National guidelines for diagnosis and treatment of thyroid cancer 2022 in China (English version)

National Health Commission of the People’s Republic of China

Contents

1.Overview

2.Diagnosis and management

2.1 Screening for high-risk group

2.2 Clinical manifestations

2.2.1 Symptoms

2.2.2 Signs

2.2.3 Invasion and metastasis

2.3 Laboratory examination

2.3.1 Routine examination

2.3.2 Special examination

2.4 Imaging

2.4.1 Ultrasonography

2.4.2 Computed tomography (CT)

2.4.3 Magnetic resonance imaging (MRI)

2.4.4 Positron emission tomography (PET)-CT

2.5 Vocal cord function assessment

2.6 Histology

2.6.1 Cytology

2.6.2 Pathology

2.7 Differential diagnosis

2.7.1 Thyroid adenoma

2.7.2 Nodular goiter

2.7.3 Subacute thyroiditis

2.7.4 Chronic lymphocyte thyroiditis (Hashimoto’s disease)

2.7.5 Fibrous thyroiditis (Riedel’s thyroiditis)

3.Diagnosis of thyroid carcinoma:classification and staging

3.1 Histopathology

3.2 Staging

3.2.1 AJCC/tumor,lymph node,metastasis (TNM) staging

3.2.2 Prognostic factors for thyroid carcinomas

3.2.3 Risk stratification for persistent/recurrent DTC

4.Surgery and complication management

4.1 Surgery for thyroid cancers

4.1.1 Principles

4.1.2 Surgery for DTC

4.1.3 Surgery for MTC

4.1.4 Surgery for ATC

4.1.5 Perioperative treatment

4.2 Common postoperative complications and management

4.2.1 Hemorrhage and hematoma

4.2.2 Injuries of recurrent laryngeal nerve (RLN) and external branch of superior laryngeal nerve (EBSLN)

4.2.3 Hypoparathyroidism

4.2.4 Infection

4.2.5 Chylous leakage

4.2.6 Seroma

4.2.7 Other complications

5.RAI therapy and TSH suppression for DTC

5.1 Pre-RAI evaluation

5.1.1 AJCC/TNM staging

5.1.2 Risk stratification

5.1.3 Response to therapy restaging system

5.2 Goals of RAI therapy

5.3 Indications of RAI therapy

5.3.1 Remnant ablation

5.3.2 Adjuvant therapy

5.3.3 RAI therapy

5.3.4 Preparations and post-therapy WBS of RAI

5.4 TSH suppression therapy

6.External beam radiotherapy

6.1 Indications of EBRT

6.1.1 DTC

6.1.2 MTC

6.1.3 ATC

6.1.4 Palliative EBRT for metastatic lesions

6.2 EBRT techniques

6.2.1 Pre-treatment assessment

6.2.2 Radiotherapy techniques

6.2.3 EBRT complications

7.Systemic treatment

7.1 Targeted therapy

7.2 Chemotherapy

7.3 Immunotherapy

7.4 Indications for targeted therapy

8.Treatment of thyroid cancer with Traditional Chinese Medicine(TCM)

8.1 Syndrome differentiation and treatment

8.2 Therapeutic strategy

8.2.1 Deficiency of healthy qi

8.2.2 Yin deficiency with effulgent fire

8.2.3 Liver-kidney depletion

8.2.4 Liver depression and qi stagnation 8.2.5 Yang deficiency with congealing phlegm

8.2.6 Binding of toxin and blood stasis

9.Multidisciplinary treatment (MDT) and follow-up

9.1 MDT

9.2 Follow-up of DTC

9.3 Management of recurrent or metastatic DTCs

9.4 Follow-up of MTC

1.Overview

Thyroid carcinoma is a malignant tumor that originates from the follicular or parafollicular epithelium of the thyroid gland.In recent years,the incidence of thyroid cancer has been increasing rapidly worldwide.According to the National Cancer Registry,the incidence of thyroid cancer among females in urban areas in China ranks 4th among all malignant tumors in females.The incidence of thyroid cancer in China is estimated to grow at an annual rate of 20% over the recent years .

According to the origin and differentiation of the tumor,thyroid cancers are mainly divided into papillary thyroid carcinoma (PTC),follicular thyroid carcinoma (FTC),medullary thyroid carcinoma (MTC),poorly differentiated thyroid carcinoma (PDTC),and anaplastic thyroid cancer(ATC).PTC is the most common one,accounting for about 90% of all thyroid cancers.While PTC and FTC are grouped together as differentiated thyroid carcinoma(DTC).The pathogenesis,biological behavior,histological pattern,clinical manifestations,treatment and prognosis of different types of thyroid cancers are significantly different.In general,well DTC has a good prognosis,while ATC has a very poor prognosis,with a median survival time of 7?10 months.MTC has an intermediate prognosis.

2.Diagnosis and management

2.1 Screening for high-risk group

Screening for thyroid carcinoma in general population without risk factors is not routinely recommended.However,it is recommended for high-risk group,including people with 1) history of childhood head and neck radiation therapy or radiation exposure;2) history of any radiation therapy;and 3) medical or family history of DTC,MTC,multiple endocrine neoplasia type II (MEN-II),familial multiple polyposis coli,or other thyroid carcinomarelated syndromes,like Cowden syndrome,Carney syndrome,Werner syndrome,Gardner syndrome,etc.

2.2 Clinical manifestations

2.2.1 Symptoms

Thyroid carcinoma is usually asymptomatic at early stage.It commonly presents as a solitary thyroid nodule discovered in cervical palpation or ultrasonography during routine health examination.With the development of disease,symptoms may include 1) cervical lump,usually grows slowly except for ATC;2) dysphagia and/or dyspnea due to esophageal or tracheal compression;3) hoarseness,hemoptysis due to tumor invasion;and 4) diarrhea,palpitation,and flushing (MTC patients).

2.2.2 Signs

Advanced thyroid carcinoma can present as thyromegaly or cervical mass.Typical mass is a firm nodule.Local compression or invasion can cause trachea displacement,voice change,dysphagia,and hemoptysis.MTC can cause chronic refractory diarrhea and electrolyte imbalance.ATC can cause serious dyspnea because of rapid growing.

2.2.3 I nvasion and metastasis

(1) Local invasion

Advanced thyroid carcinoma can invade recurrent laryngeal nerve,trachea,esophagus,cricoid cartilage,larynx,internal jugular venous,vagus nerve,common carotid artery,etc.

(2) Regional lymph node metastasis

Regional lymph node metastasis is commonly seen in PTC at the time of diagnosis.Level VI is the most common site of lymph node metastasis.Level III nodes are of high risk when the tumor is located on the upper third of the thyroid lobe.

(3) Distant metastasis

Lungs are the most common sites of distant metastases of thyroid carcinoma.Other common sites include bone,liver and brain.FTC,PDTC,and ATC have higher risk of developing distant metastases.

2.3 Laboratory examination

2.3.1 Routine examination

Routine laboratory tests include complete blood count,renal and liver function tests.Coagulation function test should be performed before invasive procedures.

2.3.2 Special examination

(1) Test of thyroid hormones

Test of thyroid hormones includes thyroxine (T4),triiodothyronine (T3),free thyroxine (FT4),free triiodothyronine (FT3) and thyrotropic-stimulating hormone (TSH).

(2) Test of thyroid auto-antibodies

Thyroid auto-antibodies include anti-thyroglobulin antibody (TgAb),thyroid peroxidase antibody (TPOAb)and thyrotropin receptor antibody (TRAb).

(3) Test of thyroid carcinoma-related tumor markers

Thyroid carcinoma-related tumor markers include thyroglobulin (Tg),calcitonin,and carcinoembryonic antigen (CEA).Tg is an important indicator for postoperative DTC patients,particularly after radioiodine therapy.As the presence of TgAb will falsely lower serum Tg determinations in immunometric assays,and thus Tg should be measured with TgAb simultaneously.The highest degrees of sensitivity for serum Tg are noted following thyroid hormone withdrawal or stimulation using recombinant human thyrotropin (TSH＞30 mU/L).

Calcitonin and CEA can be used to monitor MTC patients’ prognosis and treatment outcomes.A growing calcitonin (especially when ≥150 pg/mL) indicates progression or recurrence.Doubling time of calcitonin is a useful indicator for MTC prognosis.

(4) Test of diagnosis-related molecular feature

Molecular feature (mutation ofBRAF,RAS,rearrangement of RET/PTC,etc.) may be informative in undecisive thyroid nodules after fine-needle aspiration (FNA).It also helps make individual management in some cases.

2.4 Imaging

2.4.1 Ultrasonography

(1) Differentiation of malignant and benign lesions

Ultrasound is recommended as the first-line imaging method for differentiation of thyroid nodules.It is portable and nonradioactive with high specificity and sensitivity.Cervical ultrasound should provide information of the size,number,location,solid-cystic,shape,boundary,calcification,blood supply and relationship with surrounding tissues of thyroid nodules,and evaluate the presence of abnormal lymph nodes in the neck and their location,size,shape,blood flow and structural characteristics.

Malignant signs of thyroid nodules include microcalcification,irregular margin and taller-than-wide.Other signs include hypoechoic solid,absence of halo,extrinsic thyroid invasion,and ultrasonographic signs of abnormal cervical lymph nodes.Signs of suspicious lymph nodes include abnormal size,microcalcification,cystic changes,hyperechogenicity,peripheral blood flow,irregular or fuzzy boundaries,uneven internal echoes,and disappearance of lymphatic hilum.

The efficiency of identifying thyroid nodules and lymph nodes is highly dependent on the clinical experiences of the ultrasound examiners.Thyroid Imaging Reporting and Data System (TI-RADS) is helpful to standardize thyroid ultrasound reports.There are several TI-RADS versions at present,in which the classifications are not unified.Table 1is referred to in this guideline.Contrast-enhanced ultrasound (CEUS) and elastography are complementary imaging modalities but not recommended routinely.

Table 1 Thyroid imaging reporting and data system

(2) Ultrasound-guided fine-needle aspiration biopsy(US-FNAB)

FNAB can diagnose lesions by cytology.Ultrasound guidance can improve the satisfactory sampling and diagnostic accuracy.US-FNAB is recommended as a diagnostic method to further determine benign and malignant thyroid nodules.

1)Indications of US-FNAB:Thyroid nodules with diameter ＞1 cm and more than one malignant ultrasound signs,are recommended for US-FNAB.US-FNAB is not recommended for thyroid nodules with diameter ≤1 cm,unless the following conditions:A) abnormal cervical lymph nodes observed;B) history of neck radiation exposure or exposure to radiation contamination in childhood,family history of thyroid cancer or history of thyroid cancer syndrome;C) positive lesions in18Ffluorodeoxyglucose,18F-FDG);or D) abnormally elevated serum calcitonin levels.

2) Exclusion indications of US-FNAB:Hot nodules with functions of independent uptake confirmed by thyroid nuclide imaging,and pure cystic nodules revealed by ultrasonography.

3) Contraindications of US-FNAB:Contraindications of US-FNAB of thyroid nodules include bleeding tendency(significantly prolonged emergence and coagulation time,significantly reduced prothrombin activity,long-term use of anticoagulants),adjacent vital organs,frequent cough,swallowing and other behaviors difficult to cooperate,rejection of invasive examination,and local infection which must be treated before aspiration.Menstruation is a kind of relative contraindications.

(3) Ultrasound examination during follow-up

For patients under active surveillance,the increasing of nodule size and/or the new appearance of malignant signs should be paid more attention during follow-up with cervical ultrasound.Increased nodule size refers to an increase in volume of more than 50% or increase at least two diameters of more than 20% (greater than 2 mm).These are indications of FNAB.For cystic-solid nodules,FNAB should be based on the growth of the solid portion.During postoperative follow-ups,attention should be paid to the thyroid bed and cervical lymph nodes to locate possible insisted and recurrent lesions.It was difficult to differentiate benign lesions from recurrent lesions on the operative bed by ultrasound.Lymph nodes with minimum diameter ＞8 mm and abnormal ultrasound findings are indicated to US-FNAB.Washout Tg is recommended to be combined with cytology.Lymph nodes smaller than 8 mm can be followed up if there is no sign of growth or threat to surrounding important structures.

2.4.2 Computed tomography (CT)

Contrast-enhanced CT plays important roles in both preoperative and postoperative settings.It is good at distinguishing tumor extension,adjacent structures invasion and lymph node metastasis (especially in mediastinum,infraclavicular,retropharyngeal,and parapharyngeal regions).The recommended scan range for invasive thyroid cancer is from skull base to upper abdomen(diaphragm).Enhanced magnetic resonance scans are recommended if the patient is allergic to the enhancing contrast agent,considering non-enhanced CT provides inadequate information under the circumstance of cancer.

2.4.3 Magnetic resonance imaging (MRI)

MRI is not routinely recommended in thyroid imaging.Though its high soft tissue resolution,multiparametric imaging methods and techniques like dynamic contrastenhanced scan make it good at distinguishing lesions from surrounding tissues and differentiating benign and malignance.Its limitations like insensitivity to calcification and vulnerability to any movements during the examination and swallow artifacts stop it from contributing more in thyroid imaging.

2.4.4 Positron emission tomography (PET)-CT

PET-CT is not recommended in routine thyroid carcinoma diagnosis.18F-FDG PET-CT is considered useful in the following conditions:1) high-risk DTC patients with elevated serum Tg (generally ＞10 ng/mL) but negative radioactive iodine (RAI) imaging;2) preoperative staging for MTC;3) postoperative MTC patients with elevated calcitonin;4) initial staging and postoperative follow-ups for ATC patients;and 5) pre-RAI treatment evaluation for aggressive or metastatic DTC patients.

2.5 Vocal cord function assessment

All patients undergoing thyroid surgery are recommended to have voice assessment both preoperatively and postoperatively.Fiberoptic bronchoscopy should be performed in patients with suspected tracheal compression or invasion.

2.6 Histology

2.6.1 Cytology

Cytopathologic diagnosis of thyroid cancer consists of FNA,sample section,and the report system.

(1) FNA

Palpation-guided FNA and ultrasound-guided FNA are two ways for the acquisition of samples.Palpation-guided FNA is only indicated for palpable solid nodules.Ultrasound-guided FNA should be performed for nonpalpable nodules,cystic nodules,or nodules that have had previous unsatisfactory FNA.The needle goes into the nodule with or without a negative pressure and moves back and forth quickly at multiple angles.The number of needle insertions per nodule is 1?3,depending on the amount of the aspirated sample.For cystic nodules,the solid area should be targeted.Commonly used needles are 22?27 G.Thicker needles may be chosen for lesions with significant fibrosis,while thinner needles may be chosen for those with an abundant blood supply.

(2) Sample sectioning

Section techniques for cellular specimens include cytological smears,liquid-based cytology,and cell block section.Smears are the most common method.Cells obtained by FNA are applied directly to the slide,dried,and fixed in alcohol.If the specimen is cystic fluid,liquidbased cytology will enrich the cells,resulting in a more abundant smear than the conventional smear.For rare types of thyroid tumors such as MTC,ATC,and metastatic carcinoma,it is best to add a cell block section to facilitate immunocytochemical testing.The combination of conventional smears and liquid-based cytology can improve diagnostic accuracy.An on-site evaluation of cellular specimens can be performed to improve the satisfactory rate of sampling.

(3) Cytology report system

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is recommended (Table 2).Patients with different cytological diagnostic grades have different malignancy risks and different clinical management measures (Table 3).

Table 2 Bethesda System for Reporting Thyroid Cytopathology:Recommended diagnostic categories

Table 3 Bethesda System for Reporting Thyroid Cytopathology:Diagnostic categories and risk of malignancy

2.6.2 Pathology

(1) Preoperative core needle aspiration pathology

Preoperative ultrasound-guided core needle aspiration allows collection of tumor tissues for histopathologic diagnosis,which can be definitive if the specimen is adequate and the morphology is typical.Because of the obvious advantages of FNA in the diagnosis of thyroid cancer,core needle aspiration pathology is not a routine diagnostic test.It may have a role in some rare cases.

(2) Intraoperative frozen section

The purpose is to characterize thyroid nodules that have not been diagnosed preoperatively or have unclear diagnosis,and to clarify the presence or absence of lymph node metastases to help decision making intraoperatively.

(3) Postoperative paraffin pathology

1) Precautions for specimen preparation:A) make parallel sections every 2?3 mm perpendicular to the long axis of the lobe;B) inspect carefully,paying attention to microscopic carcinoma or small nodules;C) if there are multiple lesions suspected for malignancy,each lesion should be sampled;D) in cases of suspected encapsulated vascular infiltrative or microscopic infiltrative follicular carcinoma,all of the capsule should be sampled;E) pay attention to the relationship between the lesion and the peritoneum;and F) pay attention to the adjacent structures (strap muscles,lymph nodes,or parathyroid glands).

2) Postoperative pathology report should include:A)tumor location,number and size of lesions;B) pathological type,subtype,fibrosis and calcification;C) lymphovascular invasion and nerve invasion (small nerve invasion near the perineurium or laryngeal nerve branches);D) thyroid perineurium involvement and extra-thyroid extension;E)invasion of strap muscle;F) other lesions in surrounding thyroid tissues such as chronic lymphocytic thyroiditis,nodular goiter,adenomatous changes,etc;G) lymph node metastasis and extra-nodal extension;H) pTNM staging[American Joint Committee on Cancer (AJCC) 8th edition];and I) immunohistochemistry as necessary.

2.7 Differential diagnosis

2.7.1 Thyroid adenoma

Thyroid adenoma is more common among young people aged 20?30 years old.Typical thyroid adenoma presents as single nodules with clear border and smooth surface.It grows slow and has no metastasis.Sudden enlargement often results from intracapsular hemorrhage.

2.7.2 Nodular goiter

Nodular goiter is more common among middle-agedfemales.The course is often long and can last for decades.Typical presentation is multiple nodules of various sizes in both lobes,some of which may have cystic degeneration.Enlarged thyroid can compress trachea and esophagus,results in dysphagia and dysphagia.Nodular goiter has very low chance of turning into cancer,though it can be cancerous in some cases of elderly,large tumor and long course.Sudden accelerated enlargement is highly suspected.

2.7.3 Subacute thyroiditis

Subacute thyroiditis is commonly caused by viral infection.There is often a prodromal respiratory infection.The disease is self-limited and the course normally lasts for weeks or months.Typical presentations include fever,cervical pain (which is more prominent when swallowing,and can radiate to ears),thyroid enlargement or asymmetric nodular mass.A small number of patients have to go through surgery to rule out thyroid cancer.

2.7.4 Chronic lymphocyte thyroiditis (Hashimoto’s disease)

Chronic lymphocyte thyroiditis (Hashimoto’s disease) is most common among middle-aged females.It progresses slowly over years.In early stage,patients may not notice signs or symptoms.Over time,the thyroid may enlarge,forming a painless goiter.Sometimes it is indistinguishable from thyroid cancer.It is an autoimmune disorder and response well to glucocorticoid.Rarely,surgery or radiotherapy is needed.

2.7.5 Fibrous thyroiditis (Riedel’s thyroiditis)

Fibrous thyroiditis (Riedel’s thyroiditis) is characterized by an enlarged,stone-hard and fixed thyroid.Tracheal compression is common.It can be indistinguishable from thyroid cancer.Surgical treatment is required to relieve tracheal or esophageal obstruction.

3. Diagnosis of thyroid carcinoma:classification and staging

Note:This guideline was written before the recently published 5th edition of WHO classification of thyroid neoplasms.[Overview of the 2022 WHO Classification of Thyroid Neoplasms.Endocr Pathol.2022;33(1):27-63.]

3.1 Histopathology

In consistent with the WHO Classification of Endocrine and Neuroendocrine Tumors,thyroid neoplasms are classified into three major categories:primary epithelial neoplasms,primary non-epithelial neoplasms and secondary thyroid neoplasms (Table 4).About 95% of thyroid neoplasms originate from the thyroid follicular epithelium,while others mostly come from parafollicular cell.Neoplasms with both follicular epithelium and parafollicular cell component are rare and remained controversies whether to be a distinct entity.Thyroid lymphoma is the most frequent non-epithelial neoplasms and can be divided into primary or secondary.Entities such as thyroid sarcoma and secondary thyroid neoplasms are infrequent.

3.2 Staging

3.2.1 AJCC/tumor,lymph node,metastasis (TNM) staging

Clinical TNM staging (cTNM) and pathological TNM staging (pTNM) can be established based on preoperative assessment and postoperative histopathology,respectively.The 8thedition AJCC TNM definitions and staging guidelines are illustrated inTable 5,6.

Table 4 WHO classification of thyroid neoplasms

Table 5 TNM definitions for thyroid carcinomas

Table 6 Staging guidelines for thyroid carcinomas

3.2.2 Prognostic factors for thyroid carcinomas

Prognosis of thyroid carcinoma can be affected by multiple factors,including histopathology,tumor size,extrathyroidal invasion,vascular invasion,BRAFmutation and distant metastasis status.

(1) Histopathology:PTC patients tend to have an excellent prognosis.However,aggressive variants like tall cell,columnar cell,hobnail and solid/trabecular PTCs have more aggressive clinical behavior.Although highly invasive FTC is uncommon,80% cases develop distant metastasis.In FTC,older age,advanced staging and larger tumor volume are associated with poor prognosis.PTC and FTC share similar prognosis,with a better prognosis when tumor ≤1 cm in greatest dimension and limited to thyroid gland or micrometastasis,and worse prognosis appeared under distant metastasis or high invasiveness.

(2) Primary tumor size:PTCs with diameter ≤1 cm are known as papillary microcarcinoma and are rarely lethal,yet 20% of multifocal microcarcinoma metastasizes to cervical lymph node.Differentiated thyroid carcinoma with maximum diameter ≤1.5 cm has a lower likelihood of distant metastasis with a 30-year mortality of 0.4%,while tumor ＞1.5 cm has a 30-year distant metastasis rate of 33%and mortality of 7%.

(3) Local invasion:10% of DTC infiltrates into adjacent structures and exhibits local recurrence rate twice as high as those who are not infiltrative,and 1/3 of patients pass away due to tumor progression.

(4) Lymph node metastasis:The prognostic role of regional lymph node metastasis remains controversial.Lymph node metastasis is associated with distant metastasis,especially with bilateral cervical lymph nodemetastasis,extracapsular invasion or mediastinal lymph node metastasis.

(5) Distant metastasis:Distant metastasis can be found in 10% of PTC,25% of FTC,and 35% of Hürthle cell carcinoma or in patients ＞40 years of age.It is the leading cause of DTC mortality.

3.2.3 Risk stratification for persistent/recurrent DTC

DTC can be stratified as having low,intermediate or high risk of recurrence according to clinicopathological factors,including residual diseases,tumor number and size,histological subtype,capsular/vascular invasion,lymph node metastasis,extrathyroidal extension,postoperative TSH-stimulated Tg level and molecular characteristics (Table 7).Adjuvant therapy is strongly recommended for high-risk group and can be considered for intermediate-risk patients,whereas thyroid hormone therapy but not radioiodine treatment is advised for lowrisk patients.

Table 7 Clinical-pathological risk stratification for persistent/recurrent DTC

4.Surgery and complication management

4.1 Surgery for thyroid cancers

4.1.1 Principles

DTC is mainly treated surgically,supplemented by postoperative endocrine therapy,radioactive iodine therapy,and in some cases,radiation therapy and targeted therapy.MTC is mainly treated surgically,supplemented by radiation therapy and targeted therapy in some cases.For ATC patients,only a few have the opportunity to receive surgery.Some ATC patients may benefit from radiotherapy and/or systemic therapy.In general,the prognosis of ATC is very poor.Due to different conditions and demands of patients,it is important to note the individualization of treatment.Clinical practice may vary under general principles.

4.1.2 Surgery for DTC

(1) Treatment of primary lesions

T1 and T2 tumors are most often confined to one lobe and lobectomy is recommended.For some patients with highrisk factors,total thyroidectomy is recommended.These risk factors include multifocal lesions,lymph node metastases,distant metastases,family history,and childhood exposure to ionizing radiation.Total thyroidectomy is also indicated in some cases where postoperative nuclear therapy is considered necessary.For tumors located in the isthmus,extended isthmus resection is possible for small tumors,while total thyroidectomy may be considered for larger tumors or those with lymph node metastases.

A subset of T1 lesions is low-risk papillary microcarcinoma.Because of its slow progression and low lethality,conservative therapy,i.e.,active surveillance,can be considered.Low-risk papillary microcarcinoma that can be closely monitored has the following characteristics in general:1) the primary tumor is a single lesion;2) the primary lesion is ＜1 cm in diameter;3) the location of the primary lesion is in the central part of the thyroid gland rather than adjacent to the border of the thyroid gland or trachea;and 4) there are no regional lymph node metastases by evaluations.Some specific factors should be taken into account,such as a history of high-dose ionizing radiation exposure during childhood,family history of thyroid cancer,and the presence of hyperthyroidism.If active surveillance is performed,re-evaluation every 6 months is usually required.If the evaluation revealsprogression of the primary tumor (e.g.,2?3 mm in diameter,new tumor lesions,or clinically suspicious metastatic regional lymph nodes),surgical treatment should be considered.

For T3 lesions,total thyroidectomy is generally indicated.However,for small lesions invading the strap muscles,lobectomy along with excision of the invaded muscles may be considered.It is recommended that benefits and risks of surgery be weighed before surgery.

T4 lesions invade adjacent structures and organs,total thyroidectomy is generally recommended.T4a lesions require resection of the thyroid along with some of the affected structures,such as part of larynx,trachea,hypopharynx,and part of the esophagus,and require some reconstructive skills.T4b lesions are generally considered inoperable,but should be determined on a case-by-case basis.It may require multidisciplinary collaboration between several surgery departments.However,T4b lesions are difficult to achieve R0 resection,are associated with higher surgical risks,have more postoperative complications,and have a poor prognosis.The decision to treat surgically requires careful evaluation of the condition,with a focus on whether patients will benefit from surgery.Sometimes,palliative surgical therapy is necessary,such as tracheotomy to relieve dyspnea.

(2) Treatment of regional lymph nodes

Central compartment (levels VI?VII):For cN1a cases,the ipsilateral central compartment should be dissected,including the tracheoesophageal groove and the anterior tracheal area.The pre-laryngeal region has lower rates of lymph node metastasis and can be treated on an individual basis.For cN0 patients,central compartment dissection may be considered if there are high-risk factors (e.g.,T3?T4 lesions,multifocality,family history,childhood ionizing radiation exposure).For low-risk cN0 patients (no high-risk factors),individualized treatment is possible.The scope of central compartment is defined as the level of the superior border of the innominate artery at the inferior border,the level of the hyoid bone at the superior border,and the medial border of the common carotid artery at the lateral border,including the anterior tracheal area.In the right tracheoesophageal groove,it requires attention to the soft tissue deeper to the recurrent laryngeal nerve plane.During the central compartment dissection,the laryngeal nerve should be carefully dissected and the parathyroid glands should be preserved with reliable blood supply.Parathyroid auto-transplantation is recommended if the parathyroid glands cannot be preservedin situ.

Lateral neck (levels I?V):Lateral cervical lymph node metastases are most commonly seen in levels III and IV,followed by levels II and V.Metastasis in level I is rare.Lateral neck dissection is recommended to be performed therapeutically,i.e.,for confirmed N1b cases by preoperative evaluation or intraoperative frozen section.Recommended extent of lateral neck dissection is levels II,III,IV,and VB.Acceptable minimal extent should include levels IIA,III,and IV.Level I does not require routine dissection.The levels of the regional lymph nodes are shown inTable 8.

Table 8 Response to therapy restaging system

Parapharyngeal lymph nodes and upper mediastinal lymph nodes are recommended to be resected when metastasis is considered on imaging.

4.1.3 Surgery for MTC

Under most circumstances,MTC can be diagnosed preoperatively.Total thyroidectomy is recommended for MTC.In the case of MTC diagnosed after lobectomy,a total thyroidectomy is recommended.Sporadic microscopic MTC found incidentally after lobectomy may also be considered for active follow-up.

Simultaneous neck dissection is recommended for MTC(central or lateral neck),the extent of which should bedetermined by clinical assessment and serum calcitonin levels.Generally,surgical treatment of MTC should be more aggressive than that of DTC.

Hereditary MTC can be diagnosed by germline mutations ofRETgene.Total thyroidectomy and cervical lymph node dissection are appropriate for this group of patients.In cases of MEN-II patients,systemic conditions should be fully evaluated and treated preoperatively.In cases of combined pheochromocytoma,etc.,treatment is required before considering thyroid surgery.

4.1.4 Surgery for ATC

There is no standard treatment regimen for ATC currently.ATC patients with small tumors at the time of diagnosis may have a chance for surgery.Most ATC patients have a large neck mass with rapidly progressing diseases,and have no chance of surgery.Systemic therapy and radiation may be considered.Tracheotomy can be considered when the tumor compromising the airway.

4.1.5 Perioperative treatment

Surgical complications should be monitored and managed postoperatively.Postoperative bleeding is the most common complication within 24 h.Dexamethasone can reduce neuroedema after surgery.Parathyroid hormone and serum calcium should be monitored after total thyroidectomy.Recurrent laryngeal nerve injury can cause aspiration in elder patients.Tracheotomy is indicated for bilateral recurrent laryngeal nerve injury.Chyle leak from neck dissection should be managed before discharge.Patients can benefit from functional rehabilitation for neck and shoulder.Risk stratification should be performed.Patients should be informed of adjuvant treatment plans.

4.2 Common postoperative complications and management

Surgical complications related to the surgical treatment of thyroid diseases have a certain probability of occurrence and are not completely avoidable.

4.2.1 Hemorrhage and hematoma

The incidence of postoperative bleeding in thyroid cancer is 1%?2%.Most events occur within 24 h after surgery.Signs and symptoms of hematoma include neck swelling,pain,oozing from the suture line,ecchymosis,and respiratory distress.If the drainage is more than 100 mL per hour,active bleeding is considered and a formal wound exploration and control of hemorrhage should be performed.Symptomatic hematomas should be decompressed immediately and a bedside tracheotomy may be necessary.Risk factors for postoperative bleeding in thyroid cancer include hypertension,anticoagulants and aspirin.

4.2.2 Injuries of recurrent laryngeal nerve (RLN) and external branch of superior laryngeal nerve (EBSLN)

The incidence of RLN injury in thyroid surgery is reported to be 0.3%?15.4%.The common causes of RLN injury include adhesion,tumor invasion,and maneuver injuries during dissection.If the nerve is resected,it is recommended to perform one-stage nerve reconstruction when possible.Hoarseness and choking are common symptoms of unilateral RLN injury.Bilateral RLN injury may cause life-threatening respiratory distress and may require tracheotomy to ensure airway patency.

Injury to the EBSLN can occur during the dissection and clamping of the superior thyroid vessels.It causes paralysis of the cricothyroid muscle,impairing the production of high tones.Meticulous dissection near the upper pole of the thyroid gland can reduce the probability of EBSLN injury.

Intraoperative neuromonitoring (IONM) technique can help to locate RLN and monitor RLN function during the whole operation.IONM is recommended for cases such as revisit surgery,giant thyroid masses,and unilateral preoperative RLN palsy.

Meticulous dissection along the perineum of thyroid,intraoperative exposure of RLN,properly application of energy instruments,and standardized usage of IONM could reduce the probability of RLN injury.

4.2.3 Hypoparathyroidism

The incidence of permanent hypoparathyroidism is 2%?15%,mostly seen after total thyroidectomy.The main manifestation is postoperative hypocalcemia.Patient may feel tingling in their fingers or around their lips,which can be relieved by intravenous calcium.For temporary hypoparathyroidism,calcium may be given to relieve symptoms,with the addition of vitamin D if necessary.In permanent hypoparathyroidism,lifelong calcium and vitamin D supplements are required.Intraoperative attention should be paid to meticulous dissection along the perineum of thyroid.Also,surgeons should be careful to protect the blood supply when preserving the parathyroid glandsin situ.Autologous transplantation is recommended for parathyroid glands that cannot be preservedin situ.Some staining techniques can assist identification of parathyroid glands intraoperatively,such as carbon nanoparticles suspension injection and mitoxantrone hydrochloride injection for tracing.

4.2.4 Infection

Most thyroid surgeries are clean surgical procedures,which does not involve the larynx,trachea and esophagus.The incidence of postoperative thyroid incision infection is 1%?2%.Risk factors for incisional infections include diabetes and immunocompromise status.Clinical manifestations of incisional infection are fever,cloudy drainage fluid,redness of the incision,elevated skin temperature and local pain.If incisional infection is suspected,antibiotic treatment should be given promptly.And if there is abscess accumulation,the incision requires drainage with culture-directed intravenous antibiotics.

4.2.5 Chylous leakage

Chylous leakage happens after neck dissection.It is characterized by a continuous high flow of milky white drainage,up to 500?1,000 mL per day or even more.Prolonged chylous leakage can lead to decreased volume,electrolyte disorder,and hypoproteinemia.Parenteral nutrition is recommended as a conservative treatment.Surgery should be considered when conservative management does not work,such as cervical thoracic duct ligation,cervical transfer tissue flap to seal the leak,or thoracoscopic ligation of the thoracic duct.

4.2.6 Seroma

The incidence of seroma after thyroid surgery is 1%?6%.Retention of a drain in the operative area helps to reduce local fluid formation.Treatment includes close observation,serial needle aspirations and negative pressure drainage.

4.2.7 Other complications

Other complications include shoulder complaints(accessary nerve injury during neck dissection),pneumothorax (pleural rupture),Horner’s syndrome(injury of cervical sympathetic trunk),tongue weakness of the affected side (injury of the hypoglossal nerve),and orofacial distortion (injury to the mandibular branch of the facial nerve).

5.RAI therapy and TSH suppression for DTC

RAI therapy for DTC should be based upon the comprehensive assessment before RAI management.

5.1 Pre-RAI evaluation

Three aspects are considered upon RAI decision making:the AJCC/TNM staging,risk stratification and response to therapy restaging system,with the aim to assess the postoperative risk of death,risk of persistence/recurrence/metastasis and real-time status during follow-up,respectively.

5.1.1 AJCC/TNM staging

The eighth edition of AJCC/TNM staging is most commonly used for DTC postoperative staging system,primarily based on pathological features to estimate the risk of death,which is discussed in detail in Chapter 3.

5.1.2 Risk stratification

A triad risk stratification has been taking the lead in guiding clinical decision-making (Chapter 3) in recent years.It systematically classified clinicopathological features into low,intermediate and high risk to estimate DTC recurrent risk.

5.1.3 Response to therapy restaging system

Given both the AJCC/TNM staging and risk stratification system mainly focus on the postoperative clinicopathological features to evaluate the risk of death and recurrence,the response to therapy restaging system is being valued and integrated into pre-RAI evaluation system(Table 8).Of note,it takes the response of prior treatment into consideration,which may facilitate the accurate evaluation of the exact status of patients.

5.2 Goals of RAI therapy

The primary goals of postoperative RAI therapy may include remnant ablation,adjuvant therapy and treatment for persistent disease (RAI therapy),with an aim to destroy remnant thyroid tissues,potential tumor tissues which may or may not present and/or persistent or metastatic,respectively.

5.3 Indications of RAI therapy

5.3.1 Remnant ablation

Remnant ablation is not routinely recommended for DTC patients with low risk of recurrence and unifocal PTMC,but can be considered for the benefit of follow-up,and a low administered activity of approximately of 30 mCi is favored,while 100 mCi may be considered for patients with large remnant tissues.

5.3.2 Adjuvant therapy

Adjuvant therapy is indicated for DTC patients with high risk of recurrence,or elevated Tg/TgAb levels in the absence of imaging evidence (Tg/TgAb+,imaging?) which suggests potential biochemical recurrence.For intermediate-risk patients who harbored the clinicopathological features of aggressive histology,minor extrathyroidal extension,vascular invasion,or ＞5 involved lymph nodes (0.2?3.0 cm) were confirmed to benefit from adjuvant therapy.An unexplained increase in serum Tg/TgAb level represents possible existence of tiny or occult cancer foci that cannot be detected or displayed by current imaging technique.Although considering the influence of residual thyroid tissues,Tg/TgAb levels are not factors enrolled in the risk stratification system,suspiciously elevated ps-Tg levels (such as ps-Tg ＞10 μg/L)can also be served as indicator for adjuvant therapy.A prospective study showed that more than 90% patients with high serum ps-Tg levels were at intermediate and high risk by risk stratification,and adjuvant therapy could help reduce the risk of recurrence and tumor-related death in an administered activity of 100?150 mCi.

5.3.3 RAI therapy

RAI therapy is recommended for higher-risk DTC patients with the aim to improve disease-special survival (DSS) and disease-free survival (DFS) in an administered activity of 150?200 mCi.In patients with RAI-avid persistent,recurrent or metastatic lesions,RAI could be repeated when there was biochemical or structural response confirmed,yet when the patients showed RAI-refractory diseases who would be less likely to benefit from the next RAI therapy,no further RAI therapy should be administered.

Patients who are or plan to be pregnant within 6 months,or breast-feeding should not be considered for RAI therapy.Moreover,it should be noted that remnant ablation,adjuvant therapy,and RAI therapy are not processive,but a decision based on TNM staging,clinicopathological findings,postoperative serology and real-time imaging assessment,a comprehensive analysis combined with patients’ wishes and a pros-and-cons determination.Therefore,standard pre-RAI evaluation is the premise of appropriate RAI therapy.

5.3.4 Preparations and post-therapy WBS of RAI

Levothyroxine (LT4) withdrawal or recombinant human TSH (rhTSH) and low-iodine dietary restrictions for 3?4 weeks are essential for RAI therapy or RAI WBS preparations.Stimulated TSH is recommended ＞30 mU/L and serum iodine is recommended ＜100 μ g/L.A posttherapy WBS (RxWBS) is recommended after RAI therapy,to document the RAI avidity of any structural diseases if it is present.

5.4 TSH suppression therapy

Since TSH receptors express on DTC cell membrane,DTC responds to TSH stimulation by increasing cell growth and expressing Tg.Therefore,TSH suppression therapy is important in postoperative management of DTC,and Tg is a sensitive DTC biomarker for monitoring tumor progression.It has been realized that the optimal degree of TSH suppression varies,and thereby an individually tailored approach to deciding TSH targets in DTC patients considering risk of side effects has been raised.

(1) For patients of high risk of recurrence,initial TSH suppression to ＜0.1 mU/L is recommended.

(2) For intermediate-risk patients,initial TSH suppression to 0.1?0.5 mU/L is recommended.

(3) For low-risk patients who have undergone remnant ablation with undetectable/low Tg levels or lobectomy,TSH may be maintained to 0.5?2.0 mU/L,0.1?0.5 mU/L,and 0.5?2.0 mU/L,respectively,while continuing surveillance for recurrence.

(4) For SIR patients,initial TSH suppression to ＜0.1 mU/L is recommended.

(5) For BIR patients,initial TSH suppression to 0.1?0.5 mU/L is recommended.

(6) For patients who are high-risk at initial evaluation while become ER or IDR at follow-up,TSH suppression is recommended to 0.1?0.5 mU/L for 5 years,and then can be maintained in the mid to lower reference range (0.5?2.0 mU/L).

(7) For BIR patients,initial TSH suppression to 0.1?0.5 mU/L is recommended.

(8) For ER or IDR patients,especially with low risk,initial TSH suppression to 0.5?2.0 mU/L is recommended.

(9) For patients whose stimulated Tg＜10 ng/mL with negative WBS (Tg+I?),TSH suppression therapy is routinely recommended.

6.External beam radiotherapy

External beam radiation therapy (EBRT) is utilized mainly as an adjuvant therapy postoperatively.It should be determined according to the factors of surgical resection,pathological type,the extent of invasion,age and other factors:1) EBRT could be considered for recurrent DTC when it is unresectable;2) postoperative radiotherapy can be considered for gross residual diseases when the tumor invades important structures (such as the tracheal wall,prevertebral tissue,throat,arterial wall or venous tumor thrombus) which cannot be controlled by RAI therapy;3)young DTC patients have an excellent prognosis and can survive for a long time even if there is recurrence and metastasis,the use of EBRT after initial complete resection should be avoid;and 4) for PDTC or ATC with residual diseases or extensive lymph node metastasis after operation,large-field postoperative radiotherapy should be given in time,which was associated with improved local control and prognosis.

6.1 Indications of EBRT

6.1.1 DTC

For DTC,the current EBRT indications include:1) pT4,R1/2 resection,iodine-avid and age ＞45 years;2) pT4,R2 resection or unresectable without iodine intake;and 3)lymph nodes metastasis with extensive extracapsular extension and age ＞60 years.The commonly used indications of EBRT in China include:1) Unresectable gross residual tumors,which cannot be controlled by RAI therapy alone;and 2) postoperative residual or recurrent lesions which do not absorb iodine.

6.1.2 MTC

For MTC,EBRT is mainly used in patients with pT4,R2 resection,extensive extracapsular extension of lymph nodes,airway obstruction or local recurrence.The main purpose is to improve the local regional control rate or alleviate clinical symptoms.

6.1.3 ATC

The multi-modality treatment approach and individualized scheme design should be carried out for ATC according to the specific situation of patients.EBRT can be a part of comprehensive treatment before or after operation.It can also be used alone for radical or palliative purposes.

6.1.4 Palliative EBRT for metastatic lesions

For metastatic lesions of thyroid cancer,such as lung,liver,bone and brain metastasis,especially with obvious clinical symptoms,local therapy such as operation,EBRT or stereotactic body radiotherapy (SBRT) combined with systemic treatment or RAI therapy should be considered to reduce symptoms and delay tumor progression.

6.2 EBRT techniques

6.2.1 Pre-treatment assessment

A comprehensive evaluation should be performed to determine the location of tumor invasion and guide the design of irradiation field:hoarseness,dysphagia,and wheezing indicate the possible invasion of recurrent laryngeal nerve,esophagus,trachea,etc.Detailed examination of the neck for enlarged lymph nodes is done to determine regional lymph node metastasis.Laryngoscopy can be used to establish whether there are vocal cord paralysis and recurrent laryngeal nerve invasion or not.Neck ultrasound and CT scan should be used to the clinical concern of tumor invasion and cervical lymph node metastasis;lung CT,abdominal ultrasound and bone scan should be performed to evaluate the possibility of distant metastasis.Before adjuvant radiotherapy,surgical details,resection scope and pathological results should be comprehensively considered and analyzed.

6.2.2 Radiotherapy techniques

Both intensity modulated radiation therapy (IMRT) and conventional radiotherapy can be selected for clinical application.Compared with conventional techniques,IMRT technique has obvious advantages in dose distribution and normal tissue protection,and can significantly reduce radiation-related toxic and side effects.

(1) IMRT and three-dimensional conformal radiotherapy (3D-CRT)

1) Simulation

Selection of body position:supine position,neck gently extended,shoulders down,setup with thermoplastic mask covering head,neck,and shoulders for immobilization.

Simulation CT scanning:CT scan (3-mm cuts) with intravenous contrast should be performed from the top of the head to the bottom of both lungs,uploading to the planning system.MRI fusion with planning CT is highly recommended.

2) Target volumes

The design of irradiation field should be determined according to surgical resection,pathological type,invasion extent,and lymph node metastasis.Generally,small-field irradiation is used for highly differentiated cancer (highrisk region and unresectable area),and large-field irradiation is used for poorly differentiated or undifferentiated cancer (including lymphatic drainage area of neck and upper mediastinum).

A.Tumor bed [gross target volume tumor bed (GTVtb)]:including the area of preoperative tumor invasion and the range of metastatic lymph nodes.For those with nonstandard operation,the thyroid bed should be considered as GTVtb.

B.High-risk area [clinical target volume 1 (CTV1)]:including thyroid bed,lymph node positive areas confirmed by pathology.

C.Optional treatment area [clinical target volume 2(CTV2)]:including II?VI lymph node drainage area and upper mediastinal lymph nodes without pathological confirmation but with the potential metastasis risk.

3) Prescription dose (Table 9)

Table 9 Recommended prescription dose of EBRT

(2) Conventional radiotherapy

It is not common to conduct at present.IMRT is the recommended preferred technique.

1) Simulation

The position is the same as that of IMRT.It is recommended to use simulated CT for positioning and outline the irradiation field on the planning system.

2) Radiation field design

The commonly used techniques include wedge-shaped irradiation technology at the intersection angle of two front oblique fields,single front field irradiation of electron beam,mixed irradiation technology of X-ray and electron beam,small mantle field irradiation technology,etc.

3) Radiation source

Cobalt-60,4?6 MV high-energy X-ray,or 8?15 MeV electron line.

4) Dose prescriptions

Referring to IMRT or 3D-CRT technology,it should be noted that the dose of normal tissue (such as spinal cord)should not exceed the tolerance.

6.2.3 EBRT complications

(1) Acute complications

Grade 1?2 reaction is common (＞80%),including pharyngitis,mucositis,xerostomia,changes in taste,dysphagia,laryngitis,radiation dermatitis,etc.Grade 3 or more reactions were less,with the incidence of pharyngitis being the highest (＜10%),and the other reactions being less than 5%.

(2) Late complications

Late complications include skin and muscle fibrosis,esophageal and tracheal stenosis,pharyngeal stenosis leading to dysphagia,internal carotid arteriosclerosis,second primary cancer,etc.

7.Systemic treatment

As the conventional systemic treatment,chemotherapy is the mainstream option for patients with ATC.Targeted therapy,evolved considerably with more evidence,is preferred in the treatment of advanced DTC,MTC,and positive driver gene ATC.Immunotherapy is effective in some thyroid cancers and needs further study.

7.1 Targeted therapy

DTC is featured by the high expression of vascular endothelial growth factor receptor,and gene alterations such asBRAFV600Emutation,RETrearrangement,andRASpoint mutations.Inhibitors targeting these alterations can prolong the median progression-free survival.

Targeted therapeutic strategies demonstrate clinically significant activity in RAIR-DTC,MTC and drive gene positive ATC,with agents including multitargeted kinase inhibitors,such as lenvatinib,sorafenib,vandetanib,cabozantinib,anlotinib,apatinib and sulfatinib;BRAFV600Emutant inhibitors,such as dabrafenib;MEK inhibitor,such as trametinib;tropomyosin receptor kinase (TRK)inhibitors,such as larotrectinib or entrectinib;and RET inhibitors,such as selpercatinib or pralsetinib (Table 10).

Table 10 Targeted regimens for patients with advanced thyroid cancer

7.2 Chemotherapy

For patients with locoregionally confined (stage IVA or IVB) ATC,chemotherapy is applied as concurrent radiochemotherapy or adjuvant therapy.The drug candidates are taxanes,anthracyclines,and platinum derivatives (Table 11).Weekly regimens are recommended when administered concurrently with radiotherapy.

For patients with stage IVC ATC,chemotherapy is considered.The recommended regimens include paclitaxel plus platinum,docetaxel plus doxorubicin,paclitaxel monotherapy,and doxorubicin monotherapy (Table 12).

Table 11 Regimens of adjuvant chemotherapy or concurrent chemotherapy &radiotherapy for patients with stage IVA or IVB ATC

Table 12 Chemotherapy regimens for patients with stage IVC ATC

7.3 Immunotherapy

Clinical efficacy of immunotherapy was variable in preliminary studies that further evidence and exploration of biomarkers are needed.Patients with thyroid cancer who suffer from a progressing condition and have failed in other therapies are recommended to participate in clinical studies focusing on immunotherapy.

7.4 Indications for targeted therapy

Molecular testing is recommended before application of targeted therapy.According to current evidences,targeted therapy may prolong patients’ progression-free survival but fail to improve the overall survival.During targeted therapy,the condition would be more aggravated once the disease progresses.Therefore,it is highly recommended to prudently determine the indications for targeted therapy.Patients with DTC,in particular,are recommended to consider targeted therapy only in cases where both surgery and RAI therapy fail to control the significant progressionof the disease.

8.Treatment of thyroid cancer with Traditional Chinese Medicine (TCM)

In TCM,thyroid cancer belongs to the“goiter and tumor”category.Emotional factors are the leading cause,except that it is closely related to deficiency,phlegm,blood stasis,heat,poison,and diet.Usually,its clinical manifestation is deficiency-excess complex and combined with various pathogenic factors.

8.1 Syndrome differentiation and treatment

At present,TCM is applied for the treatment of thyroid cancer in two aspects.Firstly,TCM is a complementary therapy and end-stage support therapy in combination with surgery,chemotherapy,and radiotherapy to reduce sideeffects,improve physical strength and appetite,and inhibit tumor development.Secondly,TCM is an alternative therapy for the patient who does not accept surgery,radiotherapy,and chemotherapy.

Suitable population:patients in the period of perioperation,radiotherapy and chemotherapy,targeted therapy,recovery,and late stage after treatment.

Treatment:oral decoction,Chinese patent medicine,and other TCM therapies (external application,acupuncture,etc.).

8.2 Therapeutic strategy

8.2.1 Deficiency of healthy qi

Indication:congenital weakness or consumption of healthy qi after an operation,radiotherapy,and chemotherapy.

Representative formula:modified with Bā Zhēn Tāng,Dāng Guī Bǔ Xuè Tāng,Shí Quán Dà Bǔ Tāng,or Bǔ Zhōng Yì Qì Tāng.

8.2.2 Yin deficiency with effulgent fire

Indication:commonly seen in patients after radiotherapy or constitutional weakness.

TCM decoction:modified Zhī Bǎi Dì Huáng Wán.

8.2.3 Liver-kidney depletion

Indication:common seen in patients with bone marrow suppression after radiotherapy and chemotherapy or constitutional weakness.

Representative decoction:modified with Liù Wèi Dì Huáng Wán.

8.2.4 Liver depression and qi stagnation

Indication:emotional depression or irritability,manifestation with frequent sighing,oppressive and scurrying pain in the chest or lesser abdomen.

TCM decoction:modified with Hǎi Zǎo Yù Hú Tāng or Bàn Xià Hòu Pò Tāng.

8.2.5 Yang deficiency with congealing phlegm

Indication:manifested by clear-thin expectoration,clear and abundant urine,loose stool,bland taste in the mouth and lack of thirst,blackish complexion.

TCM formula:modified with Yáng Hé Tāng combined with Bàn Xià Xiāo lóng Wán.

8.2.6 Binding of toxin and blood stasis

Indication:manifested with tumor or nodular mass,rapid growth,or metastasis.

TCM formula:modified with Xī Huáng Wán or Xiǎo Jīn Dān.

9.Multidisciplinary treatment (MDT) and follow-up

9.1 MDT

MDT can provide thyroid cancer patients with best prognosis.Involved disciplines include surgery,pathology,diagnostic imaging,nuclear medicine,radiotherapy,endocrinology and medical oncology.Individualized and precise treatment should be implemented for different patients or different treatment stages of the same patient.Individualized and comprehensive treatment plans should be formulated in consultation with a multidisciplinary team.

9.2 Follow-up of DTC

Long-term surveillance and follow-up are required for thyroid cancer patients to achieve the following goals:1)identify recurrent/metastatic tumor at early stage;2) track disease status and treatment response for recurrent or residual DTC;3) evaluate the effect of TSH suppression treatment;and 4) monitor additional complications (e.g.,cardiovascular diseases,other malignant tumors).

For postoperative DTC,exogenous thyroxine is required and the target TSH level should be determined depending on the risk assessment.Thyroid function should be reexamined at 4?6 weeks following thyroxine dose adjustment.Follow-up terms may be extended as appropriate if results are satisfactory.

Serum Tg and TgAb should be monitored in postablative DTC (received surgery and radioiodine treatment),with Tg or sTg examined 6 months after radioiodine treatment,sTg re-evaluated at 12 months after treatment,and Tg monitored every 6?12 months thereafter.Patients with intermediate or high risk of recurrence are advised to have dynamic Tg monitoring over the course of three years.

Neck ultrasonography should be scheduled for 3 months after surgery for the high-risk group and 6 months for the low-and intermediate-risk groups.If suspicious lymph nodes are detected,the interval between scans can be further reduced,and ultrasound-guided biopsy and/or elution TG detection can be performed as appropriate.

Dx-WBS can be applied selectively during the follow-up of postablative DTCs,with scan intervals of 6?12 months for intermediate-or high-risk tumors and immediately for progressively elevated Tg or suspected recurrence.Dx-WBS is not required for low-and intermediate-risk DTC with no biochemical and structural evidence of disease and no radioiodine activity beyond the thyroid bed.

CT and MRI are not routinely required during DTC follow-up.However,they should be considered when 1)ultrasonography is not enough to evaluate extensive lesions;2) upper aerodigestive tract is involved;and 3) elevated Tg or TgAb in high-risk individuals.

18F-FDG PET is not indicated for DTC but can help with disease localization and evaluation in cases of 1)elevated Tg but negative Dx-WBS cases;2) tumors that do not accumulate radioiodine;and 3) invasive or metastatic DTC.

Long-term follow-up of DTC should also include 1)evaluation for secondary tumors and influence on reproductive system if the patient had high accumulative RAI dose;2) effect and adverse events of TSH suppression;and 3) comorbidities like severe cardiovascular diseases or malignant tumors may have higher priority for consideration.

9.3 Management of recurrent or metastatic DTCs

Local recurrence may occur in residual thyroid tissues and regional areas of the neck.Distant metastasis may occur in the lung,bone,brain and liver.The treatment options for recurrent or metastatic lesions are surgical resection (best option if resectable),131I therapy (for those with iodine uptake),observation with TSH suppression (for those with slow tumor progression,asymptomatic or without significant regional involvement such as the central nervous system),targeted therapy (refractory DTC patients with rapidly progressive disease),and approved drug clinical trials (for those with rapidly progressive disease).Patients’general status,comorbidities and previous response to therapies must be taken into consideration.

9.4 Follow-up of MTC

Postoperative thyroid function should be kept in normal range.Serum calcitonin and CEA are specific biochemical markers of MTC.For patients whose biochemical markers return to normal after surgery,the follow-up period is similar as that of low-risk DTC.For patients whose biochemical markers have not fallen into the normal range but are at lower levels,the follow-up period is similar as that of high-risk DTC.For patients whose biochemical markers are still at high levels,close follow-up should be performed.CT and MRI are necessary for patients with high-level biochemical markers.PET-CT is also indicated when necessary.

Working group members

Group leaders:Shaoyan Liu,Zhengang Xu

Group members:Ping Wang,Yu Wang,Yiming Zhu,Hui Sun,Ankui Yang,Xiaohui He,Yansong Lin,Junlin Yi,Dehong Luo,Jugao Fang,Bingyin Shi,Jianwu Qin,Ming Gao,Liang Guo,Tao Huang,Minghua Ge,Haizhen Lu,Quan Liao

Translation group members

Group leaders

Shaoyan LiuNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College

Yansong LinState Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences

Secretary

Yiming ZhuNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College (Beijing)&Hebei Cancer Hospital,Chinese Academy of Medical Sciences (Langfang)

Group members (listed alphabetically by last name)

Lin GuiNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College

Xiaorong HouPeking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College

Ziren KongNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College

Yuanlin PiaoPeking Union Medical College Hospital

Yuqing SunState Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences

Hao WangQingdao Municipal Hospital,School of Medicine,Qingdao University

Jian WangNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College

Bo ZhangChina-Japan Friendship Hospital

Ye ZhangNational Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College

Kun ZhengState Key Laboratory of Complex Severe and Rare Diseases,Peking Union Medical College Hospital,Peking Union Medical College and Chinese Academy of Medical Sciences