Key Points
Disease summary:
Paraganglia are clusters of neuroendocrine cells that comprise the sympathetic ganglia, the parasympathetic ganglia, and the adrenal medulla. A paraganglioma (PGL) is a tumor that derives from paraganglia.
The term pheochromocytoma (PHEO) is applied to catecholamine-secreting paragangliomas of the adrenal gland.
Extra-adrenal paragangliomas (ePGLs) may be categorized as either sympathetic (usually found in the abdomen) or parasympathetic (usually found in the head and neck; hnPGL) paragangliomas.
PHEOs and ePGLs most commonly present with hypertension, headache, anxiety, and/or palpitations.
hnPGLs usually present as an enlarging mass or with a mass effect such as a cranial nerve palsy (eg, Horner syndrome).
PGLs have an estimated prevalence of 1 in 5000 and an estimated incidence of 1 in 30,000.
Hereditary basis:
Approximately 30% of PGLs are associated with an identifiable germline mutation; two-thirds of these cases are apparently sporadic.
The likelihood that a germline mutation is present is strongly influenced by the clinical presentation: presence of syndromic features, presence of a family history, tumor location, age of diagnosis, greater than one primary PGL or metastatic disease.
At least 10 PHEO- or PGL-predisposing genes have been identified.
PGLs show an autosomal dominant inheritance pattern with incomplete penetrance.
The tumor risk associated with several genes is influenced by the parent of origin (SDHD, SDHAF2, MAX) where tumor risk is associated with paternal inheritance.
Differential diagnosis:
It is important to distinguish the multiorgan system syndromes that include PHEO or PGLs as a single feature (ie, von Hippel-Lindau [VHL], neurofibromatosis [NF], and multiple endocrine neoplasia [MEN]), from the familial tumor predispositions in which these tumors are the predominant feature (Table 47-1).
| Syndrome | Gene Symbol | Relative Frequency | Associated Findings |
|---|---|---|---|
| von Hippel-Lindau (see Chap. 129) | VHL | 20%-40% | Hemangioblastomas of the brain, spinal cord, and retina; renal cysts and clear cell renal cell carcinoma; and endolymphatic sac tumors. Risk of PHEO and other features are mutation specific. Mean age of PHEO is 29 years (PGL is rare). |
| Neurofibromatosis, type 1 (see Chap. 108) | NF1 | 5%-15% | Cutaneous neurofibromas, plexiform neurofibromas, cafe-au-lait macules, axillary and inguinal freckling, Lisch nodules (iris hamartomas), optic glioma, sphenoid dysplasia, tibial pseudarthrosis, first-degree relative with NF1. Pheochromocytomas occur in approximately 1% of NF1 patients. |
| Multiple Endocrine Neoplasia, Type 2 (MEN2A) (see Chap. 81) | RET | 5%-15% | Medullary thyroid carcinoma (MTC), parathyroid adenoma/hyperplasia. PGLs typically present around age 40 years (decades after medullary thyroid tends to present), is confined to the adrenal gland, has low metastatic potential, and tends to secrete increased amounts of epinephrine. |
| PGL1 | SDHD | 20%-30% | PGLs are predominantly hnPGL (80%) but PHEOs (18%), ePGL (2%), and GIST (rare) also occur. The estimated penetrance of hnPGL is 80% and of PHEO is 30%. Parent of origin effect is observed. |
| PGL2 | SDHAF2 | Rare | Primarily, if not exclusively hnPGLs. Parent of origin effect is observed. |
| PGL3 | SDHC | 3%-8% | PGLs primarily manifest as hnPGL (90%) though PHEO (5%) and ePGL (5%) do occur. Features such as renal cell carcinoma (7%) and gastrointestinal stromal tumors (GIST; 2%) are observed. |
| PGL4 | SDHB | 20%-30% | Variable PGLs are observed: ePGL (55%), PHEO (20%), and hnPGL (25%). SDHB-related PGLs are frequently malignant (20%-50%). Other features include renal cell carcinoma (3.5%) and gastrointestinal stromal tumors (GIST; 2%). |
| PGL5 | SDHA | Rare | PHEO and ePGL, GIST, Leigh syndrome (autosomal recessive) |
| PGLx | TMEM127 | 1%-5% | PHEO, often bilateral with low malignant potential. hnPGL and ePGL have been observed. |
| PGLx | MAX | 1% | PHEO, often bilateral. Phenotype not fully delineated at present. Parent of origin effect is observed. |
| PGLx | KIF1B | Rare | PHEO. Not fully established as causative. |
Diagnostic Criteria and Clinical Characteristics
At least one of the following
Single paraganglioma associated with an identified germline mutation
Multiple paragangliomas in a single individual
Paragangliomas in more than one generation
Identification of a known paraganglioma causing germline mutation
And the absence of
An alternative genetic syndrome such as NF1, VHL, or MEN2.
Pheochromocytoma or ePGL: Clinical features include intermittent hypertension, palpitations, and occasionally flushing. Familial paraganglioma is most often recognized in the setting of a single, apparently sporadic, pheochromocytoma.
Glomus or carotid body tumors or hnPGL:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
