Paraganglioma

Paragangliomas are neuroendocrine tumors arising from paraganglia of the autonomic nervous system. Sympathetic paragangliomas arise in the abdomen (the organ of Zuckerkandl, para-aortic and bladder), thorax and pelvis and usually secrete catecholamines. Parasympathetic tumors arise in the head and neck (carotid body, vagal, jugulotympanic) and are usually nonsecreting (about 95%). The adrenal counterpart is pheochromocytoma. Incidence is 2 to 8 per million people a year, with a peak at 30 to 50 years.

About 40% are hereditary, the highest proportion of any tumor type. Genes include the succinate dehydrogenase subunits (SDHB, SDHD, SDHC, SDHA and SDHAF2), VHL, RET, NF1, MAX, TMEM127 and FH. SDHB mutations carry the highest risk of metastasis (30 to 70%), and SDHD tumors show paternal transmission with multifocal head and neck disease. Metastatic disease (to bone, liver, lung and nodes) occurs in 10 to 15% overall and is defined by tumor in sites without chromaffin tissue.

Complications: hypertensive crisis, arrhythmia, catecholamine cardiomyopathy and stroke (secreting tumors), cranial nerve palsies, hearing loss and airway compromise (head and neck tumors), and bone metastases.

• Secreting tumors: episodic headache, sweating and palpitations, paroxysmal or sustained hypertension, pallor, anxiety, tremor and orthostatic hypotension. Attacks can be triggered by exercise, anesthesia, micturition (bladder tumors), drugs (metoclopramide, glucagon) or tumor palpation.
• Head and neck: a painless, slowly growing, pulsatile neck mass (carotid body), pulsatile tinnitus and conductive hearing loss (jugulotympanic), cranial nerve IX to XII palsies and hoarseness (vagal and jugular).
• Red flags: hypertensive crisis, chest pain, arrhythmia, a family history of pheochromocytoma, thyroid cancer or renal cancer, bone pain, and rapid growth.

1. Biochemistry for all suspected functioning tumors: plasma free metanephrines (sampled supine after 20 to 30 minutes of rest; normetanephrine over 2 to 3 times the upper limit is diagnostic, sensitivity about 96 to 99%) or 24-hour urinary fractionated metanephrines. Methoxytyramine is raised in SDHx tumors and head and neck tumors. Chromogranin A supports the diagnosis.
2. Anatomic imaging: MRI of the neck, chest, abdomen and pelvis (T2 hyperintense "light bulb", salt-and-pepper pattern in head and neck tumors), or CT with contrast.
3. Functional imaging: gallium-68 DOTATATE PET-CT is the most sensitive (especially in metastatic and head and neck disease), and fluorodeoxyglucose PET-CT for SDHB disease.
4. Genetic testing in every patient, with counseling.
5. Audiometry and nerve assessment for head and neck tumors, and echocardiogram for catecholamine cardiomyopathy.

Differentials: pheochromocytoma, neuroendocrine tumor, schwannoma, lymphoma, thyroid mass, metastatic carcinoma, carotid aneurysm and other vascular lesions.

1. Preoperative blockade for secreting tumors, started at least 7 to 14 days before surgery:
   • Phenoxybenzamine 10 mg orally twice daily, increasing every 2 to 3 days by 10 to 20 mg to a total of 20 to 100 mg daily (about 1 mg/kg daily), until seated blood pressure is under 130/80 mmHg with standing systolic pressure over 90 mmHg.
   • Alternatively doxazosin 2 mg orally once daily, increasing to a maximum of 32 mg daily.
   • Add a high sodium diet (over 5 g daily) and fluid intake of 2.5 to 3 litres daily to expand volume.
   • Add a beta blocker (propranolol 20 to 40 mg orally three times daily, or metoprolol) only after alpha blockade is established, for tachycardia. Never start a beta blocker first.
   • Amlodipine 5 to 10 mg orally daily as an adjunct. Metyrosine 250 mg orally four times daily, increasing to 1 to 2 g daily, for refractory cases.
   • Hypertensive crisis: phentolamine 1 to 5 mg IV bolus, then nicardipine 5 mg/h IV, increased by 2.5 mg/h every 5 to 15 minutes to a maximum of 15 mg/h, or sodium nitroprusside 0.5 to 10 micrograms/kg/min IV.
2. Surgery: laparoscopic or open resection of abdominal and thoracic tumors with an arterial line and anesthetic experience. Postoperative monitoring for hypotension and rebound hypoglycemia for 24 to 48 hours. Cefazolin 2 g IV before incision (3 g if over 120 kg).
3. Head and neck tumors: observation with serial imaging for small, slowly growing tumors (especially in older patients and SDHD carriers); surgical resection (with preoperative embolization for large carotid body and jugulotympanic tumors); and radiotherapy 45 to 50 Gy in 25 fractions or stereotactic radiosurgery 12 to 15 Gy in 1 fraction for unresectable and residual tumors.
4. Metastatic disease:
   • Observation for indolent disease.
   • Lutetium-177 dotatate 7.4 GBq IV every 8 weeks for 4 cycles with an amino acid infusion for renal protection (lysine and arginine 25 g each in 1 L over 4 hours).
   • Cyclophosphamide 750 mg/m2 IV on day 1, vincristine 1.4 mg/m2 IV on day 1 and dacarbazine 600 mg/m2 IV on days 1 and 2, every 21 to 28 days.
   • Temozolomide 150 to 200 mg/m2 orally for 5 days every 28 days (for SDHB tumors).
   • Sunitinib 37.5 mg orally once daily, or belzutifan 120 mg orally once daily (contraindicated in pregnancy, causes anemia and hypoxia, and reduces the effect of hormonal contraception).
   • Palliative radiotherapy for painful bone lesions: 8 Gy in 1 fraction or 20 Gy in 5 fractions.
5. Pregnancy: alpha blockade and surgery in the second trimester when possible.

Follow-up: plasma metanephrines and imaging at 3 to 6 months, then yearly for life (every 6 months in SDHB carriers). Counsel on genetic testing of relatives, and on drugs and situations that can precipitate a crisis.