Thyroid cancer

What is thyroid cancer?

Carcinoma of the thyroid gland is an uncommon cancer but is the most common malignancy of the endocrine system. Differentiated tumours (papillary or follicular) are highly treatable and usually curable. Poorly differentiated tumours (medullary or anaplastic) are much less common, are aggressive, metastasise early and have a much poorer prognosis.

The thyroid gland may occasionally be the site of other primary tumours, including sarcomas, lymphomas, epidermoid carcinomas and teratomas. It can also be the site of metastasis from other cancers, particularly of the lung, breast and kidney.

Types of thyroid cancer

There are a number of histological types that behave differently.

Thyroid malignancies can be separated into three rough categories:¹

1. Differentiated thyroid carcinoma, including papillary, follicular, and Hürthle cell cancers. These arise from follicular cells of the thyroid and account for 90-95% of all thyroid malignancies.

2. Medullary thyroid carcinoma arises from parafollicular cells and accounts for another 6%.

3. Anaplastic thyroid carcinoma accounts for less than 1% of thyroid malignancies.

Differentiated thyroid carcinoma

Papillary thyroid carcinoma (PTC)²

• This is the most common form of thyroid cancer. 70% of thyroid cancers are papillary.

• Usually presents between 35 and 40 years of age and is more common in women.

• Most often, it presents as micropapillary thyroid carcinoma (<1 cm in size) with an excellent long-term prognosis.

• It tends to spread locally in the neck, compressing the trachea and possibly involving the recurrent laryngeal nerve.

• Metastases most often occur in lung and bone, mediastinal lymph nodes, pelvic area, brain, and liver.

Follicular thyroid carcinoma (FTC)³

• Second most common form of thyroid cancer at about 10%.

• It tends to occur in areas of low iodine.

• It is three times more common in women and most often presents between 30 and 60 years of age.

• It may infiltrate the neck, as does PTC, but it has a greater propensity to metastasise to lung and bones.

Hürthle cell carcinoma⁴

• Accounts for about 3-10% of all differentiated thyroid cancers.

• They are composed of 75-100% Hürthle cells.

• There is a female preponderance.

• It may present from 20-85 years of age but most often between 50-60 years.

• Surgical excision is the main treatment. Other treatments include postoperative radioactive iodine-131 treatment, levothyroxine (T4) and external radiotherapy.

• Hürthle cell carcinomas behave more aggressively than other well-differentiated thyroid cancers with a higher incidence of metastasis and a lower survival rate.

Medullary thyroid carcinoma⁵

• Medullary thyroid cancer (MTC) arises from the parafollicular calcitonin-producing C cells of the thyroid.

• Up to 75% of MTC cases occur sporadically. The hereditary form of MTC (23% of cases) shows an autosomal dominant pattern of transmission. Familial MTC arises as part of multiple endocrine neoplasia (MEN) syndrome type 2A or 2B or familial MTC (FMTC).

• Medullary carcinoma of the thyroid constitutes approximately 4-10% of all thyroid cancers. Sporadic MTC has a peak incidence in the fifth or sixth decade of life; whereas, those MTCs associated with MEN 2A or MEN 2B peak around the second or third decade of life.

• Female preponderance is less marked.

• Malignant transformed C cells produce and secrete large amounts of peptides, including carcinoembryonic antigen (CEA) and calcitonin and so elevated serum calcitonin is a marker of the presence of MTC or metastatic MTC after surgery.

• Prognostic factors that predict adverse outcome include calcitonin doubling time, advanced age at diagnosis, extent of the primary tumour, nodal disease and distant metastases.

Anaplastic thyroid carcinoma⁶⁷

• Anaplastic thyroid cancer (ATC) is a rare malignancy with a poor prognosis. It is characterised by a rapid onset with local and distant metastases, local progression and distant evolution.

• The prognosis remains very poor with a one-year overall survival rate between 20% and 50%.

• ATC usually affects elderly patients, with the majority being over 60 years old with a female predominance.

• The advanced stage of the disease is the most common diagnosis presentation displaying extremely aggressive behaviour with rapid tumour progression, local invasion and/or distant metastases (lung, bone, liver and/or brain metastases).

• The clinical diagnosis is usually easy with a large, hard mass invading the neck and causing compression (dyspnoea, cough, vocal cord paralysis, dysphagia and hoarseness). Almost 50% of the patients present with distant metastases, mostly in the lungs but also in the bones, liver and brain.

Thyroid lymphomas⁸

• Thyroid lymphomas are almost always non-Hodgkin's lymphomas, representing 4-10% of thyroid malignancies.

• There is a higher prevalence in areas with higher rates of thyroiditis.

• It is more common in females and has a female-to-male ratio of 4:1. The mean age is around 65 years at the time of diagnosis.

• Patients usually present with a rapidly growing mass in the neck, which may cause symptoms of obstruction such as dyspnoea and dysphagia.

• The prognosis depends on the stage of the disease at diagnosis.

• The five-year survival rate ranges from 89% in early disease to 5% in disseminated disease.

How common is thyroid cancer? (Epidemiology)⁹

• Thyroid cancer is the 20th most common cancer in the UK, accounting for 1% of all new cancer cases (2016-2018).

• Incidence rates for thyroid cancer in the UK are highest in people aged 65 to 69 (2016-2018).

• Each year about 11% of all new thyroid cancer cases in the UK are diagnosed in people aged 75 and over (2016-2018).

• Since the early 1990s, thyroid cancer incidence rates have increased by 175% in the UK.

• Incidence rates for thyroid cancer are projected to rise by 74% in the UK between 2014 and 2035, to 11 cases per 100,000 people by 2035.

• Incidence rates for thyroid cancer are higher in the Asian and Black ethnic groups, but lower in people of mixed or multiple ethnicity, compared with the White ethnic group, in England (2013-2017).

Risk factors

• Exposure to ionising radiation. The risk is greater when exposure has occurred at a younger age. An increased incidence of thyroid cancer in children and adolescents was seen in Ukraine, Belarus and certain regions of Russia as early as four years after the Chernobyl accident. Thyroid carcinoma may first appear 20 or more years after radiation exposure.

• Other risk factors include a history of goitre, thyroid nodule or thyroiditis, family history of thyroid disease, female gender and Asian race.

• Genetics: approximately 20-25% of MTC are hereditary because of mutations in the RET proto-oncogene. Mutations in the RET gene cause multiple endocrine neoplasia type 2 (MEN 2), which is an autosomal dominant disorder associated with a high lifetime risk of MTC.

The following are also considered to be risk factors for thyroid cancer:

• Cowden's syndrome (macrocephaly, mild learning difficulties, carpet-pile tongue, with benign or malignant breast disease).

• Familial adenomatous polyposis.

• Obesity.

Classification

The tumour, node, metastasis (TNM) classification (7th edition) is recommended for thyroid cancer.

Papillary or follicular carcinoma staging

• Stage I:

  • Person younger than 45 years: tumour (any T) with or without spread to lymph nodes (any N) and no distant metastasis (M0).

  • Person 45 years and older: any small tumour (T1) with no spread to lymph nodes (N0) and no metastasis (M0).

• Stage II:

  • Person younger than 45 years: tumour (any T) with any metastasis (M1) regardless of whether it has spread to the lymph nodes (any N).

  • Person 45 years and older: a larger, non-invasive tumour (T2) with no spread to lymph nodes (N0) and no metastasis (M0).

• Stage III:

  • A tumour larger than 4 cm but contained in the thyroid gland (T3) with no spread to lymph nodes (N0) and no metastasis (M0); or

  • Any localised tumour (T1-3) with spread to the central compartment of lymph nodes (N1a) but no distant spread (M0).

• Stage IVA:

  • A tumour that has spread to nearby structures (T4a), regardless of whether it has spread to the lymph nodes (any N), but it has not spread to distant places (M0); or

  • A localised tumour (T1-3), with lymph node spread beyond the central compartment (N1b) but no distant spread (M0).

• Stage IVB: a tumour that has spread beyond nearby structures (T4b), regardless of spread to lymph nodes (any N) but no distant spread (M0).

• Stage IVC: all tumours (any T, any N) when there is evidence of metastasis (M1).

Thyroid cancer symptoms

Thyroid cancer presents as a thyroid nodule. Thyroid nodules are frequent (4-50% depending on the diagnostic procedures and the patient's age); however, thyroid cancer is rare (c. 5% of all thyroid nodules).

• Solitary thyroid nodules can vary from soft to hard. Hard and fixed nodules are more suggestive of malignancy than soft mobile nodules. Thyroid carcinoma is usually non-tender to palpation.

• Firm cervical masses are suggestive of regional lymph node metastases. Vocal cord paralysis implies involvement of the recurrent laryngeal nerve.

Differential diagnosis

• Goitre.

• Lymphoma.

• Lymphadenopathy.

• Cat scratch disease.

• HIV.

Investigations

• TFTs should be performed for any patient with a thyroid nodule. However, TFTs (most patients will be euthyroid) and thyroglobulin (Tg) measurement are of little help in the diagnosis of thyroid cancer.

• Serum calcitonin is a reliable tool for the diagnosis of MTC (5-7% of all thyroid cancers). However, the National Institute for Health and Care Excellence (NICE) recommends that calcitonin testing should not be used to assess thyroid nodules unless there is a reason to suspect medullary thyroid cancer (MTC), such as a family history or a nodule with an appearance on ultrasound that suggests MTC.¹¹

• Ultrasound:
  

  • Thyroid ultrasound is extremely sensitive for thyroid nodules and is used as a first-line diagnostic procedure for detecting and characterising nodular thyroid disease.¹²

  • Ultrasound features associated with malignancy include hypoechogenicity, microcalcifications, absence of peripheral halo, irregular borders, solid aspect, intranodular blood flow and shape (taller than wide).

  • Ultrasound should also be used to explore the neck carefully to assess the status of lymph node chains.

• Fine-needle aspiration cytology (FNAC):
  

  • The results of FNAC are very sensitive for the differential diagnosis of benign and malignant nodules, although limitations include inadequate samples and follicular neoplasia.

• Radionuclide imaging: distinguishing functioning toxic nodules and thyroid metastases from follicular and papillary carcinomas is best with ¹²³iodine uptake studies:
  

  • Normal iodine uptake is seen in 'warm' nodules. Lesions that take up excessive amounts of iodine are called 'hot' and those that do not take it up are called 'cold'.

  • 4% of hot nodules contain tumour, compared with 16% of cold nodules. This makes radionuclide imaging unreliable to exclude or confirm cancer. Low ¹²³ iodine uptake in a single palpable nodule gives a risk of malignancy of 10-25%, falling to 1-3% if multiple nodules are demonstrated on the scan.

  • About half of papillary carcinomas and a smaller number of follicular carcinomas take up enough iodine in metastases to be detected.

  • Gallium ⁶⁷ Ga is used in the diagnosis of thyroid lymphoma.

• CT and MRI scan: CT scans and MRI scans are valuable to detect local and mediastinal spread and regional lymph nodes.

The NICE guidance for thyroid cancer provides recommendations for thyroid function tests, ultrasound, fine-needle aspiration cytology (FNAC), core-needle biopsy (CNB), diagnostic hemithyroidectomy and cross-sectional imaging (CT of neck and chest, or MRI of neck and CT of chest). NICE recommends that radioisotope scans should not be used routinely for the initial diagnosis of thyroid cancer. See the reference link to the NICE guideline for further details.¹¹

Thyroid cancer treatment and management

The NICE guideline for thyroid cancer provides recommendations for the management of thyroid cancer, including active surveillance, surgery (hemithyroidectomy, total thyroidectomy, neck dissection for nodal disease), radioactive iodine, external beam radiotherapy, and thyroid-stimulating hormone suppression. See the reference link to the NICE guideline for further details.¹¹

• Patients who have an unexplained thyroid lump or any other suspicion of thyroid cancer should be referred urgently within the suspected cancer pathway, and seen within two weeks.¹⁰

• Any patient with a thyroid lump and associated stridor should be referred for same day review by a secondary care specialist, as this may be due to recurrent laryngeal nerve involvement secondary to a thyroid carcinoma.

• Because of the proximity of the right and left recurrent laryngeal nerves and risk of damage to the nerves, intraoperative nerve monitoring may be used during thyroid surgery, especially for re-operative surgery and operations on large thyroid glands.¹³

• Radioiodine remnant ablation and therapy for differentiated thyroid cancer may be considered.

• Adjuvant external beam radiotherapy for differentiated thyroid cancer may be considered for patients with a high risk of recurrence/progression.

Follow-up

The NICE guideline for thyroid cancer provides recommendations for the follow up of patients, including measuring thyroglobulin and thyroglobulin antibodies, and ultrasound. See the reference link to the NICE guideline for further details.¹¹

Medullary thyroid cancer (MTC)¹⁴

• Complete surgical resection of the thyroid tumour and any loco-regional metastases is the only curative option for loco-regional MTC. Therefore, early diagnosis and detection of MTC are very important for prognosis.

• Treatment options for recurrent or metastatic MTC include surgical resection, external beam radiation therapy, and directed local therapies or systemic therapies (eg, vandetanib or cabozantinib).

• However, the best management is still controversial in patients with recurrent MTC and distant metastases, because many patients with metastatic disease have indolent disease courses for a long time.

Anaplastic thyroid carcinoma (ATC)⁷

The goals of care may be therapeutic and/or palliative depending on staging and prognosis, comorbidities and the patient's wishes. Multimodal therapy refers to the combination of excisional surgery, when possible, external beam radiation therapy (EBRT), chemotherapy and/or targeted therapy. Chemotherapy options include doxorubicin, paclitaxel, paclitaxel and pemetrexed, paclitaxel and carboplatin, doxorubicin and cisplatin, and tyrosin kinase inhibitors. Recent results of the dabrafenib/trametinib combination for BRAF-mutated patients, and of immune checkpoint inhibitors, used alone or in combination with targeted therapies, have raised some hope toward an improvement of the prognosis.

Complications

• In expert hands surgical complications such as laryngeal nerve palsy and hypoparathyroidism are rare (<1-2%).

• The primary disease can cause nerve damage, both in benign and in malignant conditions.

Prognosis

Prognosis for thyroid cancer varies greatly depending on its type, size, patient's age and amenability to resection. In general the prognosis is good, with up to 95% five-year survival rate for patients across all ages and races. The prognosis may be worse based on the size of the tumour, the presence of extra-thyroidal extensions or metastasis, older age or unfavourable tumour types such as anaplastic which has a five-year survival rate of 5%.¹

UK survival statistics⁹

• 91.4% of people diagnosed with thyroid cancer in England survive their disease for one year or more (2013-2017).

• 87.4% of people diagnosed with thyroid cancer in England survive their disease for five years or more (2013-2017).

• It is predicted that 84.3% of people diagnosed with thyroid cancer in England survive their disease for ten years or more (2013-2017).

• Thyroid cancer survival for females is higher than for males at one and five years.

• Thyroid cancer survival in England is highest for adults diagnosed aged under 50 years (2009-2013).

• Nearly all people in England diagnosed with thyroid cancer aged 15-49 survive their disease for five years or more.

• When diagnosed at its earliest stage, all (100%) people with thyroid cancer will survive their disease for one year or more, compared with 77% of people when the disease is diagnosed at the latest stage.