Medullary Thyroid Carcinoma

Medullary thyroid carcinoma is a neuroendocrine tumor arising from the parafollicular C cells of the thyroid, which secrete calcitonin and carcinoembryonic antigen. It makes up 3 to 5% of thyroid cancers. About 75% are sporadic, with a peak at 40 to 60 years. About 25% are hereditary through activating germline RET mutations (multiple endocrine neoplasia type 2A, type 2B, and familial medullary thyroid carcinoma), inherited in an autosomal dominant pattern.

Hereditary syndromes

• Type 2A: medullary carcinoma in nearly 100% of carriers, pheochromocytoma in about 50%, primary hyperparathyroidism in 20 to 30%, cutaneous lichen amyloidosis and Hirschsprung disease (codon 634 mutations carry the most aggressive 2A disease)
• Type 2B (the M918T mutation): early aggressive carcinoma from infancy, pheochromocytoma, mucosal neuromas, marfanoid habitus and intestinal ganglioneuromatosis
• Familial medullary thyroid carcinoma: carcinoma alone, with the mildest course

About 50% have nodal metastases at diagnosis, and 10 to 15% distant metastases (liver, lung, bone). Ten-year survival is about 95% when confined to the thyroid, 75% with nodal disease, and 40% with distant metastases. Calcitonin doubling time under 6 months predicts a poor outcome. Complications: secretory diarrhea and flushing from calcitonin (advanced disease), Cushing syndrome from ectopic ACTH, and airway or vascular compression.

• A firm thyroid nodule, or neck mass (nodal metastases), usually in the upper two thirds of the lobe where C cells predominate
• Hoarseness, dysphagia and dyspnea in advanced disease
• Chronic diarrhea and flushing in advanced disease
• Features of multiple endocrine neoplasia: paroxysmal hypertension (pheochromocytoma), hypercalcemia, mucosal neuromas and a family history
• Red flags: rapidly growing mass, calcitonin over 500 pg/mL, bone pain, and a family history of early thyroid cancer

1. Neck ultrasound of the thyroid and nodes (both central and lateral compartments).
2. Fine-needle aspiration with calcitonin immunostaining on cytology, or calcitonin measurement in the needle washout.
3. Serum calcitonin and carcinoembryonic antigen: basal calcitonin correlates with tumor burden (over 100 pg/mL suggests nodal disease, and over 500 pg/mL distant disease).
4. Germline RET testing in every patient, including apparently sporadic cases.
5. Before any thyroid surgery: plasma free metanephrines (to exclude pheochromocytoma, which must be treated first), serum calcium and parathyroid hormone.
6. Staging for calcitonin over 500 pg/mL or advanced disease: CT of the neck and chest, MRI of the liver, bone scintigraphy or MRI of the spine and pelvis.

Differentials: papillary thyroid carcinoma, follicular neoplasm, anaplastic carcinoma, thyroid lymphoma, nodular goiter, metastasis, amyloid goiter.

1. Surgery: total thyroidectomy with prophylactic or therapeutic central neck dissection (level VI). Add lateral neck dissection (levels II to V) when imaging shows lateral nodes or calcitonin is above 200 pg/mL with central nodal disease. Operate for pheochromocytoma first, with alpha blockade (phenoxybenzamine 10 mg orally twice daily titrated to 20 to 100 mg daily for 7 to 14 days), and treat hyperparathyroidism at the same operation. Cefazolin 2 g IV before incision (3 g if over 120 kg).
2. Postoperative care: levothyroxine 1.6 micrograms/kg orally once daily, adjusted to a normal TSH (suppression is not needed), calcium monitoring at 24 and 48 hours, and calcium carbonate 1 to 2 g elemental calcium daily with calcitriol 0.25 to 1 microgram daily for hypoparathyroidism.
3. Prophylactic thyroidectomy in RET carriers:
   • Highest risk (M918T): within the first year of life.
   • High risk (codon 634 and A883F): at or before age 5, guided by calcitonin.
   • Moderate risk: when calcitonin rises, often after age 5, with annual surveillance.
4. Residual or recurrent disease: surgical re-exploration for localized disease, external beam radiotherapy 60 to 66 Gy in 30 to 33 fractions for unresectable or residual tumor.
5. Progressive or symptomatic advanced disease:
   • Selpercatinib 160 mg orally twice daily (120 mg twice daily if under 50 kg) for RET-mutant tumors. Monitor blood pressure, liver tests, QT interval and electrolytes.
   • Pralsetinib 400 mg orally once daily on an empty stomach.
   • Vandetanib 300 mg orally once daily (reduce to 200 mg daily if creatinine clearance is under 50 mL/min). Check ECG, potassium, calcium and magnesium at baseline, at 2 to 4 weeks, and then every 3 months, because of QT prolongation.
   • Cabozantinib 140 mg orally once daily (monitor blood pressure, wound healing, diarrhea and the risk of fistula and hemorrhage).
6. Diarrhea: loperamide 4 mg orally initially, then 2 mg after each loose stool (maximum 16 mg daily).
7. Bone metastases: zoledronic acid 4 mg IV every 4 weeks, and palliative radiotherapy 8 Gy in 1 fraction.

Follow-up: calcitonin and carcinoembryonic antigen 3 months after surgery, then every 6 months for a year, then yearly if undetectable. Calcitonin doubling time guides imaging. Offer genetic counseling and RET testing to first-degree relatives, with annual metanephrine and calcium screening in carriers.