Medullary Thyroid Carcinoma and Calcitonin
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Direct answer
Medullary thyroid carcinoma is a neuroendocrine tumour arising from parafollicular C cells, which secrete calcitonin. Most cases are sporadic, while about a quarter are hereditary, occurring in MEN 2A, MEN 2B or familial disease through RET mutations. Calcitonin and CEA are the main tumour markers, and total thyroidectomy with central neck dissection is the standard surgical treatment.
What you must remember
- Origin: parafollicular C cells, which are traditionally described as neural crest derived (ultimobranchial body) and are distinct from follicular cells, so the tumour does not take up iodine.
- Marker: calcitonin, with CEA as a second marker; calcitonin levels broadly reflect tumour burden.
- Hereditary share: roughly a quarter of cases are familial, usually through germline RET mutations.
- Codon risk: RET codon 634 is linked with MEN 2A, and codon 918 with MEN 2B, the most aggressive form.
- MEN 2 associations: phaeochromocytoma and primary hyperparathyroidism in MEN 2A; mucosal neuromas and marfanoid habitus in MEN 2B.
- Prophylactic thyroidectomy: timed by the mutation risk category, with the earliest surgery for codon 918 carriers.
- Advanced disease: tyrosine kinase inhibitors such as vandetanib or cabozantinib are used when surgery is not curative.
A pathway from nodule to surveillance
A thyroid nodule with cytology suggesting a medullary tumour needs a set order of checks. Each step guards against a complication that could otherwise be missed, and the order matters because surgery must not precede the catecholamine screen.
- Suspect on cytology: fine needle aspiration may show spindle or plasmacytoid cells in an amyloid-rich stroma, and calcitonin staining supports the diagnosis.
- Measure markers: serum calcitonin and CEA are checked, and a calcium or pentagastrin stimulation test is used when basal calcitonin is equivocal.
- Test for RET: germline RET testing is offered to all patients, and first-degree relatives are screened if a mutation is found.
- Exclude phaeochromocytoma: plasma or urinary metanephrines are measured before surgery in any MEN 2 patient.
- Operate: total thyroidectomy with central compartment node dissection is performed when nodal disease is known or suspected.
- Follow up with markers: calcitonin and CEA are followed serially, and a persistently raised calcitonin after surgery suggests residual disease.
Where students lose marks
These points are common traps in both surgery and medicine papers.
- Trap: giving radioiodine for medullary carcinoma. Correct: C cells do not concentrate iodine, so radioiodine is not useful, unlike in papillary carcinoma.
- Trap: testing only the index patient for RET and ignoring relatives. Correct: a germline mutation requires screening of first-degree relatives, and carriers need timed prophylactic surgery.
- Trap: operating on a MEN 2 patient without checking catecholamines. Correct: phaeochromocytoma must be excluded first, because surgery can precipitate a hypertensive crisis.
- Trap: using thyroglobulin as the marker. Correct: calcitonin is the marker, because thyroglobulin is produced by follicular cells.
Frequently asked questions
Why is medullary thyroid carcinoma not treated with radioiodine?
Medullary thyroid carcinoma is not treated with radioiodine because its parafollicular C cells do not concentrate iodine. Radioactive iodine therapy relies on sodium iodide uptake, which these cells lack. Surgery is therefore the mainstay, with tyrosine kinase inhibitors for advanced disease.
Which RET mutation is linked with the most aggressive medullary carcinoma?
The codon 918 mutation is linked with the most aggressive form of medullary thyroid carcinoma, which is seen in MEN 2B. Codon 634 mutations are linked with MEN 2A and also carry a high risk. Carriers need prophylactic thyroidectomy timed by their mutation risk category.
What does calcitonin measure in medullary thyroid carcinoma?
Calcitonin is the principal tumour marker in medullary thyroid carcinoma because the malignant C cells secrete it. Serum levels broadly reflect tumour burden and are used for follow-up after surgery. CEA is measured alongside it, since it often rises in more advanced disease.
Which test excludes phaeochromocytoma before surgery in MEN 2?
Plasma or urinary metanephrines are measured to exclude phaeochromocytoma before any surgery in MEN 2 patients. Phaeochromocytoma can occur in both MEN 2A and MEN 2B, and an unrecognised tumour can cause a hypertensive crisis during anaesthesia. Alpha blockade is started before surgery when the tumour is confirmed.