Table 7. Characteristics of Paraganglioma (PGL) and Pheochromocytoma (PCC) Associated with Susceptibility Genesa continued...
These findings suggest that younger patients with extra-adrenal nonsyndromic pheochromocytoma and paraganglioma are at high risk for harboring SDHB mutations and that this phenotype is associated with an earlier age of onset and a high rate of metastatic disease. Early identification of young patients with SDHB mutations using radiographic, serologic, and immunohistochemical markers could potentially decrease mortality and identify other family members who carry a germline SDHB mutation. In addition, approximately 12% of pediatric GIST patients have germline SDHB, SDHC, or SDHD mutations in the context of Carney-Stratakis syndrome.
The diagnosis of paraganglioma and pheochromocytoma relies on the biochemical documentation of excess catecholamine secretion coupled with imaging studies for localization and staging.
Measurement of plasma-free fractionated metanephrines (metanephrine and normetanephrine) is usually the diagnostic tool of choice when the diagnosis of a secreting paraganglioma or pheochromocytoma is suspected. A 24-hour urine collection for catecholamines (epinephrine, norepinephrine, and dopamine) and fractionated metanephrines can also be performed for confirmation.
Catecholamine metabolic and secretory profiles are impacted by hereditary background; both hereditary and sporadic paraganglioma and pheochromocytoma differ markedly in tumor contents of catecholamines and corresponding plasma and urinary hormonal profiles. About 50% of secreting tumors produce and contain a mixture of norepinephrine and epinephrine, while most of the rest produce norepinephrine almost exclusively, with occasional rare tumors producing mainly dopamine. Patients with epinephrine-producing tumors are diagnosed later (median age, 50 years) than those with tumors lacking appreciable epinephrine production (median age, 40 years). Patients with MEN2 and NF1 syndromes, all with epinephrine-producing tumors, are typically diagnosed at a later age (median age, 40 years) than patients with tumors that lack appreciable epinephrine production secondary to mutations of VHL and SDH (median age, 30 years). These variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of paraganglioma and pheochromocytoma for different progenitor cells with variable susceptibility to disease-causing mutations.[54,55]
Imaging modalities available for the localization of paraganglioma and pheochromocytoma include CT, magnetic resonance imaging, iodine I-123 or iodine I-131–labeled metaiodobenzylguanidine (123/131 I-mIBG) scintigraphy, and fluorine F-18 6-fluorodopamine (6-[18 F]FDA) positron emission tomography (PET). For tumor localization, 6-[18 F]FDA PET and 123/131 I-mIBG scintigraphy perform equally well in patients with nonmetastatic paraganglioma and pheochromocytoma, but metastases are better detected by 6-[18 F]FDA PET than by 123/131 I-mIBG. Other functional imaging alternatives include indium In-111 octreotide scintigraphy and fluorodeoxyglucose F-18 PET, both of which can be coupled with CT imaging for improved anatomic detail.
Treatment of paraganglioma and pheochromocytoma is surgical. For secreting tumors, alpha and beta adrenergic blockade must be optimized prior to surgery. For patients with metastatic disease, responses have been documented to some chemotherapeutic regimens such as gemcitabine and docetaxel or vincristine, cyclophosphamide, and dacarbazine.[57,58] Chemotherapy may help alleviate symptoms and facilitate surgery, although its impact in overall survival is less clear. Responses have also been obtained to high-dose 131 I-mIBG.