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Thyroid cancer 

Thyroid cancer
Chapter:
Thyroid cancer
Author(s):

Anthony P. Weetman

DOI:
10.1093/med/9780199204854.003.1305_update_003

Update:

Novel agents for the treatment of thyroid cancer.

Updated on 30 July 2015. The previous version of this content can be found here.
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Essentials

Thyroid cancers account for less than 1% of all malignancies but are much the most frequent cancers of endocrine organs.

Follicular epithelial cell cancer—the commonest type; may be induced by exposure to radiation; can be highly undifferentiated or differentiate into recognizable follicular cells, sometimes with retention of hormone biosynthesis; typically present with an asymptomatic thyroid nodule; usually diagnosed by fine needle aspiration biopsy; treatment is typically by total or near total thyroidectomy, with radio-iodine then administered to remove any remaining thyroid tissue (followed by long-term thyroid replacement therapy).

Medullary thyroid carcinoma—arises from parafollicular C cells; comprise 5 to 10% of all thyroid cancers; hereditary autosomal dominant forms associated with germ-line point mutations in the RET proto-oncogene occur as part of multiple endocrine neoplasia (MEN) type 2A or 2B, or as isolated familial medullary carcinoma; typically present with a solitary thyroid nodule, accompanied in 50% of cases by cervical lymphadenopathy; can be associated with unusual hormonal effects, including secretory diarrhoea; diagnosis often made by fine needle aspiration biopsy, also by finding raised serum calcitonin; treatment is by total thyroidectomy, followed by monitoring of serum calcitonin levels (and long-term thyroid replacement therapy); testing for the presence of RET mutations (see Chapter 13.10) allows family testing, with prophylactic thyroidectomy recommended for affected individuals.

Rare thyroid tumours—include (1) anaplastic carcinomas—present as a rapidly enlarging and fixed thyroid mass, sometimes with local pain; rapidly fatal; (2) sarcomas; and (3) primary lymphomas— usually present as a rapidly enlarging thyroid mass in a patient with Hashimoto’s thyroiditis.

Primary thyroid follicular epithelial tumours

(Table 13.5.1)

Table 13.5.1 Classification of thyroid malignancies

Primary thyroid follicular epithelial tumours

Differentiated (papillary, follicular)

Poorly differentiated (insular, other)

Undifferentiated (anaplastic)

C cell epithelial tumours (medullary carcinoma)

Primary nonepithelial tumours

Lymphoid origin (lymphoma, plasmacytoma)

Mesenchymal cell origin (sarcoma)

Other (teratoma)

Secondary nonthyroidal tumours

Metastases

Extension of tumour from adjacent structures

Aetiology

Excessive stimulation of the thyroid by thyroid-stimulating hormone (TSH) accounts for the higher proportion of follicular carcinomas compared with papillary carcinomas in iodine-deficient areas. The thyroid-stimulating antibodies of Graves’ disease do not increase the risk of developing thyroid cancer, but incidental thyroid tumours that arise in this disorder may behave more aggressively because of activation of TSH receptors. Low-dose external beam radiation (10–1500 cGy) to the head and neck increases the risk of papillary thyroid cancer over 10 to 30 years. Higher thyroid radiation doses, including those arising from radio-iodine given for treatment of hyperthyroidism, are not associated with an increased risk of malignancy because thyroid cells are destroyed rather than transformed. However, death from thyroid cancer, which is an unusual outcome, may be slightly increased by radio-iodine treatment, suggesting an effect of radiation on tumour dedifferentiation. In Belarus the incidence of papillary carcinomas in children and young adults has increased 60-fold after the disastrous release of radio-iodine and other radionuclides from the Chernobyl nuclear reactor. The increase has been greatest in those aged less than 4 years at the time of exposure and is due to the potent mutagenic effects of radio-iodine on the growing thyroid gland.

Familial forms of papillary and follicular carcinomas exist but are unusual (less than 5% of cases). There are also associations with familial adenomatosis polyposis, including the Gardner syndrome variant (OMIM 175100), Cowden’s disease (multiple hamartoma syndrome, OMIM 158350), Peutz–Jeghers syndrome (OMIM 175200), the Carney complex (OMIM 160980), and ataxia–telangiectasia (OMIM 208900).

Papillary carcinomas do not arise from hyperplastic nodules or adenomas. In about one-third of these tumours one of several distinct rearrangements of the RET proto-oncogene, a member of the receptor tyrosine kinase family, occurs. The resulting chimeric oncogenes are termed RET/PTC (for papillary thyroid carcinoma). RET/PTC3 is particularly linked to radiation. Around 40% of papillary carcinomas have mutations in the BRAF gene which encodes a serine–threonine kinase, and these tumours tend to be more aggressive and present more often with extrathyroidal invasion. Less than 10% of papillary carcinomas have mutations in the NTRK1 oncogene.

Activation of the RAS oncogene occurs in around 20% of follicular and papillary thyroid cancers. Combinations of RET, BRAF, and RAS mutations do not occur in the same tumour, implying activation of the MAPK cascade as a critical step in carcinogenesis. Follicular carcinomas probably arise, at least in some cases, from follicular adenomas. Rarely follicular carcinomas are associated with activating mutations of the genes encoding the TSH receptor or Gsα‎ protein, similar to those found in toxic adenoma. Anaplastic carcinoma may arise in a papillary or follicular carcinoma and is associated with mutations of several genes including CTNNB1 and the p53 tumour suppressor gene.

Epidemiology

Papillary microcarcinomas are tumours less than 1 cm in diameter that occur in up to 36% of autopsy specimens and up to 24% of surgical thyroidectomies. Clearly most of these do not become malignant. Excluding tumours that are found coincidentally, the annual incidence of thyroid follicular epithelial cancer is around 4 per 100 000. In iodine-sufficient countries, more than 80% of these are papillary carcinoma, about 10% are follicular carcinoma, and 5 to 10% are anaplastic carcinoma. Women are 2 to 4 times more likely to develop thyroid cancer than men, and the peak incidence is between 30 and 50 years of age.

Clinical features

Most patients present with an asymptomatic thyroid nodule; this may be noticed by themselves or their relatives, or sometimes the nodule is detected during physical examination for another complaint. The difficulty for diagnosis arises because thyroid nodules are frequent, and only about 5% of palpable thyroid nodules are malignant. Diffuse or multinodular thyroid enlargement occurs in around 10% of the population and is 4 times more common in women than in men. Solitary thyroid nodules occur in up to 5% of the population and are usually hyperplastic or colloid nodules; 5 to 20% of them are neoplastic, but this figure includes follicular adenomas as well as malignant tumours.

It can be seen that determining which thyroid nodules are malignant poses a dilemma that has been exacerbated by the widespread use of ultrasound examination of the neck. Up to 60% of adult thyroids have nodules detectable by high-resolution ultrasound scanning. Another problem is determining which nodules warrant investigation in a multinodular goitre. It seems reasonable to perform fine needle aspiration biopsy of so-called dominant nodules, as well as those nodules in which there are any suspicious ultrasonographic features (microcalcification, hypoechogenicity, and nodular hypervascularity) and any nodules that have demonstrated recent change in size.

There are usually no symptoms or signs to indicate that a solitary thyroid nodule is malignant because most tumours progress slowly and present before disease is advanced. Age and sex are important considerations, since a malignancy is more likely in a solitary nodule when the patient is a child or an adolescent, is over 60 years old, or is a man between the ages of 20 and 60 years. Previous exposure to radiation and a family history of thyroid cancer should also arouse suspicion. A carcinoma is more likely if the nodule has grown recently or is hard, irregular, or fixed on palpation. Clinical assessment should include careful examination of the cervical, submental, and supraclavicular lymph nodes. Late-presenting features include hoarseness, dysphagia, or dyspnoea which may indicate local invasion, but these symptoms can occasionally occur with an enlarging benign goitre. Rarely the diagnosis only becomes apparent when metastatic disease is detected in bone or lung.

The relatively indolent presentation of papillary and follicular thyroid carcinoma contrasts with that of anaplastic carcinoma in which a rapidly enlarging and fixed thyroid mass occurs, sometimes with local pain. Extension to the oesophagus, trachea, and/or recurrent laryngeal nerves is frequent, and the overlying skin may also be infiltrated.

Pathology

There are several variants of papillary thyroid carcinoma united by their characteristic cytological features. The nuclei are large, clear (‘Orphan Annie’, after the eyes of the cartoon character), and have longitudinal grooves and invaginations of cytoplasm (Fig. 13.5.1a). Two-thirds of tumours are unencapsulated and display papillary and follicular structures; the remainder are the encapsulated, follicular, tall cell, sclerosing, and clear cell variants.

Fig. 13.5.1 Histopathological features of thyroid follicular epithelial carcinoma. (a) Papillary carcinoma, with psammoma bodies and typical nuclear appearance. (b) Metastatic follicular carcinoma, eroding vertebral bone. (c) Anaplastic carcinoma showing pleomorphic spindle cells. All sections, original magnification ×200.

Fig. 13.5.1
Histopathological features of thyroid follicular epithelial carcinoma. (a) Papillary carcinoma, with psammoma bodies and typical nuclear appearance. (b) Metastatic follicular carcinoma, eroding vertebral bone. (c) Anaplastic carcinoma showing pleomorphic spindle cells. All sections, original magnification ×200.

(Photomicrographs by courtesy of Dr K. Suvarna.)

The encapsulated variant has a better than average prognosis and the tall cell variant a worse prognosis. One-half of papillary carcinomas contain degenerate calcified papillae, termed psammoma bodies. The tumour is multicentric in up to 80% of cases if the resected thyroid is examined carefully. Metastasis is via the lymphatics, and local lymph nodes are infiltrated in 40 to 50% of cases (more in young patients). Distant metastases are found in less than 5% of patients at presentation, with the lung being the most common site.

Follicular carcinoma is characterized by follicular differentiation with a solid growth pattern and without the nuclear features of papillary carcinoma. The tumour is encapsulated, but there is invasion of the capsule and vessels (Fig. 13.5.1b). This invasion is the crucial feature which distinguishes follicular carcinoma from follicular adenoma, self-evidently a distinction only possible by histological examination. Minimally and widely invasive subtypes are recognized, the latter having a worse prognosis. When 75% or more of the tumour cells exhibit oxyphilic staining due to mitochondrial accumulation, it is called a Hürthle (or oncocytic) cell carcinoma, which probably also has a worse prognosis. Lymph node metastases are unusual, as is multicentricity in the thyroid. Metastasis occurs via the bloodstream, typically to bone and lungs.

When follicular differentiation is poor or absent, the tumour is classified as an insular carcinoma with a poor prognosis. In anaplastic carcinoma there is no capsule, the cells are atypical, including spindle, multinuclear, and squamoid forms, and mitoses are frequent (Fig. 13.5.1c).

Diagnosis

Thyroid epithelial cancers generally fail to affect thyroid function. However, this should be evaluated in all patients presenting with a thyroid nodule; a low circulating level of TSH strongly suggests an autonomous benign nodule. Anaplastic carcinoma may occasionally cause hypothyroidism, but the most frequent cause of an elevated level of TSH with a hard, nodular thyroid is Hashimoto’s thyroiditis (OMIM 140300). Some of the glands in these cases are so irregular that a malignancy may be suspected. There is no increased or decreased risk of thyroid epithelial carcinoma in Hashimoto’s thyroiditis, but thyroid lymphoma almost always occurs in association with autoimmune thyroiditis. Therefore, any dominant or atypical area in a Hashimoto’s goitre requires careful evaluation. Thyroid peroxidase and/or thyroglobulin antibodies occur in about one-quarter of patients with thyroid follicular epithelial carcinoma, coincident with the presence of a lymphocytic infiltrate which, in turn, is associated with a slightly more favourable prognosis. Although the serum thyroglobulin concentration is extremely useful in follow-up, as discussed below, this investigation is useless in diagnosis; levels may not be elevated with some cancers and, even when elevated, cannot be causally distinguished from those that occur in benign adenoma, multinodular goitre, Graves’ disease (OMIM 275000), or destructive thyroiditis.

Neither radionuclide nor ultrasound imaging is able to diagnose malignancy accurately. Radionuclide scanning can be performed with 99mTc pertechnetate or radio-iodine (123I or 131I), with similar information being obtained from either nuclide. Most thyroid cancers fail to take up radionuclide (‘cold’ nodules), but the more frequent benign lesions such as colloid nodules, cysts, adenomas, and thyroiditis behave similarly. About 20% of nodules have normal or increased radionuclide uptake. Malignancy cannot be excluded with these appearances, however. The only exception is when the nodule is ‘hot’ and the surrounding thyroid tissue fails to take up radionuclide, indicating the presence of a toxic adenoma which is almost invariably benign. This type of nodule will cause suppression of TSH and will be suspected from routine testing of thyroid function. In summary, radionuclide scanning usually adds little to the diagnosis.

The role of ultrasonography is more controversial but it is increasingly being used in the initial evaluation. Predicting the presence of malignancy based on the echo pattern of the tumour, and more recently using colour-flow Doppler imaging, may be successful in up to 80% of cases, but this depends on the operator having considerable experience. As well as the poor specificity of ultrasonography, the technique is so sensitive that many small unsuspected nodules will be uncovered, complicating the evaluation. Ultrasonography is useful for accurate measurement of thyroid and nodule size, which can be helpful in monitoring patients, for detecting lymphadenopathy, and for guiding biopsy, although this procedure is usually performed without imaging.

Fine needle aspiration biopsy is undoubtedly the current technique of choice for investigation of a thyroid nodule. Local anaesthetic is not needed because the procedure causes little discomfort. It is usual to take two to six biopsies to increase the sample yield. Essentially three diagnoses are possible: benign (65–75% of specimens), malignant (5%), and indeterminate (20–30%), but an experienced cytopathologist is needed to obtain reliable results. Papillary carcinoma is readily diagnosed by fine-needle aspiration biopsy, and medullary carcinoma and lymphoma can also be detected by the use of immunohistochemical staining, although lymphoma frequently requires core or open biopsy for confirmation.

Follicular carcinomas cannot be distinguished cytologically from follicular adenomas, and these tumours account for the bulk of needle aspiration specimens labelled indeterminate (or suspicious). Open biopsy is the only secure diagnostic method in this setting. About 15% of biopsies reported in experienced centres are considered unsuitable for diagnosis. It is relatively simple to repeat the biopsy, but a persistently equivocal biopsy should be grounds for considering surgery since malignant tumours will be found in about one-half of these cases. A cyst may be aspirated during biopsy. If this fails to reaccumulate and no lesion remains palpable, a malignancy is highly unlikely, but recurrence of a cyst may indicate malignant disease and require surgery for definitive diagnosis. Overall, the sensitivity and specificity of fine-needle aspiration biopsy is greater than 90%.

Treatment

Surgical excision

A total or near total thyroidectomy should usually be performed since thyroid carcinomas are often bilateral and removal of thyroid tissue facilitates subsequent ablation by radio-iodine. Unilateral total lobectomy is indicated for microcarcinoma. In papillary carcinoma, the central lymph nodes should be dissected, as should all palpable nodes. Central lymph node removal is also indicated in follicular carcinoma with histological evidence of extrathyroidal spread.

Radio-iodine therapy

After surgery, radio-iodine is usually administered to remove any remaining thyroid tissue, which then allows thyroglobulin or 131I total body scanning to be used in follow-up to detect metastases. This treatment also destroys occult carcinoma and, by scanning after ablation, metastatic disease is revealed. Local policies vary, but in most centres an ablation dose of 1100 to 3700 MBq 131I is given 1 to 3 months after surgery. A pre-treatment scan is not required. In 15 to 30% of patients a second treatment dose of 131I is necessary to achieve ablation. Iodine exposure, including iodine-containing contrast media, may prevent accumulation of 131I during treatment. In patients whose tumour is less than 1.5 cm in diameter, excision alone without radio-iodine ablation is indicated. Whether all other patients require ablation is controversial, but there are persuasive arguments that low-risk patients with papillary carcinoma may not benefit from radio-iodine ablation and clinical staging scores (see below) may help to identify such patients.

High levels of stimulation by TSH are required to produce maximum uptake of 131I; this is achieved by a period of 3 to 4 weeks without thyroxine replacement and can thus lead to the development of severe hypothyroid symptoms. The short action of tri-iodothyronine, 20 µg 3 times daily, as a replacement is therefore preferable in the weeks before scanning and 131I treatment, because only 2 weeks are needed when this is stopped to increase endogenous TSH (which should be >30 mU/litre). Even this short period without thyroid hormone may be troublesome for the patient. Recombinant TSH suitable for intramuscular administration is now available and can be given without cessation of thyroid hormone replacement.

Long-term thyroid replacement therapy

The third aspect of treatment is to maintain the patient for life on thyroxine. This is given to high-risk patients at doses sufficient to suppress levels of TSH to below 0.1 mU/litre, because TSH is a growth factor for thyroid carcinoma. In almost all patients, satisfactory suppression of TSH can be achieved without inducing thyrotoxic symptoms. The effective thyroxine dosage is 2.2 to 2.8 µg/kg body weight. The optimum level of TSH is unknown, but higher levels of TSH (0.1–0.5 mU/litre) can be accepted in those low-risk patients known to be disease-free for several years.

Anaplastic carcinoma is rapidly fatal. The tumour does not take up radio-iodine. Surgery has a limited role in relieving obstructive symptoms, and external beam radiotherapy is useful in palliation. The place of chemotherapy (usually doxorubicin combined with other drugs) is unclear.

Thyroid cancerNovel agents for treatment of thyroid cancer

Thyroid cancer Thyroid cancer does not respond to conventional cancer chemotherapy, but recent trials have begun to explore the potential of novel kinase inhibitors targeted at thyroid cancer cells with specific mutations; some of these also have an effect on new blood vessel formation. In the DECISION trial of sorafenib in locally advanced or metastatic thyroid cancer, progression-free survival doubled in the treatment group, compared with the placebo group, although no patient had a complete response. The survival benefit was observed, regardless of age, extent of disease, or sites of metastases. Trials using a variety of other kinase inhibitors have commenced; these include sunitinib, pazopanib, axitinib, cabozantinib, and motesanib, with multifunctional actions, including anti-angiogenic properties. In addition, treatment with selumetinib, a MAPK kinase (MEK) 1 and MEK2 inhibitor, has been shown to produce a clinically meaningful increase in radioiodine uptake in tumours previously refractory to radioiodine treatment through loss of the sodium iodide symporter, particularly those with a RAS mutation. Vandetanib and cabozantinib, RET tyrosine kinase inhibitors with additional inhibitory effects on the vascular endothelial growth factor receptor, increase progression-free survival in locally advanced or metastatic progressive medullary thyroid cancer and provide relief from symptoms. This is a rapidly developing field, and more trials will undoubtedly help address how best to stratify patients for treatment.

Follow-up

Lifelong follow-up is necessary for papillary and follicular cancer because they may recur many years after apparent cure. As well as monitoring the concentration of TSH and performing careful neck palpation, serum thyroglobulin should be measured. Detectable levels of thyroglobulin after thyroid ablation indicate persistent or recurrent disease. Measuring thyroglobulin levels is especially valuable when the patient is not taking thyroxine replacement or after recombinant TSH stimulation, as the rise in TSH will promote thyroglobulin production and exaggerate any increase. This is particularly useful in initial follow-up and in following high-risk patients; in those at low risk it is reasonable to measure thyroglobulin routinely without withdrawing thyroxine.

If thyroglobulin is detectable, the patient should have a total body 131I scan and any recurrent disease can then be treated with a therapeutic dose of 3700 to 5500 MBq 131I. Many centres also perform a diagnostic total body scan at 6 months after initial radio-iodine ablation, but repeated scans thereafter have now been superseded by measurement of thyroglobulin and it is likely that low-risk cases may be assessed adequately by thyroglobulin measurement alone. The only exception is in the patient with thyroglobulin antibodies that interfere with many assays for thyroglobulin. If this is the case, repeated scans are the only way to ensure that the patient remains free of disease.

Ultrasonography is useful to confirm the presence of locoregional recurrence without distant metastases, and these tumour deposits are best dealt with surgically. For metastatic disease, usually in the lung, treatment with radio-iodine can be repeated every 4 to 6 months, but there is little benefit above a cumulative dose of 18 500 MBq. Bone metastases may respond to 131I or external beam radiotherapy. Preliminary trials with sorafenib and sunitinib, a tyrosine kinase inhibitor, have shown some evidence of a therapeutic effect. The best survival in metastatic thyroid cancer occurs in young patients with small metastases, indicating the overall value of early treatment for this disease.

Prognosis

At least nine scoring systems have been advocated to assess prognosis in papillary and follicular carcinoma, of which the TNM classification system is now the most popular. These systems generally take into account the age and sex of the patient, tumour characteristics (especially size, extension, and metastases), and completeness of excision. An example of the predictive power of such scoring is shown in Box 13.5.1. The risk of death increases with age, especially after 60, while tumour recurrence is commonest in those aged under 20 and over 60. Men have a slightly worse prognosis than women.

Data from Hay ID, et al. (1993). Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery, 114, 1050–8.

With appropriate treatment the rate of recurrence of papillary carcinoma is about 15%, and the cause-specific death rate is approximately 5% at 20 years. In other words, 85% of these patients present with features of the group with the best prognosis, i.e. achieving a score of less than 6 in the system described in Table 13.5.2. In follicular carcinoma, the cause-specific survival rate is 80% at 20 years after treatment and 70% at 30 years. However, in the subgroup with metastases at presentation the 10-year survival is only 20%. The median survival time for anaplastic carcinoma is 4 to 12 months and those with distant metastases at presentation have a median survival time of only 3 months.

Table 13.5.2 Types of medullary carcinoma of the thyroid

Type

Frequency (%)

Associated lesions

RET gene mutation

Sporadic

80

None

Occasional somatic mutations in tumour tissue

MEN2A

10

Phaeochromocytoma, hyperparathyroidism

Germ line: codon 634, less commonly 609, 611, 618, 620

MEN2B

3

Phaeochromocytoma, mucosal neuromas, marfanoid habitus

Germ line: codon 918, less commonly 883

Familial medullary thyroid carcinoma

7

None

Usually germ-line mutation in codons 609, 611, 618, 620, or 634, or codons in exons 13, 14, and 15

MEN, multiple endocrine neoplasia.

Prevention

In the event of a nuclear accident, prompt administration of stable iodine prevents the uptake of inhaled and ingested radioactive iodine isotopes. Emergency arrangements should be in place close to nuclear installations to provide for distribution of potassium iodate tablets, and advice is available from the World Health Organization (see ‘Further reading’).

Special problems in pregnancy

A solitary nodule in a pregnant woman should be evaluated by fine needle aspiration biopsy. If the biopsy suggests malignancy and the nodule is growing significantly, surgery can be undertaken in the second trimester, but otherwise this is best deferred until after delivery. Women receiving radio-iodine ablation should avoid pregnancy and breast feeding for 6 to 12 months after treatment.

Medullary carcinoma of the thyroid (OMIM 155240)

This accounts for 5 to 10% of all thyroid cancers. About 80% are sporadic with a peak incidence at 40 to 50 years of age. Hereditary autosomal dominant forms occur as part of multiple endocrine neoplasia type 2A (MEN2A, OMIM 171400) or type 2B (MEN2B, OMIM 162300) or as isolated familial medullary carcinoma. These forms are associated with germ-line point mutations in the RET proto-oncogene (different from those in papillary carcinoma) and preneoplastic C-cell hyperplasia (Table 13.5.2).

The pathological findings are of an encapsulated tumour with round, spindle-shaped, or polyhedral cells arranged in a variety of patterns that have no prognostic significance. There is variable fibrosis and three-quarters of tumours show marked deposition of amyloid—a feature associated with a good prognosis. Heterogeneous staining for calcitonin, a hormone of C cells, is associated with a poorer outcome, reflecting dedifferentiation. Even the smallest medullary tumours may be associated with local lymph node metastases.

The presentation of sporadic medullary carcinoma is typically with a solitary thyroid nodule, accompanied by cervical lymphadenopathy in 50% of cases. Lung, liver, or bone metastases are present at diagnosis in 10% of cases. Symptoms due to local invasion or the paraneoplastic production of polypeptides and prostaglandins, such as flushing, diarrhoea, and Cushing’s syndrome, are less common presenting features.

The diagnosis is often apparent from fine-needle aspiration biopsy. Basal serum calcitonin concentrations are almost invariably elevated and confirm the diagnosis. There is controversy over the utility of routine serum calcitonin measurement in the work-up of all thyroid nodules; most centres perform aspiration biopsy initially. Newly diagnosed patients should be screened for other evidence of MEN and a careful family history is also essential. In particular, phaeochromocytoma (OMIM 171300) occurring as part of an inherited cancer syndrome must be excluded before surgery.

Testing genomic DNA for RET mutations in the germ line is now widely available and should ideally be carried out on leucocyte DNA from all new patients. The absence of the most common mutations, coupled with a negative family history and the absence of C-cell hyperplasia or multicentric tumours in the resected thyroid, indicates that further family testing is not warranted. When a RET mutation is detected, there is a clear benefit from family testing, as prophylactic thyroidectomy in affected individuals improves outcome. However, there are some kindreds in whom familial medullary carcinoma occurs without a recognizable RET mutation and family screening must then be undertaken annually, up to the age of 35 to 40 years, using pentagastrin-stimulated serum calcitonin measurements as a guide to the presence of the inherited abnormality.

Medullary carcinoma should be treated by total thyroidectomy, with dissection of the central and other involved lymph nodes; this may require a second completion operation if the diagnosis is not made at the outset. Thyroxine replacement is needed at physiological doses rather than doses that suppress TSH. After surgery the patient should be monitored by measurement of serum calcitonin concentration. Cure, defined as a persistently normal calcitonin level, occurs in only about one-third of patients, but 80 to 90% of patients in whom there is an elevated calcitonin level and only nodal disease survive for 10 years. The best management of persistent disease is unclear, but local recurrence with identifiable lymph node involvement should be dealt with surgically. Radiotherapy and chemotherapy have a variable and at best partial effect. Profuse (secretory) watery diarrhoea is frequently a troublesome feature of extensive disease. This may respond to treatment with loperamide whereas somatostatin analogues have an inconsistent benefit.

Age, stage and size of tumour, and completeness of surgical removal are important prognostic features. Familial medullary carcinoma has the best outcome; in contrast, the tumour associated with MEN2B is very aggressive. The overall 10-year survival is around 70%, but is over 90% in those detected early by family screening. A recent trial has shown that treatment with the tyrosine kinase inhibitor vandetanib improved survival in patients with advanced or metastatic medullary carcinoma.

Primary thyroid lymphoma

Less than 5% of thyroid malignancies are non-Hodgkin’s B-cell lymphoma (OMIM 605027). The peak incidence is between 50 and 80 years of age, and women are affected 3 times more frequently than men. The typical presentation is a rapidly enlarging thyroid mass in a patient with Hashimoto’s thyroiditis. The clinical features may suggest anaplastic carcinoma. The diagnosis can be made by fine-needle aspiration biopsy and confirmed by large-needle or open biopsy. Accurate staging is then necessary to plan treatment, which is with external beam radiotherapy and anthracycline-based chemotherapy. Intensive treatment has produced 8-year survival rates of over 90%. Recent results with rituximab, a monoclonal antibody directed against B cells, have shown some evidence of therapeutic benefit.

Further reading

British Thyroid Association and the Royal College of Physicians of London (2007). Guidelines for the management of thyroid cancer in adults, 2nd edn, pp. 1–83. Royal College of Physicians, London. (http://bookshop.rcplondon.ac.uk/contents/pub223-d450dee5-a92f-48e8-a12a-4043eb995be7.pdf)Find this resource:

    Brose MS, et al. (2014). Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet, 384, 319–28.Find this resource:

      Cabanillas ME, Hu MI, Jimenez C (2014). Medullary thyroid cancer in the era of tyrosine kinase inhibitors: to treat or not to treat-and with which drug-those are the questions. J Clin Endocrinol Metab, 99, 4390–6.Find this resource:

        Cooper DS, et al. (2009). Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 19, 1167–1214.Find this resource:

        Department of Health (1993). Potassium iodate (stable iodine) prophylaxis in the event of a nuclear accident. PL/CMO(93) 1. Department of Health, London.Find this resource:

          Diehl S, et al. (2005). Modern approaches to age-old questions about thyroid tumors. Thyroid, 15, 575–82.Find this resource:

          Graff-Baker A, Sosa JA, Roman SA (2010). Primary thyroid lymphoma: a review of recent developments in diagnosis and histology-driven treatment. Curr Opin Oncol, 22, 17–22.Find this resource:

          Hackshaw A, et al. (2007). 131I activity for remnant ablation in patients with differentiated thyroid cancer: a systematic review. J Clin Endocrinol Metab, 92, 28–38.Find this resource:

          Hay ID (2006). Selective use of radioiodine in the postoperative management of patients with papillary and follicular thyroid carcinoma. J Surg Oncol, 94, 692–700.Find this resource:

          Ho AL, et al. (2013). Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med, 368, 623–32.Find this resource:

            Leboulleux S, et al. (2004). Medullary thyroid carcinoma. Clin Endocrinol (Oxf), 61, 299–310.Find this resource:

            Pacini F, et al. (2006). Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international, randomized, controlled study. J Clin Endocrinol Metab, 91, 26–32.Find this resource:

            Pacini F, et al. (2006). European Thyroid Cancer Taskforce. European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol, 154, 787–803.Find this resource:

            Pitt SC, Moley JF (2010). Medullary, anaplastic, and metastatic cancers of the thyroid. Semin Oncol, 37, 567–79.Find this resource:

            Smallridge RC, Marlow LA, Copland JA (2009). Anaplastic thyroid cancer: molecular pathogenesis and emerging therapies. Endocr Relat Cancer, 16, 17–44.Find this resource:

            Sherman SI (2011). Targeted therapies for thyroid tumors. Mod Pathol, 24, S44–52.Find this resource:

            Sturgeon C, Clark O (2005). Familial nonmedullary thyroid cancer. Thyroid, 15, 588–93.Find this resource:

            World Health Organization (1999). Guidelines for iodine prophylaxis following nuclear accidents, update 1999. (http://www.who.int/ionizing_radiation/pub_meet/Iodine_Prophylaxis_guide.pdf)

            Wu LS, Roman SA, Sosa JA (2011). Medullary thyroid cancer: an update of new guidelines and recent developments. Curr Opin Oncol, 23, 22–7.Find this resource: