Vol 73, No 2 (2022)
Guidelines / Expert consensus
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Diagnosis and treatment of thyroid cancer in adult patients — Recommendations of Polish Scientific Societies and the National Oncological Strategy. 2022 Update [Diagnostyka i leczenie raka tarczycy u chorych dorosłych — Rekomendacje Polskich Towarzystw Naukowych oraz Narodowej Strategii Onkologicznej. Aktualizacja na rok 2022]

Barbara Jarząb1, Marek Dedecjus2, Andrzej Lewiński34, Zbigniew Adamczewski5, Elwira Bakuła-Zalewska6, Agata Bałdys-Waligórska7, Marcin Barczyński8, Magdalena Biskup-Frużyńska9, Barbara Bobek-Billewicz10, Artur Bossowski11, Monika Buziak-Bereza12, Ewa Chmielik9, Agnieszka Czarniecka13, Rafał Czepczyński14, Jarosław Ćwikła15, Katarzyna Dobruch-Sobczak16, Janusz Dzięcioł17, Aneta Gawlik18, Jacek Gawrychowski19, Daria Handkiewicz-Junak1, Jerzy Harasymczuk20, Alicja Hubalewska-Dydejczyk12, Joanna Januszkiewicz-Caulier2, Michał Jarząb21, Krzysztof Kaczka22, Michał Kalemba1, Grzegorz Kamiński23, Małgorzata Karbownik-Lewińska244, Andrzej Kawecki25, Aneta Kluczewska-Gałka1, Agnieszka Kolasińska-Ćwikła26, Magdalena Kołton1, Aleksander Konturek8, Beata Kos-Kudła27, Agnieszka Kotecka-Blicharz1, Aldona Kowalska2829, Jolanta Krajewska1, Andrzej Kram30, Leszek Królicki31, Aleksandra Kukulska1, Michał Kusiński32, Krzysztof Kuzdak33, Dariusz Lange34, Aleksandra Ledwon1, Ewa Małecka‑Tendera18, Przemysław Mańkowski20, Bartosz Migda35, Marek Niedziela36, Małgorzata Oczko-Wojciechowska37, Dariusz Polnik38, Lech Pomorski22, Marek Ruchała14, Konrad Samborski1, Anna Skowrońska-Szcześniak39, Agata Stanek-Widera34, Ewa Stobiecka9, Zoran Stojčev40, Magdalena Suchorzepka-Simek9, Anhelli Syrenicz41, Ewelina Szczepanek-Parulska14, Małgorzata Trofimiuk‑Müldner12, Andrzej Tysarowski42, Andrzej Wygoda43, Klaudia Zajkowska2, Ewa Zembala-Nożyńska9, Agnieszka Żyłka2
Pubmed: 35593680
Endokrynol Pol 2022;73(2):173-300.

Abstract

The guidelines Thyroid Cancer 2022 are prepared based on previous Polish recommendations updated in 2018. They consider international guidelines — American Thyroid Association (ATA) 2015 and National Comprehensive Cancer Network (NCCN); however, they are adapted according to the ADAPTE process. The strength of the recommendations and the quality of the scientific evidence are assessed according to the GRADE system and the ATA 2015 and NCCN recommendations.

The core of the changes made in the Polish recommendations is the inclusion of international guidelines and the results of those scientific studies that have already proven themselves prospectively.
These extensions allow de-escalation of the therapeutic management in low-risk thyroid carcinoma, i.e., enabling active surveillance in papillary microcarcinoma to be chosen alternatively to minimally invasive techniques after agreeing on such management with the patient. Further extensions allow the use of thyroid lobectomy with the isthmus (hemithyroidectomy) in low-risk cancer up to 2 cm in diameter, modification of the indications for postoperative radioiodine treatment toward personalized approach, and clarification of the criteria used during postoperative L-thyroxine treatment.

At the same time, the criteria for the preoperative differential diagnosis of nodular goiter in terms of ultrasonography and fine-needle aspiration biopsy have been clarified, and the rules for the histopathological examination of postoperative thyroid material have been updated. New, updated rules for monitoring patients after treatment are also presented.
The updated recommendations focus on ensuring the best possible quality of life after thyroid cancer treatment while maintaining the good efficacy of this treatment.

Original paper

Endokrynologia Polska

DOI: 10.5603/EP.a2022.0028

ISSN 0423–104X, e-ISSN 2299–8306

Volume/Tom 73; Number/Numer 2/2022

Diagnosis and treatment of thyroid cancer in adult patients — Recommendations of Polish Scientific Societies and the National Oncological Strategy. 2022 Update

Materials and methods applied in the process of preparing Recommendations of Polish Scientific Societies and the National Oncological Strategy. Diagnosis and treatment of thyroid cancer in adult patients

Barbara Jarząb1Marek Dedecjus2Andrzej Lewiński34Zbigniew Adamczewski5Elwira Bakuła-Zalewska6Agata Bałdys-Waligórska7Marcin Barczyński8Magdalena Biskup-Frużyńska9Barbara Bobek-Billewicz10Artur Bossowski11Monika Buziak-Bereza12Ewa Chmielik9Agnieszka Czarniecka13Rafał Czepczyński14Jarosław Ćwikła15Katarzyna Dobruch-Sobczak16Janusz Dzięcioł17Aneta Gawlik18Jacek Gawrychowski19Daria Handkiewicz-Junak1Jerzy Harasymczuk20Alicja Hubalewska-Dydejczyk12Joanna Januszkiewicz-Caulier2Michał Jarząb21Krzysztof Kaczka22Michał Kalemba1Grzegorz Kamiński23Małgorzata Karbownik-Lewińska424Andrzej Kawecki25Aneta Kluczewska-Gałka1Agnieszka Kolasińska-Ćwikła26Magdalena Kołton1Aleksander Konturek8Beata Kos-Kudła27Agnieszka Kotecka-Blicharz1Aldona Kowalska2829Jolanta Krajewska1Andrzej Kram30Leszek Królicki31Aleksandra Kukulska1Michał Kusiński32Krzysztof Kuzdak32Dariusz Lange33Aleksandra Ledwon1Ewa Małecka-Tendera18Przemysław Mańkowski20Bartosz Migda34Marek Niedziela35Małgorzata Oczko-Wojciechowska36Dariusz Polnik37Lech Pomorski22Marek Ruchała14Konrad Samborski1Anna Skowrońska-Szcześniak38Agata Stanek-Widera33Ewa Stobiecka9Zoran Stojčev39Magdalena Suchorzepka-Simek9Anhelli Syrenicz40Ewelina Szczepanek-Parulska14Małgorzata Trofimiuk-Müldner12Andrzej Tysarowski41Andrzej Wygoda42Klaudia Zajkowska2Ewa Zembala-Nożyńska9Agnieszka Żyłka2
1Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
2Department of Oncological Endocrinology and Nuclear Medicine, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
3Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Lodz, Poland
4Department of Endocrinology and Metabolic Diseases, Polish Mother’s Memorial Hospital — Research Institute, Lodz, Poland
5Department of Nuclear Medicine, Medical University of Lodz, Poland
6Department of Pathology and Laboratory Diagnostics, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
7Andrzej Frycz Modrzewski Krakow University, Faculty of Medicine and Health Sciences, Department of Endocrinology and Internal Medicine, Poland
8Department of Endocrine Surgery, Third Chair of General Surgery, Jagiellonian University Medical College, Kraków, Poland
9Tumor Pathology Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland
10Radiology and Diagnostic Imaging Department, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
11Department of Paediatrics, Endocrinology, and Diabetology with a Cardiology Division, Medical University of Bialystok, Poland
12Chair and Department of Endocrinology, Jagiellonian University Medical College, Kraków, Poland
13The Oncologic and Reconstructive Surgery Clinic, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland
14Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, Poznań, Poland
15Department of Cardiology and Internal Medicine; School of Medicine, University of Warmia and Mazury Olsztyn, Poland
16Department of Radiology II, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
17Department of Human Anatomy, Medical University of Bialystok, Poland
18Department of Pediatrics and Pediatric Endocrinology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Poland
19Department of General and Endocrine Surgery, Medical University of Silesia, Katowice, Poland
20Department of Pediatric Surgery, Traumatology & Urology, Karol Marcinkowski University of Medical Sciences in Poznan, Karol Jonscher Teaching Hospital, Poland
21Breast Cancer Unit, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland
22Department of General and Oncological Surgery, Chair of Surgical Clinical Sciences, Medical University, Lodz, Lodz, Poland
23Department of Endocrinology and Radioisotope Therapy, Military Institute of Medicine, Warsaw, Poland
24Chair and Department of Oncological Endocrinology, Medical University of Lodz, Lodz, Poland
25Head and Neck Cancer Department, Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
26Department of Oncology and Radiotherapy, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
27Department of Endocrinology and Neuroendocrine Tumors, Department of Pathophysiology and Endocrinology, Medical University of Silesia, Katowice, Poland
28Collegium Medicum Jan Kochanowski University Kielce, Poland
29Endocrinology Clinic, Holycross Cancer Center, Kielce, Poland
30Pathology Department, West Pomeranian Oncology Center, Szczecin, Poland
31Nuclear Medicine Department, Medical University of Warsaw, Warsaw, Poland
32Department of Endocrine, General and Vascular Surgery, Medical University of Lodz, Poland
33University of Technology, Faculty of Medicine, Katowice, Poland
34Diagnostic Ultrasound Lab, Department of Pediatric Radiology, Medical Faculty, Medical University of Warsaw, Poland
35Department of Oncology and Breast Diseases, CMKP, Warsaw, Poland
36Department of Genetic and Molecular Diagnostics of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland
37Department of Pediatric Surgery and Organ Transplantation, The Children’s Memorial Health Institute, Warsaw, Poland
38Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Poland
39Department of Oncology and Breast Diseases, CMKP, Warsaw, Poland
40Department of Endocrinology, Metabolic and Internal Diseases, Pomeranian Medical University, Szczecin, Poland
41Cancer Molecular and Genetic Diagnostics Department, Maria Sklodowska-Curie — National Research Institute of Oncology, Warsaw, Poland
42Radiation and Clinical Oncology Department, Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland

Prof. Barbara Jarząb MD PhD, Nuclear Medicine and Endocrine Oncology Department, Maria Skłodowska-Curie National Research Institute, Gliwice Branch, Wybrzeże AK 15, 44102 Gliwice, Poland, tel. +48 32 278 93 39; e-mail: barbara.jarzab@io.gliwice.pl

Submitted: 21.03.2022

Accepted: 21.03.2022

Early publication date: 26.04.2022

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract

The guidelines Thyroid Cancer 2022 are prepared based on previous Polish recommendations updated in 2018. They consider international guidelines American Thyroid Association (ATA) 2015 and National Comprehensive Cancer Network (NCCN); however, they are adapted according to the ADAPTE process. The strength of the recommendations and the quality of the scientific evidence are assessed according to the GRADE system and the ATA 2015 and NCCN recommendations.

The core of the changes made in the Polish recommendations is the inclusion of international guidelines and the results of those scientific studies that have already proven themselves prospectively.

These extensions allow de-escalation of the therapeutic management in low-risk thyroid carcinoma, i.e., enabling active surveillance in papillary microcarcinoma to be chosen alternatively to minimally invasive techniques after agreeing on such management with the patient. Further extensions allow the use of thyroid lobectomy with the isthmus (hemithyroidectomy) in low-risk cancer up to 2 cm in diameter, modification of the indications for postoperative radioiodine treatment toward personalized approach, and clarification of the criteria used during postoperative L-thyroxine treatment.

At the same time, the criteria for the preoperative differential diagnosis of nodular goiter in terms of ultrasonography and fine-needle aspiration biopsy have been clarified, and the rules for the histopathological examination of postoperative thyroid material have been updated. New, updated rules for monitoring patients after treatment are also presented.

The updated recommendations focus on ensuring the best possible quality of life after thyroid cancer treatment while maintaining the good efficacy of this treatment. (Endokrynol Pol 2022; 73 (2): 229)

Key words: thyroid cancer; nodular goiter; fine-needle aspiration biopsy; papillary thyroid microcarcinoma; active surveillance; active follow-up; indications for hemithyroidectomy; radioiodine treatment; L-thyroxine

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. 12). 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 36. 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.

Table 1. Strength of recommendations according to the National Comprehensive Cancer Network (NCCN) [57] modified by National Oncological Strategy guidelines [382]

1

Recommendation based on high-quality evidence and a uniform or high-level consensus among the expert group

2A

Recommendation based on lower-level evidence and a uniform or high-level consensus among the expert group

2B

Recommendation based on lower-level evidence and a moderate-level consensus among the expert group

3

Recommendation based on any level of evidence to which the expert group could not reach consensus

Table 2. Quality of evidence according to the National Comprehensive Cancer Network (NCCN) and European Society of Medical Oncology (ESMO) [372], based on the National Oncological Strategy guidelines [382]

I

Evidence from at least one large randomized, controlled trial of good methodological quality (low potential for bias) or meta-analyses well-constructed randomized trials without significant heterogeneity

II

Small randomized trials or large randomized trials with suspicion of bias (lower methodological quality) or meta-analyses of such trials or trials with demonstrated significant heterogeneity

III

Prospective cohort studies

IV

Retrospective cohort studies or case-control studies

V

Studies without a control group, case reports, expert opinions

Table 3. Interpretation of recommendations for therapeutic interventions based on the strength of evidence adapted from the 2015 American Thyroid Association (ATA) guidelines (modified) [1]

Strength of recommendation (SoR)

Benefits/risk balance

Implications

1

Strong
SoR 1

The benefits definitely outweigh the risks

PATIENTS Therapeutic intervention, recommended by a strong recommendation, has an unequivocal benefit for most patients

PHYSICIANSTherapeutic intervention should be used in most patients

2

Weak
SoR 2

The benefits balance the risks

PATIENTSTherapeutic intervention recommended with a weak recommendation may be effective in many patients, but the decision may depend on individual circumstances

PHYSICIANSTherapeutic intervention may be effective in many patients, but the decision should be made on an individual basis, taking into account patient preference and indications

3

No recommendation
SoR 3

The benefit-risk balance cannot be defined

No evidence-based decision can be made

Table 4. Interpretation of recommendations for treatment interventions based on strength (SoR) and quality of evidence (QoE) adapted from the 2015 American Thyroid Association (ATA) guidelines (modified) [1]

Strength of recommendations (SoR)/quality of evidence (QoE)

Definition of the quality of evidence

Implications

1

StrongSoR 1

+++

High QoE

RCTs without significant limitations or very strong evidence from observational studies

Can be used in most patients and in most circumstances

++

Moderate

RCTs with significant limitations or relatively strong evidence from observational studies

Can be used in most patients and in most circumstances

+

Low

Observational studies, case reports

Recommendation may be revised if new high-quality scientific evidence becomes known

2

WeakSoR 2

+++

High QoE

RCTs without significant limitations or very strong evidence from observational studies

Optimal management may vary depending on circumstances or patient characteristics

++

Moderate

RCTs with significant limitations or relatively strong evidence from observational studies

Optimal management may vary depending on circumstances or patient characteristics

+

Low

Observational studies, case reports

Other alternative treatments may also be appropriate

3

No recommendationSoR 3

Insufficient

Evidence is contradictory or of poor quality or lacks scientific evidence

At the physician’s discretion, you can discuss this course of action with the patient, but you cannot recommend either for or against

Table 5. Interpretation of recommendations for diagnostic interventions adapted from the 2015 American Thyroid Association (ATA) guidelines (modified) [1]

Strength of recommendation (SoR)

Importance of the diagnostic test result relative to the risk incurred and the patient burden associated with the test

Implications

1

Strong
SoR 1

Obtaining information through an intervention is very important for further treatment and clearly outweighs the risk and burden to the patient

PATIENTS a test with a strong recommendation is unequivocally useful for diagnosing the disease and treatment plan, and a benefit far outweighs the risk and burden for the patient

PHYSICIANS the physician should offer the intervention recommended by a strong recommendation to most patients because the gain from an adequate diagnosis of the disease and an adequate treatment plan far outweighs the risk and burden to the patient

2

Weak
SoR 2

Obtaining information through an intervention/test is balanced with risk and burden to the patient

PATIENT a test with a weak recommendation warrants consideration because it may become useful for proper diagnosis of the disease and adequate planning of its treatment, and this gain balances the risk and burden for the patient

PHYSICIANS a physician may offer a patient a test recommended with a weak recommendation because the benefit of an adequate diagnosis of the disease and an adequate treatment plan outweighs the risk and burden to the patient

3

No recommendation
SoR 3

There are no clear data to compare diagnostic benefit versus risk and burden to the patient

No basis for evidence-based decisions

Table 6. Interpretation of recommendations for interventions/diagnostic tests based on strength and quality adapted from the 2015 American Thyroid Association (ATA) guidelines [1]

Strength of recommendation (SoR)/quality of evidence (QoE)

Description of the methodological quality of the supporting evidence

Interpretation

1

StrongSoR 1

+++

High QoE

Evidence is based on one or more well-designed nonrandomized studies (observationalcross-sectional or cohort) or on systematic reviews/meta-analyses of such observational studies (which do not demonstrate limitations according to EBM criteria)

The test or intervention can be used in most patients and in most circumstances

++

Moderate

Evidence is based on nonrandomized studies (observationalcross-sectional or cohort) or on systematic reviews/meta-analyses of such observational studies (with certain limitations according to EBM criteria)

The test or intervention can be used in most patients and in most circumstances

+

Low

Evidence is based on nonrandomized studies (observationalcross-sectional or cohort) or on systematic reviews/meta-analyses of such observational studies (with one or more important limitations according to EBM criteria)

The test or intervention can be used in most patients and in most circumstances, but the recommendation may change if new high-quality scientific evidence is available

2

WeakSoR 2

+++

High QoE

Evidence is based on one or more well-designed nonrandomized studies (observationalcross-sectional or cohort) or on systematic reviews/meta-analyses of such observational studies (which do not demonstrate limitations according to EBM criteria)

The use of a test or intervention is strongly dependent on the patient’s circumstances or societal value

++

Moderate

Evidence is based on nonrandomized studies (observationalcross-sectional or cohort) or on systematic reviews/meta-analyses of such observational studies (with certain limitations according to EBM criteria)

The use of a test or intervention is strongly dependent on the patient’s circumstances or societal value

+

Low

Evidence is based on nonrandomized studies (observationalcross-sectional or cohort) or on systematic reviews/meta-analyses of such observational studies (with one or more important limitations according to EBM criteria)

Other alternative management may be equally reasonable

3

No recommendationSoR 3

Evidence is contradictory or of poor quality or lacks scientific evidence to generalize

A test or intervention cannot be recommended, either for or against

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. 79) [1–3, 10].

SoR 2A QoE: IV

SoR: 1 QoE: ++

Table 7. Features of B-mode imaging, vascular options (color and power Doppler), and sonoelastography ultrasound of a focal thyroid lesion [9, 10, 373–375]

Structure

Cystic

Focal lesion:

  • well defined margins
  • with acoustic enhancement present (in case of small lesions < 3 mm it may be invisible)
  • without visible vascularization in CD/PD mode

Spongiform

A focal lesion consisting of tiny cystic spaces separated by thin septa, at least 50% of the lesion volume without visible vessels or microcalcifications

Mixed cystic-solid

A focal lesion with liquid and solid component:

  • solid-cysticwhen solid component predominates
  • cystic-solidwhen the liquid component predominates

Solid

Focal lesion entirely solid or solid lesion with single small fluid spaces

Echogenicity
(in relation to normal parenchyma* of the thyroid gland and/or the submandibular salivary gland;

in case of hypoechogenic lesions to thyroid parenchyma)

Anechoic

No internal echoes in the lesion (fluid-filled)

Normal/isoechoic

Echogenicity comparable to that of the surrounding parenchyma*

Hyperechoic

Echogenicity superior to surrounding parenchyma*

Hypoechoic

Echogenicity is lower compared to surrounding parenchyma*, but not compared to the infrahyoid muscles or sternoclavicular muscle

Markedly hypoechoic

Echogenicity comparable or lower to the infrahyoid muscles or sternoclavicular muscle

Mixed echogenicity (the dominant echogenicity should be given)

Echogenicity being a combination of the 25 defined above; dominant component (e.g., predominantly hypoechoic lesion; or heterogeneous normal/isoechoic lesion) should be given

Margins

Well-defined/regular

There is an even, clear demarcation/border/edge between the focal lesion and the surrounding parenchyma over its entire surface

Ill-defined

In cases where the demarcation/border/edge between the lesion and surrounding parenchyma cannot be determined

Irregular

Lack of an even demarcation/border/edge between the focal lesion and the surrounding parenchyma

Margins

Angular

Sharp irregularities of the edge/border of the lesion can be seen forming sharp angles

Microlobulated

The edge/border of the lesion is formed by repetitive small protrusions/lobules

Spiculated

The edge/border of the lesion is formed by radial spiculations

“Halo”

Thin

Thin (“hair-like”) sonolucent black outline around the focal lesion; often, vessels are imaged in its projection on CD/PD

Thick

Broad hypoechoic “halo” (may be incomplete), often not identified with vessels on CD/PD

Shape

Ovoid

The anteroposterior dimension is smaller than the transverse dimension on the transverse and longitudinal planes

Round

Three dimensions in a spatial arrangement (two orthogonal planes) are comparable

Irregular

Not oval, not round

Orientation of the lesion (relative to the skin surface)

Parallel

The anteroposterior dimension is smaller than the transverse and longitudinal dimension (wider than taller)

Nonparallel

The anteroposterior dimension is greater than the transverse and/or longitudinal dimension (higher than wider)

Calcifications

Macrocalcifications (> 1mm)

Spot bright echoes > 1 mm in dimension if small may or may not cause an acoustic shadow

Microcalcifications (< 1mm)

Spot bright echoes of < 1 mm in dimension if they do not form clusters most often do not cause an acoustic shadow

Ring-shaped calcification

Calcification is round in shape (the continuity of the calcification should be assessed; it often gives an acoustic shadow

Thickened colloid

Comet tail artifact

Spot bright echoes with long comet tail artifact present (> 1 mm) seen in the fluid component

Extrathyroidal invasion

Shaping of the gland and capsule

Outlining of the gland capsule may change the shape of the lobe (compared with the opposite side)

Extrathyroidal invasion

Solid tissue part crossing the capsule of the gland

Vascularity

No vascularity

No visible vessels in the lesion when the CD option is properly set (maximum velocity on the scale to about 25 cm/s; gain at the noise limit)

Peripheral

Vessels localize to the periphery of the lesion at the appropriate CD option setting (maximum velocity on the scale to approximately 25 cm/s; gain at the noise limit)

Mixed

Vessels visible in the periphery and central part of the lesion at the appropriate CD option setting (maximum velocity on the scale to about 25 cm/s; gain at the noise limit)

(It may be added with predominantly peripheral or central vascularization)

Central

Vessels localize within the lesion at the appropriate CD option setting (maximum velocity on the scale to approximately 25 cm/s; gain at the noise limit)

Elasticity/stiffness of the lesion

Deformable

Asteria 1 (SE), SR < 1.5 (SE)

E mean < 28 kPa (SWE)

Partially deformable

Asteria 2.3 (SE), SR 1.54.9 (SE)

E mean 2931 kPa (SWE)

Completely non-deformable

Asteria 4 (SE), SR > 5 (SE)

E mean > 32 kPa (SWE)

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

Table 9. Limitations to the use of sonoelastography [10]

Limitations to the use of sonoelastography in thyroid nodules

Paratracheal location

Nodule diameter > 3 cm

Profound nodule: depth > 4 cm

Macrocalcifications

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, 1012) [13].

SoR 2A QoE: IV

SoR: 2 QoE: +

Table 10. Risk-modifying features in EU-TIRADS 3 and 4 categories [9]

Increasing risk

Reducing risk

Macrocalcifications

Chaotic vascular pattern

Central vascularity

Segmental/irregular thick halo

Reduced elasticity

Cystic liquid component

The presence of the comet tail artifact

Peripheral vascularity

Thin halo

Normal elasticity

Table 11. Parts of correct ultrasound description of the thyroid gland [9]

Part of the examination

Characteristics

Notes

General information

Location of the thyroid gland

Typical, ectopic

Structure of the thyroid gland

Normal bi-lobed, hypoplasia/aplasia of any of the lobes, presence/absence of isthmus

Evaluation of the neck in the midlinealong the course of the thyroglossal duct to identify/exclude anatomical/developmental variants

E.g., pyramidal lobe, anterior neck cyst, ectopic thyroid parenchyma at the base of the tongue

3 dimensions should be given: width [mm] × thickness [mm] × length [mm]

Dimensions

3 dimensions should be given for each lobe: width [mm] × thickness [mm] × length [mm] and volume, if any, for each lobe and the entire gland

Tracheal evaluation

Assess tracheal position in cross-section: assessment of left/right displacement

Potential compression due to enlargement of the gland

Evaluation of the thyroid parenchyma

Echogenicity

Normoechoic (normal)/hypoechoic

Normoechoichigher than neck muscles (submarginal, sternoclavicular, and mastoid muscles), similar to normal submandibular salivary gland

Hypoechogenicequal to or inferior to neck muscles (i.e., as above)

Echostructure

Homogeneous/non-homogeneous

If focal lesions are present, the definition specifies the structure outside the lesions

Vascularization

Normal (well-defined large vesselsupper and lower thyroid vesselsand individual small vessels in their central and subcapsular part)

Scanty (weakly visible vessels at the poles of the lobes, usually without visible vessels in the central part)

Increased (numerous wide vessels are visibleespecially in the central part of the lobes and at the poles)

Set the color Doppler at low maximum speed values of approx. 25 cm/s and the gain at the noise limit; for the classical power Doppler option, the settings are for the gain at the noise limit

Evaluation of the focal lesions

Spatial location (concerning the long and short axis of the lobe)

In the long axis of the lobe dividing it into 3 parts:

  • upper pole
  • middle part
  • lower pole

In the short axis in relation to the gland capsule or anatomical structures:

  • anterior part
  • lateral (or lateral/carotid)
  • posterior capsule
  • medially (or paratracheally)
  • centrally (in the absence of a position tendency to any of the above)
  • on the border of the isthmus and the lobe

In case of large lesions, it is acceptable to specify, e.g., the lesion fills the lower pole of the left/right lobe

In case of multiple focal lesions, risk stratification according to EU-TIRADS-PL classification should be performed:

  • TR5high-risk lesions
  • TR4intermediate-risk lesions
  • TR3low-risk lesions
  • TR2non-suspicious lesions

For: TR5 lesions: all lesions found should be described, including location, morphologic appearance, and 3 dimensions

For TR4 and TR3 lesions:

  • can often be multiple (describe as groups of lesions — “common denominator”)
  • the location of the largest lesion in each lobe
  • morphological description of the ultrasound image of each individual lesion
  • dimensions for the largest lesion should be given

For TR2 lesions:

  • location of the largest lesion in the lobe should be indicated
  • it is acceptable to provide a maximum dimension for the indicated changes

B-mode lesion morphology

Structure

Echogenicity

Margins

Any other additional B-mode image features found during the study (Tab. 7)

3 dimensions (excluding cystic and spongiform lesions)

Color or power Doppler

See Table 7

Sonoelastography (if available)

Stiffness of the lesion in relation to the surrounding parenchyma (in case of its absence to the infrahyoid muscles or sternoclavicular muscle) — applies to static sonoelastography, in dynamicquantitative evaluation

Table 12. EU-TIRADS-PL classification. The authors of the recommendation recommend using the numerical EU-TIRADS-PL classification. Only in the EU-TIRADS-PL 5 category, it is recommended to list all the features conditioning membership in this category. Modified based on EU-TIRADS guidelines [9]

EU-TIRADS-PL
category

Ultrasonographic features

Risk of malignancy

Indications for biopsy and/or further ultrasound monitoring

1

No nodules

Close to 0%

Ultrasound follow-up depending on clinical risk factors

2

Pure cysts

Spongiform nodules

Close to 0%

FNAB not recommended (exception: therapeutic biopsy in symptomatic patients, e.g., cyst drainage); ultrasound follow-up depending on clinical risk factors

3

Normal/isoechoic or hyperechoic

Ovoid or round shape

Smooth margins

No features of category 5

24%

FNAB ≥ 20 mm

4

Hypoechoic

Ovoid or round shape

Smooth margins

No features of category 5

617%

FNAB ≥ 15 mm

5

Presence of at least one of the following features:

  • marked hypoechogenicity
  • irregular shape
  • non-parallel orientation
  • irregular margins
  • microcalcifications
  • extrathyroidal invasion*

> 26%*

FNAB ≥ 5 mm*

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

Table 13. Proposed terminology for fine-needle aspiration biopsy (FNAB) diagnoses based on 2017 Bethesda System for Reporting Thyroid Cytopathology [23, 83, 377, 378]

Bethesda Category

Recommended terminology

Risk of malignancy considering NIFTP as postoperative outcome

Cancer risk in Polish patients

Cytological diagnoses included in a particular category and other comments

I

Nondiagnostic

or

unsatisfactory

510%

510%*

Clinical context should be considered

II

Benign

03%

< 1%*

Nodular goiter

Thyroiditis, including chronic inflammations

Hyperplastic nodule

Colloid nodule (lots of colloid, sufficient cellularity)

Cytological findings suggest colloid nodules (lots of colloids, insufficient cellularity)

Thyroid cyst

III

Atypia of undetermined significance (AUS)

or

Follicular lesion of undetermined significance (FLUS)

618%

2.45.2%

This category should be used in rare cases when it is not possible to state a precise cytological diagnosis

IV

Follicular neoplasm

or

Suspicious for a follicular neoplasm

1040%

19%

At least 25% of lesions belonging to this category are not neoplastic tumors (hyperplastic nodules, inflammation). This category should not be diagnosed when nuclear features of papillary thyroid cancer are present

V

Suspicious for malignancy

4560%

75%

This category involves:

  • papillary thyroid cancer
  • medullary thyroid cancer
  • lymphoma
  • metastatic carcinoma
  • anaplastic thyroid cancer/vascular sarcoma due to the presence of necrotic tissues
  • hyalinizing trabecular tumor

VI

Malignant

9496%

95100%*

This category involves:

  • papillary thyroid cancer
  • medullary thyroid cancer
  • lymphoma
  • metastatic carcinoma
  • anaplastic thyroid cancer/vascular sarcoma

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 0.40.6 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.

Table 14. Cytologic criteria for Bethesda categories III and IV [23]

Feature

Category III

Category IV

Hypercellular aspirate (subjective)

Rather yes

Yes

Prominent population of small arrangement
(groups, nests, rosettes)

Yes

Yes

Sheets of follicular cells

Might be seen

No or single

Colloid in background

Might be seen

No or trace

Foamy macrophages

Might be present

No or single

Anisocytosis/anisokaryosis

No or little

No

Lymphocytes/plasmatic cells

No or few

No

Oncocytes

Does not matter

If > 75% cells, suspect Hürthle cell neoplasm

Oncocytes must obligatorily contain nuclei

Anisocytosis of oncocytes acceptable

Oncocytes in spatial arrangements

Indications for surgery

No

Yes, after confirmation of the diagnosis by a second pathologist

Indications for repeated FNAB

Yes

No

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: +

Table 15. Immunohistochemical markers used in the differentiation of focal thyroid lesions. Based on World Health Organisation (WHO) Classification of Tumors of Endocrine Organs 2017r, 4th Edition [162]

Tumor

Antibody

Thyroglobulin

Calcitonin

TTF1

Napsin A

p63

PAX8

GATA – 3

SOX 10

HMB 45

CDX 2

CK 5/6

RCC

CD 10

PTH

Ki-67

Renal carcinoma

+

+

+

+

Lung adenocarcinoma

+

+

+

+

Squamous cell carcinomas

+

+

Squamous cell carcinomas (of the head and neck region)

+

+

+

Breast cancer

+

+

Melanoma

+

+

+

Colorectal adenocarcinoma

+

+

Papillary and follicular thyroid carcinoma

+

+

+

Medullary thyroid carcinoma

+

+

+

Anaplastic thyroid carcinoma

+/–

+

+
> 30%

Parathyroid neoplasms

+

–­­

+

+

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: ++

Table 16. Guidelines for modification of anticoagulant treatment before planned thyroid fine-needle aspiration biopsy (FNAB)

Class

Drug name

Management before thyroid FNAB

Vitamin K antagonists

Acenocoumarol, warfarin

No withdrawal is necessary. Consider switching to low molecular weight heparin in selected cases

NOACs

Direct thrombin inhibitors

Dabigatran

Withdraw ≥ 2448 h before FNAB depending on GFR:

  • > 80 mL/minwithdraw ≥ 24 h
  • 5080 mL/minwithdraw ≥ 36 h
  • 3050 mL/minwithdraw ≥ 48 h
  • < 30 mL/minno data

Direct factor Xa inhibitors

Fondaparinux, rivaroxaban, apixaban, edoxaban

Withdraw ≥ 24 h before FNAB

Low molecular weight heparin

Enoxaparin, dalteparin, nadroparin

Last dose 812 h before FNAB

Antiplatelet drugs

ASA at a dose of up to 300 mg/day

ASA

There is no need for withdrawal

Other antiplatelet drugs

Clopidogrel, ticlopidine, ticagrelor, prasugrel, cilostazol

FNAB may be performed if absolutely indicated, and no drug withdrawal is possible for cardiac reasons

NSAIDs other than ASA

Ibuprofen, diclofenac, naproxen, meloxicam, nimesulide, celecoxib, and others

There is no need for withdrawal

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 0.40.6 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 812-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 (≥ 3648 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 612 months [49].

SoR 2A QoE: III

SoR: 1 QoE: ++

18. Two non-diagnostic FNABs in a solid nodule (EU-TIRADS-PL3) [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 618 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 612 months.

SoR 2A QoE: V

SoR: 2 QoE: +

20.1.1. Accelerated repeated FNAB at an interval of 36 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

Table 17. 2017 TNM AJCC/UICC Classification, Eight edition

T — primary tumor

Tx

Primary tumor cannot be assessed

T0

No evidence of primary tumor

T1

Tumor ≤ 2 cm in greatest dimension limited to the thyroid

T1a

Tumor ≤ 1 cm in greatest dimension limited to the thyroid

T1b

Tumor > 1 cm but ≤ 2 cm in greatest dimension limited to the thyroid

T2

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

T3

Tumor > 4 cm limited to the thyroid or gross extrathyroidal extension invading only strap muscles

T3a

Tumor > 4 cm limited to the thyroid

T3b

Tumor of any size with gross extrathyroidal extension into strap muscles (sternohyoid, sternothyroid, thyrohyoid or omohyoid muscles)

T4

Tumor of any size with gross extrathyroidal extension into major neck structures

T4a

Tumor of any size with gross extrathyroidal extension invading subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve

T4b

Tumor of any size with gross extrathyroidal extension invading prevertebral fascia or encasing carotid artery or mediastinal vessels

Note! T feature applies to all primary thyroid cancers, including undifferentiated (anaplastic) thyroid cancer

Nregional lymph nodes

Nx

Regional lymph nodes cannot be assessed

N0

N0a

N0b

No evidence of lymph node metastases

One or more cytologically of histologically confirmed benign lymph node (nonmetastatic)

No clinical or radiologic evidences of locoregional lymph node involvement

N1

Metastasis to regional lymph nodes

N1a

Metastasis to level VI (pretracheal, paratracheal, prelaryngeal) or level VII (mediastinal) lymph nodes

N1b

Metastasis to unilateral, bilateral, or contralateral (level I, II, III, IV, or V) or retropharyngeal lymph nodes

Mdistant metastases

M0

No distant metastases

M1

Distant metastases

Table 18. 2017 TNM AJCC/UICC Classification, Eight edition — clinical stages

Stage

T

N

M

Papillary, follicular, oxyphilic, and poorly differentiated thyroid carcinoma

Age at diagnosis < 55 years

Stage I

Any T

Any N

M0

Stage II

Any T

Any N

M1

Papillary, follicular, oxyphilic, and poorly differentiated thyroid carcinoma

Age at diagnosis ≥ 55 years

Stage I

T1a, T1b, T2

N0

M0

Stage II

T3

N0

M0

T1, T2, T3

N1

M0

Stage III

T4a

Any N

M0

Stage IVA

T4b

Any N

M0

Stage IVB

Any T

Any N

M1

Medullary thyroid carcinoma

Stage I

T1a, T1b

N0

M0

Stage II

T2, T3

N0

M0

Stage III

T1, T2, T3

N1a

M0

Stage IVA

T1, T2, T3

N1b

M0

T4a

Any N

M0

Stage IVB

T4b

Any N

M0

Stage IVC

Any T

Any N

M1

Undifferentiated (anaplastic) thyroid carcinoma

Stage IVA

T1, T2, T3a

N0

M0

Stage IVB

T1, T2, T3a

N1

M0

T3b, T4a, T4b

Any N

M0

Stage IVC

Any T

Any N

M1

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

Table 19. Risk-stratification system for papillary and follicular thyroid carcinomas according to the 2015 ATA [1] and 2019 European Society of Medical Oncology (ESMO) [56] criteria

Low-risk cancer

PTC with all of the features listed below:

  • no lymph node and distant metastases
  • all macroscopic tumor resected
  • no extrathyroidal invasion
  • lack of aggressive histologic subtype (e.g., tall cell, columnar cell, hobnail variant)
  • no RAI uptake outside the thyroid bed on WBS after postoperative treatmentif it is given
  • no vascular invasion
  • clinically N0 or ≤ 5 lymph node micrometastases < 2 mm in the longest diameter

Intrathyroidal well-differentiated FTC with capsular invasion, no vascular invasion, or < 4 foci of vascular invasion

Intrathyroidal papillary microcarcinoma, uni or multifocal, also with the presence of the BRAFV600E mutation

Intermediate-risk cancer

Microscopic extrathyroidal invasion

Aggressive histological subtype

PTC with vascular invasion

RAI uptake outside the thyroid bed observed in posttreatment WBS after postoperative RAI treatment

Multifocal PTMC z estrathyroidal extension and the presence of the BRAFV600E mutation

Oxyphilic (Hurthle-cell) thyroid carcinoma

Clinically N1 or > 5 metastatic lymph nodes < 3 cm

High-risk cancer

Widely invasive FTC (> 4 foci of vascular invasion),

Poorly differentiated thyroid carcinoma

Gross extrathyroidal extension

Incomplete tumor resection (R1 or R2 surgery)

Increased postoperative serum Tg level suggesting distant metastases

Metastatic lymph nodes one or more > 3 cm

The presence of extranodal extension

Distant metastases

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: +

Table 20. Classification of treatment response in differentiated thyroid carcinoma (DTC) patients according to the treatment provided [1, 59, 244]

Total thyroidectomy and postoperative RAI therapy

Total thyroidectomy

Lobectomy

Excellent response

Negative imaging studies

and

Tg suppressed < 0.2 ng/mL

or

Tg stimulated < 1 ng/mL

and

Undetectable anti-Tg

Negative imaging studies

and

Nonstimulated Tg < 0.2 ng/mL

or

Stimulated Tg < 2 ng/mL

and

Undetectable anti-Tg

Negative imaging studies

or

Stable nonstimulated Tg < 30 ng/mL

and

Undetectable anti-Tg

Incomplete biochemical response

Negative imaging studies

and

Nonstimulated Tg ≥ 1 ng/mL

or

Stimulated Tg ≥ 10 ng/mL

or

Rising anti-Tg level

Negative imaging studies

and

Nonstimulated Tg > 5 ng/mL

or

Stimulated Tg > 10 ng/mL

or

Increasing Tg concentration over time determined with comparable TSH concentrations or

Rising anti-Tg level

Negative imaging studies

and

Nonstimulated Tg > 30 ng/mL

or

Increasing Tg concentration over time determined with comparable TSH concentrations

or

Rising anti-Tg level

Incomplete structural response

Presence of persistent disease on imaging studies regardless of Tg and anti-Tg levels

Indeterminate response

Inconclusive imaging findings

or

Faint uptake in the thyroid bed on RAI scanning

or

Detectable non-stimulated Tg, but < 1 ng/mL

or

Detectable stimulated Tg, but < 10 ng/mL

or

Stable or decreasing anti-Tg levels in the absence of persistent disease on imaging studies

Inconclusive imaging findings

or

Faint uptake in the thyroid bed on RAI scanning

or

Nonstimulated Tg 0.25 ng/mL

or

Tg stimulated 210 ng/mL

or

Stable or decreasing anti-Tg levels in the absence of persistent disease on imaging studies

Inconclusive imaging findings

or

Stable or decreasing anti-Tg levels in the absence of persistent disease on imaging studies

Part III

Management of papillary thyroid microcarcinoma

1. For the preoperative diagnosis of stage cT1aN0M0 papillary carcinoma in a single focal lesion1 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: +++

Table 21. Eligibility criteria for active surveillance in low-risk papillary carcinoma cT1aN0M0 [69, 379]

Eligibility criteria for active surveillance

Eligibility criteria for surgery

1. Thyroid nodule ≤ 1cm

2. Solitary nodule

3. Well-defined margins

4. Surrounded by ≥ 2 mm normal thyroid parenchyma

5. No evidence of extrathyroidal extension

6. No lymph node and distant metastases

7. Age > 18 years

1. Multifocality

2. Subcapsular location

3. Suspicion for extrathyroidal extension

4. Suspicion for RLN or tracheal invasion

5. Lymph node or distant metastases

6. Suspicion for aggressive histological subtype

7. Age ≤ 18 years

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

SoR 2A QoE: IV

SoR: 2 QoE: +

227279.png
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; **ETEextra thyroidal extension; TTtotal thyreoidectomy; CNDcentral node dissection; MITminimally invasive techniques; EBRTexternal 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 by3mm 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 16 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 10100 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 1980s1990s 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 carcinoma2 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 12 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 (34-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 is1 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 in5 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 16 months; however, it may disappear even later, after 12 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 400800 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 36 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 12 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: ++

Table 22. 2017 World Health Organization (WHO) classification of thyroid tumors [162]

Follicular adenoma

8330/0

Hyalinizing trabecular tumor

8336/1

Other encapsulated follicular patterned thyroid tumors

Follicular tumors of uncertain malignant potential

Well differentiated tumor of uncertain malignant potential

Noninvasive follicular thyroid neoplasm
with papillary-like nuclear features

8335/1

8348/1

8349/1

Papillary thyroid carcinoma (PTC)

Papillary carcinoma

Follicular variant of PTC

Encapsulated variant of PTC

Papillary microcarcinoma

Columnar cell variant of PTC

Oncocytic variant of PTC

8260/3

8340/3

8343/3

8341/3

8344/3

8342/3

Follicular thyroid carcinoma (FTC)

FTC, minimally invasive

FTC, encapsulated angioinvasive

FTC, widely invasive

8330/3

8335/3

8339/3

8330/3

Hürthle (oncocytic) cell tumors

Hürthle cell adenoma

Hürthle cell carcinoma

8290/0

8290/3

Poorly differentiated thyroid carcinoma

8337/3

Anaplastic thyroid carcinoma

8020/3

Squamous cell carcinoma

8070/3

Medullary thyroid carcinoma

8345/3

Mixed medullary and follicular thyroid carcinoma

8346/3

Mucoepidermoid carcinoma

8430/3

Sclerosing mucoepidermoid carcinoma with eosinophilia

8430/3

Mucinous carcinoma

8480/3

Ectopic thymoma

8580/3

Spindle epithelial tumor with thymus-like differentiation

8588/3

Intrathyroid thymic carcinoma

8589/3

Paraganglioma and mesenchymal/stromal tumors

Paraganglioma

Peripheral nerve sheath tumors (PNSTs)

— schwannoma

— malignant PNST

Benign vascular tumors

— hemangioma

— cavernous hemangioma

— lymphangioma

Angiosarcoma

Smoot muscle tumors

— leiomyoma

— leiomyosarcoma

Solitary fibrous tumors

8693/3

9560/0

9540/3

9120/0

9121/0

9170/0

9120/3

8890/0

8890/3

8815/1

Hematolymphoid tumors

Langerhans cell histiocytosis

Rosai-Dortman disease

Follicular dendritic cell sarcoma

Primary thyroid lymphoma

9751/3

9758/3

Germ cell tumors

Benign teratoma

Immature teratoma

Malignant teratoma

Secondary tumors

9080/0

9080/1

9080/3

3.4. The conclusion of the histopathological report should include TumorNodeMetastasis (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: +

Table 23. A panel of immunohistochemical markers, used for suspected anaplastic thyroid cancer (ATC) and the expected expression for other thyroid cancers [58]

Marker

DTC

PDTC

ATC

MTC

SCC

Lymphoma

Pan cytokeratin

+++

+++

+++/–

+++

+++

Thyroglobulin

+++

+/–

TT-1

+++

–/+

–/+

+/–

BRAFV600E

+/–

–/+

–/+

PAX8

+++

+++

+/–

+/–

+/–

Ki-67

< 5%

530%

>30%

< 20%

> 30%

Diversely

Chromogranin

+++

Calcitonin

+++/–

CEA

+++

p53

– (rarely +)

–/+

+/–

+/–

+/–

CD 45

+++

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. 1719).

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:+++

227484.png

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 2.2.12, 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 1.13.7 GBq (30100 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., 3.75.5 GBq (100150 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 is3.7 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 68 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 levels30 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 312 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 12 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 612 months in women and 46 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 0.52.0 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 0.10.5 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 0.10.5 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 68 weeks.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.3. Serum TSH level should be measured every 36 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 7494.5% of patients diagnosed with low-risk cancer, 3661% of intermediate-risk patients, and 021% of high-risk patients [244].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.3. Incomplete biochemical treatment response is found in 311% of low-risk patients diagnosed, 1622% of intermediate-risk patients, and 1824% of high-risk patients [244].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.4. Incomplete structural treatment response is found in 12% of low-risk patients, 3.519% of patients with intermediate-risk cancer, and 2467% of high-risk patients [244].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.5. Progression to structural disease is found in 817% of patients with incomplete biochemical treatment response [242, 245].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.6. At the final follow-up, 5668% of patients with indeterminate biochemical response show no evidence of disease, while 1927% have persistent abnormal Tg values without structural lesions, and only 817% develop a structural disease over 510 years follow-up [242, 246, 247].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.7. An indeterminate response concerns 1229% of ATA low-risk patients, 823% of ATA intermediate-risk patients, and 04% 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 618 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 Tg1 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 level1 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 612 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 68 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 624 months, depending on the dynamic risk stratification;

periodic serum Tg evaluation every 624 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 1236 months;

periodic serum Tg evaluation every 1236 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 5060 Gy in the lymph drainage area and 6870 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]:

1.1. Molecularly targeted therapy (tyrosine kinase inhibitors; TKIs) is recommended for patients with advanced unresectable disease or in cases of multiple metastases refractory to RAI [296] (Tab. 24) who meet Response Evaluation Criteria In Solid Tumors (RECIST) for measurable disease and progression at 12 months before treatment start (indications for therapy are summarized in Tab. 25) [1, 56, 57, 104].

SoR: 1 QoE: II

SoR: 1 QoE: +++

Table 24. Radioiodine (RAI)-refractoriness criteria [380]
  1. 1. No RAI uptake in cancer foci on qualifying scintigraphy
  2. 2. No RAI uptake in cancer foci on prior post-therapy scintigraphy
  3. 3. RAI uptake in some but not all cancer foci
  4. 4. Disease progression despite RAI uptake in all cancer foci
  5. 5. Presence of persistent disease despite several RAI treatment cycles, high FDG uptake in cancer foci, aggressive histological subtype

Table 25. Eligibility criteria for tyrosine kinase inhibitors (TKIs) in patients with advanced thyroid cancer [1, 56, 104]
  1. 6. RAI-refractoriness (applies to DTC and PDTC)
  2. 7. Advanced, inoperable locoregional disease not eligible for local treatment or the presence of multiple distant metastases
  3. 8. Measurable disease according to RECIST (e.g., RECIST 1.1)
  4. 9. Disease progression according to RECIST (e.g., RECIST 1.1) within 14 months prior to treatment start

1.2. TKI therapy does not lead to a cure of the disease [301, 302].

SoR: 2A QoE: II

SoR: 1 QoE: +++

1.3. The decision to start TKIs should be made by a multidisciplinary team and should take into account the potential benefits and risks associated with the patient’s condition, comorbidities (Tab. 26), and possible side effects (Tab. 27). Examinations that should be performed prior to eligibility for TKI therapy and during treatment are summarized in Table 28. Before using TKIs, local treatment options should be considered.

SoR: 2A QoE: II

SoR: 1 QoE: +++

Table 26. Comorbidities limiting the use of tyrosine kinase inhibitors in advanced thyroid cancer. Based on 2015 American Thyroid Association (ATA) guidelines [1]
  1. 10. Current or recent history of the intestinal disease (diverticulitis, inflammatory bowel disease, history of surgery)
  2. 11. Liver diseases
  3. 12. Coagulation disorders, a recent history of bleeding (e.g., gastrointestinal bleeding, hemoptysis)
  4. 13. A recent cardiovascular event (acute coronary syndrome, stroke)
  5. 14. Advanced heart failure (EF < 40%)
  6. 15. History of QTC prolongation or a significant ventricular arrhythmia
  7. 16. Poorly controlled hypertension
  8. 17. Recent radiotherapy (up to 4 weeks)
  9. 18. Recent major surgery (up to 4 weeks)
  10. 19. Poor general condition, cachexia
  11. 20. Previously untreated CNS metastases
  12. 21. History of suicide attempt

Table 27. Management in the most common adverse reactions to tyrosine kinase inhibitors (TKIs) [1, 381]

Diarrhea

Loperamid, Reasec

Hypertension

Regular blood pressure monitoring, antihypertensive medications (ACEIs, beta-blockers, vascular channel blockers, sartans, diuretics)

NOTE! In patients with a diagnosis of hypertension, several days before starting therapy with sorafenib, lenvatinib, or cabozantinib, doses of antihypertensive drugs should be increased

Skin toxicity (including hand-foot skin reaction)

Avoid sun exposure, emollients, urea-based creams, cotton gloves, comfortable shoes, topical steroids, antihistamines

Mucositis

Adequate diet (avoiding hot and strongly cooled foods, strongly spiced foods, foods that can injure the mucous membranes, alcohol), adequate hydration, oiling the mucous membranes (olive oil)

Abnormal liver tests

Regular monitoring of liver function tests, especially at the beginning of therapy

Cardiac disturbances

ECG monitoring (including QTC assessment), periodically echo, adequate management of comorbidities

Hypocalcemia

Continuous monitoring of calcium levels, supplementation (especially for patients treated with sorafenib and cabozantinib

Pancreatitis

Monitoring of serum amylase and lipase levels

A general principle

In case of severe side effects, temporary discontinuation of the drug and dose reduction (whenever grade G3 or G4 symptoms have occurred)

Table 28. Tests required before initiating tyrosine kinase inhibitor therapy and during the treatment. Based on 2015 American Thyroid Association (ATA) 2015 guidelines [1]
  1. 1. Laboratory tests: hematology, bilirubin, transaminases, alkaline phosphatase, creatinine, LDH, amylase, lipase, electrolytes, calcium, magnesium, urinalysis, 24-hour urine protein, TSH, thyroglobulin, thyroglobulin antibodies, pregnancy test (for women of childbearing age)
  2. 2. ECG
  3. 3. Blood pressure measurement
  4. 4. Echocardiography
  5. 5. Imaging studies (CT, MRI, bone scanoptional)
  6. 6. Necessary oral sanitation before starting therapy

1.4. Sorafenib [301] or lenvatinib [302] can be used as first-line treatment. Sorafenib is currently reimbursed in Poland under the drug program, lenvatinib is not reimbursed [also under the Rescue Access to Drug Technology (RDTL)]. The dosage of both drugs is shown in Table 29.

SoR: 1 QoE: II

SoR: 1 QoE: +++

Table 29. Dosing of molecularly targeted drugs for the treatment of differentiated (DTC), poorly differentiated thyroid cancer (PDCT), and anaplastic thyroid cancer (ATC) [206, 207, 301, 303, 304, 362]

Drug name

Drug form

Dosage

Notes

Sorafenib (Nexavar)

Tablets 200 mg

2 × 400 mg p.o.

Lenvatinib (Lenvima)

Tablets 10 mg

Tablets 4 mg

1 × 24 mg p.o.

Cabozantinib (Cabometyx);

Tablets 60 mg

Tablets 40 mg

Tablets 20 mg

1 × 60 mg p.o.

Selpercatinib (Retsevmo)

Capsules 80 mg

Capsules 40 mg

BWT ≥ 50 kg 2 × 160 mg p.o.

BWT < 50 kg 2 × 120 mg p.o.

Pralsetinib (Gavreto)

Capsules 100 mg

1 × 400 mg p.o.

No registration in the European Union for thyroid cancer

Larotrectinib

(Vitrakvi)

Capsules 100 mg

Capsules 25 mg

2 × 100 mg p.o.

Dabrafenib

(Tafinlar)

Capsules 75 mg

Capsules 50 mg

2 × 150 mg p.o.

Combined treatment

Trametinib (Mekinist)

Tablets 2 mg

Tablets 0.5 mg

1 × 2 mg

1.5. Lenvatinib [302] or cabozantinib [303] may be used for second-line treatment. Both drugs are not reimbursed in Poland. Cabozantinib in this indication has only been registered in the United States.

SoR: 1 QoE: II

SoR: 1 QoE: +++

1.6. Selective inhibitors targeting RET fusions (Selpercatinib, Pralsetinib) or NTRK (Larotrectinib) may be used in patients who have demonstrated appropriate molecular targets in cancer cells [206, 207, 304, 305].

SoR: 1 QoE: V

SoR: 1 QoE: ++

1.7. Adverse effects of TKI therapy should be classified and monitored according to CTCAE (Common Terminology Criteria for Adverse Events; https://evs.nci.nih.gov/ftp1/CTCAE/About.html):

SoR: 1 QoE: II

SoR: 1 QoE: +++

1.7.1. If grade G3 or G4 toxicity occurs, the drug should be discontinued immediately. Therapy can be resumed at a reduced dose of the drug only when the toxicity resolves or decreases to grade G1 (for lenvatinib) [302] or G2 (for sorafenib) [301]. In justified cases, the drug should be discontinued.

SoR: 1 QoE: II

SoR: 1 QoE: +++

1.8. TKI therapy should be continued as long as the patient benefits from the treatment or until unacceptable toxicity.

SoR: 2A QoE: IV

SoR: 1 QoE: +

1.9. In the absence of other therapeutic options, TKI may be continued even in the case of radiological progression if the therapy has clinical benefit, is well tolerated, and the patient agrees to this treatment [104].

SoR: 2A QoE: IV

SoR: 1 QoE: +

1.10. Molecularly targeted therapies should be conducted in centers with experience in TKI treatment and monitoring adverse effects.

SoR: 2B QoE: V

SoR: 2 QoE: +

2. Poorly differentiated thyroid carcinoma [275]:

2.1. Sorafenib [301] or lenvatinib [302] can be used as first-line treatment. Neither of these drugs is reimbursed by the National Health Fund. Sorafenib is available under the RDTL. Lenvatinib is currently not reimbursed under the RDTL.

SoR: 1 QoE: II

SoR: 1 QoE: +++

2.2. Lenvatinib [302] or cabozantinib [303] may be used for second-line treatment. Both drugs are not reimbursed in Poland. Cabozantinib in this indication has only been registered in the United States.

SoR: 1 QoE: II

SoR: 1 QoE: +++

2.3. Selective inhibitors targeting RET fusions (Selpercatinib, Pralsetinib) or NTRK (Larotrectinib) may be used in patients who have demonstrated appropriate molecular targets in cancer cells [206, 207, 304, 305].

SoR: 1 QoE: V

SoR: 1 QoE: ++

2.4. Other recommendations for DTC (sections 1.1, 1.2, 1.3, 1.7, 1.8, 1.9, 1.10) apply to PDTC.

SoR: 2A QoE: IV

SoR: 1 QoE: +

Part XIV

Management of medullary thyroid carcinoma

1. MTC management substantially differs from that of DTC for the following reasons:

1.1. A high percentage of hereditary disease and the possibility of DNA diagnostics, including detection of genetic predisposition in family members resulting in the need for prophylactic surgery [306].

SoR: 1 QoE: III

SoR: 1 QoE: +++

1.2. The high specificity and sensitivity of the calcitonin evaluation, which allows using this test in MTC diagnosing, determining the extent of surgical treatment required, the early detection of MTC recurrence/progression, and the prognosis of MTC course [5].

SoR: 1 QoE: III

SoR: 1 QoE: +++

1.3. Broader use of elective lymphadenectomy than in DTC, an indication for it depends on serum calcitonin concentration [307, 308].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.4. High risk of pheochromocytoma in patients with hereditary MTC [309–313].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2. MTC diagnosis:

2.1. The MTC diagnosis on FNAB is difficult because it requires immunocytochemistry with anti-calcitonin antibodies or confirmation of elevated serum calcitonin level.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.2. The MTC diagnosis may be based on serum calcitonin testing and is highly probable if calcitonin level exceeds 100 ng/L [75, 314].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.3. Calcitonin stimulation test allows differentiation in doubtful cases and improves the efficiency of preoperative MTC diagnosis and its follow-up [75, 76, 315].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

2.4. The measurement of calcitonin concentration in the FNAB needle washout is helpful in MTC diagnosis.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3. DNA testing in MTC:

3.1. DNA testing should be performed in every MTC patient, even in the absence of history and physical examination data suggesting hereditary disease [316, 317].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.2. Scope of testing and risk of carrier detection:

3.2.1. The test involves analysis of RET protooncogene mutations in the patient’s germline DNA (peripheral blood is the test material) and should be performed in an accredited center [306, 317, 318]. In centers with NGS testing, this method is optimal for detecting RET mutations.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.2.2. A negative full DNA test excludes the hereditary form with approximately 95% probability.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.2.3. A positive DNA test result warrants screening of family members [306].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

3.2.4. Both the detection of an asymptomatic mutation carrier and a negative result in a family member should be confirmed in a further blood sample taken independently.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

3.2.5. Patients with a negative history of an inherited form have an approximately 10% probability of testing positive for a genetic predisposition [316].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

4. Management in families with the RET gene mutation carriers:

4.1. Hereditary MTC occurs as a symptom of multiple endocrine neoplasia type 2 (MEN 2) [319]. This name should be regarded as the official one in Polish. The formerly used names are not applicable nowadays. In typical MEN 2A and MEN 2B, MTC coexists with a pheochromocytoma. The risk of pheochromocytoma is up to 50% [5, 309, 320–322].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

4.2. In a family of a patient with hereditary MTC, the risk of MTC in a first-degree relative is 50% [306].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

4.3. In families with MEN2A/FMTC, testing for RET mutation carrying should be done in relatives and especially in children starting at the age of 23 years, necessarily before the age of 5 [5, 317].

SoR: 2A QoE: IV

SoR: 2 QoE: ++

4.4. DNA testing in MEN2B families should be performed as soon as possible, optimally within the first year of life [5].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

4.5. Depending on the location of the RET mutation and the associated risk of an aggressive MTC, ATA guidelines [5] recommend classifying the patient into one of the following risk groups: HST (highest risk), H (high risk, high), or MOD (moderate risk) (see Tab. 30).

SoR: 2A QoE: IV

SoR: 1 QoE: +++

Table 30. Diagnostic and therapeutic management depending on the localization of germline mutation in the RET protooncogene. Based on [5, 325]

ATA-HST
(RET 918)

ATA-H
(RET 634, 883)

ATA-MOD

DNA test

Immediately after birth

23 years of age

Up to 5 years of age

Or: immediately after a mutation is detected in a family member

Basal serum calcitonin

In all family members, in parallel with DNA testing, every 612 months in unoperated RET mutation carriers

Calcitonin stimulation test

First time after detection of the RET mutation, then every 612 months

Thyroid ultrasound

First time after detection of the RET mutation, then every 612 months

Prophylactic thyroidectomy

In the 1st year of life

Before or at 5 years of age

The decision to operate depends on calcitonin levels either surgery in childhood

Screening for pheochromocytoma*

From the age of 11, on average 1 × per year

From the age of 11, on average 1 × per year

From the age of 16, on average 1 × per year

Adrenal imaging studies

Only in case of abnormal biochemical test results

Serum calcium assessment

From the age of 11, on average 1 × per year

From the age of 16, on average 1 × per year

5. Diagnostic management in RET mutation carriers [5] complete diagnostics to evaluate the current stage of disease in RET mutation carriers should involve:

basal and stimulated serum calcitonin concentration;

neck ultrasound;

FNAB if focal thyroid lesions are present;

abdomen ultrasound;

biochemistry to exclude pheochromocytoma;

serum calcium assessment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

6. Prophylactic thyroidectomy in RET mutation carriers:

6.1. Prophylactic total thyroidectomy should be considered in asymptomatic RET mutation carriers [5, 323, 324]. It has been assumed that prophylactic surgery is better protection against MTC development than continuous serum calcitonin monitoring.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

7. Prophylactic total thyroidectomy is recommended [5]:

7.1. Within the first year of life of immediately after RET mutation detection in MEN 2B syndrome (In this syndrome, DNA testing is necessary within the first year of life; ATA HST group).

7.2. At or before 5 years of age in MEN 2A syndrome (ATA H group) (Tab. 30).

SoR: 2A QoE: IV

SoR: 2 QoE: ++

8. In patients with RET mutations causing later MTC development (ATA MOD group), it is acceptable to postpone prophylactic surgery beyond the age of 5 years if the patient/parents have been fully informed of and accept the risks of such postponement, baseline calcitonin levels are normal, there are no focal changes on thyroid ultrasound, and the family history indicates a relatively benign disease course [5].

SoR: 2B QoE: V

SoR: 2 QoE: +

NOTE! Because there is no clear evidence of a familiar MTC occurrence in carriers of the RET codon 791 mutation, indications for prophylactic thyroidectomy in this group should be very cautious [325–328].

SoR: 2B QoE: V

SoR: 2 QoE: +

9. In RET mutation carriers who have not yet undergone prophylactic thyroidectomy, annual stimulated calcitonin testing (in Poland, a test with intravenous calcium is used) provides earlier information about MTC development than baseline calcitonin testing [329].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

9.1. A normal increase in serum calcitonin concentration after intravenous calcium administration should not exceed 30 ng/L.

SoR: 2B QoE: V

SoR: 2 QoE: +

9.2. An increase in calcitonin levels to > 100 ng/L after calcium stimulation is interpreted as a positive result. However, this result does not uniquely confirm MTC diagnosis (because it may result from C-cell hyperplasia). Nevertheless, in RET mutation carriers, it is a clear indication for thyroid surgery [75–77].

SoR: 2B QoE: V

SoR: 2 QoE: +

9.3. Intravenous calcium administration may be an alternative to the pentagastrin test [77, 330].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

10. Diagnosis and treatment of pheochromocytoma in MEN 2 syndrome:

10.1. The indications for testing for pheochromocytoma depend on the type of the RET mutation [5, 309, 312].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

10.2. Detection of pheochromocytomas is based on biochemical testing indicated annually from age 11 in MEN2B and MEN2A RET 634 and RET 630 and from age 16 in carriers of the other types of RET mutations [5, 312] (Tab. 30).

SoR: 2A QoE: IV

SoR: 1 QoE: ++

10.3. Screening abdominal CT is not necessary for MTC patients unless there are no signs of pheochromocytoma and biochemical tests are negative. However, in a patient referred for surgery for MTC, it should be considered [312].

SoR: 2B QoE: V

SoR: 2 QoE: +

10.4. Treatment of pheochromocytoma is based on surgery, optimally cortical-sparing adrenalectomy [331–333].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

10.5. If pheochromocytoma and MTC coexist, adrenal surgery should be performed first to avoid exacerbation of pheochromocytoma symptoms.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

11. Surgical treatment of pheochromocytoma [334]:

Pheochromocytoma surgery should be preceded by at least two-week pharmacological pretreatment [331].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

11.1. For pheochromocytoma resection, cortical-sparing adrenalectomy should be undertaken, especially if a second adrenal gland is operated on, in a patient with prior unilateral adrenalectomy [331–333].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

11.2. If bilateral adrenalectomy is required, the patient should be carefully instructed in substitution therapy. One should remember that in hereditary MTC presenting as MEN 2 syndrome, a significant proportion of deaths are associated with adrenal complications hypertensive crisis or adrenal insufficiency.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

12. Diagnosis and treatment of hyperparathyroidism in MEN 2A syndrome:

12.1. Indications for testing for hyperparathyroidism depend on the type of RET mutation [335, 336]:

SoR: 2A QoE: IV

SoR: 1 QoE: ++

12.1.1. In MEN2A, annual serum calcium testing is primarily warranted in carriers of RET 634 and RET 630 mutations and may be performed less frequently in carriers of other RET mutations.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

12.1.2. The treatment of hyperparathyroidism in the course of MEN2A syndrome should follow generally accepted rules. One should remember that hyperparathyroidism is often caused by parathyroid hyperplasia; therefore, the risk of unsuccessful surgery is higher than in the case of a single adenoma [337].

SoR: 2B QoE: V

SoR: 2 QoE: +

13. Surgery in clinically apparent MTC:

13.1. If MTC is clinically overt (thyroid nodule with a positive FNAB result), thyroid surgery should always be a total thyroidectomy accompanied by central neck lymphadenectomy in both hereditary and sporadic MTC.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

13.2. The decision on lateral neck dissection depends on the diagnosis of lymph node metastases and serum calcitonin level [138].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

13.3. There is no clear indication for lateral neck dissection if there are no enlarged lateral neck lymph nodes, and at the same time, a preoperative calcitonin level is < 200 ng/L [138].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

13.4. If serum calcitonin concentration is > 400 ng/L, the results of abdominal CT should be known to the surgeon planning the extent of local surgery [307].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

13.5. One should add that the ATA guidelines specify serum calcitonin concentration of 150 ng/L as the lower limit for these indications.

SoR: 2B QoE: IV

SoR: 2 QoE: ++

14. Surgery in early detected MTC:

14.1. If the reason for surgery is an increased calcitonin level in a patient with nodular goiter, total thyroidectomy is recommended.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

15. If a small, < 10 mm MTC lesion has been incidentally detected after less than total thyroidectomy, postoperative basal and stimulated calcitonin levels are normal, and DNA testing for the RET mutation is negative, resignation from completion thyroidectomy may be considered if no other risk factors are present.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

16. Prophylactic surgical treatment in RET mutation carriers:

16.1. The indications for prophylactic thyroid resection described in section 7 should take into account the combined interpretation of DNA testing (type of RET mutation), current calcitonin levels, and the patient’s current age and family history. Therefore, surgical treatment, which in general in thyroid cancer should be performed in specialized centers, in this particular indication should be carried out in centers with extensive experience in this field.

SoR: 2B QoE: V

SoR: 2 QoE: +

16.2. Timely prophylactic total thyroid resection (see section 7) may be performed without central neck dissection if baseline calcitonin levels are normal and there is no evidence of lymph node involvement.

SoR: 2B QoE: V

SoR: 2 QoE: ++

16.3. If at the age of 5 years, a carrier of a mutation predisposing to MEN2A does not show an increase in basal Ct, a calcium stimulation test is useful to determine whether surgery can be postponed. However, the type of the RET mutation should also be considered.

SoR: 2B QoE: V

SoR: 2 QoE: +

16.4. If prophylactic surgery has not been performed at the optimal age, as defined in sections 47, and basal calcitonin level is normal, repeating a calcium stimulation test once a year reduces the risk of missing the optimal time for surgery.

SoR: 2B QoE: V

SoR: 2 QoE: +

17. Postoperative evaluation and follow-up in MTC patients:

17.1. Postoperative serum calcitonin assessment:

17.1.1. Normalization of postoperative calcitonin level or undetectable calcitonin level is the best indicator of the completeness of the surgery and favorable prognostic factor [315].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

17.1.2. Although the authors of these recommendations are aware that some American specialists consider calcium stimulation test unnecessary, the experience of many European centers supports its use in patients with normal basal calcitonin concentration. A negative result (some authors believe that optimally no increase in calcitonin should be observed) is a reliable prognostic factor.

SoR: 2B QoE: V

SoR: 2 QoE: +

17.1.3. Note that in some calcitonin assays, if calcitonin concentration is above 300500 ng/l, serum dilution is required to obtain a reliable result.

SoR: 2B QoE: V

SoR: 2 QoE: +

17.1.4. Estimation of serum calcitonin doubling time is recommended due to its prognostic and predictive value [338, 339].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

17.2. Further MTC follow-up involves:

serum calcitonin evaluation;

neck ultrasound;

serum carcinoembryonic antigen (CEA) evaluation;

imaging studies, only if serum calcitonin level exceeds 150 ng/L or rather > 400 ng/L [340].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

18. Management in asymptomatic increase in serum calcitonin level:

18.1. At calcitonin concentration < 150 ng/L, CT, MRI, or PET/ CT scans are not justified as they cannot detect cancer foci.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

18.2. If calcitonin levels rise > 4001000 ng/L, the chance of localizing a cancer focus increases [340–342].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

18.3. Even at calcitonin levels of 1501000 ng/L, there is a risk of false-negative results when attempting to locate a cancer focus.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

18.4. Central neck dissection (if not previously performed) and/or elective lateral neck dissection may be considered at an asymptomatic increase of calcitonin level.

SoR: 2B QoE: IV

SoR: 2 QoE: ++

18.5. However, one should be aware that the most common cause of an increase in serum calcitonin levels are liver micrometastases.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

19. Management in recurrent MTC:

19.1. Surgery is the basic treatment of local and locoregional recurrence.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

19.2. If distant metastases accompany local/locoregional recurrence, the indications for neck/mediastinal surgery are equivocal.

SoR: 2A QoE: V

SoR: 2 QoE: +

19.3. MTC spread rarely involves a single metastatic lesion; therefore, surgical treatment of metastatic disease, particularly of liver metastases, is generally not justified.

SoR: 2B QoE: V

SoR: 2 QoE: +

19.4. Adjuvant radiotherapy is indicated only in the case of non-radical surgery at the micro- or macroscopic level. Palliative radiotherapy is often used in bone and brain metastases, less often for other locations [280, 292]. This issue is discussed in Section XIII.

SoR: 2B QoE: IV

SoR: 2 QoE: +

19.5. Classical chemotherapy is not applicable in MTC as the first-line systemic treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

19.6. Chemotherapy may be considered a second-line treatment for patients with disease progression during TKI therapy [57].

SoR: 2B QoE: V

SoR: 2 QoE: +

19.7. Radioisotope therapy with different radiopharmaceuticals selectively taken up by cancer cells is usually a palliative treatment [342–344].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

19.8. The antiproliferative effect of somatostatin analogs in MTC has not been demonstrated [345, 346].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

19.9. Treatment with the molecularly targeted drugs (tyrosine kinase inhibitors) is recommended for MTC patients with an advanced, unresectable disease that meets RECIST criteria for progression [5, 57]:

SoR: 1 QoE: II

SoR: 1 QoE: +++

19.9.1. Vandetanib or cabozantinib may be used for first-line treatment. Both drugs are registered in Poland. Currently (March 2022), in Poland, only vandetanib is reimbursed under the drug program. Cabozantinib is not reimbursed by the National Health Fund (NFZ) but can be applied for under the Rescue Access to Drug Technology (RDTL) [5, 347–351].

SoR: 1 QoE: II

SoR: 1 QoE: +++

19.9.2. Vandetanib 300 mg once a day [347]. In patients with clinically significant comorbidities, starting therapy at a lower dose of 150 mg/d may be considered [349].

SoR: 1 QoE: II

SoR: 1 QoE: +++

19.9.3. Cabozantinib 140 mg once a day [350].

SoR: 1 QoE: II

SoR: 1 QoE: +++

19.9.4. Selective RET inhibitors (Selpercatinib, Pralsetinib) can be used in patients who have demonstrated appropriate molecular targets in cancer cells [206, 207]. These drugs are currently available in Poland only in clinical trials.

SoR: 1 QoE: V

SoR: 1 QoE: +++

19.9.5. Other recommendations for DTC (see Part XIII, sections 1.1, 1.2, 1.3, 1.7, 1.8, 1.9, 1.10) apply to MTC.

20. Molecular diagnostics to evaluate the presence of somatic mutations in MTC cells:

20.1. Assessment of somatic mutations is not currently a part of routine diagnostic management in all MTC patients. However, it may be considered in patients with advanced disease in whom systemic therapy directed at molecular targets is planned.

SoR: 1 QoE: I

SoR: 1 QoE+++:

20.2. Somatic RET mutations occur in approximately 50% of MTC patients in the Polish population, while RAS mutations in approximately 27% [352].

SoR: 2A QoE: IV

SoR: 1 QoE: +++

20.3. The presence of the RET M918T mutation in tumor cells is a negative prognostic factor associated with an aggressive disease course [353–355].

SoR: 1 QoE: III

SoR: 1 QoE: +++

20.4. In patients treated with cabozantinib, the presence of the RET M918T mutation in tumor cells is a predictor associated with improved response to therapy and prolonged overall survival [350, 351, 356].

SoR: 1 QoE: II

SoR: 1 QoE: +++

20.5. The presence of the RET V804 mutation is associated with primary resistance to vandetanib [357].

SoR: 2A QoE: IV

SoR: 1 QoE:+++

Part XV

Management of anaplastic thyroid carcinoma and thyroid lymphoma

1. Anaplastic thyroid carcinoma (undifferentiated thyroid carcinoma):

1.1. This is one of the most aggressive solid tumors with a poor prognosis. A patient with suspected anaplastic carcinoma should be promptly transferred to a center with combined treatment options including surgery, radiation therapy, possible chemotherapy, and molecularly targeted therapy.

SoR: 2A QoE: III

SoR: 1 QoE: +++

1.2. Differential diagnosis includes poorly differentiated thyroid carcinoma, laryngeal squamous cell carcinoma, sarcoma, and lymphoma immunohistochemical staining is needed.

SoR: 2A QoE: II

SoR: 1 QoE: +++

1.3. Whenever possible, the molecular profile of the anaplastic carcinoma should be analyzed to make possible molecularly targeted therapy (BRAF, RAS, TP53 mutations, RET, NTRK, and ALK rearrangements). However, one should notice that the decision regarding the treatment regimen in anaplastic cancer must be made quickly.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.4. As soon as the diagnosis is confirmed, it is necessary to evaluate the disease stage using available imaging methods, including FDG-PET/CT, the most sensitive imaging modality. Staging should not delay the initiation of treatment.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.5. Total thyroidectomy with bilateral lymph node dissection may be considered in patients without distant metastases, but radical tumor resection is rarely possible. Extensive surgical treatment including laryngectomy, esophagectomy, and major vessel resection or cytoreductive (decompressive) surgery is not recommended because it does not improve overall survival while significantly reducing the quality of life.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.6. In patients staged IVa and IVb, after radical surgery and in good general condition, the use of radiotherapy may improve overall survival.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.7. Concomitant use of radio- and chemotherapy, particularly with radiation-sensitive drugs, may improve cause-dependent survival, but, because of the significant deterioration in quality of life, this treatment should be considered in selected cases.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.8. In patients with inoperable ATC, external beam radiotherapy and chemotherapy are used as palliative treatments. Most of the data on chemotherapy are from retrospective studies or small single-center prospective studies. The therapeutic effects have been unsatisfactory, with low response rates reported with significant toxicity. Recommended regimens include monotherapy with taxanes, platinum derivatives, doxorubicin, or combination therapy (e.g., carboplatin/paclitaxel, docetaxel/doxorubicin) given weekly or every 34 weeks. Chemotherapy may be considered for local control of unresectable stage IVB disease (preferably weekly administration of radiosensitizing chemotherapy). Doxorubicin has been used in the past because of its radiosensitizing effects, but more recently, taxanes, or platinum derivatives, have been used and appear to be more effective. Radiotherapy can be given either with chemotherapy in monotherapy or in combination [56, 197, 358–361]. Chemotherapy regimens are shown in Table 31.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

Table 31. Chemotherapy regiments in anaplastic thyroid cancer (ATC). Based on 2021 the National Comprehensive Cancer Network (NCCN) guidelines [57]

Paclitaxel/carboplatin

Paclitaxel 50 mg/m2 (100 mg/m2 if M1), carboplatin AUC 2 i.v.

or

Paclitaxel 135175 mg/m2, carboplatin AUC 56 i.v.

Every week

Every 34 weeks

Docetaxel/doxorubicin

Docetaxel 60 mg/m2 i.v., doxorubicin 60 mg/m2 i.v. (+ pegfilgrastim)

or

Docetaxel 20 mg/m2 i.v., doxorubicin 20 mg/m2 i.v.

Every 34 weeks

Every week

Paclitaxel

3060 mg (90 mg, if M1)/m2 i.v.

or

135200 mg/m2 i.v. (if M1)

Every week

Every 34 weeks

Cisplatin

3040 mg/m2 i.v.

Every week

Doxorubicin

6075 mg/m2 i.v.

or

20 mg/m2 i.v.

Every 3 weeks

Every week

1.9. Selective inhibitors targeting the BRAF mutation (Dabrafenib and Trametinib), RET fusion (Selpercatinib, Pralsetinib), or NTRK (Larotrectinib) may be used in patients who have demonstrated appropriate molecular targets in cancer cells [206, 207, 304, 305, 362] (Tab. 32).

SoR: 2A QoE: V

SoR: 1 QoE: +++

Table 32. Molecularly targeted therapy regimens in anaplastic thyroid cancer (ATC) based on 2021 the National Comprehensive Cancer Network (NCCN) guidelines [57]

Drug name

Molecular target

Dosage

Dabrafenib/trametinib

BRAFV600E

Dabrafenib 150 mg p.o.

+

Trametinib 2 mg p.o.

BID

OD

Larotrectinib

NTRK fusion

100 mg p.o.

BID

Entrectinib

NTRK fusion

600 mg p.o.

OD

Pralsetinib

RET fusion

400 mg p.o.

OD

Selpercatinib

RET fusion

120 mg p.o. (< 50 kg)

or

160 mg p.o. (≥ 50kg)

BID

Pembrolizumab

TMB-H

200 mg i.v.

or

400 mg i.v.

Every 3 weeks

Every 6 week

2. Diagnosis and treatment of thyroid lymphoma:

2.1. The diagnosis of primary MALT lymphoma requires tests that exclude secondary thyroid involvement in the course of generalized lymphoma, such as ultrasound, CT or MRI [363].

SoR: 2A QoE: IV

SoR: 1 QoE: ++

2.2. In primary thyroid lymphoma, the indication for surgery is not clearly established and surgery does not improve the distant prognosis.

SoR: 2A QoE: IV

SoR: 1 QoE: ++

2.3. Radio and chemotherapy are often the mainstays of treatment, and postoperative indications depend on the stage and grade of malignancy.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

Part XVI

Quality of life in thyroid carcinoma

1. The assessment of the quality of life (QoL) in patients with thyroid disease or specifically thyroid cancer is performed using dedicated and linguistically validated questionnaires [364–371]:

SoR: 2A QoE: IV

SoR: 1 QoE: ++

1.1. Assessing QoL using dedicated and linguistically validated questionnaires is costless.

SoR: 2A QoE: IV

SoR: 1 QoE: +++

1.2. Currently, only the questionnaire assessing QoL in patients with benign thyroid diseases (ThyPROpl) is available in Polish. It is a validated language version of the original ThyPRO questionnaire. Although ThyPROpl is dedicated to the assessment of QoL in benign thyroid diseases, its use in the evaluation of QoL in patients with thyroid cancer may be a helpful tool.

SoR: 2B QoE:V

SoR: 2 QoE: +

1.3. Following completion of the linguistic validation process of the questionnaire assessing QoL in patients with thyroid cancer (EORTC QLQ-THY34), currently being conducted by the European Organisation for Research and Treatment of Cancer (EORTC), it is recommended to consider the use of this tool in patients with thyroid cancer.

SoR: 2B QoE:V

SoR: 2 QoE: ++

1.4. The use of other questionnaires assessing QoL (with a validated Polish version available), developed for example, for patients with cancer (Quality of Life of Cancer Patients; EORTC QLQ-C30) or with head and neck cancer (Head & Neck Cancer; EORTC QLQ-HN43) may also be considered.

SoR: 2B QoE:V

SoR: 2 QoE: ++

1.5. The use of a questionnaire assessing QoL should be individualized according to the potential benefits of such a survey (initial assessment before treatment and monitoring during and after treatment, frequency of measurement). The decision to implement this tool should take into account that the likelihood of reduced QoL in patients with thyroid cancer is particularly increased in the following situations:

1.5.1. Total thyroidectomy associated with increased risk of postoperative hypoparathyroidism and recurrent laryngeal nerve injury.

1.5.2. The use of RAI, associated with long-term complications such as nasolacrimal duct stenosis, decreased bone marrow function, gonadal insufficiency, and dry mouth.

1.5.3. Periodic endogenous TSH stimulation, associated with symptoms of hypothyroidism.

1.5.4. Use of L-thyroxine at doses that cause TSH suppression, associated with symptoms of thyrotoxicosis (chronic adverse effects mainly on the cardiovascular system and bones).

1.5.5. The use of tyrosine kinase inhibitors, associated with a variety of side effects (e.g., hypertension, gastrointestinal symptoms, skin lesions).

SoR: 1 QoE: II

SoR: 1 QoE: +++

1.6. Rehabilitation, psychological care, and psychotherapy an essential part of thyroid cancer management is adequate emotional and social support for patients during and after the completion of their oncological therapy, including full psychosocial recovery. Centers in which thyroid cancer is treated should offer specialized psycho-oncological and psychiatric care whenever necessary. Development of psychotherapy programs aimed at rehabilitation and complete return to the social roles held by patients prior to their treatment is recommended.

SoR: 2A QoE: V

SoR: 1 QoE: +

Conflict of interest

BJ: employment MSCNRIO Gliwice, consulting EwoPharma, Sobi Advisory Board member, honoraria AstraZeneca, AMGEN, Bayer Health Care, Eisai, Exelixis, Ipsen, Sanofi-Genzyme, Novartis, Oxigene, Pfizer, Elli Lilly, research funding AstraZeneca, Bayer Health Care, Eisai, Exelixis, Ipsen, Sanofi-Genzyme, Novartis, Pfizer, Elli Lilly, clinical trials AstraZeneca, Bayer Health Care, Eisai, Exelixis, Ipsen, Sanofi-Genzyme, Novartis, Pfizer, Elli Lilly, participation in guideline development Thyroid diseases in pregnancy: guidelines of the Polish Society of Endocrinology (2021), 2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer, European Perspective on 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: Proceedings of an Interactive International Symposium (2019), intellectual property publications, congress abstracts, lectures, patent application EPO 21460001.7-1111; MD: employment (NIO-PIB), ownership interests (private practice), clinical research (Exelixis Cosmic, ZETA); AL: employment Medical University of Lodz, Polish Mother’s Memorial Hospital Research Institute; ZA: employment CSK Łódź, ICZMP Łódź, ownership interests ADA-MED sp. z o.o.; EBZ: employment Maria Sklodowska-Curie National Research Institute of Oncology (MSCNRIO), Warsaw, Poland, Masovian specialist hospital in Ostrołęka, CMP Medical Center in Warsaw, Diagnostyka-Consillo in Warsaw; MB: ownership interests KOBAMED S.C., participation in guideline development International Neuromonitoring Study Group, Member of Steering Committe; MBF: intellectual property (publications, abstracts); AB: employment POLTREG in Gdańsk due to T reg therapy in DT1, other relationships lectures funded by IBSA, NovoNordisk, Sandoz, Pfizer, Ipsen; EC: employment specialist medical practice; EC: ownership interests specialist medical practice Ewa Chmielik; AC: employment Maria Sklodowska-Curie National Research Institute of Oncology Gliwice Branch, Gliwice, Poland individual employment agreement, participation in guideline development European Thyroid Association and Cardiovascular and Interventional Radiological Society of Europe 2021 Clinical Practice Guideline for the Use of Minimally Invasive Treatments in Malignant Thyroid Lesions; RC: employment Clinical Hospital, Affidea Polska, ownership interests specialist medical practice; JD: employment Academic Center of Pathomorphological and Genetic-Molecular Diagnostics; AG: employment GCZD, Clinical Hospital no 6, Katowice, leadership Head of the Department of Pediatrics and Pediatric Endocrinology, GCZD, Clinical Hospital no 6, Katowice, research funding ESPE Large Grant, statutory works SUM; JG: employment owner of specialist medical practice; DHJ: travel grants (Sanofi); MJ: employment MSCNRIO Gliwice, individual medical practice; honoraria Roche, MSD, Pfizer, Novartis, Eli Lilly, Exact Sciences, Gilead; Guidelines: Recommendations on diagnostic and therapeutic management in malignant neoplasms Endocrine neoplasms; Systemic treatment of patients with solid tumors during SARS-CoV-2 pandemic comprehensive recommendations of the Polish Society of Medical Oncology; patent application EPO 21460001.7-1111; JJC: employment NIO-PIB; honoraria Exelixis; KK: employment Central Clinical Hospital of the Medical University of Lodz surgeon, Krzysztof Kaczka Medical Centre Kamedi surgeon, Alfa-Medical Silesia North Hospital in Częstochowa surgeon; consulting advisory role in the project: Development of the platform for growing of 3D tumor lines of solid tumors together with Mabion SA in Konstantynów Łódzki, ownership interests Krzysztof Kaczka Medical Centre Kamedi surgeon, Bioton, SA in Warszawa flowchart shares; honoraria travel grant Asensus Surgical, NC Durham North Carolina; research funding advisory role in the project: Development of the platform for growing of 3D tumor lines of solid tumors; clinical research Role of microRNAs in the diagnosis of the thyroid cancer, Grant-Medical University of Lodz; GK: employment Military Institute of Medicine; MKL: employment Medical University of Lodz, Polish Mother’s Memorial Hospital Research Institute; AK: employment NZOZ Onkolmed; medical consuting, clinical research, consulting and lectures for BMS, Merck, MSD, Sanofi Aventis; consulting advisory boards of MSD, BMS, Merck; honoraria MSD, Merck, BMS, GSK, Sanofi; research funding MSD, Merck, BMS, GSK, Sanofi; MK: employment AkaiMed Endocrinology Clinic Gliwice, Endocrinology Clinic Gliwice Sikornik; honoraria Sympomed, Novartis; AK: employment KOBAMED S.C.; AKB: employment MSCNRIO Gliwice; patent application EPO 21460001.7-1111; AKo: employment Holycross Cancer Centre in Kielce; JK: employment NIO-PIB, individual medical practice, consulting Bayer Health Care, Ewo-Pharma, Exelixis, Loxo; honoraria Bayer Health Care, Sanofi, Ipsen; Clinical trials phase II and III in Thyroid Cancer: Eisai, Exelixis, Lilly, Sanofi-Genzyme; guidelines Choroby tarczycy w ciąży: zalecenia postępowania Polskiego Towarzystwa Endokrynologicznego 2021; patent application EPO 21460001.7-1111; AKr: employment West Pomeranian Cancer Center, Szczecin, Poland; consulting Head of Department of Pathology; LK: clinical research SAFER; MKu: employment Hospital, Medical University; KK: employment Head of Department, leadership Head of Department, ownership interests outpatient clinic; DL: employment histopathology laboratory; leadership lab manager; ownership interests; ALe: employment National Research Institute, Gliwice Branch; clinical research subinvestigator; PM: employment Clinical Hospitals PUM; participation in guideline development PAPs creation of guidelines for specialisation; BM: employment Mazowiecki Szpital Bródnowski in Warsaw; MN: consulting one-off training for NovoNordisk employees on diagnosis and treatment of short stature, including growth hormone deficiency (XI 2020, remote webinar); MOW: employment Maria Sklodowska-Curie National Research Institute of Oncology, patent application EPO 21460001.7-1111; MR: employment Medical University, Clinical Hospital; leadership Head of Department of Endocrinology; ownership interests specialist medical practice; KS: honoraria subinvestigator XL184-401, XL184-311, J2G-MC-JZJG, D4200C00097, D4200C0058; ASS: employment Department of Internal Medicine and Endocrinology, WUM; ASW: employment National Research Institute of Oncology Gliwice; ES: employment specialist medical practice; patent application EPO 21460001.7-1111; ESP: employment Medical University, Clinical Hospital, ownership interests specialist medical practice; MTM: employment University Hospital in Krakow, specialist medical practice, Luxmed; ownership interests Synthesis Therapy Centre; participation in the development of guidelines PTE Guidelines Management of thyroid diseases in pregnancy, 2021; co-author; AT: employment NIO-PIB Warszawa, KZ: employment Maria Sklodowska-Curie National Research Institute of Oncology; AŻ: employment NIO-PIB Warszawa; clinical research Exelixis

The following authors did not declare any conflict of interests: ABW, BBB, MBB, JĆ, KDS, JH, AHD, AKĆ, AKG, BKK, MK, AKu, EMT, DP, LP, ZS, MSS, AS, EZN, AW

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