The Basics of Pheochromocytoma and Paraganglioma

By Erin MacBean

 

In absolute layman’s terms – Paragangliomas are tumors similar to pheochromocytoma, in that they are made from the same tissue type, except that the tumors are found outside of the adrenal glands.

 

What is a Pheochromocytoma (Pheo)?

A pheo is a rare type of neuroendocrine tumor specifically originating from the medulla of the adrenal glands. An adrenal gland is located above each kidney, and they produce hormones that regulate stress responses (fight or flight), organ functions (heart rate and blood pressure), and many other metabolic processes. The medulla, or core, of the adrenal gland is responsible for the production of a group of hormones called catecholamines. The most known type of catecholamine is epinephrine which is commonly known as adrenaline. The other two hormones that make up the catecholamine group are norepinephrine, and dopamine.  In patients with pheo, the tumor releases an excessive amount of these hormones.

-In absolute layman’s terms - A pheochromocytoma is a tumor found in the middle part of the adrenal gland that produces an excessive amount of catecholamines. 

What is Paraganglioma (Para)?

There are two types of Paraganglioma: functioning and non-functioning.

Functioning paras (tumors that produce excessive catecholamines) are often called extra-adrenal pheochromocytoma. A functioning para is a tumor similar to a pheo, but located outside the adrenal gland. Usually functioning paras are derived from the sympathetic nerve cells of the peripheral nervous system and can be found anywhere along the sympathetic nervous system, most often located in the abdominal and thoracic (chest) regions.

Non-functioning paras are tumors usually derived from the parasympathetic tissue of the parasympathetic nervous system and do not produce hormones. These tumors are often called “silent” paraganglioma and are most often located in the head and neck areas.

 

A really good source to show where these tumors can be located is: https://science.nichd.nih.gov/confluence/download/attachments/44663505/Composite_03_HiRes.png

 

Paragangliomas are more rare than pheochromocytomas, but paras have a higher chance of being malignant (cancerous) than pheos.

 

Symptoms of Pheo and Para

Pheochromocytoma has been nicknamed “the great mimic” in that it causes symptoms similar to many other conditions, because of this, diagnosing pheo and para can be difficult.

The most common symptoms of Pheochromocytoma and Paraganglioma are:

Headache

Heart palpitations

Racing heart rate, even while resting

High blood pressure

Excessive sweating

Attacks similar to panic/anxiety attacks (these may occur in response to exercise or for no apparent reason)

Chest/Abdominal pain

Vomiting

Fever

Pallor

Flushing

Muscle weakness

Visual disturbances

**It is important to note that a patient may exhibit only some of the symptoms. Sometimes, a patient may only experience as little as one or two symptoms.

 

The Genetic Factor

Around 20% of pheos and paras are caused by a genetic mutational factor. To date, there are at least nine known genetic mutations/deletions that cause pheos and paras to form. The known genetic links are: SDHA, SDHB, SDHC, SDHD, SDHAF5, RET, NF-1, VHL, and FP/TMEM127. There are also genetic causes where the genetic link has not been found that can cause pheo and para as well, such as the Carney Triad and Carney-Stratakis syndromes.

It is the SDHx mutations and Carney syndromes that link GIST and Pheo/Para tumors together.

 

Treatment

There are different types of treatment for pheo and para patients, both in standard care as well as in clinical trials.

Drug Therapy

Patients with symptomatic pheo and para are treated with drug therapy. This may include alpha-blockers to help keep the blood pressure normal. It also helps dilate small blood vessels because norepinphrine restricts blood vessels. Beta-blockers may be introduced to pheo and para patients after a proper alpha-blockade is established to help keep the heart rate normal. Other drugs such as ACE inhibitors and calcium channel blockers may also be administered to help regulate and block the effects of the excess catecholamines.

Drug therapy is needed for at least one to three weeks minimum before surgery.

Surgery

Surgical resection is the only cure to pheo and para at this time. Once the tumor is surgically removed over 90% of the patients are fully cured and all symptoms disappear. However, in rare cases, pheochromocytoma may appear bilaterally (a pheo on each adrenal gland.) In such cases, where both adrenal glands need to be removed, life-long hormone therapy is needed to replace the hormones that were made by the adrenal glands.

Adrenal-sparing surgery may be an option for some bilateral pheo patients. This is when part of the adrenal gland is spared during the surgery so that hormone-replacement therapy may not be needed.

In cases where surgery is not an option the following treatment plans may an option:

Radiation Therapy

There is one radiation therapy available in the standardized care. It is called 131I-MIBG. The 131I-MIBG is given by infusion and some kinds of tumor cells collect this substance. This infusion carries radiation directly to pheo and para tumor cells and kills the cells with the radiation it gives off. However, not all pheos and paras take up 131I_MIBG, so a test is done before treatments.

For pheos and paras that do not take up 131I-MIBG, Chemotherapy may be an option

                Chemotherapy

Combination chemotherapy such as cyclophosphamide, vincristine, and dacarbazine (CVD) is sometimes given to pheo and para patients. The CVD regimen was originally chosen because its component drugs were effective in neuroblastoma. Today the same combination of drugs is used (but in different doses and in combination with other drugs and biotherapies) to treat gastrointestinal leiomyosarcoma, and stage IV metastatic melanoma as well as metastatic pheochromocytoma.

Other Treatment Options:

Ablation Therapy

Radiofrequency ablation uses radio waves to heat and destroy abnormal cells.

Cryoablation is a procedure that uses liquid nitrogen or liquid carbon dioxide to freeze and destroy abnormal cells.

Embolization Therapy

In a few cases of pheo, embolization therapy was used. It’s a treatment to block the artery leading to the adrenal gland, blocking the flow of blood to the adrenal gland to help kill cancer cells growing there.

Clinical Trials also offer other types of therapy and may be an option for those that have tried or don’t qualify for the standard therapies.

Targeted Therapy

Sunitinib (Sutent) is a tyrosine kinase inhibitor (TKI). This type of therapy targets and blocks signals needed for tumors to grow without harming normal cells around it.  It has seen some positive results in some GIST patients and is under trials for pheo and para patients now.

 

Other Trials include:

Y-90/LU177

 

Monitoring Pheo and Para

Pheos and Paras are usually slow growing tumors, but the pathology of these tumors makes it difficult to know if they are malignant or benign. Often times a doctor will have to weigh many factors before they can lean toward a diagnosis of tumor type. Even then, there is no certainty if a pheo or para is benign, so a yearly biochemical test to measure catecholamine counts for more than five years after the removal of a pheo or para is best.  Top medical facilities recommend life-long follow up as recurrence has been spotted many years after the removal of a primary tumor.

Those with a genetic disposition to pheo and para may accompany biochemical tests with imaging such as CT, MRI, MIBG, Octreotide, or FDG-PET scans once a year, or more depending on the risk factors, for the rest of their lives.

 

There is no standardized staging system for metastatic pheo and para.