paraganglioma

**Definition and origin:** Paragangliomas (PGLs) are neural crest-derived neuroendocrine tumors of chromaffin cells arising outside the adrenal medulla. A tumor in the adrenal medulla is a pheochromocytoma (PCC). Together they are called PPGL.

**Types:** - *Sympathetic PGL:* Found along the paravertebral sympathetic chain in the abdomen, pelvis, and thorax. Common sites are the organ of Zuckerkandl at the aortic bifurcation and the bladder wall. They usually secrete catecholamines, mainly norepinephrine and sometimes dopamine. Most are functional. - *Parasympathetic PGL:* Found in the head and neck, e.g., carotid body tumor, glomus jugulare, glomus tympanicum, and vagal PGL. They are usually nonfunctional. They present as a mass, pulsatile tinnitus, hearing loss, or cranial nerve deficits. A carotid body tumor classically shows the "lyre sign" (splaying of the internal and external carotid arteries) on imaging.

**Clinical features (functional tumors):** Episodic headache, sweating, and palpitations (the classic triad), plus paroxysmal or sustained hypertension, anxiety, pallor, and orthostatic hypotension. Triggers include surgery, anesthesia, and drugs (e.g., beta-blockers given unopposed, glucagon, metoclopramide, opioids, and corticosteroids). Complications include hypertensive crisis, arrhythmia, and catecholamine cardiomyopathy.

**Diagnosis:** - Biochemical: plasma free metanephrines (most sensitive) or 24-hour urinary fractionated metanephrines and catecholamines. Elevated methoxytyramine suggests a dopamine-secreting tumor (often SDHx-related). - Imaging after biochemical confirmation: CT or MRI. Functional imaging includes MIBG scintigraphy and ⁶⁸Ga-DOTATATE PET (especially for metastatic or SDHx-related disease). - Histology: "Zellballen" nests of chief cells surrounded by sustainer (sustentacular) cells, which are S-100 positive. The cells are chromogranin and synaptophysin positive. Malignancy cannot be determined by histology. It is defined by metastasis to non-chromaffin sites (e.g., bone, liver, lung, lymph nodes).

**Genetics (~30–40% germline):** - *SDHx* (especially SDHB): head/neck and abdominal PGL, with higher malignancy risk (SDHB). SDHD mutations show paternal imprinting and multifocal head/neck PGL. - *VHL* (von Hippel-Lindau): mostly PCC, with hemangioblastoma, clear cell renal cell carcinoma (RCC), and pancreatic tumors. - *RET* (MEN2A/2B): PCC with medullary thyroid carcinoma. MEN2A also has hyperparathyroidism, and MEN2B has mucosal neuromas and a marfanoid habitus. - *NF1:* PCC, neurofibromas, and café-au-lait spots. - Others: TMEM127, MAX. - The "Rule of 10s" (10% extra-adrenal, bilateral, malignant, familial) is outdated. Current estimates are higher for extra-adrenal disease, hereditary disease, and malignancy.

**Treatment:** - Definitive therapy is surgical resection, with **preoperative alpha-blockade first**. Use phenoxybenzamine (irreversible, nonselective) or doxazosin for ~7–14 days. Add a beta-blocker only after adequate alpha-blockade, to avoid unopposed alpha stimulation and hypertensive crisis. Also give a high-salt diet and fluids to prevent postoperative hypotension from volume contraction. - Metastatic disease: MIBG therapy (¹³¹I-MIBG), PRRT (e.g., ¹⁷⁷Lu-DOTATATE), CVD chemotherapy, or tyrosine kinase inhibitors. Belzutifan (HIF-2α inhibitor) is used for VHL- or pseudohypoxia-related tumors. - Genetic counseling and testing are recommended for all patients. Lifelong follow-up is needed.

**Board pearls:** - Catecholamine excess with episodic hypertension, headache, sweating, and tachycardia → measure plasma metanephrines. - Alpha-blocker before beta-blocker. - Pheochromocytoma = adrenal; paraganglioma = extra-adrenal. - Carotid body tumor = painless neck mass at the carotid bifurcation, which moves side-to-side but not vertically (Fontaine sign). Avoid biopsy. - SDHB → higher metastatic risk. - The tumor is derived from neural crest cells (chromaffin cells).