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With an annual incidence in the range of 2 to 8 per million, most physicians are unlikely to build experience treating PHEO/PGL. Referral to a multidisciplinary center with expert treatment teams is essential.4
Neuroendocrine tumors themselves are rare, with an annual incidence in the US of just 53 per million. PHEO/PGL is up to 25 times rarer, with an annual incidence in the range of 2 to 8 per million.
The World Health Organization (WHO) classifies PHEO, head and neck 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.
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.
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 PHEO/PGL cases is metastatic/malignant and the risk for metastases is highest in PHEO and sympathetic PGL. Unlike sympathetic PGL, parasympathetic PGL are rarely metastatic.
The most recent WHO classification of endocrine tumors has moved away from using the terms “benign” or “malignant” to describe PHEO/PGL, since even apparently benign tumors may potentially be malignant. However, these terms are still prevalent in literature and guidelines.4
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 PHEO/PGL.
The Endocrine Society Guidelines recommend referral to a multidisciplinary center for unresectable PHEO/PGL where therapy options can be discussed among a team of experts including surgeons, interventional radiologists, endocrinologists, oncologists, nuclear medicine physicians, nuclear radiologists and radiation oncologists.
PHEO/PGL is distinct, with unique implications for disease management. It is critical to understand the dual goals of treatment for this disease: tumor control and symptom reduction.
PHEO/PGL are distinguished by the production, storage, and secretion of catecholamines and their metabolites, a process specific to tumors of chromaffin origin.
PHEO/PGL can have a wide range of clinical manifestations, with many patients experiencing frequent, acute, and severe symptoms.
In metastatic/malignant cases, additional morbidity can result from tumors invading and damaging organs.
Because symptoms are vague and frequent, there is an average delay of 3 years between the onset of symptoms and final diagnosis. Up to 25% of PHEO/PGL are discovered incidentally during imaging studies for unrelated disorders. Some PHEO/PGL go undiscovered until death, with studies suggesting over 50% of all PHEO/PGL found at autopsy were not clinically suspected.
For patients with symptomology, initial biochemical testing for plasma-free or urinary fractionated catecholamines and their metabolites can help establish diagnosis.
Ninety-five percent of PHEO and 77% of PGL express the norepinephrine transporter (NET) for the uptake of norepinephrine into cells.
MIBG is structurally similar to norepinephrine and, like norepinephrine, MIBG is taken up by NET and sequestered into vesicles by VMAT. MIBG can be labeled with radioactive I-123 or I-131 for diagnostic purposes, which may help detect metastases that cannot be detected by CT or MRI. Additionally, MIBG scintigraphy can help determine whether a patient is a candidate for targeted radiotherapy with I-131 labeled MIBG. I-131 is ideal for both diagnosis and therapy, and has been used in the treatment of metastatic/malignant PHEO/PGL since 1983.
For patients with metastatic/malignant PHEO/PGL, treatment may include one or a combination of off-label treatments, including4:
For carriers of some mutations, the overall lifetime risk of developing PHEO/PGL can be greater than 80%. Genetic testing for patients and their family members is critical.
Historically, the frequency of heritable PHEO/PGL was believed to be 10%, but with increased study and the identification of specific cancer predisposition genes, that figure is now estimated at more than 30%, and up to 50% for metastatic/malignant cases. Even in non-familial cases of PHEO/PGL, approximately 12% of patients carry a new germline mutation.
Despite the growing links between PHEO/PGL and germline mutations, genetic testing to identify at-risk individuals is not yet common practice in the US. For carriers of a mutation, the overall lifetime risk of developing PHEO/PGL can be more than 80%, depending on the mutated gene.