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Melanie Cole (Host): Welcome to UF Health Med Ed Cast with UF Health Shands Hospital. I'm Melanie Cole. And today we're discussing pheochromocytoma and paraganglioma. Joining me is Dr. Hans Ghayee. He's an Associate Professor in the Division of Endocrinology and Metabolism at the University of Florida College of Medicine. Dr. Ghayee practices at UF Health Shands Hospital. Dr. Ghayee, I'm so glad to have you join us today. Fascinating topic we're discussing today. Can you please define pheochromocytoma and paraganglioma for us and tell us the difference between these two.

Hans Ghayee, DO (Guest): Sure. And thank you so much for having me Melanie. Pheochromocytomas are catecholamine producing tumors that arise from the chromaffin cells of the adrenal medulla, which is the inner most part of the adrenal gland. And there are also pheochromocytomas that are located outside the adrenal gland that we call paragangliomas. Paragangliomas arise from the sympathetic or parasympathetic chain ganglia.

So these tumors can make hormones that can affect our blood pressure, can also affect how our heart functions and as a result, it's really important for those of us that are seeing patients in clinic are thinking about these types of tumors, that a patient could potentially have.

Host: Well, thank you for that Doctor. So who is at risk? Has a genetic component been identified for these?

Dr. Ghayee: Yes. As a matter of fact, that's a great question, Melanie. We've learned in the last several years that there are over 20 genes that have been associated with pheochromocytomas and paragangliomas more than any other endocrine tumor types. So, it's become really important for us to think about a genetic mutation or a genetic driver associated with this disease.

We know about 35 to about 40% could be familial. And it's really critical that if we identify a patient, no matter how old they are, that they get genetic testing done. So, that actually will have an implication in terms of how aggressive a disease that the patient may potentially have. And also it has implications towards their family members in terms of being identified sooner.

Beyond that, with identifying certain genetic mutations that are driving a tumor that a patient could be having, those genetic mutations, could be associated with syndromes that could basically cause other tumors. That's why it's even more important for anybody that is seeing these patients is thinking about this because this is an opportunity to identify those other tumors and have them diagnosed and treated at an earlier stage.

Host: Doctor, I'm so glad that you brought up the importance of other family members being evaluated. So, if you've identified an at-risk patient, you've done your genetic testing. Tell us about any programs that you have that might help family members to receive screening and or medical management.

Dr. Ghayee: Yeah, that's a great question. And we have those opportunities here at UF Health Shands Hospital. So, if that patient's family member is identified with having a driver mutation associated with pheochromocytoma or paraganglioma, those patients would end up seeing us in the endocrinology clinic and we would order certain biochemical studies to identify whether these patients have a pheochromocytoma or paraganglioma. In addition to that, we would be ordering radiographic studies to determine whether they have a tumor that could be involved in this disease process.

Host: So, then Doctor, besides genetic testing, can you discuss evaluation? What's involved in the workup. Are there any biochemical markers you'd like to mention or radiologic imaging that augments your diagnostic and therapeutic capabilities?

Dr. Ghayee: Absolutely. So, in terms of the symptoms that patients may have, the classic triad that most textbooks would talk about is that the patient would have headaches, palpitations or diaphoresis. And it turns out about 25% of these patients actually have this classic triad. We know in the last several years, more and more patients have been discovered because of the fact that they had a CAT scan done for something else, and they were found to have an adrenal pheochromocytoma or a paraganglioma.

And also another group that is now coming into play, are those patients that were found to have a genetic mutation because they were identified as having a tumor or a family member was found to have a tumor. And then they were found to have an at-risk mutation for a pheochromocytoma or a paraganglioma.

So, you can have a patient with a pheochromocytoma or paraganglioma that may have the classic triad of headaches, palpitations, diaphoresis. And even sometimes they might have high blood pressure, but not all of these patients have that. So, that's why it's really important when a patient presents with a adrenal incidentaloma, for example, that we make sure that we do a workup for a pheochromocytoma, because even if they do not have hypertension and they do not have any symptoms, they could still have a pheochromocytoma. So, it's really important that every practitioner understands that and always rules out a pheochromocytoma or paraganglioma. Well, how do we do that biochemically? Well, we check plasma metanephrine levels or a 24-hour urine metanephrine value.

And that's how we are able to determine whether somebody has a pheochromocytoma or a paraganglioma. However rarely, a patient may have a dopamine secreting pheochromocytoma. There had been only 33 case reports published in this, in the last several years, but it's really important that practitioners are aware of that. Also in terms of biochemical testing, there have been some studies that have shown that plasma catecholomines are not a reliable testing method. Instead we should be checking plasma metanephrines. If you're worried about a dopamine secreting tumor, such as a rare pheochromocytoma, that's only making dopamine, then I would check it 24-hour urine for catecholamines.

And this way you will be able to identify some of those patients. Not only that, there are patients that have head and neck tumors that could be paragangliomas. And these tumors may not make any hormones at all. And if they do make hormones, they could just only be dopamine secreting. And so that's where that 24-hour urine for catecholomines becomes really helpful.

Now there's another marker that has shown to be quite helpful that has been discussed in the last several years. It's actually a breakdown product of dopamine called methoxytyramine. So there are opportunities in terms of testing for that. You can test a blood level for methoxytyramine like you were testing plasma metanephrines or normetanephrines.

So just as a reminder, plasma metanephrines and normetanephrines are a breakdown product of epinephrine and norepinephrine. So the same thing methoxytyramine is it's a breakdown product of dopamine. So it could be helpful, especially when we are thinking about somebody having a head and neck paraganglioma, that seems to be non-functional, but you want to do an additional test and that test could be a good test to order.

And another marker that we often think about are chromogranin A level. So chromogranin A levels have traditionally been a good neuroendocrine tumor marker to test, and it is a helpful test to order. But remember, if it's not positive, that does not necessarily mean the patient doesn't have a pheochromocytoma or a paraganglioma.

That's why it's so critical that we order our plasma metanephrines or our 24-hour urine metanephrine value in order to make sure the patient has that right diagnosis, at least biochemically. And then in terms of your question of radiological testing, if somebody has a positive biochemical test, our next step is to do a CAT scan or MRI.

So either test is actually a good test to order for these patients. So, the time that I tend to do an MRI is especially when I'm worried about a patient having a head and neck paraganglioma. That's when it seems like the MRI study might be actually a good test to order, or if the patient is pregnant or if it's a child that we are assessing.

And obviously, if somebody has allergy to a CAT scan contrast agent, then I would order an MRI. Otherwise the CAT scan is a good test to order, and it's also important for healthcare providers to understand that if a CAT scan shows low Hounsfield units, like less than 10, the chances of pheochromocytoma is extremely low.

So what I mean by that, in terms of Hounsfield units is basically a measurement of x-ray attenuation. So, if the Hounsfield units are less than 10, that basically tells us that the adrenal mass is lipid rich and the chances of that lesion being a pheochromocytoma is quite low. So that's what we do in terms of the biochemical testing a 24-hour urine for metanephrines or catacholamines. And we'd like to get plasma metanephrine and also in terms of imaging, we'd like to get a CAT scan or an MRI. If the CAT scan or MRI indicate that the patient has metastatic disease, then we turn to nuclear medicine testing. And generally for nuclear medicine testing, we would like to turn our attention to a gallium 68 dotatate PET scan. That has shown to be a useful imaging modality to look for metastatic lesions.

Especially for those patients that have aggressive and metastatic disease associated with certain mutations such as succinate dehydrogenase type B mutation. Another imaging modality that we may consider is an MIBG scan. And that has actually been around for close to 40 years. However with recent developments in nuclear medicine advances in terms of treatment, this scan has now become an important scan to order, especially if we're thinking of giving high dose MIBG treatment to those with metastatic disease.

Host: Well, then let's speak about treatment for a minute. Dr. Ghayee. What's involved in medical management? And while you're telling us that, how important is relieving symptoms as an important part of this medical care? You can speak even about symptom triggers. But also about the multidisciplinary approach and who is in charge of guiding patients' care, what types of providers are involved?

Dr. Ghayee: That's a great point, Melanie, that you brought up. So treatment for pheochromocytoma and paraganglioma basically is a multidisciplinary approach. It requires an endocrinologist. It requires a hematologist oncologist. It requires a surgeon. It requires a radiation oncologist, even radiologists and pathologists. So it's a big team that's involved in taking care of these patients. And it's also important when there is a team involved, it's not just one person running the show. It's a whole team working together. And at UF Health Shands Hospital, we have an endocrine tumor board where we discuss these patients and we come with a conclusion with the team all in sync so that the patient gets the best care. So, if a lesion is identified to begin with, from imaging, that's when the patient will be considered for surgical evaluation, but before they go for surgery, it's really important that the patient is treated with drugs called alpha blockers. So alpha blockers are really helpful in terms of helping to normalize the blood pressure. And it's really important that not only are we looking at normalizing their blood pressure and heart rate, but also making sure that the patient has enough fluid and they're also taking enough salt.

Because oftentimes many of these patients that have pheochromocytoma or paraganglioma actually are volume depleted and actually need to drink plenty of fluids. And we give them alpha blockers for at least two weeks prior to their surgery. And the other thing we like to do is also monitor their heart rate. So, only after the patient has been on alpha blockers for several days, do we add beta blockers if we need to control a fast heart rate. But we also may add other blood pressure lowering agents as well, such as calcium channel blockers too. Also ACE inhibitors or ARB agents that may be helpful in terms of getting to the goal of lowering their blood pressure to at least less than 130 or over 80 sitting. And a systolic blood pressure about 100 standing. And we'd like to aim for heart rate of 60 to 70 sitting and 70 to 80 standing. So, those are our goals when we're treating our patients. And we also like to warn our patients that when they're starting alpha blockers, that they can actually have hypotension.

And so we ask them to drink plenty of fluids so they can avoid having hypotension as a result of taking the alpha blockers. Because if they have hypotension, then they're less likely to take the medicine because it's such a terrible side effect that people can consider. And as a result, may stop their medicine.

So we don't want that to happen. So it's important that we at least warn our patients, that, our patients can definitely get hypotension and they can feel dizzy while taking this medicine. And so oftentimes we ask them to take it at night so that they're able to tolerate the medicine a little bit better. And again, drink plenty of fluids. I can't emphasize that enough. And also a day before their surgery, we'd like to admit them so they can get IV fluids so that they're volume expanded well.

Host: This is such an interesting podcast, Dr. Ghayee, and as we get ready to wrap up, can you tell us about any ongoing research studies related to pheochromocytoma and paraganglioma and any research that you're doing at UF Health Shands Hospital that other providers may not know about.

Dr. Ghayee: Yes. Thank you for asking that question, Melanie. So, if a patient has a metastatic pheochromocytoma or paraganglioma, it is really important that you have that multidisciplinary team involved and following that patient closely. We have such a program here at UF Health Shands Hospital. So we have our medical oncologist involved. We have our radiation oncologist involved. We have our surgeons involved. And we have our pathologist involved as well as our nuclear medicine doctors and endocrinologists. So, in terms of treatment for metastatic disease, these patients are continued on alpha blockers. And the only FDA approved treatment for metastatic disease is high dose MIBG therapy. That is if their MIBG scan is able to show that they do have lesions and the tumors are picking up the MIBG radionucleotide agent. So, if they do, then we would consider high dose MIBG treatment, but there's also another treatment called peptide related radionuclei therapy, or PRT or high dose dotatate therapy that patients can receive, but that has not been officially approved yet, but certainly that is in clinical trials and we're waiting for approval. Some of the guidelines are suggesting that if the patient has a positive dotatate scan, they may be a candidate for high dose dotatate treatment.

And that would need to be taken on a case by case basis in terms of which patients would get MIBG treatment versus high dose dotatate treatment, or PRT treatment. However, what has been FDA approved so far as of 2018 is high dose MIBG treatment. There are number of tyrosine kinase agent drugs that are under clinical trials right now.

And I think that does provide a lot of hope for many of our patients. However, if a patient has a rapid tumor growth, that's going on in less than a six month period of time, these patients would undergo chemotherapy. Which includes cyclophosphamide, vincristine and dacarbazine or temozolomide as an alternative. But if their tumor growth is slow to moderate, basically it takes over six months for tumors to grow, then those patients would undergo radionucleotide therapy either with a high dose MIBG treatment or with high dose dotatate treatment, depending on that circumstance, the patient has. And then there are some novel targeted therapies. The hypoxia inducible factor two inhibitor are called a HIF-2 inhibitor drugs, these drugs, one was actually approved by the FDA in August of 2021 called belzutifan. This was actually approved for Von Hippel-Lindau related disease. For those patients that may have Von Hippel-Lindau disease that have renal cell carcinoma or central nervous system hemangioblastomas or pancreatic neuroendocrine tumors.

That could be an option as part of a special clinical circumstance for a patient. And obviously it depends on what the patient has, what the driver mutation is. If it's a Von Hippel-Lindau related disease, certainly that could be a possibility for some of those patients. In terms of studies that are going on, more on the translational level. In terms of the research that we're doing at UF Health Shands Hospital, we're looking at what metabolic pathways that malignant pheochromocytomas and paragangliomas could be utilizing. One pathway we identified is the polyamine pathway. So, polyamines are essential cations for a cell. They bind to negatively charged macromolecules and their role is important for cells to function, especially for transcription, translation as well as DNA repairs. So, considering how important polyamines are for a cell's function, we therefore hypothesize that if this pathway is so important, why don't we just target this pathway? So our group was lucky enough to work with a medicinal chemist here at UF Health Shands Hospital, by the name of Dr. Raymond Bergeron, who actually synthesized a polyamine inhibitor, where we were able to test it in the laboratory and show that these inhibitors that he developed actually inhibit these aggressive tumors from growing in the laboratory. And we also were able to see this in an animal model system.

So we are currently in the process of identifying exactly how these inhibitors work in these tumors cells before they move to clinical trials. So, there's a lot of exciting developments that are happening not only in our laboratory, but we are also collaborating with a number of other laboratories around the world to find new treatments for patients that may have metastatic disease.

I think there is a lot of hope on the horizon for these patients, and I can assure anybody who is afflicted with this disease or who has family members that are afflicted with this disease, that there are a lot of people working around the world very hard to see if they can find a good treatment option for them and their loved ones.

Host: Thank you so much, Dr. Ghayee. What a fascinating episode this was, you gave us so much information. Thank you very much for joining us and sharing your incredible expertise for other providers today. To refer your patient or to listen to more podcasts from our experts, please visit UFhealth.org/medmatters. And that concludes today's episode of UF Health Med Ed Cast with UF Health Shands Hospital. Please remember to subscribe, rate and review this podcast and all the other UF Health Shands Hospital podcasts. I'm Melanie Cole.