C cell

**Location & histology:** C cells (parafollicular cells) lie between thyroid follicles, mainly in the upper-middle thirds of the lateral lobes. They are larger and paler-staining than follicular cells on H&E. They do NOT take up iodine and are not TSH-dependent.

**Embryology:** They derive from neural crest cells that migrate via the ultimobranchial body (4th/5th pharyngeal pouch) and fuse with the median thyroid anlage (which comes from the foramen cecum, endoderm). Follicular cells are endodermal; C cells are neural crest (APUD/neuroendocrine lineage).

**Function:** They secrete **calcitonin** in response to high serum calcium (sensed by calcium-sensing receptor). Calcitonin: - Inhibits osteoclast bone resorption, so it lowers serum Ca²⁺ and phosphate. - Decreases renal Ca²⁺ reabsorption. - Opposes PTH. Mnemonic: "Calcitonin tones down calcium." - It is physiologically minor in adults. Thyroidectomy does not cause hypocalcemia from calcitonin loss, and calcitonin excess does not cause clinically significant hypocalcemia. Postoperative hypocalcemia is from parathyroid injury or removal. - Calcitonin is used therapeutically for Paget disease of bone, hypercalcemia, and osteoporosis (rarely).

**Pathology — Medullary thyroid carcinoma (MTC):** - Arises from C cells (about 5% of thyroid cancers). - Histology: nests or sheets of polygonal cells in an **amyloid stroma**. The amyloid is derived from calcitonin, and Congo red staining shows apple-green birefringence under polarized light. - Tumor marker: **calcitonin** (also CEA). Patients may have diarrhea (from calcitonin, VIP, or prostaglandins) and flushing. - Spread: lymphatic spread to cervical nodes is common, and hematogenous spread to liver, lung, and bone can occur. - Treatment: total thyroidectomy with central neck dissection. It is **not** treated with radioactive iodine because C cells don't take up iodine. Targeted therapy for advanced RET-driven disease includes selpercatinib, pralsetinib, vandetanib, and cabozantinib.

**Genetics - MEN2A and MEN2B (RET proto-oncogene, chromosome 10, gain-of-function):** - Autosomal dominant. About 25% of MTC is hereditary. - **MEN2A:** MTC + pheochromocytoma + primary hyperparathyroidism (parathyroid hyperplasia). - **MEN2B:** MTC + pheochromocytoma + mucosal neuromas/marfanoid habitus (no hyperparathyroidism). - Familial MTC: isolated MTC only. - Screen for RET mutations in relatives, and offer prophylactic thyroidectomy to carriers (timing depends on the mutation risk level). Always exclude pheochromocytoma before thyroid surgery to avoid a hypertensive crisis. - C-cell hyperplasia is the precursor lesion in hereditary MTC.

**Boards pearls:** - Don't confuse C cells (calcitonin, neural crest) with follicular cells (thyroid hormone, endoderm, iodine-avid), which give papillary, follicular, and anaplastic carcinomas. - Elevated calcitonin plus amyloid on biopsy = MTC. - Pentagastrin or calcium stimulation increases calcitonin release from C cells (a historical diagnostic test). - Papillary carcinoma has Orphan Annie eye nuclei and psammoma bodies, and follicular carcinoma shows capsular or vascular invasion. These contrast with the amyloid stroma of MTC.