Management of thyroid cancer: United Kingdom National Multidisciplinary Guidelines

This is the official guideline endorsed by the specialty associations involved in the care of head and neck cancer patients in the UK. This paper provides recommendations on the management of thyroid cancer in adults and is based on the 2014 British Thyroid Association guidelines. Recommendations • Ultrasound scanning (USS) of the nodule or goitre is a crucial investigation in guiding the need for fine needle aspiration cytology (FNAC). (R) • FNAC should be considered for all nodules with suspicious ultrasound features (U3–U5). If a nodule is smaller than 10 mm in diameter, USS guided FNAC is not recommended unless clinically suspicious lymph nodes on USS are also present. (R) • Cytological analysis and categorisation should be reported according to the current British Thyroid Association Guidance. (R) • Ultrasound scanning assessment of cervical nodes should be done in FNAC-proven cancer. (R) • Magnetic resonance imaging (MRI) or computed tomography (CT) should be done in suspected cases of retrosternal extension, fixed tumours (local invasion with or without vocal cord paralysis) or when haemoptysis is reported. When CT with contrast is used pre-operatively, there should be a two-month delay between the use of iodinated contrast media and subsequent radioactive iodine (I131) therapy. (R) • Fluoro-deoxy-glucose positron emission tomography imaging is not recommended for routine evaluation. (G) • In patients with thyroid cancer, assessment of extrathyroidal extension and lymph node disease in the central and lateral neck compartments should be undertaken pre-operatively by USS and cross-sectional imaging (CT or MRI) if indicated. (R) • For patients with Thy 3f or Thy 4 FNAC a diagnostic hemithyroidectomy is recommended. (R) • Total thyroidectomy is recommended for patients with tumours greater than 4 cm in diameter or tumours of any size in association with any of the following characteristics: multifocal disease, bilateral disease, extrathyroidal spread (pT3 and pT4a), familial disease and those with clinically or radiologically involved nodes and/or distant metastases. (R) • Subtotal thyroidectomy should not be used in the management of thyroid cancer. (G) • Central compartment neck dissection is not routinely recommended for patients with papillary thyroid cancer without clinical or radiological evidence of lymph node involvement, provided they meet all of the following criteria: classical type papillary thyroid cancer, patient less than 45 years old, unifocal tumour, less than 4 cm, no extrathyroidal extension on ultrasound. (R) • Patients with metastases in the lateral compartment should undergo therapeutic lateral and central compartment neck dissection. (R) • Patients with follicular cancer with greater than 4 cm tumours should be treated with total thyroidectomy. (R) • I131 ablation should be carried out only in centres with appropriate facilities. (R) • Serum thyroglobulin (Tg) should be checked in all post-operative patients with differentiated thyroid cancer (DTC), but not sooner than six weeks after surgery. (R) • Patients who have undergone total or near total thyroidectomy should be started on levothyroxine 2 µg per kg or liothyronine 20 mcg tds after surgery. (R) • The majority of patients with a tumour more than 1 cm in diameter, who have undergone total or near-total thyroidectomy, should have I131 ablation. (R) • A post-ablation scan should be performed 3–10 days after I131 ablation. (R) • Post-therapy dynamic risk stratification at 9–12 months is used to guide further management. (G) • Potentially resectable recurrent or persistent disease should be managed with surgery whenever possible. (R) • Distant metastases and sites not amenable to surgery which are iodine avid should be treated with I131 therapy. (R) • Long-term follow-up for patients with differentiated thyroid cancer (DTC) is recommended. (G) • Follow-up should be based on clinical examination, serum Tg and thyroid-stimulating hormone assessments. (R) • Patients with suspected medullary thyroid cancer (MTC) should be investigated with calcitonin and carcino-embryonic antigen levels (CEA), 24 hour catecholamine and nor metanephrine urine estimation (or plasma free nor metanephrine estimation), serum calcium and parathyroid hormone. (R) • Relevant imaging studies are advisable to guide the extent of surgery. (R) • RET (Proto-oncogene tyrosine-protein kinase receptor) proto-oncogene analysis should be performed after surgery. (R) • All patients with known or suspected MTC should have serum calcitonin and biochemical screening for phaeochromocytoma pre-operatively. (R) • All patients with proven MTC greater than 5 mm should undergo total thyroidectomy and central compartment neck dissection. (R) • Patients with MTC with lateral nodal involvement should undergo selective neck dissection (IIa–Vb). (R) • Patients with MTC with central node metastases should undergo ipsilateral prophylactic lateral node dissection. (R) • Prophylactic thyroidectomy should be offered to RET-positive family members. (R) • All patients with proven MTC should have genetic screening. (R) • Radiotherapy may be useful in controlling local symptoms in patients with inoperable disease. (R) • Chemotherapy with tyrosine kinase inhibitors may help in controlling local symptoms. (R) • For individuals with anaplastic thyroid carcinoma, initial assessment should focus on identifying the small proportion of patients with localised disease and good performance status, which may benefit from surgical resection and other adjuvant therapies. (G) • The surgical intent should be gross tumour resection and not merely an attempt at debulking. (G)

Differentiated thyroid cancer Introduction Thyroid nodules are common, the incidence of palpable nodules in women and men being approximately 5 and 1 per cent, respectively. Use of ultrasound scanning (USS) substantially increases their detection in the general population to approximately 50-70 per cent. Thyroid cancer remains rare, with an incidence in the UK of approximately 5 per 100 000 women and 2 per 100 000 men. Thyroid cancer is the most common endocrine malignancy, but accounts for only 1 per cent of all malignancies. Evidence suggests an increasing incidence; however, the survival rates remain static.
Long-term prognosis for differentiated thyroid cancer (DTC) is excellent, with survival rates for adults being 92-98 per cent at 10-year follow-up. However, 5-20 per cent of patients develop local or regional recurrence requiring further treatment and 10-15 per cent go on to develop distant metastases. Factors influencing prognosis include gender, age at presentation, histology and tumour stage. Accurate diagnosis, treatment and long-term follow-up are essential to achieve and maintain excellent survival rates.
There have been several sets of detailed guidelines published on the diagnosis and management of thyroid cancer. Two key ones are the Guidelines for the Management of Thyroid Cancer (2014) by the British Thyroid Association and Royal College of Physicians, 1 and the Revised American Thyroid Association Guidelines (2016). 2 These documents are extensive and cover every aspect of care in great detail. Given differences in presentation, pathophysiology and outcomes, separate guidelines exist for children with DTC, 3 and consensus statements on the various surgical interventions. 4 Patients may initially be seen by a surgeon, endocrinologist, clinical oncologist or nuclear medicine physician, who must be a core member of the thyroid cancer multidisciplinary team (MDT). The goals of treatment for DTC are set out in Box I. Symptoms warranting immediate referral. Patients presenting with airway compromise, including stridor, associated with a thyroid nodule or goitre should be referred for an immediate opinion.
Symptoms warranting urgent general practitioner (GP) referral (two-week wait rule). Patients presenting with hoarseness of voice or a change in their voice associated with a thyroid nodule or goitre, children with a thyroid nodule, individuals with cervical lymphadenopathy associated with a thyroid nodule or a painless thyroid mass, which is rapidly enlarging over a period of weeks should be referred for an urgent opinion.

Investigation
Recommended clinical investigations. These include: • Clinical evaluation of thyroid, cervical and supraclavicular nodes • Thyroid-stimulating hormone (TSH) • Ultrasound of the nodule (Table I) • Fine needle aspiration cytology (FNAC) if ultrasound features are suspicious of malignancy • Documented cytological score (Table II). A core biopsy (with or without USS guidance) is warranted if a diagnosis of lymphoma is suspected • Calcitonin only in suspected cases of medullary thyroid cancer (MTC) (routine use not recommended) • Pre-operative vocal cord check • Note that a serum thyroglobulin (Tg) is not recommended.
Ultrasound of thyroid nodules. Ultrasound is very useful in the investigation of thyroid nodules and should be used to guide the need for further investigation including FNAC. Ultrasound-guided FNAC increases the yield of diagnostic cytology significantly. Current guidelines recommend that ultrasonographers use the U grade (Table I) to classify nodules according to ultrasound appearances. 5 Ultrasound evaluation of cervical lymphadenopathy. Pathological studies suggest that microscopic lymph node metastases are very common in papillary thyroid cancer (PTC). However, macroscopic disease is less common (20-50 per cent). Pre-operative ultrasonography is effective in identifying suspicious nodes in approximately 20-30 per cent of patients with PTC and may alter the surgical approach. FNAC of suspicious nodes is recommended. Tg estimation of cystic fluid may be of use in the absence of sufficient diagnostic material.

Recommendations
• Ultrasound scanning of the nodule or goitre is a crucial investigation in guiding the need for FNAC (R) • FNAC should be considered for all nodules with suspicious ultrasound features (U3-U5). If a nodule is smaller than 10 mm in diameter, USS-guided FNAC is not recommended unless clinically suspicious lymph nodes on USS are also present (R) • Cytological analysis and categorisation should be reported according to the current British Thyroid Association Guidance (R) • Ultrasound scanning assessment of cervical nodes should be done in FNAC-proven cancer (R) • Magnetic resonance imaging (MRI) or computed tomography (CT) should be done in suspected cases of retrosternal extension, fixed tumours (local invasion with or without vocal cord paralysis) or when haemoptysis is reported. When CT with contrast is used preoperatively, there should be a two-month delay between the use of iodinated contrast media and subsequent radioactive iodine therapy (R) • Fluoro-deoxy-glucose-positron emission tomography imaging is not recommended for routine evaluation (G)

Staging
The tumour, nodes and metastases (TNM) staging system (Table III) is used to stage thyroid cancers and this should be used in all cases. Post-operatively, an 'R' classification can be given which indicates the amount of residual disease present. The TNM classification can then be used in combination with patient characteristics to define likely prognosis (Table IV).

Surgery
Surgeons performing operations for confirmed or suspected thyroid cancer should be core members of the thyroid cancer MDT and should perform a minimum of 20 thyroidectomies per year. Complex surgery and lymph node surgery should be undertaken by nominated surgeons in the cancer centre with specific training in, and experience of, thyroid oncology. All patients with suspected or confirmed thyroid cancer should have pre-operative imaging with ultrasound. Cross-sectional imaging with CT or MRI may also be indicated.
In the context of thyroid cancer, surgery may be diagnostic (e.g. hemithyroidectomy following Thy 3 or Thy 4 cytology) or therapeutic.
Thyroid surgery for papillary thyroid cancer (PTC). A strategy for the surgical treatment of PTC is detailed in Table V. All cases should be discussed pre-operatively at the thyroid cancer MDT.
Initial surgery for follicular thyroid cancer. The majority of patients undergoing surgery for follicular thyroid cancer will be undiagnosed at the time of the initial surgery (Thy 3). Frozen section histology cannot currently reliably differentiate benign follicular lesions from follicular thyroid cancer, and therefore this strategy is not recommended. An operative strategy for surgical treatment of follicular cancer is outlined in Table VI.
Low-risk patients with a diagnosis of minimally invasive tumour less than 4 cm following hemithyroidectomy do not require further treatment. Hurthle cell cancers (follicular oncocytic) tend to be more aggressive and should be treated by total (completion) thyroidectomy (see Table VI).
Management of lymph nodes in differentiated thyroid cancer (DTC). Prophylactic level VI lymph node dissection is associated with a higher incidence of recurrent laryngeal nerve damage and long-term permanent hypoparathyroidism. 6 It is therefore not routinely recommended, but in individuals with high-risk tumours, this should be discussed in the spirit of personalised decision making. Prophylactic level VI nodal dissection is not recommended in low risk, small papillary and most follicular cancers.
Prophylactic level VI nodal dissection is recommended in patients with known involved lateral Completion thyroidectomy. Completion thyroidectomy is not needed in low-risk, unifocal, intrathyroidal tumours less than 4 cm in diameter, with clinically negative lymph nodes.
Locally advanced disease. Where possible, locally advanced disease should be resected. Preservation of recurrent laryngeal nerves should be attempted in almost all cases. Extensive resection of trachea, larynx and oesophagus should be considered if potentially curative. Where disease is unresectable, radiotherapy and radioiodine should be considered.
Microcarcinomas. Microcarcinomas are differentiated thyroid carcinomas less than 10 mm in maximum dimension and are predominantly papillary carcinomas. The management of papillary microcarcinomas is outlined in Figure 1.

Recommendations
• In patients with thyroid cancer, assessment of extrathyroidal extension and lymph node disease in the central and lateral neck compartments should be undertaken preoperatively by USS and cross-sectional imaging (CT or MRI) if indicated (R) • For patients with Thy 3f or Thy 4 FNAC a diagnostic hemithyroidectomy is recommended (R) • Total thyroidectomy is recommended for patients with tumours greater than 4 cm in diameter, or tumours of any size in association with any of the following characteristics: multifocal disease, bilateral disease, extrathyroidal spread (pT3 and pT4a), familial disease, and those with clinically or radiologically involved nodes and/or distant metastases (R)  Post-operative management After total or near total thyroidectomy patients should be commenced on suppressive doses of levothyroxine (2 μg/kg) or liothyronine 20 mcg tds in accordance with local protocols. Calcium levels should be routinely checked within 24 hours and hypocalcaemia treated appropriately.
Thyroglobulin levels should be checked no earlier than six weeks after surgery.
All patients with thyroid cancer should be clinically staged using the TNM classification and also scored using one of the clinicopathological scoring systems to enable planned follow-up, identification of high risk patients and those who would benefit from radio-iodine therapy. In addition, all patients should have access to a thyroid cancer clinical nurse specialist and be given written information.
Persistent voice dysfunction should be investigated and referral to a specialised practitioner for assessment and speech therapy sought.
Patients with long-term hypocalcaemia (hypoparathyroidism) should have their calcium levels regularly monitored either in association with an endocrinologist or with their GP.
Following surgery, initial post-operative risk stratification for risk of recurrence can occur.
Low-risk patients have the following characteristics: •  Intermediate-risk patients have any of the following characteristics: • Microscopic invasion of tumour into the peri-thyroidal soft tissues (T3) at initial surgery • Cervical lymph node metastases (N1a or N1b) • Tumour with aggressive histology (tall cell or columnar cell PTC, diffuse sclerosing PTC, poorly differentiated elements) or angioinvasion.

Radioiodine (I 131 ) ablation and external beam radiotherapy (EBR) in DTC
The current recommendations with regards to I 131 ablation following total thyroidectomy are outlined in Table VII.
Patients should be prepared for I 131 by having a lowiodine diet for one to two weeks prior to treatment. Recombinant TSH (rhTSH) therapy prior to I 131 is preferable to thyroid hormone withdrawal, and is preferred by patients, providing they meet the following criteria: pT1 to T3, pN0 or NX or N1, and M0 and R0 (no microscopic residual disease). Pregnancy should be excluded prior to giving I 131 . A post-ablation  scan should be performed after I 131 when residual activity levels permit satisfactory imaging. Practically, this is generally 2-10 days following treatment.
Following I 131 , TSH should be suppressed to <0.1 mIU/l pending dynamic risk stratification at 9-12 months.
Adjuvant EBR should be considered in unresectable tumours in addition to I 131 and where there is residual disease following surgical resection even if the residual tumour concentrates I 131 .
In the 9 to 12 months following surgery and I 131 for DTC with an R0 resection, patients should undergo dynamic risk stratification (Table VIII). Patients are then categorised as having either an excellent response, an indeterminate response or an incomplete response.
Monitoring Tg levels. Thyroglobulin monitoring is most effective following total or near total thyroidectomy and I 131 and is an important modality in detecting residual or recurrent disease. Physicians should be aware that Tg estimations vary according to the assay method, the individual laboratory and the presence of anti-Tg antibodies and take these considerations into account when evaluating Tg levels in individual patients.
The patient should have their Tg levels checked at 6-12 monthly intervals. Rising Tg levels are highly suspicious of recurrent disease. Thyroglobulin evaluation is most effective following TSH stimulation, either by direct rhTSH stimulation or by withdrawal of thyroid hormone replacement.
Following total or near total thyroidectomy and I 131 ablation, low-risk patients with undetectable Tg levels on TSH suppression should have a TSH-stimulated Tg assessment along with ultrasound of cervical nodes at 9-12 months following I 131 ablation. If Tg levels remain undetectable following TSH stimulation, then future recurrent disease is highly unlikely and patients may revert to yearly Tg estimation whilst remaining on TSH suppression.
A rise in Tg may be suggestive of recurrent or residual disease, but is usually from a thyroid remnant. In lowrisk patients, an expectant policy can be maintained and repeated TSH stimulated assessment performed, with the expectation that Tg levels will fall. Rising or persistently elevated Tg needs further evaluation.
The use of rhTSH-stimulated Tg estimation or rhTSH I 131 therapy is necessary in the following cases: hypopituitarism, functional metastases (suppressing TSH), severe angina, advanced disease (frail patient) and history of psychiatric disturbance from hypothyroidism.

Recommendations
• I 131 ablation or therapy should be carried out only in centres with appropriate facilities (R) • Serum Tg should be checked in all postoperative patients with DTC, but not earlier than six weeks after surgery (R) • Patients who have undergone total or near total thyroidectomy should be started on levothyroxine 2 μg/kg or liothyronine 20 mcg tds after surgery (R) • The majority of patients with a tumour more than 1 cm in diameter, who have undergone total or near-total thyroidectomy, should have I 131 ablation or therapy (R) • A post-ablation scan should be performed 3-10 days after I 131 ablation (R) • Post-therapy dynamic risk stratification at 9-12 months is used to guide further management (G)

Persistent and recurrent disease, locoregional recurrence and distant metastases
Potentially resectable disease is best managed by surgery (including local cervical nodes and soft tissue disease in the neck), followed by I 131 . Residual disease not amenable to resection or resistant to I 131 therapy is best treated with high dose palliative EBR. Therapeutic central compartment, with or without lateral compartment, nodal clearance should therefore High risk Suppress TSH < 0.1 mIU/l indefinitely * Assumes the absence of interference in the Tg assay. Tg = thyroglobulin; TSH = thyroid stimulating hormone; US = ultrasound be performed for all persistent or recurrent disease confined to the neck. Impalpable nodes greater than 5-8 mm seen on USS or cross-sectional imaging following I 131 therapy should be considered for removal. Removing nodes less than 5-8 mm has not be shown to be of benefit.
Where technically feasible, tumours invading the aero-digestive tract should be resected in combination with radiotherapy. Outcome is very dependent on completeness of resection and preservation of function. Great care should therefore be taken in the selection and discussion of such patients at the MDT.
Distant metastases develop in 5-23 per cent of patients with DTC. Sites not amenable to surgical resection should be treated with I 131 therapy. Long-term survival may be expected in patients whose tumours take up I 131 . Distant metastases are usually seen in the lungs and bones. There is no maximum limit to the cumulative dose of I 131 that patients with persistent disease may receive and pulmonary fibrosis appears to be a rare side effect. Surgical resection of bony metastases should be considered (especially in patients below 45 years of age). Metastases not cured by I 131 should be treated with EBR. Other modalities such as intra-arterial embolisation, pamidronate infusion, radiofrequency ablation or vertebroplasty may be considered in cases of painful lesions.

Clinical presentation
Patients usually present clinically with a thyroid nodule or neck mass with or without cervical lymphadenopathy (in the same fashion as with DTC). History however, may reveal other symptoms such as flushing, loose stools or diarrhoea (which suggest MTC) and is vitally important in determining a potential familial element. FNAC may be diagnostic (when combined with calcitonin staining in suspicious cases), but often is reported as Thy 3.

Investigation
When MTC is suspected (or proven) patients must undergo the following investigations prior to surgery 8 : • Calcitonin and CEA levels • Twenty-four-hours urine estimation of catecholamines and nor metanephrines (or plasma nor metanephrines) to identify or exclude phaeochromocytoma • Serum calcium and parathyroid hormone (PTH) to identify or exclude hyperparathyroidism • CT, MRI or USS of the neck are indicated as they may help guide the extent of surgical resection at initial surgery • RET proto-oncogene mutational analysis should be performed after surgery once diagnosis is established, even in the absence of a familial history.
Staging TNM staging for MTC follows the same criteria as for DTC (Table IX). Persistent or recurrent MTC Calcitonin levels are most informative six months after initial surgery. It is important to distinguish persistent locoregional disease (following either inadequate initial surgery or local lymph node metastases) from distant disease. Early local recurrence following adequate local surgery (total thyroidectomy and level VI nodes) is unusual. The likely source of raised calcitonin in this circumstance is the lateral compartment cervical nodes, i.e. persistent disease. When indicated, reoperation including further central compartment surgery and lateral neck node dissection should be performed. The primary aim should always be to control local disease.
CT, MRI, USS, selective arteriography, I 131 -metaiodobenzylguanidine, 18 Fluoro-deoxy-glucose positron emission tomography, In 111 -octreotide and direct laparoscopic visualisation of the liver may all be useful in identifying the source of a raised calcitonin, but their use in patients with calcitonin levels <400-500 pg/ ml is unlikely to identify metastases. When indicated, isolated metastases should be considered for surgical resection.

Recommendations
• All patients with known or suspected MTC should have serum calcitonin and biochemical screening for phaeochromocytoma preoperatively (R) • All patients with proven MTC >5 mm should undergo total thyroidectomy and central compartment neck dissection (R) • Patients with lateral nodal involvement should undergo selective neck dissection (IIa-Vb) (R) • Patients with central node metastases should undergo ipsilateral prophylactic lateral node dissection (R) • Prophylactic thyroidectomy should be offered to RET-positive family members (R) • All patients with proven MTC should have genetic screening (R)

Radiotherapy and chemotherapy
Radiotherapy is of use in controlling local symptoms in patients with inoperable disease and improving the relapse-free rate following central or lateral compartment surgery where residual disease is present macroscopically or microscopically. Tyrosine kinase inhibitors can be effective in controlling symptoms in patients with metastatic disease.
Somatostatin analogues may be effective in alleviating the unpleasant gastrointestinal symptoms that patients with advanced cases of MTC experience.

Recommendations
• Radiotherapy may be useful in controlling local symptoms in patients with inoperable disease (R) • Chemotherapy with tyrosine kinase inhibitors may help in controlling local symptoms (R)

Follow-up
Lifelong follow-up is recommended for all patients with MTC. Screening should include calcitonin and CEA. Thyroid-stimulating hormone suppression is not necessary. Rising calcitonin levels should trigger MANAGEMENT OF THYROID CANCER: UK GUIDELINES S159 investigations to identify potentially treatable metastatic disease.

Anaplastic thyroid cancer
The prognosis of patients with anaplastic thyroid cancer (ATC) is poor. Many patients present with a history of a rapidly enlarging thyroid mass in a longstanding goitre. Diagnosis can be established by fine needle aspiration or core biopsy. Core biopsy will help differentiate ATC from thyroid lymphoma which can present in a similar manner. Total thyroidectomy may be curative for very small cancers. In more advanced disease surgery may be of benefit if R0/R1 resection is achievable. 9 External beam radiotherapy and chemotherapy may be used as adjuvant treatments in patients with R0/R1 resection and no evidence of distant disease. 'Debulking' surgery should be avoided when complete resection cannot be achieved. Palliative chemoradiation may be of some value in selected cases. Palliative care has a principal role in management of these patients.

Recommendations
• Initial assessment should focus on identifying the small proportion of patients with localised disease and good performance status, who may benefit from surgical resection and other adjuvant therapies (G) • The surgical intent should be gross tumour resection and not merely an attempt at debulking (G)