In my article ‘Ever wonder what caused your NET’, I concluded that currently, the only known scientifically explained causes for NETs were hereditary/genetic in nature. This is mostly associated with those who have MEN syndromes (yes, they are a syndrome not a type of tumour) and a few other less common types of NET including Pheochomocytoma/Paraganglioma (Pheo/Para) and Medullary Thyroid Carcinoma (MTC) (the familial version of MTC is often referred to as FMTC). However, please note this does not mean that all those diagnosed with pancreatic, parathyroid, pituarity, Pheo/Para and MTC tumours, will have any hereditary or genetic conditions, many will simply be sporadic tumors.
In recent years, it has become increasingly apparent that a number of Neuroendocrine tumours arise as a result of germline genetic mutations and are inherited in an autosomal dominant pattern. The number of genes implicated is increasing.
Apparently, 5-10% of Gastroenteropancreatic NETs (GEP NETs) are estimated to have a hereditary background. Syndromes associated with these include Multiple Endocrine Neoplasia (MEN), Von Hippel Lindau (VHL), Neurofibromatosis Type 1 (NF1), Tuberous Sclerosis (TS) and others. People who have a genetic condition may present with the tumors (perhaps along with an associated syndrome) and so the genetic condition if there is one, may not be known at this point.
How will I know if I am affected?
Some people do worry about this, often because of what they find on the internet including inside patient forums. I suspect some people already know via family connections and I guess if you have 2 tumors found in (say) parathyroid and pancreas, it should at least raise a suspicion for MEN1.
Many people say how do I know, how do I check and this is obviously a delicate subject. Of course, your first port of call should be your NET specialist if you suspect or know of any connection.
Thus why I was interested in a paper published in Springer Link – titled “When should genetic testing be performed in patients with neuroendocrine tumours.” When reading, you’ll find it’s actually much more than that! Check it out here:
When should genetic testing be performed in patients with neuroendocrine tumours?
In this review, the authors examined the features which may lead a clinician to suspect that a patient may have an inherited cause of a NET and they outlined which underlying conditions should be suspected. They also discussed what type of screening may be appropriate in a variety of situations. If there is a way to identify which patients are likely to have a germline mutation, this would enable clinicians to counsel patients adequately about their future disease risk, and allows for earlier detection of at-risk patients through family screening. There’s a couple of minor errors in the text but I’ve contacted the authors.
The authors focused on presentations of NETs of the gastrointestinal system, chromaffin cell tumours (Pheochromocytoma and Paraganglioma) and Medullary Thyroid Carcinoma. Pituitary tumors (normally associated with MEN1), were not considered in scope for the review. Interesting, the review includes news of a move by endocrinologists to reclassify ‘Pituitary Adenomas’ as Pituitary NETs (PitNETs). Read the abstract here. This would appear to be in line with a gradual shift from the benign nomenclature associated with certain NETs to the ‘malignant’ potential of these type of tumors. The abbreviation is also in line with others, e.g. pNET, SiNET, etc. A useful reminder that we must stop using the term ‘Carcinoid‘ as this is regressing this extremely useful initiative to highlight the malignant potential of all NETs.
There also appears to be some linkage to the study looking at the possibility of familial Small Intestine NETs (SiNETs). You can read more about a US registered trial here (with apologies for use of the now defunct term ‘Carcinoid‘).
This is a complex subject and the text above is very basic. If you wish to dig further, the quoted reference is a good read. Just to emphasise, it’s aim is to provide advice about when to recommend genetic testing for NETs, and in doing so provides some useful reference information. It’s broken down into 4 distinct tumor groupings:
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. 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.
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).
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.
Pheochromocytomas are often referred to as 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 facts about Pheochromocytomas
As much as 1 in 3 are Malignant but most have undetermined biologic potential. A recent document issued by the World Health Organisation (WHO) stated that “Paragangliomas should not be termed benign”.
Around 10% of Pheochromocytomas are Bilateral (i.e. found in both adrenal glands: 90% arise in just one of the two adrenal glands)
Around 10% are Extra-Adrenal (found within nervous tissue outside of the adrenal glands … i.e. 10% are Paragangliomas)
Around 10% are found in Children (i.e. 90% in adults)
Up to 30% 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 tumor 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)
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)(one of the classic triad, 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
Nervous shaking (tremors)
Pain in the lower chest or upper abdomen
Nausea (with or without vomiting)
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 serotoninsecreting 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. Also read more here.
Genetics. The familial connection with Pheo/Para is complex. Up to 13 genes have been identified including 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.
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. Read more on scans here.
This statement and diagram was 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”
Additional Factors and Considerations
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. That said, Pheo/Para patients may be interested in a PRRT trial exclusively for Pheo/Para – read more here (see section entitled – “What about Pheo/Para”)
The adrenal cortex mentioned above is actually the site for Adrenocortical Carcinoma (ACC) – this is a totally different cancer.
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.
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 lesscommonly with Neurofibromatosis type 1.
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.
Newly Approved Drug – AZEDRA
On 30th July 2018, Progenics Pharmaceuticals Announces FDA Approval for AZEDRA® (iobenguane I 131) to Treat Unresectable, Locally Advanced or Metastatic Pheochromocytoma or Paraganglioma – read more by clicking here.
Pheochromocytomas are very complex involving many of the challenges found in the more abundant and common types of NETs. To underscore this statement, please see this case studywhere one patient was misdiagnosed with psychiatric problems for 13 years before being correctly diagnosed with a metastatic Pheochromocytoma.
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.