Neuroendocrine Tumours: a spotlight on Pheochromocytomas and Paragangliomas

I spend a lot of time talking about the most common forms of Neuroendocrine Tumours (NETs), but what about the less well-known types?  As part of my commitment to all types of NETs, I'd like to shine a light on two less common tumour types known as Pheochromocytomas and Paragangliomas - incidence rate approximately 8 per million per year. They are normally grouped together and the definitions below will confirm why.

So, let's get definitions out of the way:

Pheochromocytomas (Pheo for short)

Pheochromocytomas are tumours of the adrenal gland that produce excess adrenaline. They arise from the central portion of the adrenal gland, which is called the adrenal medulla (the remainder of the gland is known as the cortex which performs a different role and can be associated with a different tumour type). 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.  The adrenal glands are situated on top of the kidneys (i.e. there are two).  Adrenaline is also called 'epinephrine' which is curiously one of the 5 E's of Carcinoid Syndrome.

Paragangliomas

Paragangliomas are tumours that grow in cells of the 'peripheral' nervous system (i.e. the nerves outside the brain and spinal cord). Like Pheochromocytomas, they can release excess adrenaline.  There can be confusion between the two types of tumour as Paragangliomas are often described as extra-adrenal Pheochromocytomas (i.e. a Pheo external to the adrenal gland).

Going forward, I'm going to talk about both using the single term of 'Pheochromocytoma' in the context of an adrenaline secreting tumour but may refer to Paraganglioma where there might be a difference other than anatomical location.

"The 10% Tumour"

Pheochromocytomas are often referred to as the "ten percent tumour" because they do many things about ten percent of the time. The following is a fairly exhaustive list of these characteristics:

10 percent of all Pheochromocytomas are:

• Malignant (i.e. 90% are benign)
• Bilateral (i.e. found in both adrenal glands: 90% arise in just one of the two adrenal glands)
• Extra-Adrenal (found within nervous tissue outside of the adrenal glands ... i.e. 10% are Paragangliomas)
• In Children (90% are in adults)
• Familial (10% will have a family member with the same type of tumour) - (however ......my research indicates there are wide-ranging figures published of up to 50% involvement with Multiple Endocrine Neoplasia (MEN),
• Recur (10% or slightly less, will come back 5 to 10 years later)
• Present with a stroke (10% of these tumours are found after the patient has a stroke)

Symptoms

The classic symptoms of Pheochromocytomas are those attributable to excess adrenaline production. Often these patients will have recurring episodes of sweating, headache, and a feeling of high anxiety.

• Headaches (severe)
• Excess sweating (generalized)
• Racing heart (tachycardia and palpitations)
• Anxiety and nervousness
• Hypertension
• Nervous shaking (tremors)
• Pain in the lower chest or upper abdomen
• Nausea (with or without vomiting)
• Weight loss
• Heat intolerance

Diagnosing Pheochromocytomas

According to the ISI Book on NETs (Woltering, Vinik, O'Dorisio, et al), Pheochromocytomas present with a classic triad of symptoms and signs:  headache, palpitations and sweating.  This symptom complex has a high specificity and sensitivity (>90%) for the diagnosis of Pheochromocytomas.  The figure is much lower in individual symptom presentations (palpitations 50%, sweating 30%, headaches 20%). In addition to correctly diagnosing from these symptoms, Pheochromocytomas may also be found incidentally during a surgical procedure even after a diagnosis of an 'adrenal incidentaloma'

Markers.  Like serotonin secreting tumours, adrenal secreting tumours convert the offending hormone into something which comes out in urine. In fact, this is measured by 24 hour urine test very similar to 5HIAA (with its own diet and drug restrictions).  It's known as 24-hour urinary catacholamines and metanephrines. This test is designed to measure production of the different types of adrenaline compounds that the adrenal glands make. Since the body gets rid of these hormones in the urine, we simply collect a patient's urine for 24 hours to determine if they are over-produced.  Like 5HIAA, there is also a plasma (blood draw) version of the test.  According to the ISI Book on NETs, there is also an additional test called 'Vanillylmandelic Acid (VMA).  This reference also indicates the most sensitive test is plasma free total metanephrines.

Scans.  Other than the usual range of scanners, ultrasound, CT/MRI, all of which may be used to find evidence of something, the other scan of note is called MIBG.  This is a nuclear scan similar in concept to the Octreotide Scan given to many NET patients (in fact some Pheo patients my get an Octreotide scan if they have somatostatin receptors).  The key differences with MIBG is the liquid radioactive material mix which is called iodine-123-meta-iodobenzylguanidine or 131-meta-iodobenzylguanidine  (this is where the acronym MIBG originates).  Together with the markers above, the results will drive treatment.  Depending on availability, the latest PET scans may also be available potentially offering greater detail and accuracy i.e. 18F-FDOPA, 18F-FDG and Ga68.

Additional Factors and Considerations

1. This is an awareness post so I'm not covering treatment options in any detail except to say that surgery if often used to remove as much tumour as possible.   Somatostatin Analogues may also be used in certain scenarios in addition to other hormone suppression or symptom controlling drugs.
2. The adrenal cortex mentioned above is actually the site for Adrenocortical Carcinoma (ACC) - this is a totally different cancer (think Pancreatic Cancer and Neuroendocrine Tumour of the Pancreas).
3. Pheochromocytomas are probably difficult to diagnose (you only have to look at the symptoms to see that).  The differential diagnoses (i.e. potential misdiagnoses) are: hyperthyroidism, hypoglycaemia, mastocytosis, carcinoid syndrome, menopause, heart failure, arrhythmias, migraine, epilepsy, porphyria lead poisoning, panic attacks and fictitious disorders such as the use of cocaine and benzedrine.
4. Many Pheochromocytoma patients will also be affected by Multiple Endocrine Neoplasia (MEN), in particular MEN2 (there are some wide-ranging percentage figures online for this aspect).  There can also be an association with Von Hippel-Lindau (VHL) syndrome and less commonly with Neurofibromatosis type 1.
5. Given the nature of the hormones involved with Pheochromocytomas, there is a risk of intraoperative hypertensive crises. This is similar in some ways to Carcinoid Crisis but needs careful consideration by those involved in any invasive procedure.

Summary

Pheochromocytomas are very complex involving many of the challenges found in the more abundant and common types of NETs.  This is an extremely basic overview offered as an awareness message about the lesser known types of NETs.  I refer you to my disclaimer.  If you wish to learn more about Pheochromocytomas and Paragangliomas, check out the links below.

Thanks for listening

Ronny

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Research References used in this post:

ISI - Neuroendocrine Tumors 2016

http://www.amensupport.org/

http://www.pheosupportfoundation.org/

http://www.pheochromocytoma.org/

http://www.pheoparatroopers.org/

https://pheoparaproject.org/

http://endocrinediseases.org/

https://www.endocrineweb.com/

Various authoritative Neuroendocrine and Endocrine Sites.

Also ......why not take a look at Pheo vs Fabulous, a blogger who is a malignant Pheo patient - https://pheovsfabulous.wordpress.com