Differentiated, medullary and anaplastic thyroid cancer

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

The label 'thyroid cancer' hides diseases with different cells of origin, biomarkers and treatment responsiveness. Differentiated papillary and follicular tumours often follow surgery, selective radioiodine and risk-adapted TSH suppression. Medullary tumours require calcitonin/CEA assessment, RET-aware genetics and surgery that accounts for nodal disease. Anaplastic disease prioritises airway safety, rapid tissue diagnosis, resectability and early goals-of-care discussion.

NICE recommends that thyroid cancer assessment and management are coordinated by a specialist thyroid cancer multidisciplinary team. Ultrasound, cytology, cross-sectional imaging and molecular tests answer different questions; staging investigations should be selected to avoid delaying definitive treatment and should not expose an unstable airway to unsafe procedures.

Extent of thyroidectomy, neck dissection, radioiodine activity, external-beam radiotherapy and targeted systemic therapy depend on histology, TNM stage, molecular result, prior therapy, comorbidity and regional commissioning arrangements.

Key points

Papillary and follicular cancers arise from follicular cells and are grouped as differentiated thyroid cancer; papillary disease commonly spreads to cervical nodes, whereas follicular carcinoma more characteristically spreads haematogenously.
Medullary thyroid cancer arises from parafollicular C cells, may secrete calcitonin and CEA, and can be sporadic or associated with germline RET variants and MEN2; family implications begin at diagnosis.
Anaplastic thyroid cancer is an aggressive, rapidly progressive malignancy in which airway, swallowing, voice and performance status must be assessed immediately rather than after a routine diagnostic sequence.
A euthyroid result does not make a thyroid nodule benign. Ultrasound risk assessment and ultrasound-guided cytology, reported within the local thyroid cytology system, determine the diagnostic route.
NICE NG230 covers differentiated thyroid cancer but explicitly does not provide the treatment pathway for medullary cancer; use a thyroid cancer MDT and appropriate specialist guidance rather than extrapolating radioiodine practice.
Radioiodine targets iodine-avid follicular-cell tissue and has no useful role in medullary or anaplastic thyroid cancer. Its use after differentiated cancer surgery depends on recurrence risk and MDT assessment.
Serum thyroglobulin is a differentiated-cancer tumour marker only after the relevant thyroid tissue has been treated; antibodies can invalidate interpretation. Calcitonin and CEA serve a different biological pathway in medullary disease.
RET testing can affect both inherited-risk counselling and systemic treatment selection. Consent, germline-versus-somatic distinction and referral of relatives belong in clinical genetics, not an informal family blood-test plan.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Differentiated follicular-cell cancer

Papillary and follicular tumours arise from thyroid follicular cells and retain varying degrees of thyroid-specific biology relevant to surveillance and radioiodine responsiveness.

Medullary thyroid cancer

Medullary tumours arise from calcitonin-producing C cells and may have inherited RET-related risk, making genetics and family assessment clinically important.

Anaplastic thyroid cancer

Anaplastic disease reflects highly aggressive undifferentiated tumour biology, often presenting with rapid local growth and immediate airway or swallowing concerns.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
A thyroid-cell clone expands
Malignant follicular or C-cell clones grow within the gland, forming a nodule or infiltrative mass with a subtype-specific biomarker pattern.
2
Local structures become involved
Extension into recurrent laryngeal nerves, trachea, oesophagus or cervical nodes produces hoarseness, dysphagia, airway symptoms and fixed neck disease.
3
Disease disseminates
Lymphatic or haematogenous spread creates nodal and distant metastases, while degree of differentiation influences growth rate and available targeted treatment.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Suspicious thyroid presentationRed flag

A hard or fixed nodule, rapid enlargement, cervical lymphadenopathy, persistent hoarseness, dysphagia, stridor, childhood neck irradiation or relevant familial syndrome increases concern. Normal thyroid function does not lower the structural risk enough to avoid imaging.

Differentiated pattern

Papillary cancer may be multifocal and node-predominant; follicular malignancy requires demonstration of capsular or vascular invasion and therefore cannot reliably be diagnosed from cytology alone. Distant bone or lung disease can occasionally be the presentation.

Medullary patternRed flag

A thyroid nodule with raised calcitonin, diarrhoea or flushing, a family history of medullary cancer, phaeochromocytoma or hyperparathyroidism should prompt a medullary/MEN2 pathway. Exclude phaeochromocytoma before elective thyroid surgery if MEN2 is plausible.

Anaplastic emergencyRed flag

Weeks of explosive neck growth, pain, dysphonia, dysphagia, dyspnoea, stridor or skin fixation in an older adult is a time-critical pattern. Airway compromise, bleeding and inability to handle secretions require emergency escalation.

Post-treatment recurrence

New neck nodes, rising tumour marker trend, new bone pain, cough, neurological deficit or unexplained weight loss after prior cancer treatment needs specialist reassessment. Interpret biomarkers against assay, antibodies, TSH and residual tissue rather than a single number.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

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
Neck ultrasound with nodal mappingFirst step
Why
Characterise the thyroid lesion and cervical lymph-node compartments before biopsy or operation.
Interpretation and limitations
Irregular margins, marked hypoechogenicity, punctate echogenic foci, taller-than-wide shape, extrathyroidal extension and abnormal nodes increase suspicion; use the current local validated scoring and biopsy thresholds.
02
Ultrasound-guided fine-needle aspiration cytology
Why
Obtain cellular diagnosis from a qualifying nodule or suspicious lymph node.
Interpretation and limitations
Report using the UK thyroid cytology category and combine with ultrasound. Follicular-pattern cytology cannot prove invasion, while a suspicious node may also be assessed with an appropriate washout marker in specialist practice.
03
TSH and free T4
Why
Define thyroid status and identify suppressed TSH that changes the initial nodule investigation.
Interpretation and limitations
Most cancers occur with normal thyroid function. A suppressed TSH can prompt radionuclide functional assessment, but an autonomously functioning nodule is not evaluated by biochemistry alone.
04
Calcitonin, CEA and RET-directed assessment
Why
Support diagnosis and baseline burden assessment when medullary cancer is suspected or confirmed.
Interpretation and limitations
Use the laboratory method, sex-specific context and trend; marked elevation supports C-cell disease but false positives exist. Germline RET testing requires genetics processes and has implications beyond the index patient.
05
Contrast CT neck and chest
Why
Define local invasion, substernal extent, airway displacement and thoracic metastatic disease when advanced cancer is suspected.
Interpretation and limitations
Discuss iodinated contrast timing if subsequent radioiodine is contemplated, but do not withhold urgently needed staging or airway information. MRI or other imaging may be selected by the MDT.
06
Histology and molecular profiling
Why
Confirm tumour lineage and find actionable alterations in advanced disease.
Interpretation and limitations
Distinguish differentiated, poorly differentiated, medullary and anaplastic morphology. RET mutation or fusion status can affect inherited assessment and NICE-funded targeted treatment eligibility, but must be interpreted by the molecular MDT.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Benign thyroid nodule

Stable benign ultrasound and cytology features without invasive symptoms are reassuring, but clinical, sonographic and cytological discordance still requires specialist review.

Thyroid lymphoma

Rapid thyroid enlargement with compressive symptoms can resemble anaplastic cancer; tissue diagnosis distinguishes lymphoid disease and changes treatment profoundly.

Subacute thyroiditis

A painful tender gland with inflammatory markers and a transient hormone-release pattern supports thyroiditis rather than a persistent malignant mass.

Metastatic neck node

A cervical mass may arise from another head, neck or distant primary; imaging and tissue markers establish thyroid origin.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01New noduleRisk-stratified diagnostic routeFirst stepA palpable or incidentally detected thyroid lesion without current airway compromise.

1Take focused history and examination, check TSH, and arrange high-quality ultrasound that includes the central and lateral cervical nodes.
2Biopsy lesions meeting the local ultrasound threshold and any suspicious node; obtain an expedited thyroid MDT opinion for malignant, suspicious or discordant results.
3Stage confirmed cancer according to histology and risk. Avoid ordering untargeted scans that delay surgery, and communicate uncertainty when cytology cannot distinguish adenoma from follicular carcinoma.

02Differentiated cancerSurgery to risk-adapted surveillancePapillary or follicular-cell malignancy confirmed or strongly suspected by the specialist team.

1The thyroid cancer MDT chooses hemithyroidectomy versus total thyroidectomy and whether therapeutic nodal dissection is required, using tumour size, multifocality, invasion, nodes, patient factors and preferences.
2Review final histology and stage. Consider radioiodine only for the guideline-defined risk context; it is not an automatic consequence of every total thyroidectomy.
3Set an individual TSH target and surveillance plan using clinical review, ultrasound and thyroglobulin with antibody status where applicable; relax excessive suppression when recurrence benefit no longer outweighs cardiac or bone harm.

03Medullary or anaplasticLineage-specific urgent specialist careCytology, histology or clinical behaviour suggests C-cell or anaplastic malignancy.

1For medullary cancer, measure calcitonin/CEA, stage nodes and distant disease, arrange RET/genetics assessment, and exclude associated phaeochromocytoma before elective thyroid surgery when MEN2 is possible.
2For anaplastic cancer, assess ABCDE and airway with senior anaesthetic/ENT input, obtain rapid imaging and the safest tissue diagnosis, and involve thyroid oncology, surgery and palliative care at the outset.
3Use external-beam, systemic or RET-targeted treatments only through the specialist MDT and current NICE/commissioning criteria. Record treatment intent and revisit symptom control and patient priorities early.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Replaces thyroid hormone after total thyroidectomy and may suppress TSH when recurrence risk justifies that strategy.

Levothyroxine after differentiated cancer treatment

Individualised specialist dose titrated to the agreed TSH target and free T4, rather than a universal suppressive regimen.

Over-suppression can provoke atrial arrhythmia, angina and bone loss; the target changes with response to treatment, age, cardiovascular risk and osteoporosis risk.

Ablates residual iodine-avid follicular tissue or treats selected iodine-avid differentiated metastatic disease after appropriate preparation.

Radioactive iodine-131

Administered only by an authorised nuclear-medicine service at an activity selected from pathology, recurrence risk and local protocol.

It is not effective for medullary or anaplastic cancer. Apply radiation protection, pregnancy and breastfeeding exclusions, fertility counselling and salivary/lacrimal toxicity advice locally.

NICE-recommended option for defined advanced RET-mutant medullary or RET fusion-positive thyroid cancer populations.

Selpercatinib for RET-altered advanced thyroid cancer

Specialist oncology regimen according to body weight, current SmPC, interactions, organ function and NICE eligibility; do not initiate empirically.

Requires molecular confirmation and specialist monitoring for hypertension, hepatic toxicity, QT effects, haemorrhage, wound healing and drug interactions; funding criteria and prior-treatment definitions matter.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Airway compromise

Rapid tumour enlargement or tracheal invasion can narrow the airway, making early multidisciplinary airway planning central to safe assessment and treatment.

Voice and swallowing dysfunction

Recurrent laryngeal nerve or oesophageal involvement can cause hoarseness, aspiration and impaired oral intake, with major functional consequences.

Metastatic organ disease

Spread to lung, bone or other sites causes progressive respiratory, skeletal or systemic morbidity and determines the need for specialist systemic treatment.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

After differentiated cancer treatment, record the intended TSH range, check TSH and free T4 after dose changes, and review symptoms of over- or under-replacement.
Trend thyroglobulin with thyroglobulin antibodies in the same clinical framework; a change in assay, TSH stimulation or antibody concentration can mimic biological change.
For medullary cancer, specialist follow-up uses calcitonin and CEA trends plus imaging selected by marker burden, doubling time, symptoms and prior disease sites.
Reassess voice, swallowing, calcium status and wound complications after neck surgery; suspected hypocalcaemia or expanding haematoma requires urgent examination rather than routine review.
Targeted systemic therapy needs protocol-led blood pressure, ECG, liver tests, interactions and toxicity review, with treatment interruption or modification owned by the oncology service.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Histogenesis predicts therapy

Follicular-cell cancers may retain iodine handling and thyroglobulin production; C-cell cancers produce calcitonin and do not respond to radioiodine. Starting with cell of origin prevents major management errors.

Follicular cytology has a ceiling

Cytology can identify a follicular-pattern neoplasm but cannot demonstrate capsular or vascular invasion. Diagnostic surgery and histology may therefore be needed even when no cytological feature looks frankly malignant.

MEN2 changes operation sequencing

In a RET-associated presentation, an unrecognised catecholamine-secreting tumour can make anaesthesia dangerous. Biochemical evaluation for phaeochromocytoma precedes elective thyroid intervention when the syndrome is suspected.

Marker trend beats isolated value

Thyroglobulin, calcitonin and CEA answer different questions. Interpret serial values with assay conditions, antibodies, remaining tissue and structural imaging rather than declaring recurrence from one result.

Anaplastic care is parallel

Airway planning, tissue diagnosis, staging, oncological options and supportive care should proceed together. A sequential referral chain can consume a clinically important fraction of this cancer's course.

11Common pitfallsFrequent interpretation and management errors.

01
Assuming normal TSH or free T4 excludes thyroid malignancy.
02
Applying differentiated-cancer radioiodine and thyroglobulin logic to medullary disease.
03
Scheduling routine biopsy before stabilising a patient with stridor or rapidly worsening airway symptoms.
04
Removing a thyroid in possible MEN2 without first considering phaeochromocytoma.
05
Calling follicular carcinoma from fine-needle cytology when invasion has not been assessed.
06
Keeping lifelong profound TSH suppression without revisiting response, cardiac risk and bone health.