Pheochromocytoma and Paraganglioma Syndrome (PPGL) refers to a group of rare neuroendocrine tumors arising from specialized nervous system cells. These tumors are classified by location: Pheochromocytomas (PCCs) develop within the adrenal gland medulla, and Paragangliomas (PGLs) occur outside the adrenal gland. A defining feature is their ability to produce and secrete excessive amounts of catecholamines, such as epinephrine and norepinephrine, which regulate the body’s stress response. This hormonal overproduction leads to intense and unpredictable physiological effects throughout the body.
Anatomy and Symptoms of the Tumors
The distinction between the two tumor types rests on their anatomical origin within the neuroendocrine system. Pheochromocytomas (PCCs) arise from chromaffin cells in the adrenal medulla, the inner portion of the glands situated atop the kidneys. Paragangliomas (PGLs) develop from similar paraganglia tissue located outside the adrenal glands, often along sympathetic or parasympathetic nerve pathways. Approximately 85% of all PPGLs are PCCs, while 15% are extra-adrenal PGLs.
The symptoms patients experience result directly from the release of catecholamines into the bloodstream. This release can be paroxysmal, occurring in sudden, intense spells, or sustained over time. The classic triad of symptoms includes severe, pounding headaches, profuse sweating, and palpitations or a rapid heart rate (tachycardia). These occurrences are often accompanied by severe, sometimes life-threatening, hypertension which can be either episodic or persistent.
PCCs, which often produce epinephrine, are frequently associated with episodic spells and dramatic blood pressure swings. Extra-adrenal PGLs commonly secrete norepinephrine, often resulting in sustained high blood pressure. Some PGLs, particularly those in the head and neck, are non-secretory and cause symptoms only through physical presence, such as pain or nerve compression. Because the clinical presentation is varied, PPGL is often called “the great masquerader,” mimicking anxiety or panic disorder.
Understanding the Genetic Causes
Approximately 40% of PPGL cases are linked to underlying hereditary genetic mutations, making it one of the most highly heritable human tumors. This high genetic predisposition necessitates that all diagnosed patients consider genetic testing, regardless of age or family history. The most commonly implicated genes belong to the succinate dehydrogenase (SDH) complex, including SDHA, SDHB, SDHC, and SDHD.
These SDH genes act as tumor suppressors; they provide instructions for components of a mitochondrial enzyme functioning in the Krebs cycle and electron transport chain. A mutation disrupts the enzyme’s function, leading to a buildup of a substance called succinate within the cell. This buildup triggers a signaling pathway that mimics low oxygen (pseudohypoxia), promoting uncontrolled cell growth and tumor formation.
Specific genetic mutations correlate strongly with distinct tumor locations and behaviors, a concept known as genotype-phenotype correlation. For instance, SDHD mutations are often linked to multiple PGLs in the head and neck region. The SDHB mutation is particularly noteworthy because it carries a substantially higher risk of metastatic disease, with metastases reported in up to 40% of cases. Other genes, such as RET, VHL, and NF1, are also associated with PPGL as part of broader hereditary cancer syndromes.
How Doctors Confirm the Diagnosis
The diagnostic process relies on a two-pronged approach: confirming hormonal overproduction and precisely locating the tumor. Biochemical testing is the initial and most sensitive step for confirming a functional tumor. This involves measuring the levels of fractionated metanephrines and normetanephrines, which are the stable, inactive breakdown products of epinephrine and norepinephrine.
Metanephrines are consistently produced by tumor cells via an internal process, regardless of episodic catecholamine release. Measuring these metabolites in a 24-hour urine collection or a single plasma sample provides a reliable indicator of PPGL. Once biochemical evidence of catecholamine excess is established, the focus shifts to anatomical and functional imaging to locate the tumor.
Anatomical imaging, typically using computed tomography (CT) or magnetic resonance imaging (MRI), visualizes the tumor’s size and location in the adrenal glands or along the sympathetic chain. CT is often the first choice, but MRI is preferred for children, pregnant patients, and for evaluating head and neck PGLs. Functional imaging confirms the tumor’s nature and searches for metastatic or multifocal disease, especially in hereditary cases. Specialized functional scans use radiotracers taken up by tumor cells for whole-body visualization.
Treatment and Long-Term Management
The definitive treatment for non-metastatic PPGL is surgical removal of the tumor, which is curative in most cases. Surgical resection, often performed using minimally invasive techniques, aims to remove the source of excessive hormone production. Surgery is inherently risky because manipulation of the tumor can cause a sudden, massive release of hormones, leading to a severe hypertensive crisis.
To mitigate this risk, mandatory pre-operative medical management is required before surgery. This preparation involves administering alpha-adrenergic blocking agents, such as phenoxybenzamine, for one to two weeks to stabilize blood pressure and heart rate. This pharmacologic blockade prevents catecholamines from causing dangerously high blood pressure spikes during tumor manipulation. For patients with metastatic or unresectable disease, treatment options include radiometabolic therapy or systemic treatments like chemotherapy or targeted molecular therapies.
Long-term surveillance is required due to the possibility of recurrence or the development of new tumors, especially in patients with a hereditary mutation. Patients should undergo regular, lifelong biochemical screening, typically involving annual measurement of metanephrines, to monitor for tumor activity. The follow-up protocol is often tailored to the patient’s genetic mutation, as certain mutations, like SDHB, require more intensive surveillance.