112 Thyroid Disease—Malignant
Thyroid carcinoma (TC) is the most common endocrine malignancy, but it is relatively rare. Current incidence in the United Kingdom is approximately 5 per 100,000 in women; however, incidence rates are projected to rise by 74% in the United Kingdom to 11 cases per 100,000 people by 2035. It is predicted that nearly 7,000 cases of TC will be diagnosed in the United Kingdom in 2035. Despite this increasing incidence the survival rates remain static.
The cause for most TC is unknown. However, several factors are now known to be important in its causation. These are as follows:
• Natural diet-deficient iodine.
• Increased secretion of thyroid-stimulating hormone (TSH).
• Benign thyroid disease. Adenomas, multi-nodular goitres and thyroiditis.
• A previous history of ionising radiation. Patients who had radiotherapy treatment or are survivors of atomic explosions or accidents are at higher risk especially children and adolescents.
• Family history. Familial adenomatous polyposis patients have an increased risk of TC.
• Previous history of cancer. Patients who have been treated for non-Hodgkin’s lymphoma, breast cancer, oesophageal cancer and testicular cancer are at higher risk.
• Factors related to women and reproduction. Pregnancy, use of oral contraceptives, hormonal replacement therapy (HRT) and menopause have been implicated in some studies, but the evidence is not conclusive.
Other factors such as diabetes, acromegaly and obesity have also been implicated.
There are various types of thyroid tumours and these are shown in Table 112.1.
1. Papillary adenocarcinoma or papillary thyroid carcinoma (PTC) PTC (along with follicular adenocarcinoma) is a differentiated thyroid cancer (DTC) and accounts for 80% of thyroid malignancy. It occurs in all ages and is the commonest type of thyroid cancer in children. It usually presents as a solitary thyroid nodule (STN), but is often multicentric (up to 60% of cases). PTC either exists in a pure papillary form, as mixed papillary/follicular carcinoma, or as the follicular variant papillary carcinoma. It is associated with a high incidence of cervical lymphadenopathy which may, on occasion, be the only initial presenting feature. Less than 10% will have distant metastases, which are usually to the lungs.
• Follicular cell adenoma
• Hurthle cell adenoma
• Papillary carcinoma (80%)
– Pure papillary
– Mixed papillary—follicular
– Follicular variant
• Follicular carcinoma (10%)
• Hurthle cell carcinoma
• Medullary carcinoma (5%)
• Anaplastic carcinoma
• Squamous cell carcinoma
• Kidney, lung, colon and breast
2. Follicular adenocarcinoma or follicular thyroid carcinoma (FTC) FTC occurs in older age groups between 40 and 60 years and is seldom seen under the age of 30. It is less common than PTC (10% of all thyroid malignancy) and usually presents as a STN or occasionally with either distant bony metastases or cervical node involvement (about 10%). While PTC can be identified on fine-needle aspiration cytology (FNAC), it is not possible to diagnose a FTC using this technique, since it cannot distinguish an adenoma from a carcinoma. Therefore, a diagnostic/therapeutic thyroid lobectomy is usually required.
3. Medullary thyroid carcinoma (MTC) MTC accounts for about 5% of all cases of thyroid malignancy. MTC arise from the para-follicular or C cells which secrete calcitonin, and this can be a valuable tumour marker. It may occur as part of the multiple endocrine neoplasia (MEN) syndrome, as familial non-MEN disease or in sporadic form. In patients with MEN, it is frequently bilateral (90%) and multi-focal, and cervical node metastases are common. The autosomal dominant MEN2A is associated with pheochromocytomas (10%) and parathyroid hyperplasia (60%). MEN2B is medullary carcinoma associated with mucosal neuromas, pheochromocytomas, and Marfan’s syndrome. Genetic screening is now possible for familial disease using the RET proto-oncogene.
4. Thyroid lymphoma (TL) Primary TLs are uncommon and account for fewer than 5% of all lymphoma cases. They usually present as a rapidly increased swelling of the neck in an elderly woman and there is often a history of Hashimoto’s thyroiditis. The clinical presentation can be identical to anaplastic carcinoma and both these conditions should be excluded from each other by core needle or open biopsy. Once the diagnosis is made, patients require formal staging and treatment is with radiotherapy plus or minus chemotherapy.
5. Anaplastic thyroid carcinoma (ATC) ATCs are common in elderly patients and many are superimposed on a long-standing multi-nodular goitre. They present with rapid thyroid enlargement, are aggressively malignant and rapidly invade surrounding structures. They have a poor prognosis. Its histology comprises of swarms of small cells and can be difficult to distinguish from lymphoma, which has a good prognosis. Therefore, immunohistochemical staining for cytokeratin squamous cell marker and CD4/CD8 lymphoid cell markers is required. Treatment of anaplastic carcinoma has changed over the past few years. For patients with localised ATC, good performance status, and no evidence of local invasion or distant metastases, surgery could be considered to achieve local control and minimise local invasion and progression. Radiotherapy is often ineffective, a tracheostomy may be required and most patients are dead within 1 year.
112.3 Clinical and Diagnostic Evaluation and Treatment Setting
• Clinical evaluation should include history, full head and neck examination including fibre-optic laryngoscopy to assess the airway and the status of the vocal cords.
• All patients should have thyroid function (TSH, fT4 and fT3) tests and thyroid antibodies. Patient with history of MEN or MTC should have calcitonin levels.
• All patients should be investigated with ultrasound (US)-guided FNAC. US and cytological features should be documented as per current validated scoring systems including The British Thyroid Association or American Thyroid Association (Bethesda).
• In patients with suspected lymphoma, poorly differentiated carcinomas, anaplastic carcinomas or metastatic carcinomas, a core needle biopsy or incisional biopsy can be considered to establish diagnosis.
• Patients with advanced disease should have cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI). Whole body staging for lymphoma is done with positron emission tomography CT (PET-CT).
• All cases should be discussed pre-operatively at the thyroid cancer multi-disciplinary team meeting (TCMDT) or tumour board (TCTB).
All patients should be accurately staged. Staging should be done according to the latest UICC TNM staging (Table 112.2).
112.5 Prognostic Factors and Risk Stratification
It is important to assess risk in patients with DTC using prognostic scoring systems. This enables a more accurate prognosis to be given and the appropriate treatment decisions to be made. There are several, risk assessment and staging tools and any of them can be used to assign patients to high-, intermediate-, or low-risk categories. TNM and MACIS probably yield the most useful prognostic information.
Factors contributing to high-risk categories are older age, male gender, poorly differentiated histological features, tumour size, extrathyroidal extension (ETE) and metastatic spread. Adequate management at a TCMDT treatment also influences prognosis.
There is, however, controversy as to how these different risk stratification tools influence outcomes.
T1 ≤ 2 cm in greatest dimension limited to the thyroid.
T1a ≤ 1 cm, limited to the thyroid.
T1b > 1 cm but ≤ 2 cm in greatest dimension, limited to the thyroid.
T2 > 2 cm but ≤ 4 cm in greatest dimension, limited to the thyroid.
T3 > 4 cm in greatest dimension limited to the thyroid or any tumour with minimal ETE (e.g. extension to sternothyroid muscle or perithyroid soft tissues).
T4a Tumour of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, oesophagus or recurrent laryngeal nerve.
T4b Tumour invades pre-vertebral fascia or encases carotid artery or mediastinal vessels.
T4a Intrathyroidal anaplastic carcinoma.
T4b Anaplastic carcinoma with gross ETE.
N0 No regional lymph node metastasis.
N1 Regional lymph node metastasis.
N1a Metastases to level VI (pre-tracheal, para-tracheal, and pre-laryngeal/delphian lymph nodes).
N1b Metastases to unilateral, bilateral or contralateral cervical (levels I, II, III, IV or V) or retropharyngeal or superior mediastinal lymph nodes (level VII).
M0 No distant metastasis.
M1 Distant metastasis.
Under 45 years
45 years and older
Any T, any N, M0
pT1, N0, M0
Any T, any N, M0
pT2, N0, M0
pT4, N0, M0
Any pT, any N, M1
aUndifferentiated or anaplastic carcinomas are all stage IV.
Note: From 2018, the group staging will be amended to adjust for better prognosis and risk stratification, so the cutoff for group staging will be 55 years of age.
Current management of DTC, using adequate evaluation, assessment and risk stratification tools should be able to provide improved local control, disease-specific and overall survival for these patients. The concept of dynamic risk stratification (DRS) has been introduced with the aim to predict which treatments should be used, the need for post-treatment adjuvant therapies and the intensity and length of follow-up.
Surgery is the mainstay of the treatment of thyroid cancer. Surgeons performing operations for confirmed or suspected thyroid cancer should be core members of the TCMDT or TCTB. In the United Kingdom and Denmark, surgeons should be contributing to the Thyroid National Registry.
Complex and lymph node surgery should be undertaken by nominated surgeons, in cancer centres with specific training in and experience of thyroid oncology.
Table 112.3 lists patients deemed to be high risk and these patients should be considered for level VI lymph node dissection (pre-tracheal and para-tracheal nodes from the hyoid bone superiorly to the level of the sternal notch inferiorly). Lobectomy should include the isthmus in all patients. Sub-total thyroidectomy is not an appropriate operation for thyroid cancer.
Frozen section histology may be of use in confirming suspected PTC (THY4) but is not recommended for use in cases of suspected FTC (THY3).
112.7.1 Initial Surgery for Known PTC
A strategy for the surgical treatment of PTC is detailed in Table 112.4.
112.8 Initial Surgery for FTC
The majority of patients undergoing surgery for FTC will be undiagnosed at the time of the initial surgery (THY3 or Bethesda IV). Frozen section histology is not recommended. An operative strategy for surgical treatment of follicular cancer is outlined in Table 112.5.
Low-risk patients with a diagnosis of minimally invasive tumour less than 2 cm following lobectomy may be managed by lobectomy and TSH suppression alone in most cases. No clear recommendations currently exist for low-risk minimally invasive tumours of 2 to 4 cm and these cases should be discussed individually at MDT. In some cases, lobectomy and TSH suppression alone may be sufficient. Hurthle cell cancers (follicular oncocytic) tend to be more aggressive tumours and should be treated by total (completion) thyroidectomy (see Table 112.5).
High-risk DTC patients
Age > 45 y
Tumour > 4 cm
Extracapsular spread (ECS)
Extrathyroidal extension (ETE)
Abbreviation: DTC, differentiated thyroid cancer.