chromaffin cell

**Embryology/Histology:** Neural crest origin. They are called "chromaffin" because granules stain brown with chromium salts (oxidation of catecholamines). They are located in the adrenal medulla (the innermost zone of the adrenal gland) and in extra-adrenal paraganglia (e.g., organ of Zuckerkandl near the aortic bifurcation). They are polygonal cells with granular cytoplasm, arranged in nests/cords near capillaries. Chromogranin A is a classic marker, and synaptophysin is also positive.

**Innervation/Physiology:** They are functionally equivalent to postganglionic sympathetic neurons but lack axons. Preganglionic sympathetic fibers (from T5–T9 via the splanchnic nerves) release ACh onto nicotinic receptors. This causes Ca2+ influx and exocytosis of catecholamines. This is the only sympathetic pathway where preganglionic neurons synapse directly on an endocrine cell.

**Catecholamine synthesis:** Phenylalanine → tyrosine (phenylalanine hydroxylase) → DOPA (tyrosine hydroxylase, the rate-limiting step) → dopamine (DOPA decarboxylase, requires B6) → norepinephrine (dopamine β-hydroxylase, requires vitamin C, in vesicles) → epinephrine (PNMT, in the cytosol). PNMT requires cortisol from the adrenal cortex, which drains via the portal system to the medulla. So the medulla makes mostly epinephrine, while extra-adrenal paragangliomas make mostly norepinephrine. Degradation is by COMT and MAO. The end products are metanephrines and VMA (vanillylmandelic acid).

**Clinical significance:** - **Pheochromocytoma:** Tumor of chromaffin cells. It causes episodic hypertension, headache, palpitations, diaphoresis, and tachycardia. It follows the "rule of 10s" (traditional; less accurate now): 10% bilateral, extra-adrenal, malignant, or familial. Diagnosis: plasma free metanephrines or 24-hr urinary fractionated metanephrines/catecholamines. Imaging (CT/MRI) comes after biochemical confirmation. Histology shows "Zellballen" nests with sustentacular (S-100+) cells. - **Treatment:** Alpha-blockade FIRST (phenoxybenzamine, a nonselective irreversible blocker, or doxazosin), then beta-blocker, and then surgical resection. Giving a beta-blocker first causes unopposed alpha stimulation and a hypertensive crisis. - **Associations:** MEN2A/2B (RET), von Hippel-Lindau (VHL), NF1, and SDHx mutations (hereditary paraganglioma syndromes). - **Neuroblastoma:** A related neural crest tumor in children (from the adrenal medulla or sympathetic chain). It shows N-myc amplification and elevated HVA/VMA. It differs from pheochromocytoma in that it is a tumor of neuroblasts and is usually less hypertensive. - **Adrenal medulla hyperplasia** is seen in MEN2. - **Contrast with the cortex:** The cortex is mesoderm-derived (GFR: glomerulosa/aldosterone, fasciculata/cortisol, reticularis/androgens).

**Mnemonic:** The adrenal medulla is the "center" of the adrenal gland. The layers from outside in are "GFR" (Glomerulosa, Fasciculata, Reticularis), then medulla. "Salt, Sugar, Sex" for the cortex, then "epi/NE" for the medulla.