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Treatment differs and must be tailored for uncommon types of thyroid cancer such as
medullary, lymphoma, or anaplastic.
Key factors
early adulthood
hoarseness
dyspnoea
dysphagia
tracheal deviation
cervical lymphadenopathy
TSH
fine-needle biopsy
ultrasound, neck
laryngoscopy
Investigations to consider
free T4
free T3
core biopsy
CT, neck
serum calcitonin
Emerging tests
ultrasound elastography
Ongoing
newly diagnosed
recurrent or metastatic
o 1st line: radioactive iodine ablation + TSH suppression surgery
medullary
anaplastic
lymphoma
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
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
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.
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.
Key risk factors include head and neck irradiation and female sex.
The anaplastic variant is rare, but occurs after the fifth decade. [8]
hoarseness (uncommon)
dyspnoea (uncommon)
Results from tracheal pressure. Other causes should be ruled out. [16]
dysphagia (uncommon)
Strong
head and neck irradiation
female sex
Weak
FHx of thyroid cancer
Diagnostic investigations
TSH
ultrasound, neck
laryngoscopy
may show ipsilateral
A paralysed vocal cord is highly suggestive of malignancy. paralysed vocal cord
free T3
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.
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
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.
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.
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
Female sex
No extrathyroidal extension
Low-grade histology.
Ongoing
Patient group
Treatment line
Treatmentshow all
newly diagnosed
1st
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
recurrent or metastatic
1st
Primary options
radioiodine ablation
and
and
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
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]
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
Usually the role of surgery is to perform a biopsy and relieve airway obstruction.
adjunct
thyroid replacement
Levothyroxine replacement is required if total thyroidectomy was done.
Primary options
levothyroxine: 50-200 micrograms orally once daily
lymphoma
1st
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.
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]
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
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.
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
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]
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
Complicationhide all
e d
airway obstruction
short term low
Treatment is surgical if possible.
surgery-related hypoparathyroidism
surgery-related bleeding
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]
For the most common type of primary thyroid lymphoma, 5-year survival is <50%. [52]
View image