Not Just Rare, Ultra-Rare
With an annual incidence in the range of 2 to 8 per million, most physicians are unlikely to build experience treating PPGL. Referral to a multidisciplinary center with expert treatment teams is essential.
PPGL Incidence and Origin
Pheochromocytoma and paraganglioma (PPGL) are a rare subset of neuroendocrine tumors.
Neuroendocrine tumors themselves are rare, with an annual incidence in the US of just 53 per million. PPGL is up to 25 times rarer, with an annual incidence in the range of 2 to 8 per million. In total, as many as 130,000 people are living with PPGL in the US.
PPGL tumors arise from chromaffin tissue.
The World Health Organization (WHO) classifies pheochromocytoma (pheo), head and neck paraganglioma (PGL), sympathetic PGL, composite pheo, composite PGL, and neuroblastic tumors of the adrenal gland as a distinct category of disease. The majority of these tumors, 80% to 85%, are PHEO, which arise from chromaffin cells of the adrenal gland. The other 15% to 20% of tumors are PGL, arising in sympathetic chromaffin tissue or non-chromaffin parasympathetic tissue.
PPGL show no sexual predominance and can occur at any age.
There is an equal incidence in men and women, and tumors have been found in children as young as 6 and adults older than 70. The average age at diagnosis is 43, with most cases occurring in the fourth to fifth decades of life.
Advanced Disease
The presence of metastases remains the only way to define malignant disease.
None of the morphological or molecular markers that have been investigated appear to reliably indicate malignant behavior. As many as 1 out of every 3 PPGL cases is metastatic and the risk for metastases is highest in pheo and sympathetic PGL. Unlike sympathetic PGL, parasympathetic PGL (also called head and neck PGL) are rarely metastatic.
The most recent WHO classification of endocrine tumors has moved away from using the terms “benign” or “malignant” to describe PPGL, since even apparently benign tumors may potentially be malignant. However, these terms are still prevalent in literature and guidelines.
Recurrence and Follow-Up
Some patients with recurrent PPGL appear to have benign disease at diagnosis and later develop metastases.
In one study, the incidence of recurrence was 16.4% overall, with a higher risk in patients with familial disease. The 5-year probability of recurrent disease after tumor removal was estimated at 6.5% overall and at 4.7% in patients with sporadic tumors versus 15% in those with inherited tumors.
Long-term periodic follow-up is recommended for all cases of PPGL. Patients who have had prior surgery to remove a solitary PPGL should be considered at risk of recurrent disease for life, and require periodic follow-up to detect early signs of biochemical imbalance. If patients have tested positive for a genetic mutation in one of many susceptibility genes, their long-term management may be more intensive because their risk of metastatic disease may be higher.
Referral to a Multidisciplinary Center is Essential
Due to the rarity and variability of PPGL, physicians may not build sufficient experience to confidently treat this disease.
The Endocrine Society Guidelines recommend referral to a multidisciplinary center for unresectable PPGL where therapy options can be discussed among a team of experts including surgeons, interventional radiologists, endocrinologists, oncologists, genetic counselors, nuclear medicine physicians, nuclear radiologists and radiation oncologists.
