THYROID DISORDERS

Goitre and thyroid cancerVasilis Constantinides

Fausto Palazzo

AbstractGoitre, which is a generic term for thyroid enlargement, is common and

thyroid malignancy rare, but the clinical presentations of benign and ma-

lignant thyroid disease are similar. The aim of clinical assessment and in-

vestigations is to identify the small number of cancers amongst non-

malignant thyroid enlargements. Investigations include thyroid function

tests and fine-needle aspiration cytology. Benign thyroid disease requires

treatment only in the presence of dysfunction or local compressive symp-

toms. The treatment of thyroid cancer is multidisciplinary and includes

surgery, radioiodine therapy and lifelong suppression of thyroid-

stimulating hormone. The diagnosis and management of thyroid cancer

are being centralized around a multidisciplinary team structure in order

to improve outcomes in the UK.

Keywords goitre; thyroid cancer; thyroid nodule

The term goitre describes any enlargement of the thyroid gland.

It may be caused by a solitary nodule (Figure 1) or multiple

nodules (Figure 2), or by a smooth enlargement of some or all of

the gland. Goitres may be classified on the basis of epidemi-

ology, aetiology, anatomical and morphological features or

functional status (Table 1), or a combination of these criteria

(Table 2).

Endemic goitre e one that has a prevalence greater than 5%

in children under the age of 12 years (within a community or

geographical area) e is the most common form of thyroid

enlargement worldwide. The term sporadic is used if this con-

dition is not met. Palpable thyroid nodules and/or goitre are

found in up to 7% of the population in iodine-replete areas. Sub-

clinical, ultrasound-detected, thyroid nodules are found in 45%

of women and 32% of men at age 55 years.1

Thyroid cancer represents 1% of all newly diagnosed cancers

and is the most common endocrine malignancy, with a growing

incidence of up to 5 per 100,000 per annum. The challenge for

the clinician lies in the need to identify the relatively small

number of cancers in a gland in which benign thyroid nodules

occur frequently.

Vasilis Constantinides BSc(Hons) MD(Lon) FRCS(Gen) is a Specialist Registrar

in General and Endocrine Surgery at Hammersmith and Charing Cross

Hospitals, UK. Competing interests: none declared.

Fausto Palazzo MS(Lon) FRCS(Eng) FRCS(Gen) is a Consultant Endocrine

Surgeon at Hammersmith and Charing Cross Hospitals, and Honorary

Senior Lecturer at Imperial College London, UK. Competing interests:

none declared.

MEDICINE 41:9 546

Aetiopathogenesis of goitre

The most common causes of goitre are:

� iodine deficiency: the prevalence of endemic goitre should

decrease with iodine supplementation programmes2

� iodine excess: iodine-excess goitre is seen in areas of Japan

where seaweed and fish are heavily consumed

� goitrogenic drugs and foods: chronic lithium therapy and

consumption of vegetables which metabolize to the

goitrogen thiocyanate (e.g. the Brassica family)

� heavy smoking: may be associated with an increased

prevalence of multinodular goitre.3

The pathogenesis of benign goitres in iodine-replete areas re-

mains incompletely understood, although a small persistent in-

crease in serum thyroid-stimulating hormone (TSH) coupled

with even marginal iodine deficiency is thought to lead to thy-

rocyte proliferation and thyroid gland enlargement, particularly if

this occurs in youth.4 The nodules that subsequently form are

differentially sensitive to TSH stimulation, culminating in nodule

autonomy.5

Risk factors for thyroid malignancy are:

� a family history

� medullary thyroid cancer in the context of MEN2

syndrome

� familial papillary and follicular thyroid cancer6

� exposure to radiation

� evidence from survivors of the atomic bombs dropped

on Japan in 1945 and the Chernobyl incident in 1986

confirm the carcinogenic effect of radiation, which ap-

pears to be most damaging if exposure occurs in youth

and is coupled with iodine deficiency7

� the fetuses in pregnant women exposed to radiation in

Chernobyl were also at an increased risk of thyroid

malignancy in later life.8

Irrespective of the type of thyroid cancer and the perceived

aetiology of the disease, one of the key molecular pathogenetic

events in papillary thyroid cancer is the activation of the ret

(rearranged during transfection) proto-oncogene.

Clinical presentation

History

Most goitres are found incidentally by the patient, by the gen-

eral practitioner or at radiological examination.9 Nodules occur

at all ages and in both sexes but those presenting in men or at

the extremes of age should be treated with greater suspicion. A

short history of rapid enlargement in the elderly is suggestive of

malignancy, whereas in the young bleeding into a nodule or

cystic enlargement may be responsible. A slow history of

enlargement does not exclude malignancy on clinical grounds

alone. The presence of local compressive symptoms (dysphagia

and dyspnoea) should be enquired about specifically.

Dysphonia in the presence of a goitre is suggestive of thyroid

malignancy invading the recurrent laryngeal nerve and causing

vocal cord paralysis. Local compressive-type symptoms,

disproportionate to the size of the goitre, especially if coinciding

with pain, should raise the possibility of thyroiditis. The pres-

ence of symptoms of hyperthyroidism, such as weight loss,

tremor, anxiety or insomnia, is suggestive of toxicity and has

been discussed above.

� 2013 Elsevier Ltd. All rights reserved.

Goitre classifications

Criterion Groups

Epidemiology Endemic

Sporadic

Familial

Aetiology Iodine deficiency

Graves’ disease

Hashimoto’s thyroiditis

(in enlargement phase)

Neoplasia

Goitrogenous nutrients and drugs

(thiocyanates, lithium)

Dyshormonogenesis

Morphology Diffuse

Multinodular

Anatomy Cervical

Retrosternal

Functional status Euthyroid

Toxic

Table 1

Figure 1 A solitary nodule later found to be malignant on thyroid cytology.

THYROID DISORDERS

Specific risk factors for malignancy e a family history and a

history of radiation exposure e should be enquired about. Sus-

picion of medullary thyroid cancer requires a focused history

regarding MEN2 syndrome (e.g. phaeochromocytoma and

hyperparathyroidism).

Examination

Neck examination is conventionally performed from behind,

with the patient seated. Any neck lump in the anterior triangle of

the neck that rises and descends on swallowing is thyroid-

related. Once clinical thyroid status has been established the

neck lump is examined with a view to establishing its size,

shape, margins, consistency, tenderness and mobility. It is also

necessary to establish whether this is a solitary/dominant nodule

or the smooth enlargement of the whole gland. Hard nodules

with poorly defined margins and fixity to surrounding structures

raise suspicions of malignancy, but Hashimoto’s thyroiditis may

also present in a similar manner. In all patients the presence or

absence of cervical lymphadenopathy should be established. The

presence of dysphonia mandates assessment of the vocal cords

Figure 2 A large multinodular goitre causing local compression.

MEDICINE 41:9 547

with a flexible naso-endoscope, which may be performed in the

out-patient setting.

Investigation of a goitre

Laboratory investigations

The essential tests to be performed are the thyroid function tests:

serum TSH, free triiodothyronine (T3) and thyroxine (T4). In

addition, a number of accessory tests can be performed. These are:

� thyroid autoantibody concentration, if there is a suspicion

of autoimmune thyroid disease or if a lymphoma is sus-

pected (the latter occurs almost exclusively on a back-

ground of Hashimoto’s thyroiditis)

� serum calcitonin, where medullary thyroid cancer is

suspected.

Combined goitre classification

Type of goitre Example

Simple euthyroid goitre

(sporadic/endemic)

Diffuse goitre

Multinodular goitre

Toxic goitre Solitary toxic nodule

Toxic multinodular (Plummer’s)

Diffuse autoimmune (Graves’)

Thyroiditis Subacute (de Quervain’s)

Autoimmune (Hashimoto’s)

Riedel’s

Neoplasia Adenoma

Carcinoma (primary/metastasis)

Others Amyloidosis

Chronic bacterial infection (TB/syphilis)

Actinomycosis

Table 2

� 2013 Elsevier Ltd. All rights reserved.

THYROID DISORDERS

Fine-needle aspiration cytology

Fine-needle aspiration cytology is the investigation of choice in

solitary and dominant thyroid nodules. The procedure is per-

formed by the clinician including under ultrasound guidance,

The latter is mandatory for small, less well-defined or awkwardly

placed nodules.10 The investigation is well tolerated and provides

a high probability of preoperative diagnosis. The Thy1e5 clas-

sification is now almost universally adopted in the UK and forms

the basis of further management (Table 3).

Radiological investigations

Radiological investigations are undertaken with a view to

investigating a specific aspect.

Thyroid ultrasound scanning: ultrasound is seldom indepen-

dently diagnostic but may be used to guide fine-needle aspiration

cytology. Ultrasonographic criteria for thyroid malignancy (such

as hypo-echogenicity, increased central vascularity, irregular

infiltrative margins and the presence of microcalcification) may

add weight to clinical and/or cytological findings. Ultrasound is

also excellent for assessing for the co-existence of cervical

lymphadenopathy.

CT and MRI scanning of goitres: cross-sectional MRI or CT is

indicated when the extent of the goitre and/or tracheal

compression are in doubt at clinical examination. Respiratory

flow-volume loops may provide evidence of co-existing respira-

tory disease in patients with goitre but without cross-sectional

evidence of tracheal compression.

Radionuclide imaging: most thyroid malignancies do not

concentrate radioisotopes (and thus appear ‘cold’), whereas hot

nodules are associated with a low incidence of malignancy.

However, less than 20% of cold nodules turn out to be cancers,

the remaining 80% resulting from colloid nodules, haemor-

rhage, cysts or inflammatory lesions. Scintiscanning has

therefore been abandoned in euthyroid patients and has been

Thy1e5 classification of thyroid cytology

Cytology Description Acti

Thy1 Non-diagnostic smear FNA

Thy2 Non-neoplastic/benign Rep

Thy3

Thy3a

Thy3f

Follicular lesion/suspected follicular neoplasm Thy

Mos

rem

Thy4 Suspicious (but not absolutely diagnostic) of papillary,

medullary or anaplastic carcinoma, or lymphoma)

Sur

asp

Thy5 Diagnostic of malignancy (unequivocal features of

papillary, medullary or anaplastic carcinoma,

lymphoma or metastatic tumour)

Sur

all

ana

FNA: fine-needle aspiration.

Table 3

MEDICINE 41:9 548

replaced by fine-needle cytology.11 Radionuclide scanning may

however be useful in the assessment of toxic goitre to differ-

entiate between a solitary toxic nodule, toxic multinodular

goitre and Graves’ disease (TSH-receptor antibody concentra-

tion will also be raised in 80e90% of patients with Graves’

disease).

Treatment of multinodular goitre and thyroid malignancy

Multinodular goitres

Euthyroid, asymptomatic, benign, multinodular goitres do not

require treatment unless there is clinical suspicion or a history of

childhood radiation exposure.12 Patients with local compressive

symptoms are best served by surgery since the use of suppressive

doses of thyroxine to halt or delay goitre progression is usually

ineffective. Retrosternal goitres arguably require surgical inter-

vention, based on the risk of acute or chronic airway obstruction

and the malignancy risk in a location that is difficult to monitor,

and because direct questioning suggests that most patients are

symptomatic. The need for a thoracic approach (e.g. median

sternotomy or right thoracotomy) and any potential morbidity

arising from this must be assessed with a preoperative CT scan

and factored into the decision-making process.13 However, this

surgical dogma does not stand up to the rigour of an evidence-

based analysis, so patients are best considered on a case-by-

case basis.14 The threshold for surgery in younger patients with

goitres is lower since these patients are more likely to become

symptomatic.

Thyroid malignancy

Given its relatively low incidence, thyroid cancer is best managed

in a multidisciplinary team context in regional centres.

Thyroid malignancies are classified according to the cell of

origin, into those arising from thyrocytes (papillary and follicular

thyroid cancers, H€urthle cell carcinoma and anaplastic carci-

noma), those arising from parafollicular C cells (medullary

thyroid cancer), those arising from thyroidal lymphocytes (lym-

phoma), and metastatic.

on Risk of malignancy

should be repeated Indeterminate

eat to confirm diagnosis within 6 months 1e3% (for two repeated

samples)

3a (atypical) cytology should be repeated

t Thy3f should be treated by surgical

oval of the lobe for diagnosis

Thy3a (10%)

Thy3f (10e30%)

gical intervention is indicated or the

irate should be repeated

60e80%

gical intervention is indicated for nearly

primary tumours except lymphoma and

plastic cancer

99%

� 2013 Elsevier Ltd. All rights reserved.

THYROID DISORDERS

Papillary thyroid cancer (PTC)

� Accounts for 85% of thyroid malignancy.

� All age groups, more common in women in young middle

age.

� Tendency to be multifocal, can be locally invasive and

spreads to regional lymph nodes even when the cancers

are of small size.15

Treatment

� Surgery is the primary mode of treatment e the extent is

dependent on the size of the primary tumour and on the

presence or absence of lymph node metastasis. There is a

general trend towards a more comprehensive surgical

approach, including prophylactic lymphadenectomy of the

central compartment of the neck in all but low-risk

patients.16,17

� Radioiodine therapy is recommended in all high-risk pa-

tients and stage 1 and 2 patients are best addressed on a

patient-by-patient basis.

� Currently, lifelong TSH suppression is advocated although

the degree of suppression and its length are the subject of

review.

� Six-monthly thyroglobulin estimation with neck ultraso-

nography in the first 2 years are adopted to detect early

recurrence.18

Prognosis: with appropriate treatment most PTC patients do well

with only 10% dying of their disease.19

Follicular thyroid cancer (FTC)

� 10% of thyroid malignancy.

� Affects an older age group.

� Diagnosis requires histological confirmation of capsular

and vascular invasion so nodule fine-needle aspiration

biopsy identifies only potential follicular neoplasms.

� Haematogenous spread is more usual than lymphatic

(<5%).

Treatment

� Extent of thyroidectomy is determined by tumour size and

invasion. Routine lymphadenectomy is not recommended.

� Radioiodine ablation and lifelong TSH suppression therapy

with follow-up as for PTC is required.

� The less favourable prognosis of FTC is mainly related to

the older age group affected.

H€urthle cell carcinoma

� Uncommon.

� Tendency to more aggressive behaviour.

Treatment

� Similar to an aggressive PTC.

� Total thyroidectomy and central compartment

lymphadenectomy.

� Radioiodine therapy less likely to be effective due to the

lower uptake in these tumours.

Anaplastic carcinoma

� Uncommon, dedifferentiated, devastatingly aggressive

variant of PTC/FTC.

� Affects patients in their sixth decade onwards: history of

dramatic increase in goitre size.

� Few survive more than 3 months.

Treatment

� Best results are achieved using a combination of surgery,

external irradiation and chemotherapy.

MEDICINE 41:9 549

Medullary thyroid cancer (MTC)

� Sporadic or part of MEN2 syndrome.

� Spreads via lymphatics.

Treatment

� Comprehensive thyroid and lymph node surgery.

� Radioiodine not taken up.

Lymphoma

� Uncommon and occurs almost exclusively in patients with

a history of autoimmune thyroiditis.

� The treatment is chemo-radiotherapy, which can be cura-

tive in localized disease.

Metastases (rare)

� Renal, breast, uterine and melanoma. A

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