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Diseases of the Paraganglia System
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Paraganglioma
Extra-adrenal paragangliomas arise from paraganglia distributed along the paravertebral sympathetic and parasympathetic chains and include tumors arising in the carotid body, jugulotympanic body, orbit, nasopharynx, larynx, vagal body, paraspinal chain (aorticosympathetic and visceral-autonomic), urinary bladder, and the organ of Zuckerkandl. Although the most common site of paraganglioma is within the adrenal gland (referred to as pheochromocytoma), this discussion will be limited to those arising in the head and neck, which is the most common site for extra-adrenal paragangliomas.
Paragangliomas are tumors of neural crest origin and may arise as sporadic lesions or in association with hereditary tumor syndromes ( Table 29.1 ). It is now known up to half of all paragangliomas have succinate dehydrogenase (SDH) mutations; SDH mutations are present in at least 30% of head and neck paragangliomas. The SDH enzyme complex localizes to the inner mitochondrial membrane and is a member of the tricarboxylic acid cycle and electron transport chain (in which it is known as complex II) and catalyzes the oxidation of succinate to fumurate. SDH is composed of four normally and ubiquitously expressed subunit proteins: SDHA, SDHB, SDHC, and SDHD. Inactivating mutations in any of the four nuclear-encoded genes result in dysfunction of the entire SDH complex (“SDH deficient”). SDH deficiency can be detected by immunohistochemistry (see section on “ Ancillary Studies ”). Germline SDHD mutations were first identified in 2000 in a subset of patients with hereditary paraganglioma-pheochromocytoma syndrome (HPGL/PCC); since that time, mutations have also been identified in SDHA , SDHB , SDHC , and the related SDHAF 2. Most SDH-deficient head and neck paragangliomas are secondary to germline SDH mutations, and only rare somatic mutations have been reported. Mutations in SDHD are the most frequent in head and neck paragangliomas and are also associated with disease multifocality. HPGL/PCC is dominantly inherited, although transmittance of SDHD mutations appears to be paternal (unlike for SDHA , SDHB , and SDHC ), which is suggestive of imprinting. Interestingly, the distribution of specific SDH mutations differs for paragangliomas in other sites; for example, SDH-deficient thoracoabdominal paragangliomas are most commonly secondary to SDHB mutations. Carney-Stratakis syndrome is an autosomal dominant inherited syndrome due to germline mutations in one of the SDH genes, and patients develop paragangliomas and gastrointestinal stromal tumor (GIST). There are also known associations with VHL, NF1 , and RET genes for paragangliomas. Paragangliomas, with GISTs and pulmonary chondromas, comprise Carney triad, which is not known to be inherited; affected patients are mostly women who may also develop adrenal cortical adenoma, esophageal leiomyoma, and pheochromocytoma. Due to the relatively high frequency of genetic susceptibilities associated with paragangliomas and pheochromocytomas, genetic counseling is recommended for affected patients even in the absence of family history.
Paraganglioma—Disease Fact Sheet
Definition
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Neuroectodermal tumors arising from paraganglia along the parasympathetic or sympathetic nerves
Incidence and Location
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Rare (incidence estimate of 0.2-1/100,000 population)
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In the head and neck, the carotid body is the most common subsite (60%), followed by jugulotympanic and vagal
Morbidity and Mortality
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Infiltrative growth and local recurrence can lead to morbidity or death
Sex and Age Distribution
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Females > > males (especially at high altitude for carotid body tumors)
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5th-6th decades
Clinical Features
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Slowly growing, painless mass, symptoms are mass related
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Occasionally may be a pulsatile lesion
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Middle ear lesions may produce tinnitus, hearing loss, and nerve dysfunction
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Tumors in the head and neck are rarely functional
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Approximately 10% are bilateral, multiple, pediatric, or malignant, with up to 50% familial/inherited
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At least 30% of head and neck paragangliomas are succinate dehydrogenase deficient
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Germline SDHD mutations are most common in head and neck paragangliomas
Radiographic Features
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Computed tomography shows enhancing mass in characteristic location
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Hyperintense T2-weighted magnetic resonance imaging
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Angiography shows splaying of the internal and external carotid arteries with a tumor blush
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123 I-MIBG localizes tumor(s)
Prognosis and Therapy
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Good prognosis if completely resected, although may be indolent and recur/metastasize years later
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Surgery with preoperative adrenergic blockage and/or embolization
TABLE 29.1
Genetic syndromes associated with paraganglioma and pheochromocytoma
| Syndrome | Gene Locus | Gene | Paraganglia Tumor | Other Abnormalities |
|---|---|---|---|---|
| von Hippel-Lindau | 3p26 | VHL | Paraganglioma/pheochromocytoma in 10%-20% | Renal cysts and renal cell carcinoma Visceral organ cysts Hemangioblastomas |
| Hereditary paragangliomatosis | ||||
| PGL1 | 11q23 | SDHD | Multiple paragangliomas (100%) | |
| PGL2 | 11q13 | SDHAF2 | ||
| PGL3 | 1q21 | SDHC | ||
| PGL4 | 1p36.1-p35 | SDHB | ||
| PGL5 | 5p15 | SDHA | ||
| Carney-Stratakis Syndrome | Germline mutations in one of the SDH genes | Paragangliomas (90%-100%) | Gastrointestinal stromal tumors | |
| Neurofibromatosis type I (von Recklinghausen disease) | 17q11.2 | Neurofibromin | Paraganglioma/pheochromocytoma in 1%-5% | Neurofibromas Schwannomas Central nervous system gliomas |
| MEN2A | 10q11.2 | RET | Paraganglioma/pheochromocytoma in 50%-70% | Parathyroid hyperplasia Medullary thyroid carcinoma |
| MEN2B | 10q11.2 | RET | Paraganglioma/pheochromocytoma in 50%-70% | Medullary thyroid carcinoma Mucosal neuromas Skeletal abnormalities |
Clinical Features
Because normal paraganglia are located throughout the body, paragangliomas have been described in nearly every anatomic location. The head and neck is the most common location for extra-adrenal paragangliomas, accounting for up to 70% of tumors. The most common subsite is the carotid body (60% of head and neck paragangliomas), followed by the middle ear (glomus tympanicum or glomus jugulare) and the vagus nerve (glomus vagale). The carotid body tumor is considered to be derived from the oxygen-sensing chemoreceptive organ at the bifurcation of the carotid artery and can become hyperplastic in people who live at high altitudes (presumably secondary to chronic hypoxia). In the head and neck, normal paraganglia are associated with the parasympathetic nervous system and are adjacent to cranial nerves or the arterial vasculature. It must be emphasized that cervical or thoracic sympathetic paragangliomas are distinct from parasympathetic paragangliomas arising in nearby locations. Cervical sympathetic paragangliomas are separate from the carotid body and other structures, and are vanishingly rare.
Most patients with head and neck paragangliomas are in the 5th to 6th decades; females are affected more often than males (5 : 1), although male patients more often present in the setting of inherited or familial tumors. Patients present with a slowly growing, painless mass and may have mass-related symptoms depending on the location of the tumor, such as tinnitus, hearing loss, and cranial nerve dysfunction in the middle ear. In superficial locations, paragangliomas are often described clinically as a pulsatile mass. Otic examination of middle ear tumors may demonstrate a pulsatile, reddish-purple mass behind the tympanic membrane. Approximately 10% of tumors are bilateral, multiple, pediatric, or malignant, with up to 50% familial/inherited. Tumors arising in patients with a genetic syndrome are more likely to be multiple and bilateral ( Table 29.1 ).
Almost all head and neck paragangliomas are nonfunctioning; in this anatomic region only up to 4% are biochemically active. In contrast, extra-adrenal paragangliomas in the abdomen are most often associated with the sympathetic nervous system and are often functional, secreting catecholamines that produce clinical symptoms, such as headache, perspiration, palpitations, pallor, and hypertension.
Radiographic Features
The most common imaging modalities used to assess paragangliomas are computed tomography (CT), magnetic resonance imaging (MRI), angiography, and 131 I-meta-iodobenzylguanidine (MIBG) scans. These studies usually accurately define location, size, and extent of the tumor. Contrast-enhanced CT scans will demonstrate an enhancing mass and are better for detailing adjacent fine osseous changes ( Fig. 29.1 ). The Glasscock-Jackson classification is used to document the extent of involvement of middle ear tumors based on CT studies: type I, limited to the cochlear promontory; type II tumors fill the middle ear space; whereas type III tumors extend farther into the mastoid air cells; type IV, extension is beyond the middle ear space into the mastoid bone and/or external auditory canal or anteriorly toward the carotid. Paragangliomas on contrast-enhanced MRI show a characteristic hyperintense T2-weighted image. Due to their vascularity, paragangliomas have a characteristic “salt and pepper” pattern on MRI caused by high-velocity flow voids (black dots) and foci of hemorrhage or slow flow (white dots).
Angiography is often used for patients who are undergoing operative resection and will demonstrate the characteristic pronounced tumor vascularity. In carotid body paragangliomas, the tumor will splay the internal and external carotid arteries, which is a diagnostic feature ( Fig. 29.1 ). 123 I-MIBG scans have been reported to aid in localization of paragangliomas, especially in occult or familial settings. 111 In octreotide (Indium-111, a somatostatin analog) may also be sensitive for tumors greater than 1.5 cm. In some cases, ultrasound may be helpful in localizing superficial paragangliomas. Positron emission tomography (PET) using 18 fluorodeoxyglucose ( 18 FDG-PET) will show avid uptake by the tumor cells.
Pathologic Features
Paraganglioma—Pathologic Features
Gross Findings
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Gray to hemorrhagic mass with fibrous pseudocapsule
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Average size of 3.8 cm but may grow large (up to 10 cm)
Microscopic Findings
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Organoid nests (“zellballen”) of various sizes
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Polygonal cells with granular, basophilic to eosinophilic cytoplasm
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May have hyperchromatic nuclei and bizarre pleomorphism
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Network of fibrovascular septae
Immunohistochemical Findings
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Chief cells positive with chromogranin, synaptophysin, NSE
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S100 protein and/or GFAP–positive sustentacular cells
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Loss of expression of SDHB immunohistochemistry (indicating succinate dehydrogenase deficiency) in ~30% of tumors
Pathologic Differential Diagnosis
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Depends on anatomic location: includes middle ear adenoma, ceruminous adenoma, meningioma, schwannoma, medullary thyroid carcinoma, hyalinizing trabecular adenoma of thyroid, parathyroid adenoma, typical/atypical carcinoid tumor (of larynx), metastatic renal cell carcinoma
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