Radiation exposure is the most common predisposing factor to the development of thyroid cancer. This included the treatment of childhood tinea capitis and tonsilar and thymus enlargement in the past. It also includes populations exposed to nuclear fallout such as the survivors of the atomic bombs dropped on Hiroshima and Nagasaki, the Marshall Islanders who were exposed during nuclear bomb tests and those exposed by nuclear power plant accidents at Chernobyl, Three Mile Island and Fukushima (see Box 2.3). Children exposed to nuclear fallout are most at risk and develop papillary thyroid cancers with a particular molecular signature; these radiation-induced tumours are characterized by RET gene translocations but absence of point mutations of the BRAF gene. Potassium iodide prevents the uptake of radioactive iodine by the thyroid and lowers the risk of radiation-induced thyroid cancer in exposed people; so it would be helpful to have a supply of potassium iodide close at hand.

Thyroid cancer includes a number of clinical entities, ranging from the classical papillary, follicular and anaplastic tumours to the atypical Hurthle and medullary cell carcinomas, as well as thyroid lymphoma. The different histological subtypes are associated with different molecular abnormalities. Papillary thyroid cancer is the most common type accounting for around 75% of tumours. These cancers frequently carry gene mutations and rearrangements that activate the mitogen-activated protein kinase (MAPK) pathway. Amongst these changes are rearrangements of the genes of the tyrosine kinase receptors RET and NTRK1 and activating mutations of signal transduction proteins BRAF and RAS. An individual papillary thyroid cancer usually only carries one of these MAPK-activating genetic alterations. Follicular thyroid cancer accounts for 10–15% thyroid cancers and is associated with a chromosomal translocation t(2:3)(q13:p25). The consequence of this translocation is the fusion of the DNA-binding domain of the thyroid transcription factor PAX8 gene and the peroxisome proliferator-activated receptor (PPAR) gene. The hybrid fusion protein is thought to block differentiation and stimulate cell division in thyroid follicular cells. The third most common and most aggressive cancers are anaplastic thyroid cancers. The anaplastic thyroid cancers carry mutations of p53 tumour suppressor that are not found in papillary or follicular thyroid cancers. They also commonly have mutations of the beta-catenin gene (CTNNNB1). Beta-catenin protein plays a role in cell adhesion and signalling through the Wnt pathway. Finally, medullary thyroid carcinoma is associated with multiple endocrine neoplasia (MEN) types 2A and 2B (see Table 25.1). The RET gene encodes a transmembrane tyrosine kinase receptor. This gene is mutated in almost 100% of all MEN 2A patients and in 85% of patients with familial medullary thyroid carcinoma.

The most common presentation of thyroid malignancy is with a thyroid nodule or with cervical lymphadenopathy. Much less frequently, patients will present with features suggestive of advanced disease, such as vocal cord paralysis or with symptoms due to metastases.

The diagnosis of a thyroid malignancy is made following routine investigations, which should include thyroid function, thyroid isotope scanning and thyroid ultrasound. Under ultrasound control, fine-needle aspiration biopsy is used to obtain a cytological diagnosis and thereby defines treatment. Other staging investigations should include CT scanning of the neck and thorax. Serum calcitonin levels are measured in patients with medullary thyroid carcinomas, while serum thyroglobulin can be used to monitor relapse in well-differentiated carcinomas after thyroid ablation.

After initial staging, patients with thyroid malignancies proceed to surgery. In the majority of patients with thyroid cancers, the surgical options are either subtotal thyroid resection, removing the lobe bearing the tumour together with the thyroid isthmus or total thyroidectomy. Care must be taken to avoid damaging the parathyroid glands and the recurrent laryngeal nerves. Generally, partial thryoidectomy is only considered in those patients with low-risk tumours, for example those with a single focus of papillary carcinoma measuring less than 1 cm in diameter. There is no evidence that routine lymph node dissection has any added survival advantage. Subsequent to surgery, patients are treated with thyroid replacement, aiming to suppress thyroid-stimulating hormone (TSH) completely, which may be a driver for the development of recurrence.

When patients with thyroid tumours develop recurrent disease, further options for management may include surgery or radiation therapy. Surgery is the treatment of choice for patients with recurrent medullary carcinoma of the thyroid, which is relatively resistant to radiation therapy and chemotherapy. Radiation treatment is given both by using external beam radiotherapy and by treating with radioiodine (¹³¹I), which localizes to thyroid tissue. Differentiated thyroid cancer (papillary or follicular) that no longer responds to radioiodine and TSH suppression may respond to anti-angiogenic tyrosine kinase inhibitors. Sorafenib is an inhibitor of multiple receptor tyrosine kinases including RET; VEGFR1, 2 and 3; Flt3; cKIT; and wild-type and mutated BRAF. An overview of seven trials of patients with papillary, follicular and poorly differentiated thyroid cancer, medullary thyroid cancer and anaplastic cancer has concluded that the partial response rate to sorafenib is 21% and that a further 60% of treated patients have stable disease. Cabozantinib, another small-molecule tyrosine kinase inhibitor, targets hepatocyte growth factor receptor, VEGFR2 and RET, and has clinical activity in medullary carcinoma of the thyroid. In studies, the duration of response to cabozantinib is reported as “progression free survival” and is around 10 months.