Thank you for inviting me to give this talk today. I'm excited to be here. Thanks for the invitation. And so this is the title of my talk.
I was asked to talk about the diagnostics of pheochromocytoma and paraganglioma. I have no conflicts of interest. interest, but I am a member of the Medical Advisory Board for a Fiopera Alliance.
So these were the topics I was given to talk today. It's a lot of topics for 20 minutes, so we'll try to race through some of them, spending most of the time on the first two. So I want to start with a case.
This is a patient who came to see me, a 39-year-old woman with a history of prior resected adrenal pheochromocytoma, and she was referred for sweating, palpitations, and headaches. And she was very concerned that she might have a recurrent or new pheochromocytoma. Now, I think most people in this room and watching on the live stream already know about the different tests we use for screening, either plasma-free metanephrines or 24-hour urine fractionated metanephrines and catecholamines.
And these data really support the fact that with the newer testing in the last couple decades, that plasma tests and the 24-hour urine tests are really pretty equivalent. I tend to use the plasma tests to start, mostly because it's easier than a 24-hour urine collection. But honestly, either one is OK to do. One thing that physicians and clinicians need to keep in mind is that there are different ranges, though, for patients who are hypertensive and for patients when they're sitting versus when you're laying down.
And also, Oftentimes the labs don't give us those different normal ranges, so we have to know that. The Endocrine Society guidelines for Pheo and Para suggest that everyone should be lying down for 30 minutes with an indwelling catheter before the blood is taken. Now, you can imagine this is not very practical.
I don't do this on a routine basis in my practice because it's just not practical. But it's high sensitivity and specificity. So if the results come back negative in the sitting up position, you can be pretty positive that's negative.
Thank you. What happens is when you get indeterminate levels. So true levels are going to be two to four times greater than the upper limit of normal for the plasma test, three to five times for the urine test. But if the values are borderline and there's no obvious interfering substance, that's when I'll have my patients come back in and really lie down for 30 minutes before testing, or I'll try the 24-hour urine collection.
So as I said, 24-hour urine collection, just as good, it's just a little bit harder to do. And also if there's any renal... renal or kidney disease, they're less reliable. Plasma catecholamines, these are also less reliable.
They're more likely to be false positive, but they're very useful if you're looking for that dopamine secretion, and so they can be important for people who have the SDH pathogenic variants. Clonidine suppression test, I'm not even going to talk about. It's a test we used to do, but now with the high sensitivity specificity of the plasma in urine, it's really not necessary anymore in most cases.
So as asked to. mention chromogranin A. Has anyone had a chromogranin A, checked chromogranin A?
So some people. So what is it? Chromogranin A is co-stored and co-secreted with catecholamines in the chromophin cells that make up pheos and paras.
And it is increased in about 80% of patients with pheo and para. And I think it might be useful in following patients who have non-secreting disease or metastatic disease. It has very high sensitivity because almost 80% of the tumors make it, but it has very low. specificity.
And so what do I mean by that? So there is a study that came out just last month looking at chromagranin A. So on the y-axis, you can see chromagranin A levels with the normal value of 150. On the x-axis are time from surgery.
So the first column is two to three weeks before surgery for patients who have Pheo and Para. And you can see that most of those dots are above the 150 line. So chromagranin A is elevated. But some people have normal chromagranin A.
chromogranin A when they have their pheo para. And the next couple columns are different time periods after surgery, and most people's chromogranin A is normalized, but a lot of times they're not normal even after surgery and full resection. And the last column are controls, people without pheo para, and you can see that the vast majority have normal chromogranin A, but there are a lot of people with elevated chromogranin A even who do not have pheo and para.
And so this is sometimes the problem with chromogranin A. It's not very specific and so the most common thing I see is people taking proton pump inhibitors for heartburn like omeprazole or protonix nexium that can make your chromogranin a be in the several thousands and you stop that medicine and it normalizes so you have to be very careful when using chromogranin a personally I think it causes much more anxiety for people because the false positive rate is so high that when you get back a chromogranin A and it's high you worry more than it is actually helpful. There's a lot of other common things that can increase chromogranin A like irritable bowel syndrome and renal insufficiency.
So again, I am cautious with my use of chromogranin A. So I mentioned that indeterminate biochemistries are kind of the most common thing that I'm emailed about by other physicians asking me what to do with these levels. And so the number one thing I say to them is look at the medication list and ask your patients about supplements. There are a lot of medications that interfere with metanephrine and catecholamine levels, and I show some in this table here.
Common things like SSRIs and cyclobenzaprine, which is flexoril, a muscle relaxant, supplements. I live in Colorado now, so marijuana increases the plasmometanephrine and catecholamine levels. And so we need to ask our patients about these.
these things. If you can stop the interfering substances, please do before testing. If you can't, so some of the psych medications are more difficult to stop for various reasons.
So I think about my pre-test probability. The levels come back just above normal, and I'm not very concerned that Pheo is part of this diagnosis. You could probably let it go or maybe recheck in a few months. But if you think very strongly a person might have Pheo or Para, and the levels come back high and you can't stop...
the medicines, maybe you move on to imaging at that point. So if we go back to the case of the patient that's concerned her Pheo has returned, the plasma normadonephrine levels were in that indeterminate range, less than two-fold the upper limit of normal when she came to see me. So we sat down and we went over her medication and supplement list, and it turns out she bought an energy booster online. So we Googled it right there in the office, and among the 20-plus ingredients on the list were cow adrenal gland and other stimulants inside this supplement.
So she gave herself an iatrogen. pheochromocytoma. She was right.
She had those same symptoms. But she stopped the supplements, her biochemistry is normalized, and she felt much, much better. So this is just a reminder to everyone to be careful about supplements. They're sold in health stores. They're marketed as being great for you.
But be careful, because not just for pheopara, but a lot of times there can be substances in there that we don't know about that might interfere with medical testing. All right. So let's say we've now... done our screening tests and the levels come back diagnostically elevated. The next step is to localize the primary tumor and the key here is for primary tumors what I'm going to discuss and what I usually recommend is that CT and MRI is your best first option for localizing the primary tumor and I reserve functional imaging in this case for other circumstances which we will talk about and why do I say that because it's much more costly to do functional imaging there's a more radiation exposure and you have to think about what's the value of the additional clinical information you're going to get from functional imaging versus CAT scan or MRI again in your initial diagnosis of the primary tumor and there can be false positives anytime you do any tests so that's something to think about as well CT and MRI actually have very classic appearances for pheochromocytoma they're very good for diagnosing primary tumors so on CAT scan pheochromocytomas are often heterogeneous.
If they're done on an adrenal protocol, there's this less than 50% washout on delayed contrast imaging. And most importantly, perhaps, is that just about every single Pheo will have non-contrast Hansfeld units greater than 10. So what's a Hansfeld unit? Hansfeld units are just this semi-quantitative method of measuring x-ray attenuation.
Basically what I mean by that is it's a way that we measure intracellular fat or lipid within an adrenal nodule. So water was arbitrarily given the value of Hansfeld unit of zero. So fat is less dense than water, and so its Hansfeld units are going to be negative.
So if we think about our adrenal gland, it's made up of a lot of lipid and fat and cholesterol that's turned into all the hormones that come from the adrenal gland. And so benign adrenal nodules are going to have Hansfeld units less than 10 in almost every circumstance. I'm quoting Bill Young here when he he says there'll never be a pheochromocytoma with a Hansfield unit under 10. So if Hansfield units are over 10, then there's a chance it's a pheo. If it's under 10, it's almost never going to be a pheo.
Now MRI has very classic characteristics as well. Pheos are bright on T2 imaging. It's the light bulb sign. There's also the in-phase, out-of-phase imaging I'm not showing you a picture of, but that's very diagnostic for benign nodules. versus pheochromocytoma as well.
So what about functional imaging for that diagnosis of the primary tumor? I would argue there's not often a need for functional imaging for primary tumor diagnosis because CT and MRI are pretty good. There are, of course, exceptions.
So here are some exceptions. In order to understand it, this is similar to one of the figures we saw earlier today showing a chromaffin cell and the different receptors and transporters on the membrane. And I'm going to focus today on the...
net transporter on the top in red and the somatostatin transporter the second one in red up there. So for MIBG imaging we can use the norepinephrine or net transporter. It's responsible for bringing norepinephrine in and out of the cell normally. Well we can take advantage of that because MIBG is a molecule that was made to be similar looking to norepinephrine and we attach a radioactive material to it in iodine so it can be used for imaging.
or therapeutics. Now the problem with MIBG is that unfortunately only about 60% of pheos and paras are MIBG avid and that's because we heard about the de-differentiation that can occur in some tumors so they don't express that net transporter and therefore they might not light up on MIBG. The other issue is that normal adrenal glands have a net transporter and so they can light up on MIBG and sometimes it even looks asymmetric so it's a very important that there has to actually be a nodule on the CAT scan portion of this in order to diagnose a pheo. Just seeing uptake in the adrenal gland doesn't always mean there's a pheo there. Now, one way that MIBG can be really helpful in the primary tumor diagnosis is if you have an extra adrenal paraganglioma and it's non-secreting, or if the levels are borderline and you're not sure, then if this mass is positive on MIBG, like seen here, that helps you with the diagnosis.
at that point. Now this is a paper that just came out this year that combined several sites looking at MIBG for primary tumor diagnosis in the first row here and what you can see is that based on CT and MRI alone they were able to have 90% of the disease detected and that was very similar to MIBG alone or the combination of the two. So again for primary tumor diagnosis functional imaging didn't really add much over CAT scan or MRI. Now let's switch gears and talk about the DOTATATE PET scan imaging.
That takes advantage of the somatostatin receptor. So somatostatin receptors bind a molecule called somatostatin, which is similar to octreotide. And we can label that with a different radionucleotide called gallium-68. And that will attach to somatostatin receptors, which are on endocrine. glands including pheos and paras.
And we can take advantage of the DOTATATE imaging and also the Lutathera or PRRT is the same process with a different radioactive nucleotide. So this is an example from a paper of using DOTATATE in primary tumor diagnosis. This is for a head and neck carotid body tumor and you can see on panel A the cross-sectional imaging picks it up fairly well and in panels B and C which are the DOTATATE imaging match to the cross-sectional imaging, it picks it up really well.
But is that really necessary if you picked it up on the cross-sectional imaging? So this is an example from a paper where FDG PET, which is the old school PET, the DOTATATE PET we've been talking about, and MIBG all pick up this primary paraganglioma in the abdomen. In fact, here, MIBG is the best one to pick it up. So, but if cascading MRI can do it, is it really necessary?
And again, I would say not. usually mostly because of cost and radiation exposure. And often the imaging characteristics on CAT scan and MRI are enough.
But there are a lot of exceptions, which we've already heard about today. And some of those are in biochemically silent tumors, in SDH mutation carriers. Sometimes at the primary tumor diagnosis, it's helpful to make sure there's not other disease.
And if you're concerned at all for metastatic disease, or if a primary tumor is resected and the biochemistries don't normalize, there might be something that was missed on the cross-sectional imaging. When we talk about metastatic disease, it's different. Then yes, functional imaging is usually much more sensitive than cross-sectional imaging, and the avidity to either MIBG or DOTATATE might help determine what therapeutic options someone might have for their metastatic disease, and so it's very helpful in that case.
So I'm just going to go back to this table I showed you before from the paper just published and what I left off before was the bottom line which is that looking for the correct diagnosis for a metastatic disease and in the first column you can see CAT scan MRI can pick it up in about 80% MIBG alone it's only 65% because remember we said not every tumor is avid but if you use the combination it's about 89% so MIBG alone is not very sensitive for a metastatic disease But if it's avid it really helps you with treatment options because Azedra is the only FDA-approved therapy for metastatic and unresectable pheo and para at this point in time. Now, this is an example of how dotatate can be very helpful for metastatic disease. So in panel C, that's a CAT scan showing that there's no metastatic disease in this patient.
Panel A is the old-school octreotide scan that doesn't have very good spatial recognition, but it also shows no metastatic disease. metastatic disease. But panel B and D are showing what DOTATATE sees, and there are actually two sites of bony lesions for metastatic disease that were not picked up elsewhere. So if biochemistries are high and you're not finding disease, this is why DOTATATE scan can be so powerful, because it can pick up disease not seen elsewhere. Now this is combining a lot of the data that Carol showed us earlier.
These are two studies from the NIH showing 17... patients with STHB and 22 patients with sporadic disease. And I've kind of summarized the data here and you can see that the detection rates are much higher using DOTATATE PET imaging than the other imaging characteristics and other imaging techniques.
The bottom line shows the number of lesions identified though. And so what I would say here is that most patients, if you have 20 sites of metastatic disease, does it matter if you have 50 sites? It might not. But if you have no known sites and DOTATATE picks them up, that's very... important to know or if you have one or two sites that we thought could be surgically removed but in reality there are many more it's important to know and that's where do to take can be very helpful so how do you decide what imaging to do for metastatic disease I would say to consider it when you're worried about metastatic disease and and using what therapeutic option might be available if the Zedra is available it's important to know if it's MIBG avid if if and when ludithera is available outside side of clinical trial, it'll be important to know if they're DOTA-TAID-AVID.
So these will help make some of your decisions. But cost and insurance is a reality for most of us, and so that has to play a role as well. Okay, this is one very important concept about diagnosis that actually somebody, an endocrinologist, emailed me a case very similar to this last night asking me, and I said, thank you for saying this.
You have justified why I put this in my talk for tomorrow. So this is a 20-year-old female with a neck mass. The MRI confirmed a carotid body tumor, 5 centimeters. The patient went to ENT and was prepped for the OR. And I've worked with my ENT colleagues, and they send all their patients to me so they can be be screened for biochemistries.
So this patient was normotensive at the time. So what's the best first step? Can we say go ahead with surgery?
Should we recommend doing whole body imaging because they have one paraganglioma already? Or should we check plasma metanephrines and catecholamines to start? Well, I'll remind everyone that the head and neck paraganglioma are usually from the parasympathetic ganglia.
That means they're usually not secreting. So if a tumor, if a patient has a... head and neck paraganglioma, but they have elevated biochemistries, you have to look elsewhere, because it could be coming from the head and neck tumor, but it more likely is going to be coming from another primary tumor somewhere else in the body.
50% probably approximately of head and neck paragangliomas are associated with genetic mutations and conditions, and genetic mutations and conditions are often associated with more than one tumor. So again, anyone with a head and neck tumor should be evaluated for another additional primary. tumor somewhere else.
So this patient, despite having normal blood pressures, had elevated plasma normetanephrines. We went ahead and did whole body imaging, and in fact, she had a 2.2 centimeter periortic mass. Radiology described it as a metastatic lymph node, but it's much more likely to be another primary paraganglioma, be unlikely to have a metastatic lesion of one lymph node to the abdomen from a neck tumor.
Could happen, but it's less likely. So we did do a DOTATATE scan to make sure we weren't missing any other metastatic lesions, and that was clear. But this patient cannot have the head and neck surgery until she's alpha blockade with the medicine blockade and has resection of the secreting tumor before the surgery. she has resection of her neck carotid body tumor.
So it's very important that all patients be screened with the plasmometanephrines and catecholamines because there can be additional primary tumors that are found. Okay in the last minutes I'm just going to talk about the last things I was asked to discuss. One was biopsy or not.
Hopefully everyone knows it's a resounding no. These tumors are kind of like sponges. If you poke at them, if you squeeze them, they're going to release and surge. catecholamines, which is going to release a huge hypertensive issue, crisis in some circumstances.
We worry about heart attacks and strokes and, gosh forbid, even death in those circumstances. Many patients do okay with a biopsy, but it's not worth the risk. So if pheochromocytoma paraganglioma is suspected, it should not be biopsied, especially until an alpha blockade is done, and then, if absolutely necessary, can be considered.
So just real quick about predictors for additional primary tumors, recurrence, and metastatic disease. As you've already heard about, we don't have good predictors. So everyone who's had one of these tumors, even one, even without a genetic cause, should be screened for life for any sort of recurrence. And that way that we screen will be different depending on the genetic background or not.
But everyone should be tested for genetics because that does change how we screen, and it does change your risk factor. as well. So some risk factors we do know about is SDHB germline pathogenic variants, extra adrenal tumors, and tumors of a large size.
Now that does not mean that people with these characteristics are absolutely going to get metastatic disease. It does not mean that by far. It just means their risk is a little bit more elevated than someone without those characteristics.
So what about pathology? Can it help? There are a number of pathologic scoring systems out there and the And the short answer is not right now.
It doesn't really help. And this is the reason. There is so much heterogeneity.
It's very subjective how these are read. And so there's a lot of inter and intra-observer variability. So these scores by visual determinations of the tumor under the microscope are not so great at helping us predict metastatic disease. But there's a lot of research going on to try and find more molecular and genetic markers for this. And we've heard about some of these today.
And you'll hear. hear about more of them over the next day and a half that's left for this conference. So I'll just end there.
And I really want to say a thank you to patients and families in particular, especially those that participate in our research too, because you're really helping to move the field along in all of these areas. And so we thank you for that. So I guess we'll move straight into questions. Ruben, do you want to come up too? If anyone has questions for us, let us know, please.
Hi. I am a patient and I'm also a physician assistant, but I help the Facebook group that we have tried to get a grasp. We have a lot of people who come on our site with, quote, unquote, adenomas on.
imaging that might be under like three centimeters in size and have negative testing but have symptoms intermittent symptoms and then are just told oh well you have an adenoma or they're actually maybe not even told they have an adenoma and they find it because I tell them to actually get the imaging reports and actually get the actual imaging and have copies that they keep with them and then we find out like one to five years later that it really was a Pheo. How do we combat clinicians who are uneducated and how do we combat us as a team maybe working with our Alliance to educate people to actually do the testing. My dad actually also I have a from my mom's side have SDHB, but my dad actually has also a neck paraganglioma, and his ENT was not going to test him, even though, and he was a mass eye and ear specialized ENT surgeon, cancer doctor, and he was not going to test, so I sent him to another doctor and did the testing myself, but how do we combat all these doctors who are not doing the genetic testing and are telling patients that they have adenomas and that they don't need any...
follow-up so it's a great and complicated question but I think it starts with exactly what you're saying which is the conferences like these where we educate our colleagues where we educate people in the healthcare field where we Educate patients and families to be advocates for themselves as well. And so I think you're right. I think it's very important for, you know, that old model of paternalistic physician-provider really shouldn't exist anymore in my mind.
I think it really should. be teamwork between patient and provider. And so, first looking at your test results, asking questions, I think is a very important first step.
And then education. And I see my job as an endocrinologist who sees these patients to educate. So I'm always being yelled at that my notes are too long and I spend way too much time on them.
And part of that is because I try to educate within my notes so that it goes back to the other providers for that patient so they understand my thinking and all of that. It's probably not best for all of my sanity and writing the notes, but I think it's an important part of it. But it's a very complicated question. And I think teaching is really important. from all aspects.
I mean, what's difficult is not all endocrinologists are created equal. And you could have one, they will tell you the proper information, and you reach 50 who are still back in the 5, 5, 5 percents and have not stayed updated on anything on the last 20 years. And that's where the education, I think, comes in, really.
And then what do you suggest for the adenomas for us that are on the group, people who are having intermittent symptoms? Lately, I've been just asking. asking them to re-ask for a repeat testing around when they've had symptoms so that then maybe they could catch some biochemical changes.
But I'm trying not to be a clinician on that group. No, but it's true, but also not to be too set in one diagnosis because if you may, you know, pheos and paras are rare. Most people with those symptoms, as we heard in this wonderful talk, was that those symptoms are very common. A lot of us have those symptoms.
And so you... We don't want people to get set in a diet thinking they have a diagnosis. They have an adenoma already, so I'm just trying to...
But even with an adenoma, again, if you have a good radiologist, they should be able to differentiate adenomas from pheos. So having an adenoma doesn't mean you have a pheo in most cases. And those symptoms could be coming from hyperthyroidism. It could be coming from anxiety disorder.
It could be coming from sympathetic nervous system problems. That doesn't mean to discount pheo. It... It just means you don't want people to be stuck in that diagnosis, but I think checking when they're having symptoms and someone maybe who has episodic symptoms is an important thing as well. Yeah, we have at least, I think, 30 to 50 people in our group that were diagnosed with adenomas, so they did not have proper radiological evaluation.
And I just want to add onto it, I think this is where for your para-alliance, adding on their physician finding tool, that will be very helpful for you as patients. to find the appropriate physicians who have knowledge of the field. We have a question from a live stream. I think this is a physician question here. So I'm going to try to pronounce all this correctly here.
Patient has post-micturian headache, so concerned about bladder PGL, 24-hour urine norm metanephrine elevated five times normal value, but random plasma testing is normal. Why? Is it a possibility of bladder?
or PGL should we proceed to imaging ASAP? It's a very specific question. It's always hard to answer these questions because we don't have all the data, and so it's difficult to say. But I would take this question to be there's a discrepancy between the urine tests and the plasma tests, and so how do we handle that? So I think interfering substances is one very important thing to look at to really make sure that there's nothing that is either falsely lowering the plasma tests or falsely.
elevating the urine test. And so I usually start there when I see a discrepancy like that. And then you have to deal with your pre-test probability. And so if the urine, if there's no interfering substances whatsoever, and the urine tests are five times the upper limit of normal, maybe your pre-test probability is higher, and you might move on to imaging.
It's unusual to have that type of discrepancy though between plasma and urine tests. So I probably would retest and I probably would look for interfering substances as sort of my first step there. And I think getting to the right lab is also equally important. You have to go to a reliable lab, which is doing these assays, has standardized assays for both urine as well as plasma.
Thank you. I think we're out of time for questions. One more? Sure. First of all, thank you for your wonderful two lectures.
Excellent points made by both of you. Very crisp lectures. Very important because while these lectures were geared...
nicely towards the patients. I think for primary care doctors, for all the physicians, it's very important. As a surgeon, I personally get lots of requests to remove something.
The zadenoma issue is a very well-pointed-out issue by Dr. Fishbein. As not every adrenal lesion that is very common is a surgical lesion, we must make sure that they are functional. In my career at the NIH, we have had quite a few patients with what we call biochemically silent pheochromocytomas or perigangliomas, even in a sympathetic chain.
even the adrenal. Nevertheless, those do have very distinct characteristics, and I completely agree with Dr. Schirschbaum that the adenomas usually are not those that less than 10 house feed units are not pheos. We still check them, and I'd like to make sure that we all accept the fact that just because we often reassure patients that those are unlikely to be pheochromocytomas, we still should perform biochemical evaluation. for pheochromocytomas. And I think it's very important that just because things look like an adenoma, we still should rule out pheochromocytoma, cortisol-producing tumor, and at least do at least a basic metabolic panel to make sure that we're not adrenal with aldosterone-producing adenoma.
And one other comment I would like to, just a question for Dr. Fishbein. As I often am dealing with a very interesting cohort, of patients who have obviously both pheochromocytomas and renal cell carcinomas and recently I had a patient who presented with bilateral renal masses she had VHL she had a functional pheochromocytoma on one side and yet she had a relatively sized lesion renal cell carcinoma on the other side I did not wish to do bilateral procedure at the same time time. So I needed to choose one.
And maybe I broke your principle where you said that you should take care of a functional tumor first. I did block the patient, but still proceeding in treating the known cancer as I felt that that had a higher metastatic potential. So perhaps in the case that you described with a periganglioma by the aorta that was functional, depending on the severity and the danger of that carotid tumor, I have found that the periganglioma is a very important tumor.
that in select cases it may be okay when patients are blocked to still proceed with treatment of a more threatening tumor? It's just a question and a thought. Yeah, I mean, I think there's, you know, nothing in medicine is black and white, and I think if you're worried about a progressive malignant cancer, then a patient could be blocked, and that could be dealt with first if you're very concerned.
I think in the case of a carotid body tumor, they're usually indolent and slow-growing, although every... millimeter counts depending on where it is, but I still think you can recover from a laparoscopic surgery in the abdomen within two months and go back for your neck paraganglioma surgery. So I don't think it delays it in most cases very long, and I think that in most cases the adrenaline secreting mass should be removed first for safety purposes.
But there are exceptions if there's a metastatic cancer that's rapidly progressive that needs to be dealt with. Thank you. Thank you. Thanks to both our speakers. Thank you.