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Paraganglioma - Point Wise

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1. Definition & Origin

• Paragangliomas (PGLs) are neoplasms arising from neuroendocrine cells (chromaffin/chief cells) associated with the sympathetic and parasympathetic nervous systems
• They originate from neural crest-derived paraganglionic cells distributed throughout the body
• The adrenal medullary pheochromocytoma is the most common paraganglioma, accounting for 80-85% of all cases
• Extra-adrenal paragangliomas represent the remaining 15-20%; approximately 70% of these occur in the head and neck
• Robbins, Cotran & Kumar Pathologic Basis of Disease

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2. Classification by Location

A. Paravertebral (Sympathetic) Paragangliomas

• Arise from paravertebral sympathetic ganglia and the organ of Zückerkandl (near the aortic bifurcation)
• Have sympathetic connections
• Stain positively for chromaffin - indicating catecholamine production
• More likely to be functionally active (secrete catecholamines)

B. Head & Neck (Parasympathetic) Paragangliomas

• These are innervated by the parasympathetic system
• Only rarely produce catecholamines (up to 5% in H&N)
• Scott-Brown's Otorhinolaryngology; Robbins

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3. Epidemiology

• Rare, slow-growing, painless masses
• Peak incidence: 5th and 6th decades of life
• Laryngeal paragangliomas: 3x more common in women
• Incidence is higher at high altitudes (possible hypoxic stimulus)
• Usually solitary and sporadic, but ~10% are multifocal
• Robbins; Cummings Otolaryngology

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4. Genetics & Hereditary Syndromes

• 30-40% of all pheochromocytomas/paragangliomas harbor an oncogenic germline mutation
• Hereditary cases are typically younger at presentation and more often bilateral

Key Genetic Associations:

• SDH mutations are the most frequent cause of hereditary PGL; loss-of-function mutations in SDH subunits alter cellular metabolism ("pseudohypoxia" phenotype)
• SDHB mutation carries the highest metastatic risk (30-50%)
• PGL types 1-4 (SDH gene syndromes) typically involve head and neck paragangliomas
• Robbins, Cotran & Kumar Pathologic Basis of Disease, Table 24.10

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5. Pathology / Morphology

Gross

• Carotid body tumor: rarely exceeds 6 cm, arises at or envelops the carotid bifurcation
• Red-pink to brown, well-circumscribed
• Highly vascular - embolization targets

Microscopy

• Characteristic Zellballen pattern: nests of round-to-oval chief cells surrounded by delicate vascular septae
• Chief cells: neuroectodermal origin; abundant clear or granular eosinophilic cytoplasm; uniform nuclei; few mitoses
• Sustentacular cells: spindle-shaped supporting stromal cells around nest periphery

Immunohistochemistry

• Electron microscopy: well-demarcated neuroendocrine granules in paravertebral tumors (scant in non-functioning tumors)
• Robbins

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6. Clinical Features

By Location:

• Glomus tympanicum: pulsatile tinnitus, conductive hearing loss, red pulsatile mass behind tympanic membrane
• Glomus jugulare: cranial nerve palsies (CN IX-XII), pulsatile tinnitus
• Carotid body tumor: painless lateral neck mass at carotid bifurcation ("lyre sign" on angiography); splays the carotid vessels
• Vagal paraganglioma: high cervical mass, CN X palsy, hoarseness
• Functional tumors: hypertension (paroxysmal or sustained), palpitations, headache, diaphoresis (due to catecholamine secretion)

General:

• Most are painless and slow-growing
• Symptoms mainly arise from compression of adjacent structures
• ~1-3% of glomus jugulare tumors secrete catecholamines
• Cummings; Scott-Brown's

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7. Malignancy

• All PGLs should be considered potentially malignant - the terms "benign" and "malignant" are no longer recommended per current classification
• The term "metastatic paraganglioma" is used when metastatic disease is present
• Histologic features (mitoses, pleomorphism, vascular invasion) do NOT reliably predict metastatic behavior
• SDHB mutations = highest metastatic risk (30-50%)
• Metastatic behavior is more common in extra-adrenal PGLs (20-40%)
• Up to 50% of metastatic paragangliomas are ultimately fatal, mainly due to infiltrative growth
• Carotid body tumors may metastasize to regional lymph nodes and distant sites despite benign histology
• Robbins

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8. Imaging

• Carotid artery involvement and intracranial invasion must be specifically sought
• Angiography reveals multi-compartment blood supply with arteriovenous shunts
• Avoid biopsy of vascular lesions - diagnose preoperatively on imaging + octreotide scan to avoid hemorrhage
• Scott-Brown's; Cummings

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9. Treatment

Surgery

• Surgical excision is the definitive treatment for most PGLs
• Carotid body tumors: resection with vascular control
• Laryngeal PGLs: lateral thyrotomy or lateral pharyngotomy (open approach preferred for hemostasis); transoral CO2 laser not recommended due to hemostasis difficulty
• Neck dissection NOT indicated for laryngeal paragangliomas (they do not metastasize to cervical nodes)
• Pre-operative embolization is used as an adjuvant to reduce intraoperative blood loss

Radiation Therapy

• Glomus jugulare (Fisch class C/D): stereotactic radiosurgery (SRS) is the preferred method - better cranial nerve preservation vs. surgery, similar/better local control
• Fisch class A/B (middle ear confined): surgery preferred
• PGLs respond to RT but incompletely; RT is mainly for growth control, not cure

Embolization

• Pre-operative embolization due to highly vascular nature
• Particles sized to penetrate peripheral arteries (~90 microns); multiple injections needed due to multi-compartment supply
• Percutaneous/intra-operative direct puncture with liquid embolic agent may be used where AV shunts present
• Embolization alone (without surgery/RT) can provide symptomatic relief and stabilize growth

Functional Tumors

• Pre-operative alpha-adrenergic blockade (phenoxybenzamine) + beta-blockade to prevent hypertensive crisis

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10. Key Concepts Summary

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• Robbins, Cotran & Kumar Pathologic Basis of Disease (Chapters 16 & 24)
• Cummings Otolaryngology Head and Neck Surgery
• Scott-Brown's Otorhinolaryngology Head & Neck Surgery

1. Definition & Origin
2. Classification by Location (with table)
3. Epidemiology
4. Genetics & Hereditary Syndromes (full gene table + highlighted SDHB warning)
5. Pathology / Morphology (gross, microscopy, IHC table)
6. Clinical Features (by-location table)
7. Malignancy (with red alert box on current classification)
8. Imaging (modality table)
9. Treatment (surgery, SRS, embolization, functional tumors)
10. Key Concepts Summary table