PPGL syndrome is a term for conditions that lead to rare neuroendocrine tumors called pheochromocytomas (PCC) or paragangliomas (PGL). These tumors can produce excessive amounts of powerful hormones known as catecholamines. The tumors can be linked to inherited genetic changes or may occur without a known family history.
Understanding Pheochromocytoma and Paraganglioma
The distinction between pheochromocytomas and paragangliomas is their location. Pheochromocytomas are tumors that arise from chromaffin cells within the adrenal medulla, the inner part of the adrenal gland situated on top of each kidney.
Paragangliomas, also known as extra-adrenal pheochromocytomas, develop from similar cells outside of the adrenal glands. These tumors can be found anywhere from the base of the skull to the pelvic floor, often along nerve pathways in the head, neck, chest, and abdomen.
Both tumor types can release catecholamines, primarily adrenaline (epinephrine) and noradrenaline (norepinephrine). These hormones mediate the body’s “fight-or-flight” response. In PPGL, the unregulated release of these hormones causes the body to exist in a persistent state of high alert, unlike the short bursts seen in healthy individuals.
Symptoms and Clinical Presentation
The overproduction of catecholamines leads to symptoms that often manifest in sudden, unpredictable episodes or “spells.” The frequency of these attacks can range from multiple times a day to once every few months. The classic triad of symptoms includes episodic headaches, profuse sweating, and a racing heart (palpitations).
High blood pressure (hypertension) is the most common sign. This hypertension can be sustained and persistently high, or it can occur in sudden surges. Some individuals might instead experience orthostatic hypotension, which is a drop in blood pressure upon standing.
Other reported symptoms can include:
- Visible paleness of the skin (pallor)
- Tremors
- Feelings of severe anxiety or panic attacks
- Nausea and weight loss
Some individuals, especially those with non-secreting paragangliomas, may not experience obvious symptoms. The tumor is often discovered incidentally during imaging for another medical reason.
Genetic Links and Sporadic Occurrences
PPGL can arise from inherited genetic factors or random, non-hereditary events. Around 40% of cases are linked to an inherited gene mutation passed down through families. In these hereditary syndromes, mutations affect genes responsible for suppressing tumor growth.
Several genes predispose individuals to PPGL, including:
- The succinate dehydrogenase (SDH) gene family (SDHA, SDHB, SDHC, SDHD)
- Von Hippel-Lindau (VHL)
- RET
- Neurofibromatosis type 1 (NF1)
Mutations in the SDHB gene, for example, are associated with a higher risk of tumors becoming malignant and spreading.
The remaining cases are “sporadic,” arising without a known inherited predisposition, though non-inherited mutations can be found in the same genes. Due to the high percentage of cases with a genetic basis, genetic counseling and testing are recommended for all patients. This helps identify potential risks for family members and guides long-term management.
The Diagnostic Pathway
Diagnosing PPGL begins with biochemical testing to detect hormonal excess. The screening method involves measuring levels of catecholamines and their metabolites, metanephrines, in a blood or 24-hour urine sample. Consistently elevated levels of metanephrines are a strong biochemical confirmation of the disease.
After biochemical confirmation, the next step is locating the tumor(s) using medical imaging. A computed tomography (CT) scan or magnetic resonance imaging (MRI) of the abdomen, pelvis, and chest is used to search for tumors in and around the adrenal glands.
If a tumor is difficult to locate or if metastatic disease is suspected, specialized nuclear imaging scans are used. A metaiodobenzylguanidine (MIBG) scan uses a radioactive tracer absorbed by neuroendocrine cells to help identify tumors. Another technique is a DOTATATE PET/CT scan, which is highly sensitive for detecting these tumors.
Therapeutic Approaches and Long-Term Monitoring
Managing PPGL involves medical preparation before surgery. Patients are prescribed alpha-blockers for at least 10-14 days to control high blood pressure and normalize blood volume. After blood pressure is stabilized, beta-blockers may be added to manage a rapid or irregular heart rate.
The definitive treatment for a localized PPGL is the complete surgical removal of the tumor. When feasible, surgeons use minimally invasive laparoscopic techniques, which involve small incisions and allow for a quicker recovery. The goal is to remove the entire tumor while minimizing the risk of a hypertensive crisis during the operation.
After surgery, lifelong annual monitoring is necessary due to the risk of recurrence or new tumor development. This follow-up includes regular biochemical testing, such as annual blood or urine tests, to check for elevated metanephrine levels. For patients with metastatic or inoperable tumors, treatments like radionuclide therapy or targeted systemic therapies may be considered.