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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 PHEO/PGL. Referral to a multidisciplinary center with expert treatment teams is essential.4

PHEO/PGL Incidence and Origin

Pheochromocytoma and paraganglioma (PHEO/PGL) are a rare subset of neuroendocrine tumors.

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.

Out of 1,000,000 people, 5,180 are diagnosed with cancer, 673 are diagnosed with rare cancer, and fewer than 8 are diagnosed with PHEO/PGL each year.
PHEO/PGL tumors arise from chromaffin tissue.

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.

PHEO/PGL 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.


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 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

As many as 1 in 3 PHEO/PGL cases are metastatic/malignant.

Recurrence and Follow-Up

Some patients with recurrent PHEO/PGL appear to have benign disease at diagnosis and later develop metastases.
16.4% of apparently benign PHEO/PGL cases recur after initial surgery.

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.

Referral to a Multidisciplinary Center is Essential

Due to the rarity and variability in the course, physicians may not build sufficient experience to confidently treat this disease.

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.

A Disease Unlike Any Other

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.

Symptoms: Cause and Variety

PHEO/PGL are distinct from most other neuroendocrine tumors in their ability to produce catecholamines.
PHEO/PGL tumors are distinguished by the production and secretion of catecholamines.

PHEO/PGL are distinguished by the production, storage, and secretion of catecholamines and their metabolites, a process specific to tumors of chromaffin origin.

The symptoms associated with PHEO/PGL are the result of tumor-produced catecholamines dysregulating the autonomic nervous system.

PHEO/PGL can have a wide range of clinical manifestations, with many patients experiencing frequent, acute, and severe symptoms.

  • Common signs & symptoms include:
    • Sustained or paroxysmal hypertension
    • Episodes of palpitations
    • Sweating
    • Constipation
  • Other signs and symptoms include:
    • Pallor
    • Weight loss
    • Fatigue
    • Anxiety and panic
    • Hyperglycemia
    • Fever

In metastatic/malignant cases, additional morbidity can result from tumors invading and damaging organs.

Tumor-produced hormones cause over 100 different signs and symptoms.

Challenges to Diagnosis

Patients often endure symptoms for years before a definitive diagnosis is reached.

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.

25% of PHEO/PGL are discovered incidentally. Over 50% of PHEO/PGL found at autopsy were unsuspected.

Role of MIBG Imaging

The high expression of norepinephrine transporter is an established and specific signature of tumor cells of chromaffin origin.

Ninety-five percent of PHEO and 77% of PGL express the norepinephrine transporter (NET) for the uptake of norepinephrine into cells.

Meta-iodobenzylguanidine (MIBG) is a well-recognized, specific targeting agent for PHEO/PGL.

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.

MIBG targets the signature pathway of PHEO/PGL, the norepinephrine transporter.

Dual Goals of Disease Management

With no cure for metastatic/malignant PHEO/PGL, the goals of disease management are:
The dual goals of treating PHEO/PGL are tumor control and symptom reduction.
  • Controlling tumor growth: Tumor progression is the most frequent cause of death, indicating that controlling tumor growth should be the primary goal of disease management.
  • Reducing symptoms: Excessive catecholamine secretion can lead to cardiovascular disease and gastro-intestinal dysfunction, which should not be neglected. Symptoms related to tumors secreting abnormally high levels of catecholamines, including hypertension and constipation, cause up to 30% of metastatic/malignant PHEO/PGL deaths.

Available Treatments

Surgery can be curative for benign PHEO/PGL, but it is rarely an option in a metastatic/malignant setting.

For patients with metastatic/malignant PHEO/PGL, treatment may include one or a combination of off-label treatments, including4:

  • Chemotherapy
  • External beam radiotherapy
  • MIBG radiotherapy

A Diverse Set of Germline Mutations

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.

Genetics of PHEO/PGL

PHEO/PGL are more commonly associated with an inherited mutation than any other cancer type.
PHEO/PGL is caused by inherited genetic mutations more than any other cancer.

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.

Importance of Genetic Testing

Genetic testing enables early identification and proactive management for at-risk family members.

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.