Thyroid Cancer

Thyroid cancer is a group of malignancies arising from the thyroid gland. The histological subtype determines prognosis and the treatment and surveillance approach.

• Differentiated thyroid cancer (papillary and follicular subtypes) together accounts for the great majority of cases and generally carries a favourable prognosis with appropriate treatment.
• Medullary thyroid cancer arises from the parafollicular C cells, with a distinct biology and a recognised association with multiple endocrine neoplasia type two in a proportion of cases.
• Anaplastic thyroid cancer is a rare, highly aggressive, poorly differentiated malignancy carrying a very poor prognosis despite aggressive multimodal treatment.

Most patients with differentiated thyroid cancer are identified through the structured thyroid nodule evaluation pathway.

Classification and pathophysiology

• Papillary thyroid cancer is the commonest subtype overall. It typically shows an indolent biology with a strong propensity for regional lymph node metastasis rather than distant spread. Prognosis is generally excellent, particularly in younger patients.
• Specific genetic alterations, including BRAF mutations and RET rearrangements, are recognised in a substantial proportion of papillary cases.
• Follicular thyroid cancer is less common than papillary disease. It characteristically spreads via haematogenous rather than lymphatic routes. Distant metastasis, particularly to bone and lung, is somewhat more common at presentation than with papillary disease.
• Diagnosis of follicular cancer requires histological demonstration of capsular or vascular invasion. Fine needle aspiration cytology cannot assess invasion, so it cannot make the diagnosis. Indeterminate cytology therefore frequently requires diagnostic surgical excision for histological characterisation.
• Medullary thyroid cancer arises from the calcitonin producing parafollicular C cells rather than the follicular epithelium. It occurs sporadically in the majority of cases.
• A meaningful proportion are associated with multiple endocrine neoplasia type two (and isolated familial medullary thyroid cancer), reflecting germline RET proto-oncogene mutations in these hereditary forms.
• Genetic testing is therefore essential in every confirmed case. It has implications for the individual patient (screening for associated multiple endocrine neoplasia type two manifestations including phaeochromocytoma) and for family cascade screening.
• Anaplastic thyroid cancer is rare and highly aggressive, and typically arises in older patients. There is often evidence of dedifferentiation from a pre-existing, previously unrecognised differentiated thyroid cancer.
• It characteristically presents with rapid, locally invasive growth. Prognosis is very poor, with median survival typically measured in months despite aggressive multimodal treatment.

• The great majority of differentiated thyroid cancers present as an asymptomatic thyroid nodule, identified incidentally or through the structured evaluation pathway (see thyroid nodules).
• Concerning clinical features raise suspicion: rapid growth, firm fixed texture, associated cervical lymphadenopathy, and hoarseness reflecting recurrent laryngeal nerve involvement.
• Medullary thyroid cancer may present similarly as a thyroid nodule. It can also present with diarrhoea, reflecting the biological effect of significantly elevated circulating calcitonin.
• With underlying multiple endocrine neoplasia type two, there may be symptoms of an associated phaeochromocytoma or primary hyperparathyroidism. Consider and screen for this syndromic association in confirmed cases.
• Anaplastic thyroid cancer characteristically presents with a rapidly enlarging, often painful neck mass. Compressive symptoms (dysphagia, dyspnoea, hoarseness) are frequent, reflecting its aggressive, locally invasive nature.
• Anaplastic thyroid cancer is an oncological emergency, because of the rapid progression and the risk of airway compromise.
• Specifically seek a history of prior head or neck irradiation, or a family history of thyroid cancer or a hereditary syndrome. These are relevant to risk assessment and, where a hereditary syndrome is relevant, to genetic testing and family screening.

• The structured thyroid nodule evaluation pathway is the primary route by which the great majority of differentiated thyroid cancers are identified and confirmed. It uses ultrasound risk stratification followed by fine needle aspiration cytology where indicated (see thyroid nodules).
• Measure serum calcitonin where medullary thyroid cancer is suspected from clinical features or family history.
• Germline RET proto-oncogene genetic testing is part of the diagnostic and screening pathway for this subtype, and is done in every confirmed case of medullary thyroid cancer.
• After confirmed diagnosis, stage with neck ultrasound to assess regional lymph node involvement, which is essential for surgical planning.
• Where clinically indicated by tumour size, histological subtype or other risk factors, add cross sectional imaging (computed tomography).
• For suspected distant metastatic disease in differentiated thyroid cancer, use radioactive iodine whole body scanning following initial surgical treatment.
• Staging guides the extent of initial surgery and subsequent treatment planning.
• Anaplastic thyroid cancer typically presents rapidly and aggressively. It generally requires urgent core biopsy, not fine needle aspiration cytology alone, because architectural tissue assessment is needed to confirm the diagnosis.
• Urgent staging imaging is also needed, given the typically advanced stage at presentation and the time critical nature of treatment decisions.

• Differentiated thyroid cancer (papillary and follicular subtypes) is managed with surgical resection as the primary treatment. Individualise the extent of surgery (thyroid lobectomy versus total thyroidectomy) to tumour size, extrathyroidal extension or lymph node involvement, and other risk factors.
• Smaller, lower risk, unifocal papillary cancers are increasingly managed with lobectomy alone in appropriately selected patients. This is an important evolution toward more conservative surgery than historical practice.
• Radioactive iodine ablation follows total thyroidectomy and is used selectively according to postoperative risk stratification (tumour size, histological features, extent of local invasion, and lymph node status).
• It is reserved for patients at intermediate to high risk of recurrence, where the anticipated benefit outweighs the treatment burden. The benefit is eliminating residual thyroid tissue to support thyroglobulin based surveillance, and treating any microscopic residual or metastatic disease.
• Low risk patients after lobectomy or total thyroidectomy alone are increasingly managed without radioactive iodine, given the favourable prognosis with surgery alone.
• After total thyroidectomy (with or without radioactive iodine ablation), give levothyroxine at a dose sufficient to achieve a degree of thyroid stimulating hormone suppression. Individualise the target to the patient's recurrence risk category. Thyroid stimulating hormone has a growth stimulatory effect on any residual differentiated thyroid cancer cells.
• Balance adequate suppression for oncological benefit against the risks of iatrogenic subclinical hyperthyroidism (cardiac and bone health). Revisit this over time as surveillance confirms sustained remission.
• Long term surveillance for differentiated thyroid cancer comprises serial serum thyroglobulin measurement with concurrent thyroglobulin antibody testing, which is critical to correct result interpretation (see thyroid antibodies). Add periodic neck ultrasound.
• A rising or detectable thyroglobulin, or a new suspicious lesion on ultrasound, prompts further investigation for possible recurrence.
• Medullary thyroid cancer is managed with total thyroidectomy together with central neck lymph node dissection, because of the propensity for early regional lymph node metastasis. Add lateral neck dissection where indicated by preoperative assessment.
• Postoperative surveillance for medullary thyroid cancer uses serial calcitonin and carcinoembryonic antigen measurement rather than thyroglobulin, given the distinct cell of origin.
• Confirmed germline RET mutation carriers need ongoing screening for other manifestations of multiple endocrine neoplasia type two. This includes regular biochemical screening for phaeochromocytoma before any subsequent surgical procedure, because unrecognised phaeochromocytoma during anaesthesia and surgery is life threatening.
• Offer cascade genetic testing of at risk family members. Consider prophylactic thyroidectomy in confirmed paediatric mutation carriers at an age determined by the mutation's associated risk profile.
• Anaplastic thyroid cancer requires urgent, aggressive multimodal treatment, given the typically advanced stage and rapid progression at presentation. Individualise the approach to the extent of disease and resectability.
• Treatment incorporates surgery where feasible, external beam radiotherapy, and systemic therapy, including targeted molecular therapy where relevant tumour mutations such as BRAF are identified.
• Give urgent attention to airway management, given the risk of airway compromise from local tumour invasion. Integrate palliative care early, given the generally very poor prognosis despite aggressive treatment.
• Multidisciplinary team management underpins coordinated care across thyroid malignancy. It incorporates endocrinology, endocrine surgery, oncology and, for medullary thyroid cancer, clinical genetics input.
• Individualise the approach and intensity of initial treatment and long term surveillance to the histological subtype and risk category of the patient.