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.
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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 papillary carcinoma, 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 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 metastasis, 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.
- In 2008, 2,154 people were diagnosed with thyroid cancer in the UK (age-standardised incidence rate 3.2 per 100,000 population). Thyroid cancer caused 354 deaths in the UK in 2008.
- There is a male:female ratio of 1:3. It has been estimated that the lifetime risk of developing thyroid cancer in 2008 was 1 in 650 for men and 1 in 243 for women in the UK.
- Thyroid cancer is rare in children, while in adults the incidence rates rise steadily with age. Rates peak in 35-39 year-olds 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.
- Several recent studies have reported an increase in the incidence of thyroid cancer during the last decades, mainly due to an increase in micropapillary (<2 cm) carcinomas. 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 medullary thyroid carcinomas 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 medullary thyroid carcinoma.
- Thyroid cancer presents as a thyroid nodule. Thyroid nodules are frequent (4-50% depending on the diagnostic procedures and the patient's age), but 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 medullary thyroid cancer (5-7% of all thyroid cancers).
- Thyroid ultrasound 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 123 Iodine 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.
- 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 reoperative surgery and operations on large thyroid glands.
- 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 preoperatively suspected and/or intraoperatively proven lymph node metastases.
- Surgery is usually followed by the administration of iodine-131 aimed at ablating any remnant 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) 'tumour, node, metastasis' (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 levothyroxine therapy (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
- 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 preoperative 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
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 in both benign and 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 5-year survival of 5%.
- Despite increasing incidence, the mortality from thyroid cancer has declined over the last 30 years. The mortality rate in the UK in 2008 was 0.4 per 100,000 population.
Further reading & references
- Guidelines for radioiodine therapy of differentiated thyroid cancer, European Association of Nuclear Medicine (2008)
- Thyroid Cancer, National Cancer Institute (US)
- Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up; European Society for Medical Oncology (2010)
- Aytug S et al, Hurthle Cell Carcinoma, Medscape, Jan 2012
- Thyroid cancer statistics - UK, Cancer Research UK
- Sharma PK et al, Thyroid Cancer, Medscape, Jun 2011
- Mehanna HM, Jain A, Morton RP, et al; Investigating the thyroid nodule. BMJ. 2009 Mar 13;338:b733. doi: 10.1136/bmj.b733.
- Guidelines for the management of thyroid cancer, British Thyroid Association and Royal College of Physicians (2007)
- Intraoperative nerve monitoring during thyroid surgery, NICE Interventional Procedure Guideline (March 2008)
|Original Author: Dr Hayley Willacy||Current Version: Dr Colin Tidy||Peer Reviewer: Dr John Cox|
|Last Checked: 13/06/2012||Document ID: 12136 Version: 2||© EMIS|
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