A Disease Unlike Any Other

PPGL 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

PPGL tumors 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.

PPGL tumors are distinguished by the production, storage, and secretion of catecholamines and metanephrines, a process specific to tumors of chromaffin origin.

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

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

  • Common signs & symptoms include:
    1. Sustained or paroxysmal hypertension
    2. Episodes of palpitations
    3. Headaches or fever
    4. Excessive sweating
    5. Constipation
    6. Tremors
    7. Anxiety and panic attacks
    8. Weakness or fatigue
    9. Nausea, vomiting, or weight loss
    10. Pallor

In metastatic 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.

Over half of PPGL tumors are discovered incidentally during imaging studies for unrelated disorders. Some PPGL go undiscovered until death, with studies suggesting over 50% of all PPGL found at autopsy were not clinically suspected.

25% of PHEO/PGL are discovered incidentally. Over 50% of PHEO/PGL found at autopsy were unsuspected.
PPGL may be misdiagnosed as a more common condition.

Due to the rarity of PPGL tumors and the vague and paroxysmal nature of the signs and symptoms, patients are at risk for a mistaken diagnosis. These diagnoses may include endocrine, psychiatric, or cardiovascular causes.

Common PPGL misdiagnoses include:

  • Diabetes
  • Primary hypertension
  • Hyperthyroidism
  • Generalized anxiety disorder
  • Carcinoid syndrome
  • Menopause
  • Cardiomyopathy
  • Panic disorder

For patients experiencing symptoms, initial biochemical testing for plasma-free or urinary fractionated catecholamines and their metabolites can help establish diagnosis.

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 PPGL.

MIBG is structurally similar to norepinephrine and, like norepinephrine, MIBG is taken up by NET and sequestered into vesicles by vesicular monoamine transporter (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 MIBG is ideal for both diagnosis and therapy, and has been used in the treatment of metastatic PPGL since 1983.

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

Dual Goals of Disease Management

With no cure for metastatic PPGL, 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 gastrointestinal 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 PPGL deaths.

Treatment Urgency

Prognosis for patients with metastatic PPGL can be highly variable.

While some patients can survive with metastatic disease for many years with minimal disease progression, others have extremely poor prognosis requiring urgent and decisive treatment. For patients with metastatic PPGL, 5-year overall survival can be as low as 12%, increasing the need for rapid intervention to improve outcomes.

Available Treatments

Surgery can be curative for solitary, resectable PPGL tumors, but it is rarely an option for metastatic disease.

Based on the NCCN Clinical Practice Guidelines In Oncology (NCCN Guidelines®), for patients with unresectable or metastatic PPGL, treatment may include one or a combination of FDA-approved and off-label treatments, including36:

  • Chemotherapy
  • Radiation therapy with cytoreductive resection, when possible
  • High-specific-activity iobenguane I-131 radiotherapy, if eligible
  • Low-specific-activity MIBG radiotherapy, if eligible
  • Peptide receptor radiotherapy (PRRT), if eligible
  • Somatostatin analog therapy, if eligible