Poorly Differentiated Thyroid Carcinoma

Poorly differentiated thyroid carcinoma is a follicular derived thyroid cancer with solid, trabecular or insular growth, convoluted nuclei, mitoses and necrosis, with behaviour between differentiated and anaplastic carcinoma. Five year survival is about 50% to 70%, and treatment is surgery, radioiodine where tumour takes it up, and systemic therapy for advanced disease.

It forms about 2% to 15% of thyroid cancers, with a median age of 55 to 65 and a female predominance (about 2 to 1). It can arise de novo or by dedifferentiation of papillary or follicular carcinoma, and often follows long standing goitre.

Risk factors are iodine deficiency, previous head and neck radiation, and longstanding differentiated carcinoma or goitre.

Pathophysiology. Common alterations are RAS mutations, BRAF V600E, TERT promoter mutation, TP53 mutation and CTNNB1, with fusions (RET, NTRK, ALK) in a minority. Loss of sodium iodide symporter expression reduces radioiodine uptake.

Diagnostic criteria. Solid, trabecular or insular growth pattern, with at least one of convoluted nuclei, 3 or more mitoses in 10 high power fields, or tumour necrosis, and no features of anaplastic carcinoma.

Behaviour. Extrathyroidal extension, nodal and distant metastasis (lung, bone) are common (about 30% to 50% at diagnosis). Radioiodine avidity is variable, and many tumours become radioiodine refractory.

• Thyroid nodule or enlarging neck mass, often hard and fixed, with rapid growth.
• Hoarseness (recurrent laryngeal nerve invasion), dysphagia, stridor, and cervical lymphadenopathy.
• Bone pain, cough or dyspnoea from distant metastases.

Red flags.

• Stridor or airway compromise.
• Rapid enlargement over weeks (consider transformation to anaplastic carcinoma).
• Cord compression from vertebral metastasis.

• Neck ultrasound with fine needle aspiration cytology (cytology suspicious for or diagnostic of malignancy), and cervical lymph node assessment. Tissue diagnosis on resection or core biopsy, since cytology often cannot separate this tumour.
• Contrast CT or MRI of the neck and chest for local extent and staging, and FDG-PET-CT (FDG-avid tumours suggest dedifferentiation).
• Laryngoscopy for vocal cord function. Thyroglobulin and anti-thyroglobulin antibodies after surgery, and calcium and PTH.
• Molecular testing for BRAF, RAS, RET, NTRK, TERT and ALK to guide systemic therapy.
• Histopathology with immunohistochemistry (thyroglobulin, TTF-1, PAX8 positive, Ki-67, p53).

Differential diagnosis.

• Anaplastic thyroid carcinoma and medullary thyroid carcinoma
• Papillary carcinoma variants (solid, tall cell, hobnail) and follicular carcinoma
• Thyroid lymphoma and metastasis to the thyroid
• Hürthle cell carcinoma

Management is multimodal and planned by a thyroid cancer team.

Surgery. Total thyroidectomy with central compartment neck dissection and lateral neck dissection for involved nodes, with resection of invaded structures when feasible.

Radioiodine. Radioiodine ablation after surgery for tumours that concentrate iodine on scanning.

• Radioiodine: radioiodine (iodine-131) 1.1 to 3.7 GBq orally once for low risk or intermediate risk disease, and 3.7 to 7.4 GBq once for high risk disease, after TSH stimulation (recombinant TSH 0.9 mg IM on 2 consecutive days, or thyroid hormone withdrawal to TSH over 30 mU/L) and a low iodine diet for 1 to 2 weeks; maximum 7.4 GBq in one administration and cumulative activity of about 22 GBq in total over a lifetime; monitoring: whole body scan 3 to 7 days after dosing, thyroglobulin at 6 to 12 months, FBC, salivary gland symptoms, sodium; adjustment: exclude pregnancy before dosing and avoid pregnancy for 6 to 12 months afterwards, reduce activity and plan with nuclear medicine when eGFR is under 30 mL/min/1.73 m2, hydrate and give sialogogues

TSH suppression.

• Levothyroxine: levothyroxine 1.6 micrograms/kg orally once daily on an empty stomach 30 to 60 minutes before breakfast, titrated to a target TSH (0.5 to 2 mU/L for low risk, 0.1 to 0.5 mU/L for intermediate risk and under 0.1 mU/L for high risk or persistent disease), for life; maximum about 2.5 micrograms/kg daily for full suppression; monitoring: TSH and free T4 6 to 8 weeks after each change and then every 6 to 12 months, heart rate, atrial fibrillation, bone density; adjustment: start at 25 to 50 micrograms daily in older adults or coronary disease and increase every 6 weeks, separate from calcium, iron and bile acid binders by 4 hours, avoid full suppression in osteoporosis or atrial fibrillation

External beam radiotherapy. For residual or unresectable neck disease, extrathyroidal extension with positive margins, and radioiodine refractory local disease (60 to 66 Gy in 30 to 33 fractions), and palliative radiotherapy for bone and brain metastases.

Systemic therapy for progressive radioiodine refractory disease (after molecular testing).

• Lenvatinib: lenvatinib 24 mg orally once daily until progression or unacceptable toxicity (for radioiodine refractory disease); maximum 24 mg daily; monitoring: blood pressure at each visit, urine protein, liver tests, TSH, QTc, calcium, signs of fistula or haemorrhage; adjustment: reduce stepwise to 20 mg, 14 mg then 10 mg, use 14 mg daily in severe hepatic impairment or creatinine clearance under 30 mL/min, withhold for grade 3 toxicity or urine protein over 2 g in 24 hours until grade 1 or 2, stop for arterial thromboembolism, severe haemorrhage, gastrointestinal perforation or fistula
• BRAF V600E mutant tumours, dabrafenib with trametinib: dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily until progression or unacceptable toxicity, for BRAF V600E tumours in adults and in adolescents weighing 51 kg or more (weight banded doses set by a paediatric oncology pharmacist below 51 kg); maximum dabrafenib 300 mg daily and trametinib 2 mg daily; monitoring: left ventricular ejection fraction at baseline, 1 month and then every 2 to 3 months, skin and eye examination, blood pressure, liver tests, glucose, temperature; adjustment: reduce dabrafenib stepwise to 100 mg then 75 mg twice daily and trametinib to 1.5 mg then 1 mg daily, hold both for fever of 38.5 C or more, stop for a fall in ejection fraction of over 10 points to under the lower limit of normal, avoid strong CYP3A4 or CYP2C8 inducers and inhibitors, no renal adjustment for mild to moderate impairment
• RET fusion positive tumours, selpercatinib: selpercatinib 160 mg orally twice daily (120 mg twice daily when body weight is under 50 kg) for RET fusion positive disease, until progression or unacceptable toxicity; maximum 320 mg daily; monitoring: ALT and AST every 2 weeks for 3 months then monthly, blood pressure, QTc, electrolytes, glucose, haemorrhage; adjustment: reduce by 40 mg steps for toxicity, 80 mg twice daily in severe hepatic impairment or with strong CYP3A4 inhibitors, avoid with proton pump inhibitors unless taken with food, hold for grade 3 to 4 toxicity
• NTRK fusion positive tumours are treated with a TRK inhibitor at a specialist centre.

Bone metastases. Local radiotherapy, surgery or ablation, and bone modifying drugs given with calcium and vitamin D, with dental review before use.

Monitoring. Thyroglobulin every 3 to 6 months (with anti-thyroglobulin antibodies), neck ultrasound and CT of the chest every 6 to 12 months, with FDG-PET for suspected recurrence. Calcium after thyroidectomy.

Referral and escalation.

• Referral to a thyroid cancer centre on suspicion.
• Emergency airway assessment for stridor.
• Same day assessment for symptomatic hypocalcaemia after surgery.

Special groups.

• Pregnancy: surgery in the second trimester, with radioiodine deferred until after delivery and breastfeeding.
• Older adults: reduced intensity treatment and lower targets for TSH suppression where cardiac disease exists.
• Young patients: counselling about fertility and cumulative radioiodine activity.