Paraganglioma

Definition and Origin

Classification by Location

1. Sympathetic (Paravertebral) Paragangliomas

• Arise from paravertebral paraganglia (e.g., the organ of Zuckerkandl)
• Stain positively for chromaffin (catecholamine-producing cells)
• Often functional - secrete catecholamines
• Locations: adrenal medulla (pheochromocytoma), retroperitoneum, pelvis

2. Parasympathetic (Head and Neck) Paragangliomas

• Arise near the great vessels of the head and neck (aortico-pulmonary chain)
• Major subtypes:
  • Carotid body tumor - most common head & neck PGL, at carotid bifurcation
  • Jugulotympanic (glomus jugulare / glomus tympanicum) - ~50% of temporal bone PGLs
  • Vagal paraganglioma - from the ganglion nodosum
  • Laryngeal, orbital, nasopharyngeal, and other sites
• Only rarely produce catecholamines (~5%)
• Scott-Brown's Otorhinolaryngology Head & Neck Surgery

Epidemiology

• Rare, slow-growing, usually painless masses
• Most commonly arise in the 5th and 6th decades of life
• About 10% are multifocal (especially in familial cases)
• Approximately 5% secrete catecholamines (head and neck PGLs)
• Incidence is higher at high altitudes (possibly due to chronic hypoxic stimulation)
• Approximately one-third of head and neck PGLs are associated with germline mutations

Genetics and Hereditary Syndromes

Succinate Dehydrogenase (SDH) Mutations - Most Common

Other Hereditary Associations

• MEN2 (RET mutations) - adrenal pheochromocytoma predominant
• Von Hippel-Lindau (VHL) - pheochromocytoma / paraganglioma
• Neurofibromatosis type 1 (NF1) - ~3% develop catecholamine-secreting tumors (usually solitary adrenal pheochromocytoma)
• All are autosomal dominant

Pathology / Morphology

Histology (characteristic of all PGLs)

• Zellballen pattern - nests of round-to-oval chief cells with abundant clear or granular eosinophilic cytoplasm, surrounded by delicate vascular septa
• Sustentacular cells - spindle-shaped supporting cells at the periphery of nests
• Chief cells: positive for chromogranin, synaptophysin, INSM1, CD56 (neuroendocrine markers)
• Sustentacular cells: positive for S-100 protein
• Little cellular pleomorphism; mitoses scant
• Electron microscopy: well-demarcated neuroendocrine granules (variable)

Clinical Features

Functional PGLs (sympathetic / catecholamine-secreting)

• Forceful heartbeat, palpitations
• Headache (throbbing)
• Diaphoresis
• Pallor / peripheral vasoconstriction (cool hands/feet)
• Tremor
• Hypertension - sustained (~50%) or paroxysmal (~33%); ~15% normotensive

Non-functional (Parasympathetic) Head and Neck PGLs

• Pulsatile tinnitus (glomus tympanicum)
• Cranial nerve palsy (glomus jugulare, vagal PGL)
• Neck mass (carotid body tumor)
• Conductive hearing loss
• Pain

Diagnosis

Biochemical Testing (for functional PGLs)

Imaging

• CT with high-resolution parameters is best for assessing bony involvement (temporal bone, skull base)
• MRI best demonstrates soft tissue character and vascular involvement
• Intra-arterial angiography: used pre-embolization; shows enlarged feeding arteries, early intense tumor blush, centripetal arteriolar architecture with AV shunts

Malignancy

• Metastases occur in ~10% of pheochromocytomas and ~20% of paragangliomas
• Common metastatic sites: lymph nodes, bone, liver, lung, peritoneum
• SDHB mutations carry the highest metastatic risk (30-50%)
• Up to 50% of metastatic PGLs are ultimately fatal, largely from infiltrative growth
• Carotid body tumors may metastasize to regional nodes and distant sites despite benign histology

Management

Pre-operative Preparation (Functional PGLs)

• Alpha-adrenergic blockade is mandatory before surgery to prevent hypertensive crisis
  • Phenoxybenzamine (non-selective, irreversible) - traditional agent
  • Selective alpha-1 blockers (doxazosin, prazosin) increasingly used
  • Beta-blockers may be added only AFTER adequate alpha-blockade
• Adequate volume expansion
• Minimum 10-14 days of preparation before surgery

Surgery

• Surgical resection is the primary treatment for all resectable PGLs
• Approach depends on location:
  • Carotid body/neck: open surgical excision; laryngoscopic or open approach for laryngeal PGLs (lateral thyrotomy, lateral pharyngotomy)
  • Adrenal/retroperitoneal: laparoscopic or open adrenalectomy
  • Temporal bone: specialized skull base surgery
• Pre-operative embolization (24-48 hours before surgery) significantly reduces intraoperative blood loss for highly vascular lesions; used as adjunct to surgery

Radiation Therapy

• Used when surgery is inappropriate or incomplete
• PGLs respond to radiation but incompletely
• Stereotactic radiosurgery for skull base/intracranial disease

Metastatic Disease

• ¹³¹I-MIBG therapy (100-300 mCi doses over 3-6 cycles) - treatment of choice for scintigraphically documented metastases
• Somatostatin receptor ligand therapy (PRRT with ¹⁷⁷Lu-DOTATATE)
• Chemotherapy (CVD regimen: cyclophosphamide, vincristine, dacarbazine)
• Targeted therapies (sunitinib, cabozantinib) under investigation

Key Concepts Summary

• 80-85% of all PGLs are adrenal pheochromocytomas; 70% of extra-adrenal PGLs are in the head and neck
• SDH gene mutations (SDHB, SDHC, SDHD, SDHAF2, SDHA) are the most common hereditary cause; SDHB carries the highest malignancy risk
• Zellballen architecture with chief cells (chromogranin+, synaptophysin+) and sustentacular cells (S-100+) is the histologic hallmark
• Histology cannot reliably predict malignancy - only metastasis confirms it
• Plasma free metanephrines are the most sensitive biochemical test
• ⁶⁸Ga-DOTATATE PET/CT and ¹⁸F-DOPA PET/CT have the highest sensitivity and specificity for imaging
• All functional PGLs require alpha-blockade before surgical resection
• Familial PGLs associated with SDHD/SDHAF2 exhibit maternal imprinting