Summary

Most commonly presents as an asymptomatic thyroid nodule detected by palpation or

ultrasound in a woman in her 30s or 40s.

The most important diagnostic test is fine-needle aspiration.

Treatment is usually total thyroidectomy followed by radioactive iodine ablation and

TSH suppression (papillary or follicular).

Treatment differs and must be tailored for uncommon types of thyroid cancer such as
medullary, lymphoma, or anaplastic.

Prognosis depends on risk-group stratification.

History & exam

Key factors

presence of risk factors

palpable thyroid nodule

Other diagnostic factors

early adulthood

FHx of thyroid cancer

hoarseness

dyspnoea

dysphagia

tracheal deviation

cervical lymphadenopathy

rapid neck enlargement

History & exam details

Diagnostic investigations
1st investigations to order

TSH

fine-needle biopsy

ultrasound, neck

laryngoscopy

Investigations to consider

free T4

free T3

I-123 thyroid scan and uptake

core biopsy

CT, neck

serum calcitonin

genetic testing for familial syndromes

Emerging tests

ultrasound elastography

molecular analysis of cytology specimens

sentinel node biopsy

Diagnostic investigations details

Step by step management

Ongoing

papillary, follicular, or Hurthle

newly diagnosed

o 1st line: surgery + radioactive iodine ablation + TSH suppression

recurrent or metastatic
 o 1st line: radioactive iodine ablation + TSH suppression surgery

o 2nd line: sorafenib or lenvatinib

medullary

o 1st line: surgery

o adjunct: thyroid replacement

o 2nd line: vandetanib

o adjunct: thyroid replacement

anaplastic

o 1st line: palliative surgery + chemoradiation

o adjunct: thyroid replacement

lymphoma

o 1st line: chemotherapy + external radiation

Step by step management

Definition

Four types account for more than 98% of thyroid malignancies: papillary, follicular, anaplastic,
and medullary. [1]

Epidemiology

Thyroid cancer is the most common endocrinological malignancy and is more common in
women than in men. [6] Incidence rates vary geographically, with the highest rates occurring in
North America (15.1 per 100,000 females) and the lowest rates in Middle Africa (1.2 per 100,000
females). [7] France has the highest incidence rate in the European Union, with 18.6 per 100,000
females affected, compared with the rate in the UK of 4.8 per 100,000. [7] In the US, thyroid
cancer accounts for 1% to 1.5% of all new cancer cases reported annually. [8] It is estimated that
about 30,000 new cases of thyroid cancer are diagnosed annually in the US and about 1400
people die of the disease. [9] The median age at diagnosis is 40 to 45 years.

Aetiology
Genetic alterations are thought to underlie thyroid cancers. Papillary thyroid carcinomas often
harbour mutations (e.g., BRAF mutations) that activate effector signalling through a mitogen-
activated protein kinase. [10] [11] Follicular thyroid carcinomas often have a chromosomal
translocation that fuses the paired box gene 8 with the peroxisome proliferator-activated receptor
(PPAR) gamma gene. This in turn acts as an oncogene. [10]

Medullary thyroid cancer is associated with mutations in the REarranged during Transfection
(RET) proto-oncogene, which codes for a tyrosine kinase receptor expressed in neural crest-
derived tissues. [8] These mutations characterise multiple endocrine neoplasia (MEN) type IIA
(medullary thyroid cancer, phaeochromocytoma, hyperparathyroidism), type IIB (medullary
thyroid cancer, phaeochromocytoma, marfanoid features, mucosal neuromas/neurofibromas), or
isolated familial medullary thyroid cancer.

Pathophysiology

The pathophysiology of thyroid cancer is not completely defined. Alterations of several

molecular factors have been associated with thyroid malignancy. These include proliferative
factors such as growth hormones and oncogenes, and apoptotic and cell-cycle inhibitory factors
such as tumour suppressors. [12]

Physiological behaviour depends on tumour type. Thyroid cancer is thought to reflect a

continuum from well differentiated to anaplastic, characterised by early and late genetic events.
[13] Up to one third of patients with differentiated thyroid cancer experience tumour de-
differentiation, accompanied by increased tumour grade and loss of thyroid-specific functions
such as iodine accumulation. [14]

Papillary carcinoma tends to spread to local lymph nodes, whereas follicular and Hurthle cells
more often spread haematogenously. Anaplastic thyroid cancer is a rare, aggressive,
undifferentiated carcinoma with a high propensity for local invasion and metastatic spread.
Nodal spread is common with thyroid lymphomas.

Classification

Types of thyroid cancer

Papillary: the most common type and accounts for 80% of thyroid cancers. [2] It is
usually well differentiated with a tendency towards multi-centricity and lymph node
involvement.View image

Follicular: accounts for about 10% of thyroid cancers. [2] It spreads through direct
haematogenous invasion rather than lymph nodes. Early forms are indolent, whereas
widely invasive forms are aggressive. Hurthle cell is a sub-type of follicular cell. It is
more likely to have distant than lymph node metastasis.View image
 Medullary: originates in thyroid parafollicular C cells and accounts for about 4% of
thyroid cancers. [3] It occurs in sporadic and familial forms. A minority (about one
quarter) of cases are familial: for example, part of multiple endocrine neoplasia (MEN)
syndromes. There is a tendency to multi-centricity and early lymph node spread.

Anaplastic: an undifferentiated neoplasm with mitosis and vascular invasion. It usually

presents with local encroachment into the recurrent laryngeal nerve and trachea, muscle,
and/or oesophagus.

Lymphoma: generally a B cell-type non-Hodgkin's lymphoma. It generally arises in the

setting of pre-existing Hashimoto's thyroiditis.

Primary prevention

Early diagnosis and intervention based on genetic testing is indicated when there is a family
history of inherited thyroid cancer. [15] Prophylactic surgery as early as 6 years of age is
recommended for carriers of familial REarranged during Transfection (RET) mutation,
especially for multiple endocrine neoplasia (MEN) type IIA. Some investigators recommend a
more conservative approach, with stimulated calcitonin levels or later surgery for young patients
who do not have evidence of medullary tumour and who have germline mutations with
unaggressive phenotypes (e.g., exon 13).

In the case of a nuclear accident, [17] local age-specific guidelines should be immediately
consulted regarding potassium iodide prophylaxis

Secondary prevention

People with a family history of multiple endocrine neoplasia (MEN) type IIA or IIB syndromes
or familial medullary cancer should receive genetic counselling and testing.

History & examination

Key diagnostic factorsshow all

presence of risk factors (common)

Key risk factors include head and neck irradiation and female sex.

palpable thyroid nodule (common)

The risk of malignancy in a cold (hypofunctioning) nodule in a

multinodular goitre is about 5% to 8%, similar to that of solitary cold
nodules. [16]
Other diagnostic factorsshow all
early adulthood (common)

Thyroid cancer is most common in the third and fourth decades.

The anaplastic variant is rare, but occurs after the fifth decade. [8]

The risk of thyroid cancer in a nodule is higher in childhood or

adolescence and in older people. [16]

Therefore, nodules at extremes of age are considered of greater

significance (age <14 or >70 years). [16]

FHx of thyroid cancer (uncommon)

Responsible for a small number of cases.

Some patients have medullary carcinoma as part of familial or multiple

endocrine neoplasia (MEN) syndromes.

hoarseness (uncommon)

Suggests recurrent laryngeal nerve involvement. Other causes should

be ruled out. [16]

dyspnoea (uncommon)

Results from tracheal pressure. Other causes should be ruled out. [16]

dysphagia (uncommon)

Results from oesophageal pressure. Other causes should be ruled out.

[16]

tracheal deviation (uncommon)

Caused by an enlarged gland. Can also be due to a large benign goitre.

cervical lymphadenopathy (uncommon)

Suggests neck metastasis.

rapid neck enlargement (uncommon)

Suggests thyroid lymphoma, especially in the setting of Hashimoto's

thyroiditis.
 It can also occur with anaplastic cancer or after haemorrhage into a
benign or malignant nodule. [16]

Risk factorsshow all

Strong
head and neck irradiation

Radiation may have been previously given for treatment of another

malignancy.

Accidental exposure may have occurred.

Older patients may have a remote history of radiation treatment for

acne, thymic enlargement, or lymphadenopathy.

A significant risk factor for malignant thyroid nodules when exposure is

in youth (<16 years), but not common.

female sex

Differentiated thyroid carcinoma is diagnosed twice as often in females

as in males. [15]

Although thyroid cancer is more common in women, men have a

higher prevalence of malignancy in thyroid nodules. [16]

Weak
FHx of thyroid cancer

Diagnostic investigations

1st investigations to ordershow all

Test Result

TSH

Initial screening test. Usually normal.

A suppressed (lower than normal) TSH level suggests

hyperthyroidism or the possibility of a hyperfunctioning (hot) normal
nodule. The incidence of carcinoma in hyperfunctioning
thyroid nodules is very low.

Normal range is 0.4 to 4.0 milli-international units/L.

fine-needle biopsy

Done if TSH is not suppressed.

Papillary cancer: intranuclear holes and grooves, "Orphan

Annie" eyes, and psammoma bodies. [16] View image

Follicular neoplasms: hypercellularity, microfollicles, and

absence of colloid.View image
cytology suggests
Medullary cancer: eosinophilic cells arranged in nests or histological features
sheets separated by amyloid and vascular stroma.
Immunohistochemical staining positive for calcitonin.

Anaplastic thyroid cancer may be distinguished from other

cancers metastatic to the thyroid by cytokeratin and
thyroglobulin (when present). [8]

Lymphoma may be identified by flow cytometry and nuclear

atypia.

ultrasound, neck

Thyroid ultrasound and Doppler can be used to define

dimensions of nodules and solid/cystic component(s). [18]

Suspicious features include micro-calcifications, a more-tall- nodule

than-wide shape, hypervascularity, marked hypoechogenicity, number/characteristi
[16] or irregular margins. cs

Can be used to guide fine-needle biopsy.

Also used to pre-operatively evaluate cervical lymph nodes

in people with medullary cancer.

laryngoscopy
may show ipsilateral
A paralysed vocal cord is highly suggestive of malignancy. paralysed vocal cord

Investigations to considershow all

Test Result
free T4

If not available, alternative is total T4 plus a measure of binding.

Required if TSH is abnormal. Elevated free T4 suggests normal

hyperthyroidism.

Normal range is 10 to 23 picomols/L (0.8 to 1.8 nanograms/dL).

free T3

Alternative test is total T3 plus a measure of binding.

Required if TSH is abnormal. Elevated free T3 suggests

hyperthyroidism. normal

Normal range for free T3 is 3.5 to 6.5 picomols/L (230 to 420

picograms/dL) and total T3 is 1.23 to 2.77 nanomols/L (80 to 180
nanograms/dL).

I-123 thyroid scan and uptake

Scan should be ordered for patients with overt or subclinical

hyperthyroidism. A hyperfunctioning (hot) nodule is almost hot nodule ruled
always benign. in/out

Most nodules are hypofunctioning (cold). Most of these are

benign, but malignant nodules are also cold.

core biopsy
may confirm
When fine-needle biopsy suggests lymphoma. lymphoma

CT, neck

Evaluates cervical lymph nodes in people with medullary cancer. may show
lymphadenopathy
Also occasionally needed to evaluate large or rapidly expanding
neck masses (e.g., suspected lymphomas).
serum calcitonin

Normal is <10 nanograms/L. Levels are obtained only when there high in medullary
is suspicion for medullary carcinoma, rather than for every cancer
nodule.

genetic testing for familial syndromes

The REarranged during Transfection (RET) proto-oncogene

codes for a tyrosine kinase receptor, which is expressed in neural
crest-derivative tissues. [8] Mutations of this gene may be found may detect RET
in people with multiple endocrine neoplasia (MEN) type IIA proto-oncogene
(medullary thyroid cancer, phaeochromocytoma, germline
hyperparathyroidism), type IIB (medullary thyroid cancer, mutations
phaeochromocytoma, marfanoid features, mucosal
neuromas/neurofibromas), or isolated familial medullary thyroid
cancer.

Emerging testsshow all

Test Result

ultrasound elastography
may
Preliminary data suggest that elasticity may provide a tool in choosing show low
patients for surgery when cytology is indeterminate. [21] [22] elasticity

molecular analysis of cytology specimens

Molecular analysis of cytology specimens may enhance interpretation of may

indeterminate cytology, for example detecting BRAF, RET/PTC, or RAS show
mutations. However, some papillary or follicular carcinomas do not mutation
harbour mutations. [24] [25] [26] [27]

sentinel node biopsy positive

Sentinel node biopsy using blue dye, radioisotope, or combined techniques

has been trialled as a technique to possibly avoid prophylactic lymph node
surgery in people with clinically node-negative thyroid cancer. A positive
sentinel node was seen in about 40% of patients with papillary thyroid
cancer with an identified sentinel node; the rate may be higher with
 immunohistochemical assessment. [28]

Differential diagnosis
Condition Differentiating signs/symptoms Differentiating investigations

Fine-needle biopsy
generally shows benign
cytology with abundance
These may lack hard consistency,
of colloid.
Benign fixation, or associated adenopathy.
thyroid Vocal cord paralysis is generally
nodule For follicular cell
absent. However, these findings are
not diagnostic. adenomas, permanent
surgical pathology shows
lack of vascular and
capsular invasion.

Diagnostic approach

The most common presentation is an asymptomatic thyroid nodule in a female in her 30s or 40s.

Risk factors for thyroid cancer include a history of head and neck irradiation, which is a strong
but uncommon factor. Thyroid cancer is more common in women, but men have a higher
prevalence of cancer in thyroid nodules. [16] Rarely, thyroid cancer occurs as part of a familial
syndrome such as a multiple endocrine neoplasia (MEN) syndrome.

Examination and detection

The nodule might be found on physical examination or else incidentally on neck ultrasound or
CT. PET-positive thyroid nodules found incidentally may have a higher risk of malignancy and
should be investigated appropriately. A study evaluating the use of 2-[18F]-fluoro-2-deoxy-D-
glucose PET/CT (F-18-FDG-PET/CT) in detecting thyroid incidentalomas found around one
third of focal thyroid uptakes to be malignant, of which most were papillary thyroid carcinomas.
[4] Clinical examination may be unremarkable, or neck lymphadenopathy may be palpable.
Locally advanced cancer may present with hoarseness due to a paralysed ipsilateral vocal cord,
or with dyspnoea or dysphagia. The trachea may be deviated to the opposite side, and the nodule
itself may be firm to hard in consistency. Rapid neck enlargement is unusual, but suggests
lymphoma (usually in the setting of Hashimoto's thyroiditis), haemorrhage into a nodule, or
anaplastic cancer.

Tests
A TSH level should be ordered initially. If TSH is suppressed, thyroid hormone levels and a
radioactive iodine scan are the next steps. The scan may identify a hyperfunctioning (hot)
nodule, which is almost always benign.

If TSH is normal, the next diagnostic step is fine-needle aspiration of the thyroid nodule. Non-
palpable nodules should be biopsied under ultrasound guidance. In the US, the American Thyroid
Association and the American Association of Clinical Endocrinologists (AACE) also recommend
sonography before fine-needle aspiration of palpable nodules to assess size, location, and cystic
component(s). [2] [16] [18] Most cystic nodules are in fact solid-cystic, for which the risk of
malignancy is the same as for solid nodules. However, ultrasound can help to guide aspiration of
any solid component. In multi-nodular goitres, fine-needle aspiration of cold nodules should be
done based on suspicious features rather than size. [16] The AACE recommends against fine-
needle biopsy of thyroid nodules <1 cm, unless ultrasound findings are suspicious or the patient
has a high-risk history. [16]

Cytology may suggest thyroid cancer type. However, while histology can identify follicular
neoplasms, it does not distinguish between follicular adenomas and carcinomas. In these cases
the nodule must be removed to look for capsular or vascular invasion. Indeterminate cytological
results should be viewed as suspicious for malignancy. [16] View imageView image

If biopsy is suspicious for lymphoma, a core biopsy may be used for confirmation. However,
core biopsy is not recommended for the identification and evaluation of thyroid lesions, although
some centres still perform this procedure. [19]

Serum calcitonin level should be checked if medullary carcinoma is suspected: for example,
when there is a family history suggestive of familial medullary cancer or a multiple endocrine
neoplasia (MEN) syndrome. Genetic testing is also required for people with family history of
MEN syndromes. Patients with suspected medullary cancer should undergo pre-operative neck
imaging studies to evaluate lymph nodes (ultrasound and CT).

All patients require laryngoscopy, which may show a paralysed vocal cord in patients with
hoarseness.

Serum thyroglobulin is useful for post-treatment monitoring of papillary or follicular cancer but
not for diagnosis of thyroid malignancy. It is also useful for predicting future disease-free status
before radioiodine remnant ablation, whereby low pre-ablation thyroglobulin levels may be
considered a favourable risk factor in patients with differentiated thyroid cancer. [20]

Emerging investigations

Preliminary data suggest that low sonographic elasticity may provide a tool in choosing
patients for surgery when cytology is indeterminate. [21] [22]
 Pre-operative ultrasonography may be a valuable technique for pre-operative lymph node
staging of papillary thyroid carcinoma. [23] However, further high-quality prospective
studies are needed to evaluate its use in evaluating cervical lymph node status.

Molecular analysis of cytology specimens may enhance interpretation of indeterminate

cytology, for example detecting BRAF, RET/PTC, or RAS mutations. [11] However,
some papillary or follicular carcinomas do not harbour mutations. [24] [25] [26] [27]

Sentinel node biopsy using blue dye, radioisotope, or combined techniques has been
trialled as a technique to possibly avoid prophylactic lymph node surgery in people with
clinically node-negative thyroid cancer. A positive sentinel node was seen in about 40%
of patients with papillary thyroid cancer with an identified sentinel node; the rate may be
higher with immunohistochemical assessment. [28]

Diagnostic criteria

Clinical prognostic stratification [29]

Used to guide treatment of papillary or follicular cancer. The staging system for differentiated
thyroid carcinoma is based on the American Joint Committee on Cancer (AJCC) system and
Metastasis, Age, Completeness of Resection, Invasion, and Size (MACIS). [30] [31] The
following are favourable prognostic factors:

Female sex

Age <45 years

Size of nodule <4 cm

No extrathyroidal extension

Absence of metastatic disease

Low-grade histology.
Ongoing

Patient group

Treatment line

Treatmentshow all

papillary, follicular, or Hurthle

newly diagnosed

1st

surgery + radioactive iodine ablation + TSH suppression

Options for surgery are total thyroidectomy (most patients) or hemithyroidectomy
(selected low-risk patients). The risk of complications is higher, but follow-up easier,
after total thyroidectomy. Risks include bleeding, infection, recurrent laryngeal nerve
damage, and hypoparathyroidism.

Radioactive iodine ablation is generally done 4 to 6 weeks after total thyroidectomy,

except for patients with early micro-papillary carcinoma (<1 cm). Conventionally,
patients must be hypothyroid at the time of scanning (TSH >25 milli-international
units/L). The scan is used to survey for metastatic disease and ablate any remaining
thyroid tissue at the same time. Following ablation, thyroglobulin is a sensitive test for
post-operative follow-up.

Although radioactive iodine is generally safe, adverse effects include nausea, vomiting,
and dryness of the mouth.

Radioactive iodine ablation is also used for recurrent disease. Selecting an optimal dose
of radioiodine for successful ablation is challenging in patients with differentiated thyroid
carcinoma after thyroidectomy. A study found post-operative ablation of residual thyroid
cancer tissue with I-131 at the higher dose of 3700 MBq (100 mCi) was more successful
than the lower dose of 1110 MBq (30 mCi). [38] Another study has found low-dose I-131
plus thyrotropin alfa was as effective as high-dose I-131, but with fewer side effects. [39]

All patients receive levothyroxine with the goal of suppressing TSH below normal levels.
Doses are higher than for replacement. Bone loss is a potential adverse sequela of TSH
suppression in post-menopausal, non-oestrogen-treated women, [2] [40] but the effect of
TSH suppression on fracture rate is unclear. [B Evidence]
Primary options
surgery

and

radioiodine ablation

and

levothyroxine: 100-300 micrograms orally once daily

recurrent or metastatic

1st

radioactive iodine ablation + TSH suppression surgery

Patients who have had a total thyroidectomy can be followed up with thyroglobulin
levels. An elevated thyroglobulin is investigated with radioactive iodine whole-body
scan. Recurrent disease or metastases are ablated with I-131. Selecting an optimal dose of
radioiodine for successful ablation is challenging in patients with differentiated thyroid
carcinoma after thyroidectomy. A study found post-operative ablation of residual thyroid
cancer tissue with I-131 at the higher dose of 3700 MBq (100 mCi) was more successful
than the lower dose of 1110 MBq (30 mCi). [38] Another study has found low-dose I-131
plus thyrotropin alfa was as effective as high-dose I-131, but with fewer side effects. [39]

If recurrence or metastasis is surgically accessible in the neck, surgery is also performed

to remove the metastasis.

Primary options
radioiodine ablation

and

levothyroxine: 100-300 micrograms orally once daily

and

surgery: surgery is performed if recurrence or metastasis is surgically resectable

2nd
sorafenib or lenvatinib
Metastatic differentiated thyroid cancer can be refractory to radioactive iodine. There are
systemic treatments available, such as sorafenib and lenvatinib. Both of these kinase
inhibitors are associated with improved outcomes; however, there can be significant
toxicities. [41] [42] Sorafenib and lenvatinib should only be given to patients where there
is documented evidence of progression of disease and the toxicities are manageable. [41]
[42]

Primary options
sorafenib: 400 mg orally twice daily

or

lenvatinib: 24 mg orally once daily

medullary

1st

surgery
Surgery for medullary thyroid cancer is total thyroidectomy. Patients without lymph node
involvement undergo central neck lymph node dissection.

Those with microscopic or clinical lymph node involvement undergo modified radical
neck dissection on the side of metastasis.

Recurrences are treated with additional surgery, plus radiotherapy if local control cannot
be achieved.

adjunct

thyroid replacement
Replacement rather than suppression is required, because medullary cancer is not TSH-
sensitive.

Primary options
levothyroxine: 50-200 micrograms orally once daily

2nd
vandetanib
Vandetanib, an oral multi-targeted tyrosine kinase inhibitor, is considered for the
treatment of aggressive and/or symptomatic locally advanced or metastatic medullary
thyroid cancer in adult patients who are not suitable for surgery. [43] [44] [A Evidence]

Contraindications include long QT syndrome.

Primary options
vandetanib: 300 mg orally once daily

adjunct

thyroid replacement
Replacement rather than suppression is required, because medullary cancer is not TSH-
sensitive.

Primary options
levothyroxine: 50-200 micrograms orally once daily

anaplastic

1st

palliative surgery + chemoradiation

Total thyroidectomy is done when possible. [45]

Usually the role of surgery is to perform a biopsy and relieve airway obstruction.

Treatment is adriamycin- or platinum-based chemotherapy plus radiation. See local

specialist protocol for dosing guidelines.

adjunct

thyroid replacement
Levothyroxine replacement is required if total thyroidectomy was done.

Primary options
levothyroxine: 50-200 micrograms orally once daily
lymphoma

1st

chemotherapy + external radiation

Management approach

Once fine-needle biopsy is suspicious for thyroid cancer, treatment should be based on the type
of malignancy. Thyroid cancer should be managed by a multi-disciplinary team.

Papillary, follicular, or Hurthle cell

The standard approach is surgery followed by radioactive iodine ablation and suppression of
TSH for most patients.

Total thyroidectomy makes it easy to subsequently do a radioactive iodine nuclear scan to look
for metastatic disease and to follow up with thyroglobulin levels. Papillary cancer may also be
multi-centric. The decision to perform a total thyroidectomy is based on the presence of any
unfavourable prognostic factors, such as male sex, older age, or greater extent/size of the nodule.
[8] The staging system for differentiated thyroid carcinoma is based on the American Joint
Committee on Cancer (AJCC) system and Metastasis, Age, Completeness of Resection,
Invasion, and Size (MACIS). [30] [31] Hemithyroidectomy (lobectomy plus isthmectomy
followed by TSH suppression alone) is reserved for unilateral differentiated carcinomas
measuring <1 cm in patients who have no unfavourable prognostic risk factors. [16] Pre-tracheal
neck nodes are removed during total thyroidectomy. [32] Unilateral selective neck dissection is
done in patients who have adenopathy. Prophylactic central neck dissection is controversial. In
some centres it is recommended, but there is a lack of definitive evidence demonstrating
improvement in outcomes such as recurrence and mortality. [33] [34] [35] Routine wound
drainage after thyroidectomy offers no benefit to improve outcomes, such as prevention of post-
operative fluid collection, but does increase length of stay. [36]

Complications of total thyroidectomy include a 2% risk of recurrent laryngeal nerve damage or

hypoparathyroidism. [8] The risk of permanent hypoparathyroidism is higher for total than for
sub-total thyroidectomy. The patient should be referred to an experienced surgeon.

Some patients may undergo a hemithyroidectomy after fine-needle aspiration suggests follicular
neoplasm, and are then found to have follicular carcinoma on final pathology. Fine-needle
aspiration does not reliably distinguish between benign (adenoma) and malignant (carcinoma)
follicular neoplasms; the distinction may be difficult even on frozen section. There are three
treatment options:
 Return to theatre to complete the thyroidectomy, followed by radioactive iodine ablation
and TSH suppression

Ablate the remaining lobe with radioactive iodine, followed by TSH suppression

Forego further surgery and suppress TSH alone.

The decision is clinical and based on the same prognostic risk factors as for papillary cancer. [37]

After initial treatment, detected recurrent disease or metastases are ablated with I-131.View
image Selecting an optimal dose of radioiodine for successful ablation is challenging in patients
with differentiated thyroid carcinoma after thyroidectomy. A study found post-operative ablation
of residual thyroid cancer tissue with I-131 at the higher dose of 3700 MBq was more successful
than the lower dose of 1110 MBq. [38] Another study has found low-dose I-131 plus thyrotropin
alfa was as effective as high-dose I-131, but with fewer side effects. [39] If recurrence/metastasis
is surgically accessible in the neck, surgical removal is also performed. TSH suppression is also
continued. Bone loss is a potential adverse sequela of TSH suppression in post-menopausal, non-
oestrogen-treated women, [2] [40] but the effect of TSH suppression on fracture rate is unclear.
[B Evidence]

Metastatic differentiated thyroid cancer can be refractory to radioactive iodine. There are
systemic treatments available, such as sorafenib and lenvatinib. Both of these kinase inhibitors
are associated with improved outcomes; however, there can be significant toxicities. [41] [42]
Sorafenib and lenvatinib should only be given to patients where there is documented evidence of
progression of disease and the toxicities are manageable. [41] [42]

Medullary

Surgery for medullary thyroid cancer is total thyroidectomy. Patients without node involvement
will undergo central neck lymph node dissection. When neck adenopathy is found (on clinical
examination, on imaging, or intra-operatively) and the histology is consistent with metastatic
disease (based on fine-needle biopsy or frozen section), patients should undergo modified radical
neck dissection on the side of metastasis.

Prophylactic thyroidectomy is done when a genetic predisposition to medullary cancer (multiple

endocrine neoplasia [MEN] or familial syndrome) is found.

Recurrences are treated with additional surgery, plus radiotherapy if local control cannot be
achieved.

For advanced medullary thyroid cancer, vandetanib, an oral multi-targeted tyrosine kinase
inhibitor, has been shown to be effective when compared with placebo. [43] [44] [A Evidence]
Vandetanib is considered for use in patients with aggressive and/or symptomatic locally
advanced or metastatic medullary thyroid cancer who are not suitable for surgery.
Contraindications include long QT syndrome.

Levothyroxine is only required for post-surgical thyroid replacement, rather than for treatment of
the underlying malignancy, because medullary cancer is not TSH-sensitive; [8] therefore,
suppressive doses of levothyroxine are not required.

Anaplastic

If possible a total thyroidectomy is done. Usually the role of surgery is to perform a biopsy, and
if necessary to relieve airway obstruction by isthmectomy and tracheostomy. The patient is
treated with combined chemotherapy and radiation. Chemotherapy is usually an adriamycin- or
platinum-based regimen. [45]

Thyroid lymphoma

Primary thyroid lymphoma is treated with a combination of radiation and chemotherapy. The
most common chemotherapy regimen is CHOP (cyclophosphamide, doxorubicin, vincristine,
and prednisolone).

Emerging treatments

Molecular and immune targets

Adenosine triphosphate-competitive kinase inhibitors for BRAF-mutant thyroid carcinoma have
been studied in vitro as a possible molecular target in thyroid carcinoma cells. [46] [47] Other
areas of study include tyrosine kinase inhibitors and modulators of growth, apoptosis,
angiogenesis, or immune function. [2] [27] Cabozantinib, a tyrosine kinase inhibitor, has shown
some benefit in metastatic medullary thyroid cancer. Toxicities associated with the drug can be
significant but manageable. [48]

Robot-assisted endoscopic thyroid surgery

Robot-assisted endoscopic thyroid surgery utilises unique 3D vision and precise simulation-
based technology. This technology has achieved successful radical thyroidectomy with central
and lateral neck lymph node dissection while maintaining operative results and cosmetic
outcomes similar to or better than conventional endoscopic surgery. [49] However, the use of
robotic systems for thyroid surgery is still controversial and has not been widely adopted.

Monitoring
Papillary, follicular, or Hurthle cell
 Total thyroidectomy should be followed by radioactive iodine scan post-operatively when
the patient becomes hypothyroid (generally in 4 to 6 weeks). The scan detects residual
thyroid tissue in the neck and also metastases.View image This is usually followed by
ablation with radioiodine (I-131). After ablation, levothyroxine should be started for
replacement and TSH suppression.

During follow-up the best investigations are thyroglobulin and clinical examination.
Thyroglobulin is an important investigation if the patient has undergone total
thyroidectomy and radioiodine ablation. Any rise in thyroglobulin is suggestive of
recurrent thyroid carcinoma, most of which is recurrence in either the central
compartment of the neck or the lateral neck. However, thyroglobulin is not accurate in
the presence of thyroglobulin antibodies. [8]

Although there is no definitive cut-off for thyroglobulin, >2 micrograms/L (2

nanograms/mL) is considered worrisome and >10 micrograms/L (10 nanograms/mL)
suggests recurrent thyroid carcinoma. Thyroglobulin may be performed twice yearly for
the first 5 years and subsequently once yearly (if normal).

In the presence of thyroglobulin antibodies, ultrasound is done at baseline, 1 year, and 3

years. If these are negative, patients can be followed with clinical examination. In the
absence of thyroglobulin antibodies, ultrasound is indicated when thyroglobulin level is
elevated or if clinical examination suggests lymphadenopathy. Ultrasound may detect
recurrent disease in the thyroid bed, the paratracheal area, or the lateral neck.

An elevated thyroglobulin is generally investigated with radioiodine whole-body scan.

Traditionally this required thyroxine withdrawal, but recombinant TSH (rTSH) has been
used instead, with improved comparative quality of life scores. [55] [56] [57] Two
injections of rTSH raise serum TSH level to >25 milli-international units/L. Recurrent
disease or metastasis is ablated with I-131. Surgery may also be used for accessible
disease.

PET/CT can be used to look for recurrent disease in patients with raised thyroglobulin
and negative radioactive iodine scan. [58]

Medullary

Medullary cancer is monitored with serum calcitonin every 3 months for 2 years,
followed by every 6 months for 3 years. If levels are undetectable they can then be
followed annually. If serum calcitonin is elevated, ultrasound and CT of the neck/chest
are indicated. If both are negative, PET scan may detect lesions missed by CT. [58]

Hypocalcaemia
 Incidence of permanent hypocalcaemia due to parathyroid injury is extremely low. If
post-operative hypocalcaemia persists for >3 weeks, it is more likely to be permanent.
Treatment is with oral calcium and vitamin D.

Patient instructions
Some protocols require patient isolation for radioactive iodine doses >29.9 millicuries (mCi)
(1110 megabecquerels [MBq]). Outpatients given radioactive iodine should wash hands
frequently. Close contact with others should also be avoided, particularly with children and
pregnant women. Patients who receive radioactive iodine are generally advised not to become
pregnant for a period of at least 6 months. [59]

Complications
Timefram Likelihoo
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airway obstruction
short term low
Treatment is surgical if possible.

surgery-related hypoparathyroidism

see our comprehensive coverage of Hypoparathyroidism

Risk is low with an experienced surgeon.

Symptoms include peri-oral numbness, carpopedal spasm, or

in severe cases, tetany.
short term low
Usually occurs after the first post-operative day and resolves
within 1 week; permanent hypocalcaemia is rare.

Transient mild asymptomatic hypocalcaemia is treated with

oral calcium and vitamin D. Severe or symptomatic
hypocalcaemia is treated with IV calcium.

surgery-related recurrent laryngeal nerve damage short term low

Risk is low with an experienced surgeon.

Majority of nerve injuries are temporary and improve in 2 to

3 months.
 Timefram Likelihoo
Complicationhide all
e d

Likelihood of developing permanent hoarseness is low. If

there is no improvement after 3 months, the injury is most
likely to be permanent and treatment is started with speech
therapy.

Operative procedures can be performed, such as medialisation

of the vocal cord to improve quality of voice.

surgery-related bleeding

Can present as dyspnoea, or as swelling around the operative

site.
short term low
Treatment includes opening the wound to drain the
haematoma and ligate the bleeding vessel.

TSH-suppression-related atrial fibrillation

see our comprehensive coverage of Chronic atrial fibrillation

long term medium
The risk of atrial fibrillation in people aged >60 years with a
fully suppressed TSH is about 20% over 10 years. [53] [B
Evidence]

radioiodine-related dryness of mouth

Total doses in excess of 200 to 300 millicuries (mCi) are

likely to lead to dryness of the mouth, most of which is long term low
temporary. However, in a small percentage of patients it may
be long-lasting.

TSH-suppression-related bone mineral loss

see our comprehensive coverage of Osteoporosis

variable low
An adverse sequela of TSH suppression is bone loss in post-
menopausal, non-oestrogen-treated women. [2] [40] Effect on
fracture rate is unclear. [B Evidence]
 Timefram Likelihoo
Complicationhide all
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pathological fracture
variable low
Rarely caused by metastatic thyroid cancer. [54]

Prognosis

The incidence of thyroid carcinoma has risen by 14.6% over the past 40 years, but the overall
survival rate has improved due to early diagnosis and management. [50] Overall, thyroid cancer
has an excellent prognosis.

The most common type, papillary carcinoma, is indolent, with an average 10-year
survival >90%. Recurrence and risk of metastasis are low after surgery. Surgical
complications are few when surgery is done by experts. Nodal metastases in papillary
carcinoma increase the risk of recurrence but do not affect overall survival. [8] If a
patient has undergone PET scanning, positive scan is an indicator of worse prognosis
than a negative result. Most patients who undergo PET scanning are older patients who
have poorly differentiated tumours.

Follicular carcinoma has a slightly worse prognosis than papillary and tends to have
systemic metastasis.View image Hurthle cell carcinoma has a worse prognosis than
papillary and follicular, with 10-year survival of about 70%. [51]

Overall 5-year survival for medullary cancer is 80%. [15]

For the most common type of primary thyroid lymphoma, 5-year survival is <50%. [52]
View image

Anaplastic thyroid carcinoma is aggressive, with average survival generally a few

months. This type of tumour has a high propensity for local invasion and metastatic
spread.