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 – with an incidence rate of approximately 8 per million per year. They are normally grouped together, and the definitions below will confirm why.  If you think it’s difficult to diagnose a mainstream NET, this particular sub-type is a real challenge.

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 (but I’m in no way suggesting this group of tumours are related to the syndromes associated with serotonin secreting tumours from other types of NET).

Paragangliomas (Para for short)

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).

Pheochromocytomas and Paragangliomas were once called the “ten percent tumour” because as a rule of thumb they do many things about ten percent of the time. However, these figures are slowly changing, so this label is gradually becoming less apparent. The following is a fairly exhaustive list of these characteristics:

A few numbers about Pheochromocytomas and Paragangliomas (these figures change as new epidemiological data is release)

• As much as 1 in 3 are Malignant but most have undetermined biologic potential and should not be labelled benign.  This was emphasised in the 2017 update for Endocrine Systems (4th edition).
• Around 10% of Pheochromocytomas are Bilateral (i.e. found in both adrenal glands: 90% arise in just one of the two adrenal glands)
• Paragangliomas are less common than Pheochromocytomas at around 10% of the total.
• Around 10% are found in children (i.e. 90% in adults)
• Up to 30-40%% are Familial potentially rising to 50% for metastatic cases and Multiple Endocrine Neoplasia (MEN) involvement.
• The recurrence rate is around 16%, i.e. about 1 in 6 patients have a tumour that comes back after surgery.  Tumors that come back also have the potential to be malignant. If you have pheo or para and have surgery to remove it, be sure to continue to check in with your doctor to monitor for any returning tumors.
• Present with a stroke (10% of these tumours are found after the patient has a stroke)
• Approximately 85% of paragangliomas are in the abdomen, 12% are found in the chest, and only about 3% are in the head and neck. Paraganglioma in the head and neck are less likely to be metastatic than tumors in the chest, abdomen and pelvis.

Grading of Pheo/Para

There are different classification systems for Pheochromocytoma and Paraganglioma introduced in 2017 based on the WHO ‘blue book’ for “Endocrine Systems” These grades are based on molecular profiles (the future way for many cancers and the first time for a NET). They have a system of grading called GAPP (grading of adrenal pheochromocytoma and paraganglioma) and they are clustered into the metastatic risk (this is the beauty of molecular methods). So, they are different than regular NETs and they now have 3 differentiations, loosely related to grade. It’s much more complex.  Read more about this here.

Staging of Pheo/Para

This may differ between regions, but I attach the US version here from my pathology source (based on the official sources) – they are not normally too different.  Read here.

Symptoms

The classic symptoms of Pheochromocytomas and Paragangliomas 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) (one of the classic triad of symptoms, see below)
• Excess sweating (generalized) (one of the classic triad, see below)
• Racing heart (tachycardia and palpitations) (one of the classic triad, see below)
• Anxiety and nervousness 
• Hypertension
• Nervous shaking (tremors)
• Pain in the lower chest or upper abdomen
• Nausea (with or without vomiting)
• Weight loss
• Heat intolerance

Anxiety and pheochromocytoma/paraganglioma symptoms are difficult to differentiate. A detailed psychiatric history may be helpful. In addition, anxiety is rarely the predominant symptom patients will complain about; it’s secondary. Patients will complain of palpitations, pounding heartbeat, etc.

Diagnosing Pheochromocytomas and Paragangliomas

The 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 (Woltering et al).  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 like 5HIAA (with its own diet and drug restrictions).  It’s known as 24-hour urinary catecholamines and metanephrines. This test is designed to measure the production of the types of adrenaline compounds that the adrenal glands make. Since the body gets rid of these hormones in the urine, the collection of a patient’s urine for 24 hours to determine if they are over-produced.  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. Also read more here.  Elevated levels of Chromogranin A could also help to support a diagnosis.
• Genetics.  The familial connection with Pheo/Para is complex. Many genes have been identified including (but not limited to) NF1, RET, VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2(SDH5), TMEM127, MAXm EPAS1, FH, MDH2.  Read more here (recent update).  The NIH also have a useful section – click here.  Note:  The genetics of this type seem to be changing quickly so I cannot guarantee this is the most up-to-date list. 
• 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 may get an Octreotide scan if they have somatostatin receptors).  The key difference 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.  Read more on scans here.
• Biopsies can be dangerous due to adrenaline release so only deal with someone who is an expert.  Read about Adrenal Crisis here.
• The undiagnosed. Even though pheochromocytomas are uncommon, a significant number of these tumours are found during biopsies. One study suggested 0.05% of all autopsies found a pheochromocytoma.  Sounds like a small percentage but consider that against the total amount of deaths in a single year if this is an average in the general population.  The most famous undiagnosed patient was the late President Eisenhower.  Read more about undiagnosed NET patients by clicking here.
• Treatment. This statement and diagram were provided by Dr Mark Lewis who is an Oncologist and MEN patient.  “The algorithm for working up a hyperadrenergic state is attached (and was developed by Dr. Young at Mayo Clinic). It outlines the most reliable testing for a pheo or Paraganglioma”

Great video on diagnosing Pheo/Para here – click