapy, the addition of a beta-antagonist or angiotensin-converting enzyme inhibitor should be considered to prevent myocardial hypertrophy.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

3. Dosage of L-thyroxine:

3.1. The dose of L-thyroxine is determined individually and administered once a day, fasting, at least 30 minutes before a meal. Although the l-thyroxine forms registered in Poland are treated as equivalent, there are some minor differences in their bioavailability, and therefore one drug should not be exchanged for another without justification and conscious medical decision, as this may affect precise control of target TSH levels.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.2. If the L-thyroxine dose requires modification, small dose changes are acceptable (in general, not higher than 25 μg daily), and subsequent assessment of TSH level should be done in 6–8 weeks.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.3. Serum TSH level should be measured every 3–6 months, using a third-generation assay, in the morning before L-thyroxine dose intake. The interval between tests can be varied according to risk stratification.

SoR 2A QoE: IV

SoR: 1 QoE: +++

3.4. In patients treated with chronic suppressive doses of L-thyroxine, calcium therapy may be considered under the control of calcemia and PTH levels, while vitamin D should be administered according to the recommendations formulated for the general population, usually 2000 IU/d.

SoR: 2B QoE: V

SoR: 2 QoE: +

4. L-thyroxine treatment in other types of thyroid cancer:

4.1. Patients diagnosed with MTC, poorly differentiated, and ATC require substitutive L-thyroxine doses only.

SoR: 2A QoE: III

SoR: 1 QoE: +++

Part IX

Dynamic risk stratification

1. Dynamic risk stratification is conducted according to principles adopted by the ATA in 2015 (see Part II, Tab. 20) [1, 59, 242–244]:

1.1. Depending on the results obtained, the treatment response may be classified as excellent, incomplete biochemical, incomplete structural, or indeterminate (Tab. 20).

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.2. Excellent response to primary treatment is achieved in 74–94.5% of patients diagnosed with low-risk cancer, 36–61% of intermediate-risk patients, and 0–21% of high-risk patients [244].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.3. Incomplete biochemical treatment response is found in 3–11% of low-risk patients diagnosed, 16–22% of intermediate-risk patients, and 18–24% of high-risk patients [244].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.4. Incomplete structural treatment response is found in 1–2% of low-risk patients, 3.5–19% of patients with intermediate-risk cancer, and 24–67% of high-risk patients [244].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.5. Progression to structural disease is found in 8–17% of patients with incomplete biochemical treatment response [242, 245].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.6. At the final follow-up, 56–68% of patients with indeterminate biochemical response show no evidence of disease, while 19–27% have persistent abnormal Tg values without structural lesions, and only 8–17% develop a structural disease over 5–10 years follow-up [242, 246, 247].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.7. An indeterminate response concerns 12–29% of ATA low-risk patients, 8–23% of ATA intermediate-risk patients, and 0–4% of ATA high-risk patients [242, 246].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2. Evaluation of the efficacy of the combined treatment:

2.1. In patients who do not show an increase in Tg levels during L-thyroxine treatment, evaluation of treatment efficacy should be performed 6–18 months after postoperative RAI treatment [56].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.2. DTC remission can be diagnosed if the patient, after total thyroidectomy and postoperative RAI treatment, shows an excellent response, i.e., no evidence of disease on imaging studies or an increase in Tg ≥ 1 ng/mL on TSH stimulation in the absence of anti-Tg antibodies.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.3. Trace of RAI uptake in the thyroid bed is not conclusive of unsuccessful ablation or an indication for subsequent RAI treatment if:

— other tests do not indicate persistent disease;

— stimulated Tg levels are < 1 ng/mL;

— no thyroid remnants are found on ultrasound.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3. Follow-up of patients with excellent treatment response. The criterion for maintenance of remission after completion of primary treatment is the combined finding of a negative neck ultrasound and a stimulated Tg level ≤ 1 ng/mL in the absence of anti-Tg antibodies and other features of persistent or recurrent disease [1, 29, 244, 248–250] (Tab. 20):

SoR: 2A QoE: IV

SoR: 1 QoE: +++ ATA GL R49

3.1. The frequency of examinations is specified below, but at least one confirmatory test should be performed 3-5 years after initial confirmation of DTC remission.

SoR: 2B QoE: V

SoR: 2 QoE: +

3.2. WBS is currently not routinely performed to follow-up the subsequent course of the disease in patients with excellent treatment response:

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.2.1. However, the authors of these recommendations believe that there is no need to resign from performing WBS simultaneously with the evaluation of treatment efficacy by determination of stimulated Tg concentration because if an increase in Tg concentration is found, information about the existence and location of RAi-avid foci is obtained.

SoR: 2B QoE: V

SoR: 2 QoE: +

3.2.2. In a patient who has an excellent treatment response in the first post-treatment evaluation and is asymptomatic in the subsequent course of the disease, Tg control does not require TSH stimulation.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.3. There is no evidence for the safety of the above-described scheme in high-risk patients who show an excellent response to treatment.

SoR: 2B QoE: V

SoR: 2 QoE: +

4. Follow-up of patients with incomplete biochemical treatment response:

4.1. Evaluation of Tg concentration dynamics at 6-month intervals.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

4.2. Neck US at 6-month intervals.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

4.3. If Tg levels are increasing, imaging studies (primarily neck ultrasound and chest CT scan).

SoR: 2A QoE: IV

SoR: 1 QoE: +++

4.4. If these tests fail to localize the cancer focus, RAI treatment may be considered, but only for stimulated Tg > 100 ng/mL.

SoR: 2B QoE: IV

SoR: 2 QoE: +

5. Interpretation of serum Tg results in a DTC patient [251, 252]:

5.1. Since the decisive criterion for the search for a recurrence of disease, while monitoring the DTC course is the rise in Tg levels over time, efforts should be made to have these tests performed at a single center and by a single method.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

5.1.1. Optimally, methods standardized to Certified Reference Material 457 (CRM 457) should be used. Each laboratory should also characterize the functional sensitivity of its Tg determination method. The available super-sensitive methods for the determination of Tg are the methods of choice [249, 253].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

5.2. Tg monitoring should be accompanied by anti-Tg antibody testing [254–258], which should be performed at least once a year:

SoR: 2B QoE: V

SoR: 2 QoE: ++

5.2.1. In the presence of anti-Tg antibodies, low Tg levels cannot be a fully reliable criterion for treatment response.

SoR: 2A QoE: III

SoR: 1 QoE: +++

5.3. Interpretation of Tg level should refer to earlier Tg results, anti-Tg antibody level, current and previous TSH levels, and the extent of previous surgery and RAI treatment.

SoR: 2A QoE: V

SoR: 1 QoE: +++

5.4. Ultra-sensitive methods for serum Tg evaluation are recommended (functional sensitivity 0.1 ng/mL) [249].

SoR: 2A QoE: III

SoR: 1 QoE: +++

5.5. In the first 5 years after completion of primary treatment in patients with excellent response and in the absence of other risk factors, the cycle of Tg testing every 12 months should be maintained and later these intervals may be longer [259].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

5.6. If the patient did not undergo total thyroidectomy and/or RAI therapy, the serum Tg level might be higher than 1 ng/ml, and only increasing Tg levels may raise suspicion of cancer progression [260–262]. These tests should be performed at intervals at least as in section 5.5, and more frequently if indicated.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

5.7. Tg concentration cannot be the only test to monitor remission in DTC patients. In addition to the history and physical examination, it should be accompanied by at least a neck ultrasound, performed at a similar time period [263].

SoR: 2A QoE: III

SoR: 1 QoE: +++

6. Principles of the follow-up of a DTC patient who is found to have anti-Tg antibodies:

6.1. Neck ultrasound is the primary monitoring study in patients with thyroid cancer after radical surgery in whom the presence of anti-Tg antibodies makes reliable Tg level measurements and its interpretation impossible. One should remember that medical history and physical examinations are necessary to determine the indications for other imaging studies.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

7. Neck ultrasound in the evaluation of DTC treatment efficacy and follow-up [29, 264, 265] — neck ultrasound should be performed every 6–12 months for the first 5 years, then intervals may be less frequent. If recurrence is suspected, the intervals should be shorter. The finding of focal lesions in the thyroid bed and/or lymph node enlargement is an indication for FNAB, especially if the examination of the cervical lymph nodes reveals features that increase the likelihood of metastasis (round shape, loss of hilar architecture, heterogeneity, cystic degeneration, calcifications [29]) (see also Part I, Section 9.2):

SoR: 2A QoE: IV

SoR: 1 QoE: +++

7.1. If the suspicious lymph node is < 1 cm in size in the short diameter, an observational strategy can be accepted, and FNAB performed if it continues to grow [29].

SoR: 2B QoE: IV

SoR: 1 QoE: ++

7.2. Tg testing in FNAB washouts may be helpful in the diagnosis of nodal metastasis [266].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

7.3. Normal Tg level does not exclude lymph node metastasis [263].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

8. RAI whole-body scan:

8.1. Radioisotopic studies (especially neck and whole-body scintigraphy) are useful for a first assessment of the effectiveness of RAI treatment but are not mandatory:

SoR: 2A QoE: IV

SoR: 1 QoE: ++

8.1.1. RAI scans be waived if studies performed during RAI treatment indicated a very low risk of recurrence in a patient with a low DTC stage who underwent radical surgery.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

8.1.2. If an increase in Tg is observed (tested during L-thyroxine treatment or during TSH stimulation), neck and whole-body scintigraphy is necessary to detect and localize RAI-avid foci and determine indications for RAI treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

8.1.3. Routine periodic WBS for continued monitoring of patients in remission is not necessary, as the risk of detecting RAI-avid recurrence without a prior rise in Tg levels is low.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

9. Imaging and functional studies:

9.1. CT and/or MRI are performed if recurrence is suspected due to increased Tg levels or other indications. However, it should be remembered that contrast-enhanced CT impairs the RAI uptake in cancer foci for approximately 6–8 weeks.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

9.2. With an increase in Tg levels, a lung CT scan should be performed first.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

9.3. Suspicion of bone metastases based on history or physical examination or additional tests performed is an indication for bone scintigraphy.

SoR: 2A QoE: III

SoR: 1 QoE: +++

9.4. 18FDG PET-CT is useful in the localization of local recurrence and distant metastases of thyroid cancer, especially in patients in whom an increase in Tg concentration is not accompanied by the detection of focal changes on classical imaging examinations or on RAI WBS [224, 267, 268]:

SoR: 2A QoE: IV

SoR: 1 QoE: +++

9.4.1. 18FDG PET-CT can be performed both during TSH stimulation (exo- and endogenous) and without stimulation. However, some published data indicate a higher sensitivity if it is performed during TSH stimulation.

SoR: 2B QoE: IV

SoR: 2 QoE: +

9.4.2. Indications for the study are a stimulated Tg level > 10 ng/mL and a short Tg doubling time < 2 years under TSH suppression.

SoR: 2A QoE: IV

SoR: 2 QoE: ++

9.4.3. 18FDG PET-CT should also be considered before planned surgical treatment of lymph node metastases and distant metastases to assess the stage of the disease.

SoR: 2B QoE: V

SoR: 2 QoE: +

9.4.4. Negative result of 18FDG PET-CT does not exclude DTC metastases [224].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

Part X

Follow-up of thyroid cancer and borderline thyroid tumors

1. In DTC, the risk of recurrence in DTC is highest during the first 5 years, but must be considered throughout the patient’s life. Therefore, the patients require ongoing follow-up at a treatment center every 5 to 10 years [269].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2. The optimal approach is to conduct follow-up at the center previously providing primary treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +

3. Low-risk patients showing an excellent treatment response can be followed by a local endocrinologist after five years. If there is a suspicion of cancer recurrence, the patient should be referred to the center [270] with the capacity for further diagnosis and treatment if relapse is suspected.

SoR: 2A QoE: IV

SoR: 1 QoE: +

4. Postoperative monitoring of patients with low-risk thyroid cancer is performed by local endocrinology or oncology centers. The list of centers conducting such monitoring is presented on the websites of the Polish Society of Endocrinology, the Polish Society of Oncological Endocrinology, and the Polish Society of Oncology, which will establish cooperation for this purpose. The center should apply to the appropriate Society and provide all required data.

SoR: 2B QoE: V

SoR: 2 QoE: +

5. Qualification of the patients to a low-risk group is based on TNM, the 2015 ATA risk stratification system [1], and dynamic risk stratification (see Part II and Tab. 20) [59, 242, 271, 272].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

6. Qualifying patients for the low-risk group, it is necessary to assess whether the extent of surgical treatment is appropriate to the postoperative histopathological diagnosis.

SoR: 2A QoE: III

SoR: 1 QoE: +++

7. Follow-up scheme for patients diagnosed with intermediate-risk cancer depends on achieved response to treatment (see Part IX).

SoR: 2A QoE: IV

SoR: 1 QoE: ++

8. There are no reliable data regarding the follow-up scheme for high-risk patients. According to the authors of the Recommendations, the schedule of visits should be made individually together with the patient.

SoR: 2A QoE: V

SoR: 1 QoE: +

9. The follow-up of DTC patients is based on [1, 273]:

— physical examination;

— the evaluation of postoperative complications and adequate clinical management;

— periodic neck US every 6–24 months, depending on the dynamic risk stratification;

— periodic serum Tg evaluation every 6–24 months;

— periodic serum TSH evaluation to check the adequacy of L-thyroxine treatment;

— RAI WBS and imaging studies depending on clinical indications.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

10. The follow-up of borderline thyroid tumors (FT-UMP; WDT-UMP; NIFTP) is based on [274]:

— physical examination;

— the evaluation of postoperative complications and adequate clinical management;

— periodic neck US every 12–36 months;

— periodic serum Tg evaluation every 12–36 months;

— periodic serum TSH evaluation to check the adequacy of L-thyroxine treatment.

SoR: 2B QoE: V

SoR: 2 QoE: +

Part XI

Thyroid cancer recurrence/persistent disease

1. Differentiated thyroid cancer [275]:

1.1. Management of the locoregional recurrence:

1.1.1. The mainstay of therapy for local/locoregional recurrence is surgery. RAI treatment is applied if indicated.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.1.2. In inoperable, RAI-refractory recurrences, in the absence of iodine sensitivity, showing progression despite previous treatment, teleradiotherapy is used [273], or other local treatment options may be considered, e.g., radiofrequency thermoablation, or ultrasound-guided percutaneous ethanol injection [104].

SoR: 2B QoE: IV

SoR: 1 QoE: +

1.2. RAI treatment of metastatic/local DTC recurrence:

1.2.1. For the treatment of distant metastases, RAI therapy is usually given after the L-thyroxine withdrawal [1].

SoR: 2A QoE: IV

SoR: 1 QoE: +++ ATA GL R53

1.2.2. Treatment of distant metastases with thyrotropin alfa should be used in patients who have contraindications to L-thyroxine withdrawal or in whom endogenous stimulation cannot be achieved.

SoR: 2A QoE: III

SoR: 1 QoE: +++

1.3. Management of distant metastases:

1.3.1. RAI treatment is the 1st line of treatment. It is indicated if all the cancer foci show RAI avidity or the RAI-refractory foci can be treated with local methods.

SoR: 2A QoE: V

SoR: 1 QoE: +++

1.3.2. For of a single metastasis, local treatment [surgery or external beam radiotherapy (EBRT)] should be considered if resection is feasible and other metastases have been excluded with a high probability [103]. Stereotactic radiotherapy with radical intent should be considered for oligometastatic disease:

SoR: 2A QoE: IV

SoR: 1 QoE: ++

1.3.2.1. In the central nervous system metastases, surgery or EBRT is the mainstay of treatment. Additional radiotherapy to the tumor bed may be considered. For RAI-avid lesions, RAI treatment may be considered.

SoR: 2B QoE: V

SoR: 2 QoE: ++

1.4. Palliative treatment of metastases involves teleradiotherapy [276] or other symptomatic therapeutic options may be considered, including laser ablation for tumor intratracheal and intrabronchial infiltration, percutaneous interventional techniques: transarterial embolization and chemoembolization, radiofrequency current thermoablation, cementoplasty for bone metastases [100, 104, 277].

SoR: 2B QoE: V

SoR: 2 QoE: +

2. Poorly differentiated thyroid cancer [275]:

2.1. Management of local recurrences:

2.1.1. The mainstay of treatment is surgery. RAI treatment is used if indicated. For inoperable lesions that are RAI-resistant to or in the case of progression, teleradiotherapy and other local treatments, discussed in section 1.3 may be applied.

SoR: 2B QoE: V

SoR: 2 QoE: +

2.2. Management of distant metastases:

2.2.1. Surgery should be considered for the treatment of a single metastasis if resection is possible and other metastases have been excluded with high probability. For oligometastatic disease, stereotactic radiotherapy with radical intent may be considered.

SoR: 2B QoE: V

SoR: 2 QoE: +

2.2.2. For multiple metastases, although less effective than in DTC, RAI therapy is the first-line treatment.

SoR: 2B QoE: V

SoR: 1 QoE: +

2.2.3. Palliative treatment of metastases involves teleradiotherapy or other symptomatic therapeutic options may be considered, including laser ablation for tumor intratracheal and intrabronchial infiltration, percutaneous interventional techniques: transarterial embolization and chemoembolization, radiofrequency current thermoablation, cementoplasty for bone metastases [104, 278].

SoR: 2B QoE: V

SoR: 2 QoE: +

Part XII

Radiotherapy and chemotherapy in thyroid cancer

1. Radiotherapy [275]:

1.1. Teleradiotherapy to the neck and mediastinal region is indicated [275, 276]:

— in undifferentiated thyroid carcinoma;

— after non-radical surgery in DTC when completed surgery or RAI treatment is not possible;

— should be considered after non-radical surgery in MTC.

SoR: 2A QoE: IV

SoR: 1 QoE: +

1.2. Adjuvant teleradiotherapy:

1.2.1. In radically operated DTC, there is generally no indication for adjuvant teleradiotherapy. It may be considered in locoregionally advanced cases after R1/R2 surgery [276, 279].

SoR: 2B QoE: IV

SoR: 2 QoE: +

1.2.2. In MTC, complementary radiotherapy after a radical surgery has not been proven effective.

SoR: 2B QoE: IV

SoR: 2 QoE: +

1.2.3. It may be considered in MTC patients with lymph node metastases who do not have normalized calcitonin levels after surgery or in patients after R1/R2 non-radical surgery as long as there are no data signaling the presence of distant metastases [280].

SoR: 2B QoE: V

SoR: 2 QoE: +

1.3. Conducting teleradiotherapy:

1.3.1. Radical teleradiotherapy typically uses doses of 50–60 Gy in the lymph drainage area and 68–70 Gy for the tumor/thyroid bed [276, 281, 282].

SoR: 2B QoE: V

SoR: 2 QoE: +

1.3.2. Dose-intensity modulated conformal radiotherapy is recommended [283–287].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

1.3.3. Palliative teleradiotherapy is used in inoperable thyroid cancer [288–290]. In special cases, an attempt at radical treatment may be considered, with doses as in adjuvant therapy.

SoR: 2B QoE: V

SoR: 2 QoE: +

1.3.4. Palliative teleradiotherapy for metastases, including analgesic teleradiotherapy, is used in thyroid cancer according to the principles applied in other cancers [288, 290, 291].

SoR: 2A QoE: V

SoR: 1 QoE: +

1.3.5. Small primary tumors, if surgery is not possible, can be treated with external beam radiation using a stereotactic technique [292].

SoR: 2A QoE: V

SoR: 2 QoE: +

2. Pharmacological treatment:

2.1. L-thyroxine treatment is a DTC hormonal treatment (see Part VIII).

SoR: 2A QoE: III

SoR: 1 QoE: ++

2.2. In patients with bone metastases, consider the inclusion of intravenous bisphosphonates, initially monthly, then the time between doses can be extended to 3 months or denosumab in patients with contraindications to bisphosphonates.

SoR: 2B QoE: V

SoR: 2 QoE: +

3. Chemotherapy [275]:

3.1. There is no scientifically proved indication for chemotherapy in DTC.

SoR: 2A QoE: V

SoR: 1 QoE: +

3.2. Poorly differentiated carcinoma is a rare tumor, so there is no standardized treatment regimen to date. Available options include EBRT, RAI therapy (taking into account the possibility of preserving the partial RAI uptake of the cancer cells), and chemotherapy, but due to the lack of randomized trials, treatment options depend mainly on the experience of individual centers. Chemotherapy may be considered for progressive and/or symptomatic disease in the absence of other treatment options or inability to be included in clinical trials. Data on cytotoxic treatment are scarce. Of the various drugs, anthracyclines and platinum compounds appear to be the most effective, with an average response rate of 30% in various series. Unfortunately, the responses are short term [293–300].

SoR: 2B QoE: V

SoR: 2B QoE: +

Part XIII

Molecularly targeted therapy in thyroid cancer

1. Differentiated thyroid cancer [275]: