Papillary Thyroid Carcinoma, Tall Cell Variant

Tall cell variant of papillary thyroid carcinoma is an aggressive variant in which at least 30% of tumour cells are tall (height at least twice to three times their width) with abundant eosinophilic cytoplasm. It carries higher rates of extrathyroidal extension, nodal and distant metastasis and recurrence than classic papillary carcinoma.

It forms about 1% to 10% of papillary carcinomas, depending on the cut off used, and typically occurs in patients in their 50s to 60s. The incidence of papillary carcinoma is about 10 to 15 cases in 100,000 people each year, with a female predominance, although the proportion of men is higher in the tall cell variant.

Risk factors are ionising radiation to the neck in childhood, iodine sufficiency, obesity and familial non-medullary thyroid cancer.

Pathophysiology. BRAF V600E is present in about 80% to 95% of tall cell tumours, with TERT promoter mutation in many, which together mark aggressive disease. Tumours often have reduced radioiodine avidity because of lower expression of the sodium iodide symporter.

Behaviour. Extrathyroidal extension, vascular invasion, nodal metastases (about 60%) and distant metastases (about 10% to 15%) are frequent. Mortality is higher than for classic carcinoma, with 10-year survival of about 70% to 80%.

Risk classification. Tall cell histology places a tumour at least in the intermediate recurrence risk group, and high risk with extrathyroidal extension, positive margins, extensive nodal disease or distant metastasis.

• Thyroid nodule or neck mass, often larger than classic papillary carcinoma, and cervical lymphadenopathy.
• Hoarseness, dysphagia, dyspnoea or haemoptysis from local invasion.
• Cough, dyspnoea or bone pain from distant metastases (lung, bone).

Red flags.

• Rapid growth, stridor or vocal cord palsy.
• Cord compression from vertebral metastasis.

• Neck ultrasound with fine needle aspiration cytology (cytology suspicious for or diagnostic of malignancy), and cervical lymph node mapping with aspiration and thyroglobulin washout.
• Cross-sectional imaging (CT with contrast or MRI) of the neck and chest when extrathyroidal extension, bulky nodes or distant disease is suspected. Iodinated contrast delays radioiodine treatment by 4 to 8 weeks, which is accepted when needed for surgical planning.
• Laryngoscopy for cord function, serum calcium and PTH.
• Final histology after surgery: proportion of tall cells, invasion, margins, lymph nodes. Molecular testing (BRAF, TERT, RET and NTRK fusions) in advanced disease.
• Postoperative thyroglobulin and anti-thyroglobulin antibodies, and diagnostic imaging as indicated.

Differential diagnosis.

• Classic papillary carcinoma and other aggressive variants (hobnail, columnar cell, solid)
• Poorly differentiated and anaplastic carcinoma
• Medullary thyroid carcinoma

Surgery. Total thyroidectomy with prophylactic or therapeutic central neck dissection, and lateral neck dissection for biopsy proven nodes, with experienced surgical technique to protect the parathyroid glands and recurrent laryngeal nerves.

Radioiodine. Adjuvant radioiodine is given after surgery to most patients with tall cell tumours because of the risk of recurrence.

• 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

Radioiodine refractory or progressive disease. External beam radiotherapy for unresectable local disease, and systemic therapy.

• BRAF V600E 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
• 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
• 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

Surveillance after treatment. Stimulated or unstimulated thyroglobulin at 6 to 12 months, with neck ultrasound, and further imaging only for rising thyroglobulin or symptoms.

Monitoring. Neck ultrasound and thyroglobulin every 6 months for 2 years and then yearly. Calcium and PTH after surgery, and TSH and free T4 every 6 to 12 months once stable.

Referral and escalation.

• Referral to a thyroid cancer centre on suspicion.
• Same day assessment for post-thyroidectomy hypocalcaemia or airway compromise.

Special groups.

• Pregnancy: surgery in the second trimester if needed, with radioiodine deferred.
• Older adults: lower targets for TSH suppression when atrial fibrillation or osteoporosis is present.
• Children: treated at a paediatric thyroid centre.