parafollicular cell

**Location/Histology:** Found in the interstitium between thyroid follicles (and in the upper-lateral lobes, where density is highest). They appear as pale-staining cells with clear cytoplasm on H&E and do not border the colloid. This distinguishes them from follicular cells, which make thyroglobulin and thyroid hormone.

**Embryology:** C cells arise from neural crest cells that migrate through the ultimobranchial body (4th/5th pharyngeal pouch derivative) and fuse with the median thyroid anlage (from the foramen cecum). Follicular cells are endodermal. Ectopic or residual tissue can persist in the lateral thyroid.

**Physiology:** - Secrete **calcitonin** in response to hypercalcemia (sensed by the calcium-sensing receptor, CaSR). - Calcitonin **inhibits osteoclast** bone resorption and increases renal calcium excretion. This lowers serum Ca²⁺ ("tones down" calcium). - Its role in humans is minor. Total thyroidectomy does not cause clinically significant calcium dysregulation from calcitonin loss. PTH and vitamin D are the dominant regulators. - Opposes PTH in net effect on bone.

**Pathology: Medullary thyroid carcinoma (MTC)** - Neuroendocrine tumor of C cells. It makes up about 5% of thyroid cancers. - Histology: sheets or nests of polygonal or spindle cells in an **amyloid stroma**. The amyloid is derived from calcitonin and stains with **Congo red** (apple-green birefringence under polarized light). - Tumor markers: elevated **calcitonin**, plus CEA. Chromogranin positive. - Can cause diarrhea (from calcitonin, VIP, or other peptides). The calcitonin level is not associated with hypocalcemia. - Spread: lymphatic spread to cervical nodes. It does not take up radioiodine, so RAI is ineffective. Treatment is total thyroidectomy with central neck dissection. - Genetics: **RET proto-oncogene** mutations (a receptor tyrosine kinase on chromosome 10). - **MEN 2A** (Sipple): MTC + pheochromocytoma + primary hyperparathyroidism (parathyroid hyperplasia) - **MEN 2B**: MTC + pheochromocytoma + mucosal neuromas/marfanoid habitus (no parathyroid disease) - **Familial MTC**: MTC only - Sporadic MTC also occurs (somatic RET mutations). - Prophylactic thyroidectomy is recommended in RET-positive family members. Always rule out pheochromocytoma before thyroid surgery to avoid a hypertensive crisis under anesthesia. Selective RET inhibitors (selpercatinib, pralsetinib) and vandetanib/cabozantinib are options for advanced disease.

**C-cell hyperplasia** is the precursor lesion in hereditary MTC.

**High-yield contrasts:** - Follicular cells: thyroglobulin, T3/T4, TSH-responsive, endoderm → papillary/follicular/anaplastic carcinoma - Parafollicular cells: calcitonin, neural crest, no TSH dependence → medullary carcinoma - Chief cells (parathyroid): PTH → raise calcium

**Mnemonic:** "C cells = Calcitonin = Carcinoma with Congo red amyloid; Calcitonin decreases Calcium (puts Ca in bone)."