01OverviewDefinition, clinical context and the essential points that orientate the chapter.
Thyroid cancer is not one disease. Papillary carcinoma is the commonest and often spreads to cervical nodes while retaining an excellent prognosis in low-risk cases. Follicular carcinoma is defined by capsular or vascular invasion and favours haematogenous metastasis. Medullary carcinoma arises from calcitonin-producing C cells and may be the first manifestation of germline RET-associated MEN2. Anaplastic carcinoma is a rapidly lethal invasive cancer that can threaten the airway over days or weeks. Histotype therefore determines biomarkers, imaging, operation, genetics and systemic treatment.
A nodule pathway starts with history, neck and vocal assessment, TSH and structured ultrasound including lymph nodes. Features such as marked hypoechogenicity, irregular margins, punctate echogenic foci, taller-than-wide shape, extrathyroidal extension and abnormal nodes increase suspicion. Ultrasound-guided FNA is offered at the threshold of the grading system. Cytology can diagnose papillary nuclear morphology, but follicular-pattern cytology cannot prove carcinoma because invasion is an architectural diagnosis made after excision.
Treatment is risk adapted. Selected solitary microcarcinomas may be observed or treated by hemithyroidectomy, whereas bilateral, larger, invasive, nodal or otherwise high-risk differentiated disease may require total thyroidectomy and therapeutic compartment-oriented node dissection. Radioiodine is used when recurrence or mortality benefit is expected, after appropriate stimulation, rather than as an automatic postoperative ritual. Levothyroxine targets are adjusted after early response assessment: persistent disease may justify stronger suppression, while excellent low-risk response permits relaxation to reduce cardiac and skeletal harm.
Medullary cancer requires serum calcitonin and CEA, neck staging, total-thyroid and nodal planning, germline RET counselling and investigation for MEN2-associated pheochromocytoma and hyperparathyroidism. Pheochromocytoma is controlled before thyroid surgery to avoid a catecholamine crisis. Radioiodine and thyroglobulin do not work for C-cell disease. Anaplastic cancer needs immediate airway assessment, core biopsy, staging and rapid molecular testing because resection, radiotherapy, targeted systemic treatment and symptom care must be coordinated without the delays acceptable in an indolent nodule pathway.
Key points
- Most thyroid nodules are benign; malignancy risk is determined by clinical context, structured ultrasound appearance and ultrasound-guided cytology rather than size or thyroid function alone.
- First-line imaging for a thyroid nodule is greyscale ultrasound using an established grading system, with cervical-node survey; CT is not the routine first test for a simple nodule.
- Check TSH and thyroid function, but a normal TSH does not exclude cancer. A suppressed TSH directs assessment for an autonomous nodule and changes whether cytology is useful.
- Offer ultrasound-guided FNA when the established ultrasound threshold is met; the definitive distinction between follicular adenoma and carcinoma requires histological capsular or vascular invasion.
- Do not measure calcitonin routinely for every nodule under NICE NG230; measure it when family history, ultrasound or another feature raises medullary thyroid cancer.
- Papillary and follicular cancers are differentiated follicular-cell tumours; medullary cancer arises from C cells, and anaplastic cancer is a separate rapidly invasive emergency.
- Surgery ranges from active surveillance or hemithyroidectomy for selected low-risk disease to total thyroidectomy with therapeutic node management for higher-risk disease.
- Radioactive iodine is selective, not automatic after every differentiated cancer, and has no therapeutic role in medullary or anaplastic carcinoma.
- After differentiated cancer, levothyroxine both replaces hormone and sets a response-adapted TSH target; maximal lifelong suppression is not appropriate for every survivor.
- All medullary thyroid cancer requires inherited RET consideration. If MEN2 is possible, exclude and control pheochromocytoma before thyroid surgery.
- Thyroglobulin is useful only after follicular-cell cancer in the correct anatomical and antibody context; calcitonin and CEA are used for medullary disease.
- Rapid enlargement, vocal-cord palsy or stridor needs urgent airway, core tissue and multidisciplinary planning for anaplastic cancer or lymphoma rather than routine nodule flow.
02AetiologyUnderlying causes, associations and risk factors, with why each one matters.
Ionising radiation
Childhood or adolescent head-and-neck irradiation and environmental radioiodine exposure increase differentiated, particularly papillary, thyroid cancer risk after a long latency.
Inherited susceptibility
Germline RET variants cause MEN2-associated medullary cancer, while APC, PTEN, DICER1 and other rare syndromes increase risk of particular follicular-cell tumours.
Sporadic molecular drivers
BRAF V600E, RAS-pathway changes and RET or NTRK fusions arise somatically in differentiated cancer; TERT-promoter change often marks more aggressive behaviour.
Demographic and thyroid context
Thyroid nodules and differentiated cancer are more common in women, while malignancy probability and aggressive histology rise at the extremes of age and with suspicious ultrasound features.
03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.
- 1Papillary carcinoma spreads through lymphatics
Follicular-cell transformation produces papillary nuclear features and often multifocal intrathyroidal disease with central or lateral cervical nodal metastasis.
- 2Follicular carcinoma invades vessels
Diagnosis requires capsular or vascular invasion, which cytology cannot demonstrate; haematogenous spread to bone and lung is more characteristic than early nodal disease.
- 3Medullary cancer arises from C cells
Parafollicular C-cell tumour secretes calcitonin and sometimes CEA, follows RET-driven biology and neither concentrates radioiodine nor produces thyroglobulin.
- 4Anaplastic cancer loses differentiation
Accumulated genomic injury produces a rapidly infiltrative tumour that invades trachea, oesophagus, nerves and vessels and often has metastatic disease at presentation.
- 5Iodine handling enables targeted treatment
Differentiated tumour may retain sodium–iodide transport and thyroglobulin production, permitting selected radioiodine treatment and biochemical surveillance; dedifferentiation removes both advantages.
04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.
A hard fixed enlarging nodule, abnormal cervical node, radiation history, family cancer syndrome or vocal change increases concern despite normal thyroid function.
An incidental or slowly enlarging thyroid nodule with central or lateral cervical nodes is typical, although many small lesions are ultrasound findings.
A solitary encapsulated nodule may be cytologically indeterminate; bone pain or lung deposits can reveal vascular invasion and haematogenous spread.
A thyroid nodule with high calcitonin, diarrhoea or flushing in advanced disease, or MEN2 family history raises C-cell cancer.
Very rapid firm enlargement, pain, dysphagia, hoarseness, stridor and fixation in an older person requires an emergency invasive-tumour pathway.
Perioral or acral tingling, cramps, carpopedal spasm, laryngospasm or seizure after surgery suggests clinically important low ionised calcium.
05InvestigationsWhat to request, why it matters and how to interpret it.
Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.
- 01
First-line structured thyroid and neck ultrasoundFirst stepFirst line - Why
- Characterise each nodule and cervical nodes using an established malignancy-risk grading system and select lesions for sampling.
- Interpretation and limitations
- Record composition, echogenicity, margin, shape, echogenic foci, extrathyroidal extension and nodal features; offer FNA when the grading threshold is met rather than from size alone.
- 02
TSH and thyroid function - Why
- Identify overt dysfunction and detect a suppressed TSH that changes the nodule pathway.
- Interpretation and limitations
- Normal TSH does not exclude cancer. With suppressed TSH, assess autonomous function according to the thyroid-disease pathway because a demonstrably hot nodule is seldom malignant.
- 03
Ultrasound-guided FNA cytology - Why
- Classify a suspicious nodule or node using the UK Thy category and guide observation, repeat sampling or surgery.
- Interpretation and limitations
- Repeat or use core tissue for selected non-diagnostic lesions. Thy3 follicular-pattern cytology estimates neoplasia risk but cannot demonstrate capsular or vascular invasion.
- 04
Definitive surgical histologyDefinitive - Why
- Establish tumour type, size, capsular and vascular invasion, margins, extrathyroidal extension and node pathology.
- Interpretation and limitations
- This is the reference standard for follicular carcinoma and completes pathological risk assessment after hemithyroidectomy or total thyroidectomy.
- 05
Calcitonin, CEA and RET assessment when MTC is suspected - Why
- Support C-cell tumour diagnosis, establish a biochemical baseline and identify inherited MEN2 risk.
- Interpretation and limitations
- Do not use calcitonin indiscriminately for all nodules. Confirm unexpectedly high results, perform genetics with counselling and screen relatives when a pathogenic germline RET variant is found.
- 06
Metanephrines and calcium in medullary cancer - Why
- Detect MEN2-associated pheochromocytoma and primary hyperparathyroidism before thyroid surgery.
- Interpretation and limitations
- Plasma free or urinary fractionated metanephrines assess pheochromocytoma; an identified catecholamine-secreting tumour must be treated first to prevent perioperative crisis.
- 07
Contrast CT or MRI for invasive disease - Why
- Define tracheal, oesophageal, vascular, mediastinal, retropharyngeal and bulky nodal involvement and distant staging targets.
- Interpretation and limitations
- Do not withhold necessary contrast imaging from an airway or resectability decision merely to avoid delaying radioiodine; coordinate timing with nuclear medicine.
- 08
Post-treatment biochemical surveillance - Why
- Detect residual or recurrent disease with a marker matched to histological origin.
- Interpretation and limitations
- Use thyroglobulin with simultaneous antibodies after differentiated cancer and calcitonin plus CEA after medullary cancer; interpret trends with anatomy and treatment history.
06Differential diagnosisRealistic alternatives and the features that help distinguish them.
Benign colloid or hyperplastic nodule
Most nodules are benign and may be solitary or multinodular; ultrasound pattern and cytology determine risk more reliably than palpation alone.
Thyroiditis
Hashimoto, subacute and immune-therapy thyroiditis cause enlargement, heterogeneity, pain or abnormal function and can coexist with a discrete malignant nodule.
Thyroid lymphoma
Rapid painless enlargement with compressive symptoms, often on Hashimoto background, requires core tissue with flow cytometry because treatment is not primary thyroidectomy.
Metastasis or adjacent neck tumour
Renal, lung and other cancers can metastasise to thyroid, while parathyroid, nodal and laryngeal lesions may appear intrathyroidal on limited examination.
Haemorrhage into a benign nodule
Sudden painful swelling after exertion or anticoagulation may reflect intranodular bleeding, but airway status and residual suspicious tissue still require assessment.
07ManagementImmediate care, first-line treatment, alternatives and escalation.
01Thyroid noduleRisk-stratify before samplingFirst stepA palpable or incidental thyroid nodule is identified without immediate airway compromise.+
- 1Take radiation, family, growth, voice and compressive history, examine thyroid and all neck levels and check TSH while arranging structured thyroid and nodal ultrasound.
- 2Offer ultrasound-guided FNA only when the established ultrasound threshold is met, sampling suspicious nodes as well; follow non-diagnostic and indeterminate results through repeat, core, surveillance or diagnostic surgery pathways.
- 3Discuss cytology, imaging, age, comorbidity and preference at the thyroid MDT and avoid over-treating a low-risk incidental lesion or under-treating invasive features.
02Differentiated cancerMatch treatment intensity to recurrence riskPapillary or follicular-cell cancer is confirmed or strongly suspected.+
- 1Choose active surveillance, hemithyroidectomy or total thyroidectomy and therapeutic node dissection according to tumour size, multifocality, invasion, nodes, distant disease, contralateral findings and patient preference.
- 2Review final histology for completion surgery and selective radioiodine indications, using stimulated treatment preparation and radiation-safety counselling through nuclear medicine where benefit is expected.
- 3Prescribe levothyroxine to a response-adapted TSH target and use clinical review, neck ultrasound and thyroglobulin with antibodies at risk-appropriate intervals, relaxing suppression when excellent response makes harm exceed benefit.
03Medullary cancerProtect the family and exclude pheochromocytomaCytology, histology, calcitonin or family history suggests medullary thyroid carcinoma.+
- 1Measure calcitonin and CEA, stage neck and distant disease and arrange germline RET counselling and testing without waiting for a relative to become symptomatic.
- 2Check metanephrines and calcium or parathyroid status; if pheochromocytoma is found, prepare and treat it before thyroid surgery.
- 3Plan total thyroidectomy and compartment-oriented nodal treatment with the specialist MDT, then follow calcitonin and CEA doubling trends and use molecularly selected therapy for unresectable progressive disease.
04Rapid invasive massSecure airway and obtain rapid core diagnosisA rapidly enlarging fixed thyroid mass causes voice, swallowing or breathing symptoms.+
- 1Call airway and thyroid or ENT surgical teams, assess vocal cords and obtain urgent contrast imaging only if the patient can tolerate it without delaying a controlled airway.
- 2Obtain adequate core tissue with pathology alerted to anaplastic cancer and lymphoma, and complete rapid molecular and systemic staging rather than performing a reflex diagnostic thyroidectomy.
- 3At an urgent MDT, select resection, radiotherapy, systemic or targeted treatment and early palliative support based on resectability, molecular findings, performance and the patient's priorities.
05Postoperative calciumRecognise and treat hypocalcaemiaSymptoms, low calcium or low parathyroid hormone follows total or completion thyroidectomy.+
- 1Check adjusted and preferably ionised calcium, magnesium, phosphate, PTH, ECG and symptom severity and look for laryngospasm, seizure or arrhythmia.
- 2Give intravenous calcium with cardiac monitoring for severe symptomatic hypocalcaemia, and use oral calcium plus active vitamin D for stable or persistent hypoparathyroidism according to the local protocol.
- 3Repeat calcium closely, correct magnesium, avoid overshoot and provide a written taper or long-term endocrine plan because delayed recurrence can occur after discharge.
Key medicines and prescribing safety3 treatments · regimens, roles and cautions+
Levothyroxine after thyroid cancer surgery
After total thyroidectomy, a common initial full-replacement estimate in a younger otherwise healthy adult is about 1.6 micrograms/kg orally once daily, then titrated to the histology- and response-specific TSH target; start lower in older people or cardiac disease.Take consistently apart from calcium, iron and interacting foods or medicines. Recheck TSH and free T4 after dose changes; excessive suppression causes palpitations, atrial fibrillation and bone loss, while medullary cancer needs replacement but not oncological TSH suppression.
Calcium and calcitriol for postsurgical hypoparathyroidism
For stable symptomatic or persistent hypocalcaemia, use a local endocrine regimen such as oral calcium providing 1 to 2 g elemental calcium daily in divided doses plus calcitriol 0.25 micrograms once or twice daily, titrated to symptoms and serial calcium.Severe symptoms, laryngospasm, seizure or ECG change require intravenous calcium gluconate with monitoring. Correct magnesium and monitor renal function, phosphate and urinary calcium because overtreatment causes hypercalcaemia, stones and nephrocalcinosis.
Selpercatinib for eligible RET-altered disease
Use the licensed oral weight-based schedule, commonly 160 mg twice daily for adults weighing 50 kg or more and 120 mg twice daily below 50 kg, only within the current funded RET-fusion or RET-mutant thyroid-cancer indication.Confirm the alteration and current NICE indication. Monitor blood pressure, liver tests, QT interval, electrolytes, bleeding, wound healing and interactions; hold or modify for toxicity according to the product protocol.
08ComplicationsImportant consequences, why they occur and why they matter clinically.
Airway, oesophageal and neural invasion
Advanced tumour causes stridor, dysphagia, aspiration, vocal-cord palsy and major-vessel involvement, complicating biopsy, anaesthesia and surgical clearance.
Nodal and distant metastasis
Papillary cancer favours cervical nodes, follicular cancer often spreads to bone or lung, and medullary and anaplastic cancers may disseminate early.
Postoperative hypocalcaemia
Parathyroid injury or devascularisation can produce transient or permanent hypoparathyroidism with tingling, spasm, seizure or arrhythmia after total thyroidectomy.
Recurrent-laryngeal nerve injury
Unilateral injury causes dysphonia and aspiration; bilateral palsy may cause acute airway obstruction and requires immediate laryngeal assessment.
Treatment-related late morbidity
Radioiodine can injure salivary and lacrimal tissue, while excessive long-term TSH suppression increases atrial fibrillation and bone-loss risk.
09Monitoring and follow-upTreatment response, safety checks and longer-term review.
- After surgery, monitor airway, neck swelling, voice, swallowing, wound, drain, calcium, magnesium and PTH; urgent flexible laryngoscopy is required for stridor or significant voice change.
- After differentiated cancer, combine clinical review, neck ultrasound and thyroglobulin with thyroglobulin antibodies; marker trend is more informative than an isolated value.
- Reassess response after initial treatment and adjust the TSH target rather than continuing maximal suppression automatically; review heart rhythm and bone risk during long-term suppression.
- After radioiodine, follow radiation-protection instructions and review salivary, lacrimal, taste, fertility and marrow effects according to administered activity and cumulative exposure.
- After medullary cancer, follow calcitonin and CEA level and doubling time, neck imaging and RET-family pathway; thyroglobulin is not the tumour marker.
- For active surveillance of low-risk disease, use a documented ultrasound and clinical schedule with clear triggers for biopsy or surgery, including growth, new nodes and patient preference.
- For kinase inhibitors, measure blood pressure, ECG, electrolytes, liver and renal function, interactions, adherence, radiological response and patient-defined symptom burden at protocol intervals.
10Special situationsVariants, exceptions and circumstances that change the usual approach.
Normal TSH does not reassure
Most thyroid cancers arise in euthyroid glands, so thyroid function identifies pathway and treatment issues but does not serve as a malignancy screen.
Follicular cytology has a ceiling
FNA can identify a follicular-pattern neoplasm but cannot see invasion through the capsule or into vessels; definitive classification may require an excised capsule.
A hot nodule changes the branch
Suppressed TSH prompts functional assessment because a proven autonomous nodule is rarely malignant and should not automatically enter the same FNA route.
Pheochromocytoma comes first
In MEN2, thyroid surgery before diagnosing and alpha-blocking a catecholamine-secreting tumour can precipitate a life-threatening perioperative crisis.
Markers follow cell of origin
Thyroglobulin tracks follicular-cell differentiation, whereas calcitonin and CEA track medullary C-cell disease; applying the wrong marker gives false reassurance.
Contrast is not forbidden
Iodinated contrast may postpone effective radioiodine uptake, but necessary airway and resectability imaging takes priority and timing can be coordinated later.
Suppression is a moving target
A patient with persistent structural disease and one with an excellent low-risk response should not receive the same lifelong TSH target.
11Common pitfallsFrequent interpretation and management errors.
- 01
Reassuring a patient with a suspicious nodule because TSH is normal.
- 02
Requesting CT rather than structured ultrasound as the routine first investigation for an uncomplicated thyroid nodule.
- 03
Calling follicular carcinoma from FNA alone when capsular or vascular invasion has not been assessed.
- 04
Measuring calcitonin indiscriminately despite NICE advice to reserve it for a reason to suspect medullary cancer.
- 05
Proceeding to thyroidectomy for MEN2-associated medullary cancer before excluding pheochromocytoma.
- 06
Offering radioiodine for medullary or anaplastic cancer, which does not retain the relevant follicular-cell iodine biology.
- 07
Maintaining maximal TSH suppression indefinitely after an excellent low-risk response without considering cardiac and skeletal harm.
- 08
Sending a stridulous patient with a rapidly invasive mass to supine imaging or biopsy before a controlled airway plan.
- 09
Interpreting thyroglobulin without simultaneous antibodies or remaining normal thyroid tissue context.
- 10
Treating severe postoperative hypocalcaemia with oral tablets alone despite seizure, laryngospasm or ECG change.