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, and may 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.
Papillary thyroid carcinoma (PTC)
- This is the most common form of thyroid cancer. 70% of thyroid cancers are papillary.
- It usually presents between 35 and 40 years of age and is three times 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.
Follicular thyroid carcinoma (FTC)
- This is the 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.
Medullary thyroid carcinoma (MTC)
- Medullary thyroid cancer arises from the parafollicular calcitonin-producing C cells of the thyroid and accounts for between 5% and 8% of all thyroid malignancies.
- 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.
- 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).
- Prognostic factors that predict adverse outcome include calcitonin doubling time, advanced age at diagnosis, extent of the primary tumour, nodal disease and distant metastases.
- Thyroid lymphomas are almost always non-Hodgkin's lymphomas, representing 4-10% of thyroid malignancies.
- Mainly women aged over 50 are affected and they often have Hashimoto's thyroiditis.
- Patients usually present with a rapidly growing mass in the neck, which may cause symptoms of obstruction such as dyspnoea and dysphagia.
- Thyroid lymphoma arises in a pre-existing chronic thyroiditis with subclinical or overt hypothyroidism in 70-80%.
- 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.
Hürthle cell carcinoma
- Hürthle cell carcinoma 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 the ages of 50-60 years.
- It is impossible to distinguish benign from malignant tumours on fine-needle aspiration (FNA).
- 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.
Anaplastic thyroid carcinoma (ATC)
- Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid tumour and one of the most aggressive cancers in humans.
- ATC arises from the follicular cells of the thyroid gland but does not retain any of the biological features of the original cells, such as uptake of iodine and synthesis of thyroglobulin.
- The peak incidence is in the sixth to seventh decades (mean age at diagnosis 55-65 years) and the prevalence is very low (<2% of all thyroid tumours).
- In most cases, ATC develops from a pre-existing well-differentiated thyroid tumour, which has undergone additional mutational events.
- 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.
- The mean overall survival is often less than six months, whatever treatment is performed.
- The annual incidence data for thyroid cancer in the UK from 2008 show 5.1 per 100,000 for women and 1.9 per 100,000 for men. Thyroid cancer is the most common malignant endocrine tumour but represents only about 1% of all malignancies.
- Thyroid cancer is rare in children, while in adults the incidence rates rise steadily with age. Rates peak in those aged 35-39 years and again in the over-70s. There is a substantial number of cases at younger adult age. Almost half of all cases occur in people aged less than 50 years.
- Thyroid cancer incidence is increasing all over the world - mostly due to an increase in the detection of small tumours that were previously undetected.However, an increased incidence of all sizes of thyroid tumour has recently been reported in the USA.
- There has been no significant change in the incidence of the follicular, medullary and anaplastic cancers.
- Exposure to ionising radiation. The risk, especially for papillary carcinomas, 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 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.
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 (T3) with no spread to lymph nodes (N0) and no metastasis (M0); or
- Any localized 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 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.
Red flag features
- A family history of thyroid cancer.
- History of previous irradiation or exposure to high environmental radiation.
- A child with a thyroid nodule.
- Unexplained hoarseness or stridor associated with goitre.
- A painless thyroid mass enlarging rapidly over a period of a few weeks.
- Palpable cervical lymphadenopathy.
- Insidious or persistent pain lasting for several weeks.
- 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).
- Thyroid ultrasound is extremely sensitive for thyroid nodules and is used as a first-line diagnostic procedure for detecting and characterising nodular thyroid disease.
- 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):
- This should be performed in any thyroid nodule >1 cm and in those <1 cm if there is any clinical (history of head and neck irradiation, family history of thyroid cancer, suspicious features on palpation, presence of cervical lymphadenopathy) or ultrasound suspicion of malignancy.
- 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.
- Patients who have suspicious features (red flags - as above) should be referred urgently to a secondary care physician with expertise in the diagnosis and management of thyroid cancer, and seen within two weeks.
- 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.
- Solitary thyroid nodules that are malignant, suspicious or indeterminate on FNA require operation.
- Total thyroidectomy is recommended for patients with tumours greater than 4 cm in diameter, or tumours of any size in association with multifocal disease, bilateral disease, extra-thyroidal spread, familial disease, and those with clinically or radiologically involved nodes and/or distant metastases.
- 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.
- Radioiodine remnant ablation and therapy for differentiated thyroid cancer:
- Patients in the definite indications include tumour larger than 4 cm, or any tumour size with gross extra-thyroidal extension or distant metastases.
- Patients with no indications include tumour 1 cm or smaller, classical papillary or follicular variant or follicular minimally invasive without angioinvasion and no invasion of thyroid capsule.
- Adjuvant external beam radiotherapy for differentiated thyroid cancer should be considered for patients with a high risk of recurrence/progression with:
- Gross evidence of local tumour invasion at surgery with significant macroscopic residual disease; or
- Residual or recurrent tumour that fails to concentrate radioiodine, ie loco-regional disease where further surgery or radioiodine is ineffective or impractical.
- Until recently, no truly effective treatment options have existed for patients with radioactive iodine-refractory differentiated thyroid cancer, which has a poor prognosis. A targeted multikinase inhibitor (sorafenib) has been shown to improve progression-free survival substantially. A number of other targeted agents are under investigation.
- Annual lifelong follow-up is recommended.
Differentiated thyroid carcinoma (DTC)
- The initial treatment for DTC is total or near-total thyroidectomy whenever the diagnosis is made before surgery and the nodule is >1 cm, or regardless of the size and histology (papillary or follicular) if there is metastatic, multifocal or familial DTC.
- Less extensive surgical procedures may be acceptable in the case of unifocal DTC diagnosed at final histology after surgery performed for benign thyroid disorders, provided that the tumour is small, intrathyroidal and of favourable histology.
- The benefit of prophylactic central node dissection in the absence of evidence of nodal disease is controversial.
- Compartment-oriented microdissection of lymph nodes should be performed in cases of pre-operatively suspected and/or intra-operatively proven lymph node metastases.
- Surgery is usually followed by the administration of iodine-131 aimed at ablating any remnant of thyroid tissue and potential microscopic residual tumour. This decreases the risk of loco-regional recurrence and allows long-term surveillance based on serum Tg measurement and diagnostic radioiodine whole body scan.
- Radioiodine ablation is recommended for all patients except those at very low risk (those with unifocal T1 tumours, <1 cm in size, with favourable histology, no extrathyroidal extension or lymph node metastases).
- Effective thyroid ablation requires adequate stimulation by thyroid-stimulating hormone (TSH). The method of choice for preparation to perform radioiodine ablation is based on the administration of recombinant human TSH (rhTSH) while the patient is on levothyroxine (LT4) therapy.
Staging and risk assessment
- Several staging systems have been developed. The most popular is the American Joint Committee on Cancer/International Union Against Cancer (AJCC/IUAC) TNM staging system, based mainly on the extent of tumour and age.
- A European Consensus Report defined three categories of risk (very low, low and high) to establish the indication for radioiodine ablation therapy: no indication for radioiodine ablation in very low-risk patients.
- Most local recurrences develop and are detected in the first five years after diagnosis. However, in a minority of cases, local or distant recurrence may develop in late follow-up, even 20 years after the initial treatment.
- Two to three months after initial treatment, TFTs - FT3, FT4, TSH - should be obtained to check the adequacy of LT4 suppressive therapy. At 6-12 months the follow-up is aimed at ascertaining whether the patient is free of disease, based on physical examination, neck ultrasound, basal and rhTSH-stimulated serum Tg measurement, with or without diagnostic whole body scan. At this time most patients will have low risk with normal neck ultrasound and undetectable stimulated serum Tg in the absence of serum Tg antibodies. These patients may be considered to be in complete remission and their rate of subsequent recurrence is very low (<1.0% at 10 years).
- The subsequent follow-up of patients considered free of disease at the time of their first follow-up will consist of physical examination, basal serum Tg measurement on LT4 therapy and neck ultrasound once a year.
- During the evaluation of metastatic patients, positron emission tomography (PET) using radioisotope fluorodeoxyglucose (18 F) (FDG-PET) scanning is increasingly being used as a diagnostic and prognostic tool.
- Treatment of locoregional disease is based on the combination of surgery and radioiodine therapy. External beam radiotherapy may be indicated when complete surgical excision is not possible or when there is no significant radioiodine uptake in the tumour.
- Distant metastases are more successfully cured if they take up radioiodine, and are of small size, located in the lungs (not visible at X-rays). Bone metastases have the worst prognosis. Brain metastases are relatively rare and usually carry a poor prognosis.
- Chemotherapy is no longer indicated due to lack of effective results. However, initial trials of tyrosine kinase inhibitor drugs have shown promising results and targeted therapy might become the first-line treatment of metastatic refractory thyroid cancer in the future.
- Thyroid hormone suppression therapy is also an important part of the treatment of thyroid cancer and is effective in stopping the growth of microscopic thyroid cancer cells or residual thyroid cancer. Several reports have shown that hormone-suppressive treatment with LT4 benefits high-risk thyroid cancer patients but no significant improvement has been obtained by suppressing TSH in patients with low-risk thyroid cancer.
Medullary thyroid carcinoma (MTC)
- For MTC patients with no evidence of lymph node metastases by physical examination and cervical ultrasound, the treatment consists of total thyroidectomy and prophylactic central lymph node dissection. Lateral neck dissection may be best reserved for patients with positive pre-operative imaging.
- Postoperatively, the TNM classification and other factors, such as the postoperative calcitonin level and the calcitonin and CEA doubling times, should be used to predict outcome and to help plan long-term follow-up.
- In patients with detectable calcitonin levels after surgery, imaging techniques are used to detect metastatic disease, although many patients may have elevated calcitonin levels without evidence of disease.
- Distant metastases occur predominantly in patients who present initially with a large-sized tumour, extra-thyroidal growth and lymph node involvement. Distant metastases often affect multiple organs, including the lungs, bones and liver and, more rarely, the brain, skin and breast.
- Radiotherapy is often used in the presence of local invasion.
- Chemo-embolisation may be effective in reducing tumour mass of liver metastases.
- Preliminary evidence indicates that tyrosine kinase inhibitor drugs may have important clinical benefits.
Anaplastic thyroid carcinoma (ATC)
Treatment of ATC has not been standardised and there is not yet an effective treatment. The most common single cytotoxic agent used against anaplastic carcinomas is doxorubicin alone or in combination with cisplatin but results are disappointing.
- 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.
- This depends upon type and stage but most thyroid cancer has a good prognosis with 90% survival at 10 years, higher in young people without local or metastatic spread. The exception is anaplastic cancer, with a five-year survival of 5%.
- 10-year relative survival mortality rates for differentiated (papillary or follicular) thyroid cancer are: Stage I 98.5%; Stage II 98.8%; Stage III 99%; Stage IVA 75.9%; Stage IVB 62.5%; Stage IVC 63%.
- Postoperative risk stratification for risk of recurrence of differentiated thyroid cancer:
- Low-risk patients have the following characteristics:
- No local or distant metastases.
- All macroscopic tumour has been resected.
- No tumour invasion of loco-regional tissues or structures.
- The tumour does not have aggressive histology or angioinvasion.
- Intermediate-risk patients have any of the following characteristics:
- Microscopic invasion of tumour into the perithyroidal soft tissues (T3) at initial surgery.
- Cervical lymph node metastases (N1a or N1b).
- Tumour with aggressive histology or angioinvasion.
- High-risk patients have any of the following characteristics:
- Extra-thyroidal invasion.
- Incomplete macroscopic tumour resection.
- Distant metastases (M1).
- Despite increasing incidence, the mortality from thyroid cancer has declined over a period of 30 years. The mortality rate in the UK in 2008 was 0.4 per 100,000 population.
Further reading and references
Thyroid Cancer; National Cancer Institute (USA)
Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2010)
British Thyroid Association Guidelines for the Management of Thyroid Cancer; British Thyroid Association (July 2014)
Thyroid cancer statistics - UK; Cancer Research UK
Vaisman F, Carvalho DP, Vaisman M; A new appraisal of iodine refractory thyroid cancer. Endocr Relat Cancer. 2015 Dec22(6):R301-10. doi: 10.1530/ERC-15-0300. Epub 2015 Aug 25.
Mehanna HM, Jain A, Morton RP, et al; Investigating the thyroid nodule. BMJ. 2009 Mar 13338:b733. doi: 10.1136/bmj.b733.
Intraoperative nerve monitoring during thyroid surgery; NICE Interventional Procedure Guidance, March 2008
Worden F; Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer. Ther Adv Med Oncol. 2014 Nov6(6):267-79. doi: 10.1177/1758834014548188.
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