Neuroendocrine Tumor Day: Spotlight Pheochromocytomas

Photo credit to MLobliner via Flickr

Photo credit to MLobliner via Flickr

Pheochromocytomas are rare, usually benign tumors that develop in the small glands that sit on top of the kidneys, called the adrenal glands.  Everyone has two adrenal glands that produce hormones that travel throughout the body to give instructions to other organs and tissues.  Although the adrenal glands are the most common location of pheochromocytomas (pheos), pheos can also be found in other parts of the body, usually in the abdomen (also called extra-adrenal tumors or sometimes paragangliomas).  Tumors are often classified based on the body system they originate from.  Pheos are considered a neuroendocrine tumor (originating from nervous (neuro) or endocrine (hormone producing) because pheos often produce hormones. NeuroEndocrine Tumors are often abbreviated NET. 

Photo credit to NET Cancer Day 

Photo credit to NET Cancer Day 

Pheos are generally benign (non-cancerous); however, a small percentage of the time they are cancerous.  Most people who develop a pheo are between the ages of 20 and 50, but the tumor can develop at any age.

Because pheos impact the amount of hormones that are produced in the body, symptoms may include: high blood pressure, sweating, rapid heartbeat, tremors, shortness of breath and headache. These symptoms often occur in brief spells of 15 to 20 minutes. Spells can happen several times a day or less often. Certain activities, situations, foods or medications may trigger symptoms. 

 

Symptoms of a pheochromocytoma can include:

  • Physical exertion
  • Anxiety or stress
  • Changes in body position
  • Bowel movements
  • Labor and delivery
  • Certain foods that are contain a high amount of a substance called tyramine which is common in foods that are fermented, aged, pickled, cured, overripe or spoiled.
  • Certain medications

If left untreated, a pheo can result in severe or life-threatening damage to other body systems, especially the cardiovascular system. Surgery to remove the tumor is usually required.

Most individuals who develop a pheo do not have any previous history of these tumors or any family history of these tumors.  However, research has shown that even in these apparently isolated cases, approximately 24% of individuals have a hereditary predisposition to develop these tumors. In this study, younger age of diagnosis, multifocal tumors, and extra-adrenal tumors were significantly associated with the presence of a mutation.  Learning about a possible hereditary predisposition is important for that individual’s medical care as well as that of their family members.

 

Pheos can be associated with the following hereditary syndromes:

1. von Hippel-Lindau disease (VHL)

  • Caused by mutations within the VHL gene
  • Average age of pheo diagnosis is 30 years
  • 88% of pheos are adrenal, hormone producing tumors and 12% are extra-adrenal
  • Other clinical findings may include benign tumors of the brain, spinal cord or eyes called hemangioblastomas, kidney cancer and tumors of the pancreas. 
  • Relatively high rate of new (de novo) VHL mutations, meaning that the mutation occurs for the first time in that individual.  This may explain why features of this syndrome are often not seen in previous generations

2. Multiple Endocrine Neoplasia Type 2 (MEN2)

  • Associated with mutations in the RET gene.
  • Pheos commonly diagnosed between 30-40 years of age and can be the first sign in 9-27% of cases
  • Most pheos are adrenal tumors and produce hormones
  • Other clinical findings may include medullary thyroid cancer and overactive parathyroids.

3. Hereditary Paraganglioma-Pheochromocytoma Syndrome

  • Characterized by benign tumors in structures called paraganglia. Paraganglia are groups of cells that are found near nerve cell bunches called ganglia. A tumor involving the paraganglia is known as a paraganglioma.
  • A Pheochromocytoma is a type of paraganglioma.  A paraganglioma is called a pheo when it is found in the adrenal glands.
  • This syndrome can be caused by mutations in the SDHB, SDHC, SDHD or SDHAF2 genes
  • Individuals with mutations in the SDHC, SDHD and SDHAF2 genes typically develop paragangliomas in the head or neck region.
  • Individuals with mutations in SDHB usually develop extra-adrenal paragangliomas in the abdomen and have a higher-risk for these tumors to be cancerous. 
  • Tumors in this syndrome are typically diagnosed in a person's 30s.
  • Mutations in SDHD and SDHAF2 genes can only be inherited from the father.
  • Mutations in the SDHB and SDHC genes can be inherited from the mother or the father.

4. Neurofibromatosis 1

  • Caused by mutations in the NF1 gene
  • Characterized by multiple coffee-with-milk colored, flat skin findings, freckling in the armpits and genital area, multiple, usually benign tumors of the nerves that are located on the skin’s surface (neurofibromas) and pigmented nodules found on the iris of the eye called Lisch nodules.
  • The presence of pheos in NF1 is much lower than other hereditary pheo syndromes; however, they are more likely to spread than pheos found in other syndromes.
  •  If present, pheos usually appear in the early 40s and are hormone-producing.

5.  Other genes associated with Pheochromcytomas

  • Mutations in the TMEM127, MAX and HIF2A have been associated with pheos, largely due to rapid advances in genetic testing that allow a larger number of genes to be analyzed in the clinical and research settings.
  • TMEM127 mutations are a rare cause of pheos and patients usually present in their early 40s with benign pheos that secrete hormones.
  • MAX mutations are thought to contribute to ~1% of presumed sporadic pheos, although bilateral adrenal pheos and tumor spread have been reported.  These mutations are thought to be inherited from the father, only.
  • HIF2A mutations have been seen in individuals with pheos and a higher concentration of hemoglobin in the blood (polycythemia).

Individuals should be referred for genetic counseling if they have:

  1. Pheo diagnosis before age 50
  2. Multifocal disease
  3. Extra-adrenal tumors
  4. Families with multiple cases of isolated pheos
  5. Personal and/or family history of any of the above additional clinical findings
  6. Known family history of any of the above syndromes

 

References:

JNCI (2003) 95 (16): 1196-1204   

NEJM (2002) 346 (19): 1459-1466

J Hum Hypertens (2013) 27:141–147

Horm Metab Res (2012) 44:328–333

Clin Cancer Res (2012) 18:2828–2837

Clin Endocrinol (Oxf) (2013) 79(6):817-23

Nat Genet (2010) 42:229–233

Endocrinology (2011) 152:2133–2140