Papillary Thyroid Carcinoma

Papillary thyroid carcinoma is a well-differentiated malignancy of follicular cells and accounts for 80 to 85% of thyroid cancers. Incidence is about 10 to 15 per 100,000 people a year and has risen with detection of small tumors. Women are affected about three times as often as men, with a peak at 30 to 50 years.

Risk factors are childhood head and neck irradiation, radiation fallout exposure, a family history of thyroid cancer, and hereditary syndromes (familial adenomatous polyposis, Cowden syndrome, Carney complex). Molecular drivers are BRAF V600E (about 60%), RET-PTC rearrangements (higher after radiation and in children), RAS mutations, and TERT promoter mutations, which mark aggressive disease.

Variants

• Classic
• Follicular variant
• Tall cell, columnar cell and hobnail: more aggressive
• Diffuse sclerosing: young patients, diffuse involvement and lung metastases

Spread is lymphatic, to central and lateral neck nodes (clinically apparent in 30%, microscopic in up to 80%). Distant metastasis (lung, bone) occurs in under 5%. Ten-year survival is over 95%, lower with age over 55, extrathyroidal extension, large size and distant disease. Complications are recurrence in the neck, recurrent laryngeal nerve invasion, tracheal invasion and, in elderly patients, dedifferentiation.

• A painless thyroid nodule found by the patient or on imaging, or a firm lateral neck node
• Hoarseness, dysphagia, dyspnea or neck tightness when invading local structures
• Most patients are euthyroid
• Red flags: a hard fixed nodule, vocal cord palsy, rapidly growing node, childhood radiation, and a family history

1. Serum TSH. A low value suggests an autonomous nodule, in which malignancy is rare.
2. Neck ultrasound of the thyroid and all neck node compartments: suspicious features are a solid hypoechoic nodule, taller-than-wide shape, microcalcifications, irregular margins and extrathyroidal extension. Suspicious nodes are rounded, cystic, calcified or hyperechoic with absent hilum.
3. Fine-needle aspiration of nodules of 1 cm or larger with suspicious features. Reports are grouped as nondiagnostic, benign, atypia of undetermined significance, follicular neoplasm, suspicious for malignancy and malignant. Add molecular testing to indeterminate cytology and thyroglobulin washout to nodal aspirates.
4. Laryngoscopy for hoarseness, voice change, or before reoperation.
5. Contrast CT or MRI of the neck and chest for invasive or bulky disease. Iodinated contrast delays radioiodine by 4 to 8 weeks.
6. Serum calcitonin when medullary carcinoma is possible.

Differentials: benign nodule, follicular neoplasm, medullary carcinoma, lymphoma, anaplastic carcinoma, metastasis to the thyroid.

1. Active surveillance for papillary microcarcinoma (under 1 cm) without extrathyroidal extension, nodes or high-risk cytology: ultrasound every 6 to 12 months, with surgery for growth over 3 mm or new nodes.
2. Surgery:
   • Lobectomy for tumors of 1 to 4 cm without extrathyroidal extension, nodal metastasis or radiation history.
   • Total thyroidectomy for tumors over 4 cm, extrathyroidal extension, nodal or distant disease, bilateral nodules, or radiation history.
   • Therapeutic central neck dissection for involved central nodes, and lateral dissection (levels II to V) for lateral node involvement on biopsy.
   • Cefazolin 2 g IV before incision (3 g if over 120 kg).
3. Postoperative care: calcium check at 24 hours, calcium carbonate 1 to 2 g elemental calcium daily with calcitriol 0.25 to 1 microgram daily for hypoparathyroidism, and levothyroxine 1.6 micrograms/kg orally once daily on an empty stomach.
4. Risk-adapted TSH targets: low risk 0.5 to 2 mIU/L, intermediate risk 0.1 to 0.5 mIU/L, high risk under 0.1 mIU/L.
5. Radioactive iodine for intermediate and high-risk disease:
   • Remnant ablation or adjuvant therapy: 30 to 100 millicuries (1.1 to 3.7 GBq).
   • Metastatic disease: 100 to 200 millicuries (3.7 to 7.4 GBq) every 6 to 12 months while the tumor concentrates iodine.
   • Preparation: TSH over 30 mIU/L after levothyroxine withdrawal for 3 to 4 weeks, or recombinant TSH 0.9 mg IM on two consecutive days, with a low-iodine diet for 1 to 2 weeks, a pregnancy test, and avoidance of contrast and amiodarone.
   • Adverse effects: sialadenitis (sour sweets, hydration), taste change, nasolacrimal duct obstruction, and a small risk of second malignancy. Avoid conception for 6 to 12 months afterward.
6. Radioiodine-refractory progressive disease: lenvatinib 24 mg orally once daily (start 14 mg if risk of toxicity), sorafenib 400 mg orally twice daily, dabrafenib 150 mg orally twice daily with trametinib 2 mg once daily (BRAF), selpercatinib 160 mg orally twice daily (RET), larotrectinib 100 mg orally twice daily (NTRK). Monitor blood pressure, proteinuria, liver tests and QT interval.
7. Bone metastases: external beam radiotherapy 20 Gy in 5 fractions and zoledronic acid 4 mg IV every 4 weeks.
8. Children: more advanced at presentation. Radioiodine activity is weight-based.

Follow-up: TSH, thyroglobulin and anti-thyroglobulin antibodies at 6 to 12 months, then yearly, with neck ultrasound. An excellent response means thyroglobulin under 0.2 ng/mL on suppression or under 1 ng/mL stimulated, with normal imaging. Counsel on levothyroxine adherence and pregnancy planning.