Thyroid cancer

Abstract

Thyroid neoplasms represent the most-common endocrine tumour and constitute an extremely varied spectrum of disease. At the most severe end, they may have a very poor prognosis. Malignant thyroid tumours constitute around 1% of cancers and cancer-specific deaths in the UK, with just under 3000 new diagnoses each year and around 350 deaths annually in the UK alone. Although the incidence has doubled over the last 20 years, the mortality rate among men has not changed, although survival rates have improved in women. Thyroid cancer originates from follicular or parafollicular thyroid cells that can give rise to cancer that is well-differentiated to poorly differentiated. Most tumours retain endocrine differentiation, however, and may cause problematic symptoms from aberrant hormone levels.

The GP curriculum and thyroid cancer

Clinical module 3.15: Care of people with ENT, oral and facial problems requires GPs to:

Understand how to recognise rarer but potentially serious conditions such as oral, head and neck cancer

Know the epidemiology of head and neck cancers, including the risk factors, and identify unhealthy behaviour

Clinical module 3.17: Care of people with metabolic problems states that:

Biochemical tests can be diagnostic and often necessary for monitoring metabolic and endocrine diseases, so it is important for GPs to know which tests are useful in a primary care setting and how to interpret these tests and understand their limitations

Thyroid diseases including goitre, hypothyroidism, hyperthyroidism, benign and malignant tumours, thyroid eye disease, thyroiditis, neonatal hyper- and hypo-thyroidism

Presentation

One of the first signs of thyroid cancer is a lump in the thyroid region of the neck. Although many adults have nodules, with 3–7% of the population estimated to have nodules on palpation alone (Hegedüs, Bonnema, and Bennedbæk, 2003), the vast majority are benign. An essential question is how to discriminate benign nodules from those harbouring malignancy. Taking a good history is important to elicit features that may suggest a sinister cause, including family history, radiation exposure, and features suggestive of local compression such as anterior neck pain and voice changes due to recurrent laryngeal nerve involvement (Cooper et al., 2006). Abnormal thyroid function tests (TFTs) are not always found, although raised thyroid-stimulating hormone (TSH) is correlated with the presence of thyroid cancer, giving rise to the hypothesis that TSH stimulates growth of thyroid malignancy (Jonklaas, Nsouli-Maktabi, and Soldin, 2008). Patients may also report symptoms related to cervical lymphadenopathy, persistent sore throat, dysphagia, dyspnoea and where there are thyroid hormone abnormalities, changes associated with thyroid hormones such as altered bowel habit, mood and temperature. Box 1 lists some clinical features associated with increased probability of malignancy.

Box 1.

Features associated with increased probability of malignancy.

• Age less than 20 or more than 60 years:

▪ Firm nodule on palpation

▪ Rapid growth

▪ Fixation to adjacent structures

▪ Vocal cord paralysis

▪ Regional lymphadenopathy

▪ History of neck irradiation

▪ Family history of thyroid cancer

Source: Kumar et al. (1999).

Causes

Thyroid cancers are considered to be due to a combination of environmental and genetic factors, but exposure to ionising radiation, such as increasing use of X-ray and computed tomography (CT) scans, is considered to contribute to a rise in incidence. Following the Chernobyl nuclear disaster, thyroid cancer incidence rose significantly in those affected by the nuclear fallout, especially the paediatric population, and those exposed to radioactive iodine isotopes (Nikiforov, 2010). Genetic contributions include multiple endocrine neoplasia-2 (MEN-2), which is inherited in an autosomal dominant pattern and is associated with a significant risk of medullary thyroid carcinoma by the age of 70 years, alongside risk of phaeochromocytoma and parathyroid tumours (Moline & Eng, 2011).

Referral

The National Institute for Health and Care Excellence (NICE) guidelines suggest that when a patient presents with a thyroid lump and symptoms of tracheal compression, such as stridor at rest, immediate admission to hospital is necessary (NICE, 2016).

An urgent 2-week wait referral to a thyroid surgeon or endocrinologist is indicated if the lump is unexplained, if there are unexplained voice changes associated with a thyroid mass, when there is cervical lymphadenopathy with associated thyroid mass, and with a painless but rapidly growing thyroid mass (British Thyroid Association, 2014; NICE, 2016). Thyroid surgery may be undertaken by ear, nose and throat, endocrine or general surgeons depending on local availability. Children with a thyroid nodule should also be referred urgently (2-week wait) to a general paediatrician or paediatric endocrinologist (NICE, 2016).

Patients with an unchanging nodule or goitre, with no other concerning features (such as lymphadenopathy, breathing or voice changes or family history of thyroid cancer) can be managed in primary care, as well as those with non-palpable, asymptomatic nodules less than 1cm ,AQ3/>found incidentally on a scan without other concerning features (British Thyroid Association, 2014; NICE, 2016). Figure 1 shows an algorithm for a patient presenting with a thyroid lump in general practice.

Figure 1.

Algorithm of pathway for a patient with a thyroid lump presenting to a GP.

Diagnosis

Following a thorough history and examination, ultrasound is an extremely sensitive investigation with high specificity and increases the quality of diagnostic fine needle aspiration cytology (FNAC) samples (Hambly et al., 2011). Thyroid function tests should be performed, and thyroid autoantibodies if there is suspicion of autoimmune thyroid disease, (British Thyroid Association, 2014) ,AQ2/>as well as calcitonin and carcinoembryonic antigen if medullary thyroid cancer is suspected (Elsei et al., 2004).

Magnetic resonance imaging or CT scanning should be considered if the limits of the goitre cannot be determined, but iodinated contrast media should be avoided, as this can delay iodine-based treatments of malignant thyroid cancer. Cytology by FNAC is the preferred way to obtain a tissue diagnosis. Core biopsy with ultrasound guidance can be used if FNAC does not yield a diagnosis and tissue diagnosis would alter management (particularly where lymphoma is suspected) (British Thyroid Association, 2014).

Use of a ‘one stop shop’ can enable patients with a suspicious neck lump to receive an ultrasound scan, FNAC and review of sample adequacy by a cytopathologist. This reduces the need for patients to return to the clinic, as non-diagnostic cell samples and a repeat can be taken on the same day if necessary. This approach to diagnosis improves patient care and reduces anxiety and delays in diagnosis. The patient and their GP should be informed of any subsequent diagnosis promptly, with appropriate supporting information. Ultrasound images are graded via the ‘U’ classification system, with U1 (normal), U2 (benign), U3 (indeterminate), U4 (suspicious), U5 (malignant) and should be used to determine which thyroid nodules should be subjected to FNAC (British Thyroid Association, 2014).

FNAC is cost-effective and aids in triage for diagnostic surgery or may provide a definitive diagnosis (Bajaj, De, & Thompson, 2006). FNAC, however, has limitations as samples may be inadequate or fail to differentiate between the benign and malignant lesions or variants of papillary thyroid carcinoma (Bajaj et al. 2006; Yang, Fried, Takoushina, and Schreiner, 2013). The FNAC should be examined by a pathologist with experience in head and neck cytology, with immediate assessment reducing the rate of unsatisfactory samples, improving cost-effectiveness and providing a prompt diagnosis to facilitate ongoing management (Poller and Kandaswamy, 2013). Cytological diagnosis should follow guidelines laid out by the Royal College of Pathologists, which mirror the Bethesda categories used in the USA (Royal College of Pathology, 2016). Table 1 shows the Thy criteria for cytology, interpretation and the action required.

Table 1.

Thy cytology criteria.

Classification	Interpretation	Action
Thy1	Non-diagnostic	Repeat FNAC
Thy2	Non-neoplastic (benign)	Correlate with clinical and radiological findings
Thy3a	Atypical features present	Repeat FNAC- Thy3a on repeat sample requires multidisciplinary team discussion
Thy3f	Follicular neoplasm suspected	Diagnostic hemithyroidectomy
Thy4	Suspicious for malignancy	Diagnostic hemithyroidectomy
Thy5	Diagnostic of malignancy	Treatment appropriate for tumour type

Classification

The classification of thyroid cancers depends on their histological characteristics, with papillary thyroid cancer constituting approximately 80% of all thyroid cancers (Katoh, Yamashita, Enomoto, and Watanabe, 2015). Most papillary thyroid cancers have a good prognosis, although approximately 10% may have lymph node and lung metastasis. Approximately 10% of thyroid cancers are of the follicular carcinoma type, with a worse prognosis than papillary thyroid cancer.

Differentiating follicular adenoma from carcinoma may be difficult histologically; the distinction is based purely on the finding of tumour capsule invasion or vascular invasion, which may be inconspicuous. The appearance of the tumour cells can be very similar in both cases. However, the distinction is important, as follicular adenoma has a very good prognosis whereas the prognosis of follicular carcinoma is poor.

Hürthle cell carcinoma is thought to be a variant of follicular thyroid cancer, but the prognosis is worse (Lopez-Penabad et al., 2003). Medullary thyroid carcinoma is a neuroendocrine tumour that secretes calcitonin, and constitutes less than 5% of thyroid cancers. Around 20–30% are familial and are frequently seen as part of MEN2A and MEN2B. Five-year survival is around 85% (Katoh et al., 2015). Anaplastic thyroid carcinoma is an extremely aggressive and poorly differentiated tumour. Although constituting less than 2% of thyroid cancers, it represents around 40% of all deaths from thyroid cancer, with a median survival from diagnosis of 6 months (Untch & Olson, 2006). The tumour invades surrounding structures in the neck at an early stage and rapidly metastases, particularly to lung, adrenal glands, liver and brain (Besic & Gazic, 2013). The tumour can be classified using the TNM classification (Brierley, Gospodarowicz, & Wittekind, 2017). Box 2 outlines the TNM classification for thyroid cancer.

Box 2.

TNM classification of thyroid cancer.

TX : Primary tumour cannot be assessed

T0 : No evidence of primary tumour

T1a : Tumour less than or equal to 1 cm, limited to the thyroid

T1b : Tumour more than 1 cm but less than or equal to 2 cm in greatest dimension, limited to the thyroid

T2 : Tumour more than 2 cm but less than or equal to 4 cm, limited to the thyroid

T3 : Tumour more than 4 cm in greatest dimension limited to the thyroid, or gross extrathyroid extension invading only strap muscles

T3a : Tumour more than 4 cm in greatest dimension, limited to the thyroid

T3b : Tumour of any size with gross extrathyroid extension invading strap muscles

T4a : Tumour of any size extending beyond thyroid capsule

T4b : Tumour invades prevertebral fascia or encases carotid artery or mediastinal vessels

NB: : All anaplastic carcinomas are considered pT4 tumours

pT4a : Anaplastic carcinoma limited to thyroid

pT4b : Anaplastic carcinoma extends beyond thyroid capsule

Nx : Regional lymph nodes cannot be assessed

N0 : No regional lymph node metastasis

N1 : Regional lymph node metastasis

N1a : Metastases to level VI (pretracheal, paratracheal and prelaryngeal lymph nodes)

N1b : Metastasis to unilateral, bilateral or contralateral cervical (Levels I, II, III, IV, V) or retropharyngeal or superior mediastinal lymph nodes (level VII)

M0 : No distant metastasis

M1 : Distant metastasis

Reproduced from Brierley, J. D., Gospodarowicz, M. K., & Wittekind, C., (2017). TNM classification of malignant tumours. 8th edn. Wiley-Blackwell, Oxford, with permission from John Wiley and Sons.

Treatment

Following diagnosis, the initial treatment is a thyroidectomy with or without neck dissection, with total thyroidectomy indicated for large tumours or those considered to have additional risk factors, as this is associated with better survival and reduced recurrence of the tumour (Pelizzo et al., 2007). In tumours (T2 or less) that are 4 cm or smaller (greatest dimension) without additional risk factors, hemithyroidectomy can be considered. Following thyroidectomy, radioactive Iodine (¹³¹I) can be used in patients with papillary or follicular thyroid cancer, where the aim is to treat residual, recurrent or metastatic disease (British Thyroid Association, 2014). Although there is possible prolonged survival and reduced risk of local and distant tumour recurrence (Sawka et al., 2004), there are important complications of which to be aware. After radioactive iodine, female patients need to avoid pregnancy for at least 6 months. Male patients should not father a child for 4 months after treatment, and all patients should remain a safe distance from others for a short period of time. Other complications include dry mouth, an unpleasant taste in the mouth, pulmonary fibrosis and increased risk of secondary malignancy. Although there are no licensed medications for thyroid cancer, this is expected to change (British Thyroid Association, 2014). In patients where a palliative approach is required, it is important to have robust advanced care plans in place, particularly as neck compression may lead to airway obstruction by the tumour. Consideration should be given to the need for a surgical airway and whether this is in the best interests of the patient.

Follow-up and prognosis

Thyroid cancer and treatment can cause aberrations in hormone levels, such as TSH and calcitonin. However, patients who have undergone a hemithyroidectomy alone do not require TSH suppression or long- term follow-up (British Thyroid Association, 2014). Those who have undergone a thyroidectomy or are more complicated will require follow up 6 monthly, then yearly after the first year if responding well to treatment. Patients with more significant disease or incomplete response to treatment require more frequent monitoring. Those who received radioactive ¹³¹I require lifelong follow up. The treatment of thyroid cancer can cause patients to become hypothyroid and their TSH levels rise. These patients will require lifelong levothyroxine, and the effects of abnormal thyroid hormones require monitoring, due to risks such as atrial fibrillation and osteoporosis (British Thyroid Association, 2014). Calcium levels should also be monitored, particularly where parathyroid glands have been affected by treatment.

As previously discussed, some specific subtypes are associated with a greater rate of mortality. Quality of life for patients post-thyroid cancer has been shown to be impaired (Singer et al., 2012), and may be related to instability in thyroid hormone levels and calcium homeostasis, as well as the psychological, social and financial pressures patients experience following a cancer diagnosis. Avoiding abnormal thyroid levels, treating hypoparathyroidism should it arise, monitoring calcium levels and reducing the risk of osteoporosis are important considerations in the follow-up of patients in general practice (British Thyroid Association, 2014).

Depending on the subtype of thyroid malignancy, TSH may act to promote tumour proliferation, and so an important therapeutic aim is to suppress this effect. The dose of levothyroxine is therefore often higher than in normal replacement, as the therapeutic aim is to suppress TSH to <0.1 mU/L. Although this should be managed by the thyroid cancer multidisciplinary team, the GP must be made aware of target TSH levels. Patients with hypocalcaemia and on calcium supplements should be monitored with the aim of keeping calcium within normal limits (British Thyroid Association, 2014).

Summary

Thyroid cancer constitutes around 1% of all cancer deaths, with variable prognosis depending on the cancer type. The incidence is rising, and is responsible for around 350 deaths in the UK each year. Although treatment options are available, the mainstay is surgery plus radiotherapy. The consequences of treatment can have significant and life-changing effects for the patient. Patients will require lifelong monitoring of thyroid function and calcium homeostasis.

KEY POINTS

Thyroid cancer accounts for around 1% of all cancer deaths in the UK

Suspicious thyroid lumps with normal TFTs should prompt urgent referral to a specialist

Prognosis is very variable with papillary and medullary carcinomas usually having a good prognosis

Follicular carcinomas have an intermediate prognosis and anaplastic carcinomas a very poor prognosis

Patients may experience long-term side effects as a result of treatment

Patients will require lifelong monitoring of thyroid function and calcium levels

ORCID iD

Dr Jonathan Mills http://orcid.org/0000-0002-5998-8434

References

Bajaj

Thompson

(2006) Fine needle aspiration cytology in diagnosis and management of thyroid disease. The Journal of Laryngology & Otology 120(06): 467–469. doi:10.1017/S0022215106000703.

Besic

Gazic

(2013) Sites of metastases of anaplastic thyroid carcinoma: Autopsy findings in 45 cases from a single institution. Thyroid 23(6): 709–713. doi: 10.1089/thy.2012.0252.

Brierley

J. D.

Gospodarowicz

M. K.

Wittekind

(2017) TNM classification of malignant tumours, eighth edition, Oxford, UK: Wiley-Blackwell.

British Thyroid Association, Perros

Boelaert

Colley

Evans

R. M.

Gerrard

B. A.

Moss

(2014) Guidelines for the management of thyroid cancer. Clinical Endocrinology 81(s1): 1–122. doi: 10.1111/cen.12515.

British Thyroid Foundation. (2015). Thyroid cancer. Retrieved from www.btf-thyroid.org/information/leaflets/35-thyroid-cancer-guide.

Cooper

D. S.

Doherty

G. M.

Haugen

B. R.

Kloos

R. T.

Lee

S. L.

Mandel

S. J.

Tuttle

R. M.

(2006) Management guidelines for patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Taskforce. Thyroid 16(2): 109–142. doi: 10.1089/thy.2006.16.109.

Elisei

Bottici

Luchetti

Di Coscio

Romei

Grasso

Pacini

(2004) Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: Experience in 10,864 patients with nodular thyroid disorders. The Journal of Clinical Endocrinology & Metabolism 89(1): 163–168. doi:10.1210/jc.2003-030550.

Hambly

N. M.

Gonen

Gerst

S. R.

Jia

Mironov

Hann

L. E.

(2011) Implementation of evidence-based guidelines for thyroid nodule biopsy: A model for establishment of practice standards. American Journal of Roentgenology 196(3): 655–660. doi: 10.2214/AJR.10.4577.

Hegedüs

Bonnema

S. J.

Bennedbæk

F. N.

(2003) Management of simple nodular goiter: Current status and future perspectives. Endocrine Reviews 24(1): 102–132. doi: 10.1210/er.2002-0016.

10.

Jonklaas

Nsouli-Maktabi

Soldin

S. J.

(2008) Endogenous thyrotropin and triiodothyronine concentrations in individuals with thyroid cancer. Thyroid 18(9): 943–952. doi: 10.1089/thy.2008.0061.

11.

Katoh

Yamashita

Enomoto

Watanabe

(2015) Classification and general considerations of thyroid cancer. Annals of Clinical Pathology 3(1): 1045.

12.

Kumar

Daykin

Holder

Watkinson

J. C.

Sheppard

M. C.

Franklyn

J. A.

(1999) Gender, clinical findings, and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology. Thyroid 9(11): 1105–1109. doi: 10.1089/thy.1999.9.1105.

13.

Lopez-Penabad

Chiu

A. C.

Hoff

A. O.

Schultz

Gaztambide

Ordonez

N. G.

Sherman

S. I.

(2003) Prognostic factors in patients with Hürthle cell neoplasms of the thyroid. Cancer 97(5): 1186–1194. doi: 10.1002/cncr.11176.

14.

Moline

Eng

(2011) Multiple endocrine neoplasia type 2: An overview. Genetics in Medicine 13(9): 755–764. doi: 10.1097/GIM.0b013e318216cc6d.

15.

NICE. (2016). Clinical knowledge summaries. Neck lump, scenario: Thyroid lump. Retrieved from https://cks.nice.org.uk/neck-lump#!scenario:2.

16.

Nikiforov

Y. E.

(2010) Is ionizing radiation responsible for the increasing incidence of thyroid cancer? Cancer 116(7): 1626–1628. doi: 10.1002/cncr.24889.

17.

Pelizzo

M. R.

Boschin

I. M.

Toniato

Piotto

Pagetta

Gross

M. D.

Rubello

(2007) Papillary thyroid carcinoma: 35-year outcome and prognostic factors in 1858 patients. Clinical Nuclear Medicine 32(6): 440–444. doi: 10.1097/RLU.0b013e31805375ca.

18.

Poller

D. N.

Kandaswamy

(2013) A simplified economic approach to thyroid FNA cytology and surgical intervention in thyroid nodules. Journal of Clinical Pathology 66(7): 583–588. doi:10.1136/jclinpath-2012-201339.

19.

RCGP. Clinical module 3.15: Care of people with ENT, oral and facial problems. Retrieved from www.rcgp.org.uk/training-exams/gp-curriculum-overview/online-curriculum/applying-clinical-knowledge-section-2/3-15-ent-oral-and-facial-problems.aspx.

20.

RCGP. Clinical module 3.17: Care of people with metabolic problems. Retrieved from www.rcgp.org.uk/training-exams/gp-curriculum-overview/online-curriculum/applying-clinical-knowledge-section-2/3-17-metabolic-problems.aspx.

21.

Royal College of Pathologists. (2016). Guidance on the reporting of thyroid cytology specimens. Retrieved from www.rcpath.org/resourceLibrary/g089-guidancereportingthyroidcytology-jan16.html.

22.

Sawka

A. M.

Thephamongkhol

Brouwers

Thabane

Browman

Gerstein

H. C.

(2004) A systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. The Journal of Clinical Endocrinology & Metabolism 89(8): 3668–3676. doi: 10.1210/jc.2003-031167.

23.

Singer

Lincke

Gamper

Bhaskaran

Schreiber

Hinz

Schulte

(2012) Quality of life in patients with thyroid cancer compared with the general population. Thyroid 22(2): 117–124. doi:10.1089/thy.2011.0139.

24.

Untch

B. R.

Olson

J. A.

(2006) Anaplastic thyroid carcinoma, thyroid lymphoma, and metastasis to thyroid. Surgical Oncology Clinics of North America 15(3): 661–679. doi: 10.1016/j.soc.2006.05.006.

25.

Yang

G. C.

Fried

Yakoushina

T. V.

Schreiner

A. M.

(2013) Encapsulated follicular variant of papillary thyroid carcinoma: Fine-needle aspiration with ultrasound and histologic correlation of 41 cases. Acta Cytologica 57(1): 26–32. doi:10.1159/000342986.