Clinical presentation

In all cases, a detailed history is required. Clinical features associated with an increased risk of malignancy in individuals with a thyroid nodule include:

• • age younger than 20 or older than 60 years

• • firmness of the nodule on palpation

• • rapid growth

• • fixation to adjacent structures

• • vocal cord paralysis

• • associated lymphadenopathy

• • history of neck irradiation

• • family history of thyroid cancer

• • history of Hashimoto's thyroiditis (risk factor for thyroid lymphoma).

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.

Table I U grading of thyroid nodules

FNAC = fine needle aspiration cytology

Table II Thyroid FNAC diagnostic categories

* Hemithyroidectomy consists of removal of a thyroid lobe and the isthmus

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).

Table III Tumour, nodes and metastases 7th edition staging system for differentiated thyroid cancer

MDT = multidisciplinary team

Table IV Group staging and survival for differentiated thyroid cancer

* Undifferentiated or anaplastic carcinomas are all stage 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.

Table V Initial surgery for papillary thyroid carcinoma

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.

Table VI Initial surgery for follicular thyroid cancer

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).

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 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 recommended for patients without clinical or radiological evidence of lymph node involvement, provided they meet all of the following criteria: classical type PTC, below 45 years, unifocal tumour, less than 4 cm, no extrathyroidal extension on US (R)

• • Patients with metastases in the lateral compartment should undergo therapeutic lateral and central compartment neck dissection (R)

• • Patients with follicular tumours greater than 4 cm should be treated with total thyroidectomy (R)

Fig. 1 Flow diagram outlining management of papillary microcarcinomas. Multiple risk factors may tip the balance in favour of total thyroidectomy.

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:

• • No local or distant metastases

• • All macroscopic tumours have been resected, i.e. R0 or R1 resection

• • No tumour invasion of locoregional tissues or structures

• • The tumour does not have aggressive histology (tall cell or columnar cell PTC, diffuse sclerosing PTC, poorly differentiated elements) or angioinvasion.

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.

High-risk patients have any of the following characteristics:

• • Extrathyroidal invasion

• • Incomplete macroscopic tumour resection (R2)

• • Distant metastases. (M1)

Radioiodine (I¹³¹) ablation and external beam radiotherapy (EBR) in DTC

The current recommendations with regards to I¹³¹ ablation following total thyroidectomy are outlined in Table VII.

Table VII Indications for I¹³¹ ablation following total thyroidectomy for differentiated thyroid cancer

Patients should be prepared for I¹³¹ by having a low-iodine diet for one to two weeks prior to treatment. Recombinant TSH (rhTSH) therapy prior to I¹³¹ 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 I¹³¹. A post-ablation scan should be performed after I¹³¹ when residual activity levels permit satisfactory imaging. Practically, this is generally 2–10 days following treatment.

Following I¹³¹, 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 I¹³¹ and where there is residual disease following surgical resection even if the residual tumour concentrates I¹³¹.

In the 9 to 12 months following surgery and I¹³¹ 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.

Table VIII Dynamic risk stratification following treatment for DTC and TSH suppression targets for patients treated with total thyroidectomy and I¹³¹ ablation with R0 resection

* Assumes the absence of interference in the Tg assay. Tg = thyroglobulin; TSH = thyroid stimulating hormone; US = ultrasound

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 I¹³¹. Residual disease not amenable to resection or resistant to I¹³¹ therapy is best treated with high dose palliative EBR.

Therapeutic central compartment, with or without lateral compartment, nodal clearance should therefore 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 I¹³¹ 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 I¹³¹ therapy. Long-term survival may be expected in patients whose tumours take up I¹³¹. Distant metastases are usually seen in the lungs and bones. There is no maximum limit to the cumulative dose of I¹³¹ 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 I¹³¹ 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.

Long-term follow-up

Lifelong follow-up of DTC is recommended to monitor for late recurrence (often treatable and curable), effects of long-term TSH suppression (atrial fibrillation and osteoporosis) and late side effects of I¹³¹. Clinical examination and history, Tg determination, TSH suppression and where necessary calcium monitoring should all be performed. Ultrasound scanning as per established protocols may also be undertaken.

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 surgeryReference Wells, Asa, Dralle, Elisei, Evans and Gagel 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).

Table IX Group staging for medullary thyroid cancer

Management-surgery for MTC

All patients with MTC should undergoReference Wells, Asa, Dralle, Elisei, Evans and Gagel ⁸ :

• • Total thyroidectomy and central compartment node clearance (level VI). This should be performed even in the presence of disseminated metastases to control local disease.

• • In the presence of central compartment lymph node metastases, ipsilateral prophylactic neck dissection is recommended as up to 70 per cent of patients will have lateral nodal metastases.

• • Patients with clinically involved lateral compartment nodes should have a therapeutic lateral neck dissection to eradicate local disease.

• • All T2–T4 tumours should also undergo prophylactic bilateral selective neck dissection IIa–Vb.

• • Intra-thoracic disease below the level of the brachiocephalic vein should be resected via sternotomy where feasible.

• • Prophylactic thyroidectomy should be offered to RET-positive family members. Timing and extent of surgery are dependent on genotype (codon mutation), the calcitonin level and age at detection of RET positivity.

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, re-operation 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, I¹³¹-metaiodobenzylguanidine, ¹⁸Fluoro-deoxy-glucose positron emission tomography, In¹¹¹-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.

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.

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 investigations to identify potentially treatable metastatic disease.