Paraganglioma

Definition and Origin

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 694

Classification by Location

1. Sympathetic Paragangliomas

• Arise from paravertebral paraganglia (e.g., organ of Zuckerkandl - aortic bifurcation)
• Stain positively for chromaffin (cells producing catecholamines)
• More likely to be functional (secreting catecholamines)

2. Parasympathetic Paragangliomas (Head and Neck)

• Carotid body tumor - most common; arises at the bifurcation of the common carotid artery
• Glomus jugulare (jugulotympanic) - arises from the jugular bulb; can fill the middle ear
• Glomus tympanicum - arises from the cochlear promontory
• Vagal paraganglioma - from the ganglion nodosum of the vagus nerve
• Laryngeal paraganglioma - 3rd most common neuroendocrine tumor of the larynx; 3x more common in women

• Scott-Brown's Otorhinolaryngology Head & Neck Surgery

Histopathology

• Chief cells (type I): neuroectodermal origin; abundant clear or granular eosinophilic cytoplasm; uniform round-to-ovoid nuclei. Stain positively for: chromogranin, synaptophysin, INSM1 (insulinoma-associated protein 1), and CD56
• Sustentacular cells (type II): spindle-shaped supporting cells at the periphery of nests; positive for S-100 protein

• Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 694

Fig. 16.17 (Robbins) - (A) H&E: classic Zellballen nests separated by vascular septa. (B) Chromogranin immunohistochemistry: strong positivity in tumor cells.

Genetics

• Goldman-Cecil Medicine, Sabiston Textbook of Surgery, Robbins

Clinical Features

• Rare, slow-growing, usually painless masses
• Peak incidence: 5th-6th decades
• Incidence is higher at high altitudes (carotid body tumors - chronic hypoxia)
• ~10% of patients have multifocal tumors
• ~5% of head/neck PGLs secrete catecholamines (vs. ~50% of sympathetic PGLs)

• Carotid body tumor: painless neck mass at the carotid bifurcation; Fontaine sign (limited vertical mobility, some lateral mobility); may cause cranial nerve palsies
• Glomus tympanicum: pulsatile tinnitus; red pulsatile mass visible behind intact tympanic membrane ("rising sun" sign)
• Glomus jugulare: pulsatile tinnitus + conductive hearing loss; cranial nerve IX, X, XI palsies (jugular foramen syndrome)
• Vagal PGL: neck mass with vagal palsy (hoarseness, dysphagia)

• Goldman-Cecil Medicine, Cummings Otolaryngology

Malignancy

• Histologic features (mitoses, pleomorphism, vascular invasion) do not reliably predict malignancy
• Malignancy is defined by the presence of metastases in sites where paraganglionic tissue is not normally found (e.g., lymph nodes, liver, lung, bone)
• SDHB mutations carry the highest metastatic risk: 30-50%
• Up to 50% of metastatic PGLs are ultimately fatal, largely due to infiltrative growth
• Carotid body tumors may metastasize to regional lymph nodes despite benign appearance
• Robbins, p. 694-695

Imaging and Diagnosis

• CT (high-resolution): best for bony involvement (skull base erosion in glomus jugulare)
• MRI: best for soft tissue extent, intracranial invasion, and vascular encasement; classic "salt and pepper" appearance on T2 due to signal voids from flow
• Octreotide scan / 68Ga-DOTATATE PET: somatostatin receptor scintigraphy - highly sensitive for functional imaging
• Angiography: enlarged feeding arteries with intense early tumor blush; used pre-embolization; confirms centripetal arterioles with arteriovenous shunts
• Biopsy warning: highly vascular - pre-biopsy imaging to confirm diagnosis first; risk of severe hemorrhage. Radiographic evidence is often sufficient for diagnosis.
• Biochemistry: 24-hr urinary/plasma metanephrines and catecholamines in secretory tumors

Treatment

• Cummings Otolaryngology, p. (block34)

• Treatment of choice for most resectable tumors
• Glomus tympanicum: amenable to excision with minimal morbidity; ~80-95% success
• Glomus jugulare: significant risk to cranial nerves VII, IX, X, XI
• Carotid body tumor: risk of stroke and cranial nerve injury
• Preoperative embolization (24-48 hrs before surgery): reduces intraoperative blood loss; particularly for temporal bone and large carotid body PGLs; recent meta-analysis (PMID: 38942141) assessed its role in jugular PGL surgery
• Laryngeal PGL: lateral thyrotomy/pharyngotomy preferred; transoral laser discouraged due to hemostasis difficulties

• External beam radiation and stereotactic radiosurgery (Gamma Knife) both used
• As primary modality: halts tumor growth in >90% of cases but may not relieve symptoms
• Also used as adjuvant for residual or recurrent disease
• Responds but incompletely to RT

• Pre-operative alpha-blockade (phenoxybenzamine or doxazosin) MANDATORY before surgery
• Beta-blockade added ONLY after adequate alpha-blockade
• For metastatic/unresectable: sunitinib, MIBG therapy (MIBG-avid tumors), CVD chemotherapy (cyclophosphamide, vincristine, dacarbazine), peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE for SSTR-positive tumors

Syndromes with Paraganglioma

Key Concepts Summary

• Paragangliomas = neuroendocrine tumors of paraganglia; pheochromocytoma is the adrenal subtype
• 70% of extra-adrenal PGLs are in the head/neck (parasympathetic, rarely secretory)
• Zellballen architecture; chief cells positive for chromogranin/synaptophysin; sustentacular cells positive for S-100
• Highly heritable: SDH gene mutations in majority of hereditary cases; SDHB = highest malignancy risk
• Malignancy defined only by metastasis - not by histologic features
• Preoperative embolization for vascular control; mandatory alpha-blockade before surgery if secretory
• SDHB pathogenic variant outcomes - systematic review (2024), PMID 38605204
• Preoperative embolization in jugular PGL surgery - meta-analysis (2024), PMID 38942141