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BACKGROUND

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Pheochromocytomas (PCCs) and paragangliomas (PGLs) arise from chromafin cells originating in the neural crest, and can develop in any location containing sympathetic or parasympathetic tissue. Although the terminology is not completely standardized, PCC typically refers to tumors of adrenal origin while PGL describes lesions found outside the adrenal gland. While most PCC and PGL are benign, malignant disease does occur and is distinguished by behavior such as metastasis and invasion into other structures. Identifying benign disease with potential to become malignant is exceedingly difficult as there is currently no reliable gene signature or histologic feature that clearly identifies malignancy. Even more importantly, metastasis can occur 15 to 20 years after resection of apparently benign disease, and this makes it difficult to accurately study PCC and predict malignancy.

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EPIDEMIOLOGY

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The estimated incidence of PCC and PGL ranges from 0.4 to 9.5 per 1 million.1 Although PCC is traditionally considered a tumor of 10s with 10% being malignant, the actual incidence may be greater than 25% depending on the characteristics of the population being studied.2 Specific mutations (see below) confer heightened risk for malignancy while others are very rarely associated with cancer. The peak age for diagnosis is in the third decade of life with men and women at equal risk. Recent developments in gene sequencing technology have demonstrated that 20% to 30% of even sporadic appearing PCC and PGL carry a hereditary component, and this has prompted some to recommend referral to genetic counselors for any individual diagnosed with PCC or PGL.3-5

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RISK FACTORS AND MOLECULAR BIOLOGY

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Despite being a rare disease, a remarkable number of mutations that increase risk of developing PCC and PGL have now been identified. These genes are associated with distinct clinical syndromes and differing risk of malignancy (Table 43-1).

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Table Graphic Jump Location
TABLE 43-1:

Mutations Associated with PCC and PGLa

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Succinate Dehydrogenase

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Succinate dehydrogenase (SDH) plays an important role in the electron transport chain and the Krebs cycle. When adequate oxygen is available, SDH catalyzes conversion of succinate to fumarate and generates ATP for cellular metabolism.6 Under conditions of oxygen deprivation, however, cell functions ...

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