Papillary Thyroid Carcinoma, Follicular Variant

Follicular variant of papillary thyroid carcinoma is a papillary carcinoma composed almost entirely of follicles lined by cells with papillary nuclear features. It comprises two behavioural groups: encapsulated tumours that are noninvasive (now classed as noninvasive follicular thyroid neoplasm with papillary like nuclear features, a low risk neoplasm) or minimally invasive, and infiltrative tumours that behave like classic papillary carcinoma.

It forms about 10% to 20% of papillary carcinomas and occurs in adults in their 40s to 50s, with a female predominance of about 3 to 1. The incidence of papillary carcinoma is about 10 to 15 cases in 100,000 people each year.

Risk factors are previous neck radiation, iodine sufficiency and a family history of thyroid cancer.

Pathophysiology. Encapsulated tumours usually carry RAS mutations (like follicular adenoma and carcinoma), and are rarely metastatic to nodes. Infiltrative tumours show BRAF V600E or BRAF-like profiles, with nodal metastasis rates similar to the classic type.

Behaviour. Encapsulated noninvasive tumours have a very low risk of recurrence (under 1%). Encapsulated tumours with capsular or vascular invasion spread by blood to the lung and bone, with limited nodal disease. Infiltrative tumours spread to lymph nodes in about 20% to 30%.

Prognosis. The 10-year survival exceeds 95% for most patients. Vascular invasion (4 or more foci), extrathyroidal extension and distant metastasis worsen outcomes.

• Painless thyroid nodule, often found incidentally on imaging or examination.
• Neck lymphadenopathy in infiltrative tumours.
• Hoarseness or dysphagia only in advanced local disease. Distant metastases (lung, bone) are uncommon at presentation.

• Neck ultrasound: solid or isoechoic nodule with regular margins or suspicious features, with assessment of cervical nodes.
• Fine needle aspiration cytology: often indeterminate (indeterminate cytology: atypia or follicular neoplasm), because cytology cannot separate encapsulated tumours from follicular adenoma. Molecular testing (RAS, BRAF, TERT) can help.
• Diagnostic thyroid lobectomy for indeterminate nodules, with final histology (capsular and vascular invasion, nuclear features, extent, margins) deciding the diagnosis.
• TSH, calcium, and thyroglobulin after surgery. CT or MRI of the neck and chest for extensive disease.

Differential diagnosis.

• Follicular adenoma and follicular carcinoma
• Noninvasive follicular thyroid neoplasm with papillary like nuclear features
• Classic papillary carcinoma and hyperplastic nodule in goitre
• Hürthle cell neoplasm

Treatment is risk adapted, and avoids overtreatment of low risk tumours.

Surgery.

• Thyroid lobectomy is sufficient for noninvasive encapsulated tumours (low risk neoplasm) and for small (up to 4 cm), unifocal, intrathyroidal carcinoma without nodal disease, with surveillance.
• Total thyroidectomy for tumours over 4 cm, extrathyroidal extension, nodal or distant metastasis, extensive vascular invasion, bilateral disease, or a history of neck radiation, with neck dissection for involved nodes.
• Completion thyroidectomy after lobectomy when final histology shows higher risk features.

Radioiodine. Not given for low risk disease. Selective radioiodine is considered for intermediate or high risk tumours.

• 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 and replacement.

• 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 disease. The systemic drug options that apply to other differentiated thyroid carcinoma are used.

• 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 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

Monitoring. Neck ultrasound and thyroglobulin at 6 to 12 months and then yearly for 5 years or more, with less frequent follow up for those with excellent response. After lobectomy, ultrasound and TSH.

Referral and escalation.

• Referral to an endocrine or thyroid surgery team for indeterminate nodules.
• Same day assessment for stridor or symptomatic hypocalcaemia after surgery.

Special groups.

• Pregnancy: observation or surgery in the second trimester, with radioiodine deferred to after delivery and breastfeeding.
• Older adults: avoid full TSH suppression when atrial fibrillation or osteoporosis is present.
• Children and young adults: lower threshold for total thyroidectomy and treatment at a specialist centre.