This week, here at the Carling Adrenal Center, we are highlighting the pheochromocytoma and paraganglioma awareness week. We see multiple pheochromocytoma and paraganglioma patients every week. Pheochromocytoma and paraganglioma are some of the most misunderstood diseases. Each week, Dr. Carling consults on several patients who, when a detailed history is undertaken, clearly have dealt with this tumor for years, if not decades.

Pheochromocytomas were, in the past, thought to be very rare. However, these tumors are not that rare for us. We see pheochromocytomas every week, and extra-adrenal paragangliomas (which are rarer) regularly. Many patients, doctors and health care providers are confused by pheochromocytoma and paraganglioma. So here, we will address some of the background of pheochromocytoma and paraganglioma and clarify some important aspects of the disease. Sometimes, pheochromocytoma and paraganglioma are thought to be the same. They are similar but there are distinct differences between pheochromocytoma and paraganglioma.

Top 6 Differences Between Pheochromocytoma and Paraganglioma:

1. Pheochromocytoma and paraganglioma tumors have different locations
2. The underlying genetics of pheochromocytoma and paraganglioma are different
3. Pheochromocytomas tend to secrete adrenaline (A), whereas paragangliomas overproduce noradrenaline (NA)
4. Pheochromocytomas more frequently have classic episodic symptoms (“spells”) of adrenaline excess than paragangliomas
5. A paraganglioma more frequently spreads (metastasizes) than a pheochromocytoma
6. The Mini Back Scope Adrenalectomy (MBSA) is the best operation for almost all pheochromocytomas, whereas the treatment for paraganglioma is more varied

#1 Difference Between Pheochromocytomas and Paragangliomas:

Pheochromocytoma and paraganglioma tumors have different locations

Pheochromocytomas are tumors of the adrenal gland that produce excess adrenaline-type hormones (also referred to as catecholamines: epinephrine, norepinephrine, and dopamine). Pheochromocytomas arise from the central portion of the adrenal gland, which is called the adrenal medulla (so called chromaffin cells). The adrenal medulla is responsible for the normal production of adrenaline, which our body requires to help maintain blood pressure and to help cope with stressful situations.

Paragangliomas are similar to pheochromocytomas and arise from the same cell type (extra-adrenal chromaffin cells) but arise outside of the adrenal gland.  Paragangliomas are frequently inside the abdomen, located in the retroperitoneum (deep inside your belly, close to the big vessels, the aorta, and the inferior vena cava). Paragangliomas can be found along the aorta, including near where the aorta splits into arteries down your legs (the aortic bifurcation; this area is called the “organ of Zuckerkandl”). However, paragangliomas may be encountered anywhere from the base of the skull to the urinary bladder, and other common extra-adrenal locations include the chest and neck areas. Sometimes, paragangliomas are referred to as “extra-adrenal pheochromocytomas”.

Thus, if the tumor is in the adrenal gland, it is a pheochromocytoma, per definition.

Figure 2. CT scan of a right pheochromocytoma. A yellow arrow indicates the tumor. Notice how the pheochromocytoma is pushing (but not invading) the right kidney.

#2 Difference Between Pheochromocytomas and Paragangliomas:

The underlying genetics of pheochromocytoma and paraganglioma are different

Altogether, a germline genetic mutation (this is a DNA alteration you inherit from a parent) in a known tumor gene is identified in 35-40% of patients with pheochromocytoma and paraganglioma. In addition, tumor-specific alterations (these are DNA alterations tumor cells acquire that enable them to become a tumor) occur in these genes in up to 70% of cases. An inherited germline mutation is more common in paraganglioma than pheochromocytoma. Dr. Carling and others recommend that all patients with these tumors are offered genetic testing and counselling.

The most commonly altered pheochromocytoma and paraganglioma susceptibility genes are: RET, VHL, NF1, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127 and MAX.

Broadly, the types of genetic alterations can be divided in 3 clusters:

• pseudohypoxia-related clusters 1A and 1B
• kinase signaling–related cluster 2
• Wnt signaling–related cluster 3.

To read more about the underlying molecular genetics of pheochromocytoma and paraganglioma go to the reference at the end of this post (nice review by Dr. Svenja Nölting and colleagues):

Figure 3. The underlying genetics of pheochromocytoma and paraganglioma are different, which results in distinct hormone production: Paragangliomas tend to produce noradrenaline (NA) hormones (Norepinephrine and Dopamine), whereas pheochromocytomas produce adrenaline (A; Epinephrine).

#3 Difference Between Pheochromocytomas and Paragangliomas:

Pheochromocytomas tend to secrete adrenaline (A), whereas paragangliomas overproduce noradrenaline (NA)

Paragangliomas tend to produce noradrenaline (NA) hormones (Norepinephrine and Dopamine), whereas pheochromocytomas produce adrenaline (A; Epinephrine). This is what doctors call a noradrenergic/dopaminergic phenotype. Most paraganglioma patients present with a noradrenergic phenotype. This means that noradrenaline (norepinephrine) and its breakdown product normetanephrine are elevated but the metanephrine or epinephrine may be normal. Interestingly, paragangliomas tend to have a lower level of catecholamine production, but it is more constant. This is reflected clinically since a paraganglioma patient tends to have sustained high blood pressure whereas pheochromocytoma patients have more episodic blood pressure elevation. Also, if the tumor is overproducing dopamine, it is more likely to be a paraganglioma.

Pheochromocytomas tend to have an adrenergic biochemical phenotype, overproducing adrenaline (epinephrine, measured as its breakdown product metanephrine). The levels tend to be higher than in paraganglioma patients, and more episodic. Not surprisingly, about 50% of patients with pheochromocytoma have a normal baseline blood pressure, but the systolic pressure may spike during spells to 200, 250 or even over 300 mmHg.

Read more about biochemical testing for paraganglioma and pheochromocytoma.

#4 Difference Between Pheochromocytomas and Paragangliomas:

Pheochromocytomas more frequently have classic symptoms of adrenaline excess than paragangliomas

Given that the types and degree of hormone overproduction of adrenaline-type hormones are different between paraganglioma and pheochromocytoma, it is no surprise that the symptoms can be distinct. As mentioned above paraganglioma patients tend to have sustained high blood pressure whereas pheochromocytoma patients have more episodic blood pressure elevation. “Spells” are more common in pheochromocytoma.

Also, pheochromocytomas and paragangliomas have been called the great “mimicker” because the symptoms mimic those of many other diseases. Nonetheless, the patients that do have symptoms are often characterized by paroxysm (“spells”).

This list summarizes a typical paroxysm (“spell”) from a pheochromocytoma or paraganglioma

• Headache, sweating, and palpitations
• Very high BP (frequently with tachycardia)
• Chest or abdominal pain
• Pallor/flush
• Apprehension (sense of impending doom)
• Duration (5 min to an hour or longer)
• Spells may be spontaneous or precipitated by change in body position, anxiety, medications (e.g., metoclopramide, anesthetic agents), and maneuvers that increase intraabdominal pressure (e.g. going to the bathroom).

Other typical signs and symptoms include:

• Headaches (severe)
• Excess sweating (generalized)
• Racing heart (tachycardia and palpitations)
• Anxiety and nervousness
• Nervous shaking (tremors)
• Pain in the lower chest or upper abdomen
• Nausea (with or without vomiting)
• Weight loss
• Heat intolerance
• Recent onset of hypertension
• Severe or malignant hypertension
• Marked blood pressure lability
• Carbohydrate intolerance or overt new onset diabetes mellitus
• Adrenal mass on imaging
• Orthostatic hypotension in untreated state
• Family history of pheochromocytoma
• Unanticipated prominent changes in BP (up or down) in response to drugs or diagnostic manipulations

Learn more about the symptoms of paraganglioma and pheochromocytoma.

#5 Difference Between Pheochromocytomas and Paragangliomas:

A paraganglioma more frequently spreads (metastasizes) than a pheochromocytoma

All paragangliomas and pheochromocytomas have the potential to spread (metastasize), which is why they are no longer classified as “benign” or “malignant”. However, as a group, paragangliomas are more commonly aggressive and can metastasize. Many of these aggressive tumors harbor a genetic alteration in one of the SDHx genes, most often SDHB. The most common sites that metastatic paraganglioma and pheochromocytoma spread to are lymph nodes, liver, lungs and bone. Surgery is the mainstay of treatment and offers the best chance of cure for paraganglioma and pheochromocytoma, and all patients need lifelong annual follow-up. For metastatic disease, recent advances in the management of these challenging cases are a reason for hope. Much research has been performed on therapies using radionuclides, Tyrosine kinase inhibitors, the mTORC1 inhibitor everolimus, and immunotherapies.

Figure 4. CT scan of a right neck paraganglioma. A yellow arrow indicates the tumor. The paraganglioma is very vascular and all the major vessels including the internal jugular vein the common carotid artery, the external carotid artery (ECA) and, the internal carotid artery (ICA) are all intimately involved with the tumor.

#6 Difference Between Pheochromocytomas and Paragangliomas:

The Mini Back Scope Adrenalectomy (MBSA) is the best operation for almost all pheochromocytomas, whereas the treatment for paraganglioma is more varied

In our experience, the best adrenal operation for roughly 95% of pheochromocytomas is the posterior retroperitoneal adrenalectomy, or more simply put, the Mini-Back Scope Adrenalectomy (MBSA).

The Mini Back Scope Adrenalectomy (MBSA) is the best adrenal operation. It is faster than other techniques, since the scopes are placed directly into the space where the adrenal glands are, requiring less dissection. This is extremely important in every surgery, but in particular, an adrenal operation for pheochromocytoma. A fast operation means that your surgeon is skilled and efficient with an excellent team in-place to best care for you. A faster operation means less time under general anesthesia, less opportunity for blood pressure and heart rate fluctuations, which can be extreme during an adrenal operation for pheochromocytoma. Even though general anesthesia is very safe, the longer duration of time that you are under anesthesia, the greater the risk of anesthesia-related complications such as nausea, vomiting, blood clots, pulmonary embolism (blood clots to the lungs), headache, and in some cases, long-term effects on cognition and memory. 

As mentioned, paragangliomas may be encountered anywhere from the base of the skull to the urinary bladder, and other common extra-adrenal locations include the chest and neck areas. Thus, the surgical approach is dependent on the location, involvement of major vessels, and the body habitus of the patient.

Learn more about surgery for paraganglioma and pheochromocytoma.

Figure 6. Typical right pheochromocytoma after it was removed by the Mini Back Scope Adrenalectomy (MBSA) surgery by Dr. Carling. Although the tumor was large (same tumor as in Figure 2 CT scan), the operation took only 23 minutes.  The tumor is dark. Pheo = dark (ancient greek), chromo = color

Pheochromocytoma is sometimes associated with a specific type of thyroid cancer and parathyroid tumor(s). 

Read about thyroid disease and thyroid surgery, and parathyroid disease and hyperparathyroidism.

Additional Resources: 

• Learn more about the Carling Adrenal Center
• Learn more about our sister surgeons at the Norman Parathyroid Center, Clayman Thyroid Center and Scarless Thyroid Surgery Center
• Learn more about the Hospital for Endocrine Surgery

References:

Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A, Pacak K. Personalized Management of Pheochromocytoma and Paraganglioma. Endocrine Reviews. 2022 Mar 9;43(2):199-239

https://pubmed.ncbi.nlm.nih.gov/34147030/