Speaker 1:
Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now, let's meet the endocrine experts who will be talking with us today.

Sina Jasim, MD, MPH:
Hi, welcome to AACE Podcasts. I'm Dr. Sina Jasim, the Editor-in-Chief of AACE Clinical Report Journal and Associate Professor at Washington University in St. Louis. Today we have the pleasure of hosting Dr. Amir Hamrahian and Dr. Ezra Baraban to discuss their published case on ACCR, on histopathologic differences between Adrenocorticotrophic Hormone-dependent and independent adrenal hyperplasia Cushing syndrome. Dr. Amir Hamrahian is an endocrinologist and he's Associate Professor and Medical Director of the Comprehensive Adrenal Center at Johns Hopkins University School of Medicine. Dr. Ezra Baraban is an assistant professor of pathology at Johns Hopkins University School of Medicine. Dr. Hamrahian, Dr. Baraban, thank you so much for joining us today.

Amir H Hamrahian, MD:
It's a pleasure to have. Thank you.

Ezra Baraban, MD:
Thank you.

Sina Jasim, MD, MPH:
So why don't you please tell us a little bit about yourself. Start with Dr. Hamrahian, to tell us about yourself and your work.

Amir H Hamrahian, MD:
Yeah, so I have been in practice for the past 24 years. I joined Johns Hopkins from Cleveland Clinic about six years ago and there was a vacuum about adrenal center in this institution. So I had the opportunity to develop it, work with my colleagues in different department divisions, including pathology and endocrine surgery, radiology, and put together the Adrenal Center. So most of my focus in patient care is in adrenal disorders. I do also some pituitary, helping Dr. Salvatore with pituitary cases, too, and I also do some clinical research, so mostly sponsored by pharmaceutical companies. That's it short.

Sina Jasim, MD, MPH:
Thank you. Dr. Baraban?

Ezra Baraban, MD:
So I am a surgical pathologist in Johns Hopkins Department of Pathology, and I have subspecialty training in both general surgical pathology as well as in genitourinary surgical pathology because as you know, sometimes the adrenal gland is, I guess, sort of an orphan in the world of pathology. Some institutions it may be more handled by the endocrine folks, which is how it was where I did my residency training at University of Pennsylvania. Whereas in other institutions, it may be more the domain of the urologic pathologist, which is the case here. So I deal with a lot of different organ systems including prostate, kidney, testis, bladder, adrenal. So see a nice variety of different types of pathology.

Sina Jasim, MD, MPH:
Excellent. Welcome both and thank you for joining us today. So you shared an interesting case in the visual vignette with us at ACCR and I'm interested in summarizing the highlight of those cases, actually you shared two cases with our audience.

Amir H Hamrahian, MD:
Yeah, so one of the things I have noticed that many programs may not have a significant amount of adrenal disorders variety and so I thought for fellows, especially for who wants to know more about these diseases, the adrenal disorders when I came across these two cases, and one of them is with the ACTH-independent and one with the ACTH-dependent Cushing syndrome, having adrenal abnormality on imaging studies, and, of course, Dr. Baraban is going to talk about the pathologies, I thought would be interesting especially for the fellows to learn about it more and know about the differences in the imaging characteristic and also on the pathology. So the first case was about a patient about, I think, 64 years old who had bilateral macronodular adrenal disease, having more... I think the left side was bigger than the right side and the patient wanted to have surgery done but was turned down because of being a poor surgical candidate, having significant cardiac issues.

Amir H Hamrahian, MD:
And then when the patient... And this was go down to 2015, and then the patient was admitted in 2021, again, because of worsening heart condition, I was involved as an attending of the service and we evaluate the patient and we thought that maybe there should be a change in the treatment of the patient. The patient was treated with ketoconazole for six years before admission and there was a continued worsening of the patient despite being on medical therapy. So that is why we involved the endocrine surgery team again. And after discussing with the patient, and I can go more maybe details later on, a decision about bilateral adrenalectomy was done and the patient has been doing very well. I mean, I was looking at the chart just before of this discussion and he has lost about 80 pounds in surgery and his A1C has cut down from 8% to about 6%. So he has done very well for after surgery...

Sina Jasim, MD, MPH:
Absolutely. And now that you mentioned that, I'm going to use your expertise to tell us a little bit about the steps and approach in diagnosing Cushing syndrome, especially now we have two cases, one adrenal-source and the other ectopic and given bilateral sources, I wanted to see your thoughts about when do you get the sampling to see which adrenal's producing more or that's less likely used in Cushing cases. So if you can touch base on that, that would be wonderful.

Amir H Hamrahian, MD:
Sure. So the Cushing syndrome is generally divided to the ACTH-dependent and ACTH-independent Cushing syndrome. So historically, we have had about 70% of the Cushing syndrome from pituitary Cushing disease, about 20% from adrenal gland and 10% being ectopic.

However, there has been more attention nowadays on mild autonomous cortisol secretion or autonomous cortisol secretion, used to be called a subclinical Cushing syndrome, and that probably makes a good chunk of the patient with the hypercortisolism, nowadays, with the prevalence of about 5% adrenal tumors in an average patient about 50 years old and about up to 30%-40% of those patients can have elevated abnormal cortisol levels.

So depends on my degree of suspicion, I may use one or more than one test for my evaluation. I mean, generally there are three tests that we do for evaluation of patient with Cushing syndrome. These are the urinary free cortisol, the salivary cortisol, late night salivary cortisol, and one milligram dexopression test. And all of those have some advantage or disadvantage, but when it comes to the mild autonomous cortisol secretion, the appropriate test would be the one milligram dexopression test because the salivary test is not reliable in this population and UFC can be frequently normal in this particular population. So for that population, the one milligram would be the best test to go forward and then, we can get additional testing, supporting tests like ACTH and DHEAS that will support the diagnosis. And, of course, when a patient has abnormal result, we may get additional testing through the UFC or saliva test. We just have a better picture of the whole HPA axis.

Regarding the patient with the overt Cushing syndrome, I would say that I may start with the saliva and the urinary cortisol first and then, because it's easier to do and then, maybe add the one milligram dexopression test later on. And then, of course, when we have a patient with an abnormal result, usually, historically, we use two out of three tests being positive, but this can really differ from patient to patient and there can be some cases with only one abnormality or some patient with all of those abnormal. Then we measure the ACTH, basal fasting ACTH, and based on the level, usually a level about less than 15 picogram per ml indicating adrenal theology most people with overt will have a suppressed or undetectable ACTH. And then, above 20-25 picogram per ml would indicate that they are AC-dependent. And the levels between 15 to 25 can be borderline and usually my approach is to repeat the level at a couple of different times and then get a better sense and sometimes you used to do CRH tests or nowadays Desmopressin stimulation tests to further differentiate these cases, but most of the time when you repeat the level a few times, you're able to get a sense of whether this is AC-dependent or independent.

And then, of course, if they're the AC dependent one, we do the pituitary imaging and based on the level of the... I mean, for example, in our series with MD Anderson, all our patients with ectopic Cushing syndrome had the level of urine frequency three times above the normal range. So based on the result, ACTH level, we didn't have anyone with the pituitary Cushing with ACTH above 225. So these are the things to look for, 225 picogram per ml. So these are the things that make me to do more additional imaging. Look at the chest, abdomen, pelvis, sometimes neck, for example. And then, in cases with pituitary, when there is no discrete tumor on the pituitary gland, usually we use a six millimeter. Based on some of the studies, there is a tumor less than six millimeter in size. And then, we may consider we have a low threshold to do IPSS in our hands. So we do IPSS in this patient when they don't have a clear cut tumor on the pituitary image. And then, sometimes a nuclear medicine study like a PET-CT may be used or they'll delay the scan for further fine ectopic source. I think I gave you a whole.

Sina Jasim, MD, MPH:
Absolutely. Very much appreciated.

Amir H Hamrahian, MD:
I hope I didn't go too fast.

Sina Jasim, MD, MPH:
No, you're perfectly great. The other question I had, when you're having lesion, bilateral adrenal lesion, do you routinely do adrenal sampling in these cases? Like the first case?

Amir H Hamrahian, MD:
Yeah, Dr. Jasim, this is an excellent question and the AACE, I had the privilege of being part of the AACE group to publish on this topic this year. So it was published in endocrine practice and I think it's a good paper to get more information on that. So in general, the adrenal venous sampling can be helpful in certain situation, in patient with bilateral disease. One of the things that comes up always is that when we do the ABS for the patient with primary aldo, you use cortisol as an indicator of the successful catalyzation. Now when you're dealing with a patient who's making excess cortisol, what would you use as a successful intervention? And in our hands, we have tried both androstenedione and metanephrine and they do very well. So we are able to, very high confidence, say that the patient, that the radiology was in the adrenal venous sampling. As you know, the epinephrine or no-epinephrine or metanephrine or no-metanephrine ratios changes when you cover up the adrenal vein to the periphery, you have much higher epinephrine and metanephrine in the adrenal vein and more epinephrine and more metanephrine there in the periphery.

So that can also... That change in the ratio also can help you to make sure that you have it in place. And then, some people have recommended to use absolute cortisol, but we think that probably normalizing the cortisol for androstenedione makes more sense because the position of catheter, the distance from the adrenal gland, may make a difference in concentration. So usually we use a normalization of the cortisol for androstenedione when we want to compare for lateralization.

Is the test perfect? Has there been a lot of publication on this? I don't think so, and we recently reviewed this issue in that review paper, too, but I think when a patient has adrenal nodule that are not very different in size, then maybe that can be considered to give a better understanding to which one to go after. But when there is a significant discrepancy in the sizes, one may argue that going after the largest mass would be reasonable. In the case that we had here, the first case we discussed, the patient had much larger mass on the left side, however, it was such a poor health condition and deteriorating condition that the surgeon told me, "You have one shot at this patient, I don't think we are going to do one adrenal first and then reevaluate and do the second adrenal later on." So that was a decision we made, that it's better just take both adrenal glands out and because many of these cases may actually start to recur after a while, the other adrenal gland will start to make more. So we did the bilateral adrenalectomy in this patient because of that, the fact that patient was another very great surgical candidate to start with.

Sina Jasim, MD, MPH:

Gotcha. Yes. So sometimes the decision will be based on the patient's situation and sometimes I heard of stage adrenalectomy depending on the size. So that's very insightful. Thank you. Dr. Baraban, now I have a question for you, if you can kindly describe the pathological changes and differences between the two cases and how is it relevant clinically when it comes to these cases? So if you don't mind, can you tell us a little bit about the pathology and your findings on both cases?

Ezra Baraban, MD:

Absolutely. So let me start with the first case where the patient had bilateral nodular adrenal masses. So histologically, the most striking thing about the adrenal glands in this particular patient was their multi-nodularity. They are very much composed of multiple discrete, separate, small, rounded nodules, which we used to refer to, pathologically, as adrenal cortical hyperplasia. So I think among our group, we thought this was a great counterpart to the second case because it encapsulates why, from the pathology standpoint, we've shifted the nomenclature fairly recently away from nodular adrenal cortical hyperplasia in comparison to the term of true cortical hyperplasia, which I'll get to in relationship to the second case.

So basically, previously, historically we used to refer to nodular adrenal glands, which have multiple discrete small benign cortical nodules as hyperplasia. But fairly recently as molecular analysis of endocrine tumors has become, or endocrine glands has become much more feasible and widespread, it's become apparent that even cases that were based on traditional pathologic criteria hyperplastic, these are actually in many instances clonal. They're benign neoplasms. Oftentimes each nodule has a separate genetic makeup. And my understanding is that in many instances, these patients actually have germline mutations that predispose them to forming adrenal cortical nodules.

And so, there's been a shift in nomenclature for that reason, because hyperplasia doesn't really reflect the clonal nature, the fact that at the molecular level these are actually neoplastic. And so, there's been a slight shift, but I think a meaningful shift, in the terminology for adrenal cortical hyperplasia when it's nodular like this to nodular adrenal cortical disease, rather than hyperplasia. Because in general, from a pathology standpoint, when something is hyperplastic, that typically connotes that it's not genetically mutated, it's not neoplastic, classically, in terms of medical school pathology. And if something is hyperplastic, maybe there's some stimulus that if you withdraw, the lesion will get smaller. That's not the case because these are autonomous clonal benign neoplasms.

Contrast that with case two where the patient had a metastatic tumor that was secreting ACTH. This is a beautiful case because it's a rare example of true cortical hyperplasia of the adrenal gland, and that's beautifully reflected histologically because there is no nodularity to this gland whatsoever. It is as smooth as can be, but it's just too thick. So once you've seen a certain minimum number of adrenal glands, you get a basic sense of the thickness and layering that's normal histology. But even from low power, this is a very thickened adrenal gland but is homogeneously so.

So there is absolutely nothing wrong with this adrenal gland genetically. It is responding perfectly appropriately just like yours or mine would if someone gave you a bolus of ACTH, and this is exactly normal response to the exogenous ACTH that was, in this case, secreted by a metastatic tumor. So this is a rare example of true cortical hyperplasia that even as soon as you see this adrenal gland histologically from low power, you can bet anything that this patient has an elevated ACTH. This is the histologic counterpart of ACTH-dependent Cushing's.

Sina Jasim, MD, MPH:

I see. Fascinating. Going back to Dr. Hamrahian. Curious, when do you make a decision between medical versus surgical approach, when you see bilateral adrenal tumors? Is it the patient's clinical status, if it's autonomous cortisol secretion versus overt Cushing? How do you make that decision?

Amir H Hamrahian, MD:

That's again an excellent question. I would say that that depends on each patient. So we would individually evaluate each patient separately and go from there. So in the patient with mild autonomous cortisol secretion and who have, of course, by definition these patient usually don't have any overt cushingoid features, I think if they have a unilateral disease and cannot be the case in patient-bilateral, then going after the adrenal nodule on one side would be very reasonable to do because medical therapy is going to be for long-term. And, of course, there's an expense and monitoring and there's a single nodule that would be much easier to go after that.

And we can also sometimes look at the image on the other side and we may be able to even see some atrophy under contralateral side. When there's a bilateral nodule, if there is a significant asymmetry in the size of the adrenal nodules on both sides, then one may consider, argue, that going after the larger adrenal nodules would be reasonable surgically when they have similar, or the sizes are close to each other. In those cases, I would say for a patient with a mild autonomous cortisol secretion, definitely going after both adrenal glands would be very aggressive approach and I don't think that for most of my patients I would consider that.

So in those cases, medical therapy. And sometimes these people, it depends on the degree of abnormality, if they don't have any comorbidities, monitoring them will be also reasonable observation. So monitoring in very mild cases without significant comorbidities, getting help from the AVS and depending on that, considering a surgical approach in one side, going after the larger nodule on one side or medical therapy would be reasonable.

Now, one thing maybe I should say here, that many of these patients have normal urinary-free cortisol. Many of the treatment that we have, for example, available, they are based on the clinical trials, based on the normalization of the urinary cortisol. And that becomes difficult to use in these patients.

For that reason, one approach can be to use a secondary marker like, for example, ACTH in this patient, that by raising the ACTH to upper half, this is just something at my own personal approach, raising the ACTH to upper half of the normal range in a patient who have a low or suppressed ACTH levels can be considered in some as a guide to treatment because many of these people have the normal urine-free cortisol and our other choice would be to use a glucocorticoid receptor antagonist in this population.

So I have used both approaches, both as a estrogenesis inhibitor and using the ACTH and the patient clinical status as my guide. And sometimes if they become symptomatic, I may have used a block and replace approach, for example. They may have, for example, 10 milligram hydrocortisone in the morning for this patient if I feel that they start to have become symptomatic or use a glucocorticoid receptor antagonist and use the ACTH again as a guide in the clinical picture.

Sina Jasim, MD, MPH:

I see. That's reasonable. So I have a question, Dr. Hamrahian, if you can summarize the important teaching points or clinical relevance about this case or two cases that was shared with us to our audience.

Amir H Hamrahian, MD:

Well, sometimes I think that I have learned definitely some lessons from this case. Case number two had a significant hypokalemia and patient very high cortisol problem with the blood pressure. Sometimes in these cases, if you are not quick enough and don't act very fast, we may lose the patient. So they have a high risk of blood clot and the hypokalemia and opportunistic infections. So one lesson is that when you have a patient with a significantly metastatic disease, with a malignancy and they have a ectopic ACTH syndrome, don't waste too much time, go for bilateral adrenalectomy in this patient because it can be a life-saving procedure. So that was a lesson, something that we have done and we have had results from this approach. So I think that would be for case number two.

Case number one was also interesting in a way that this patient initially was turned down for bilateral adrenalectomy or surgery, at least going after the larger tumor, because they thought the patient was a poor surgical candidate. And then, we saw the patient six years later while being on medical therapy for six years and we thought that the patient should have something more drastically done. So this patient could definitely have been better, maybe have more preserved cardiac function if the surgery was done six years ago. I mean, whatever you do with medical therapy, you're not able to achieve a state for most patients. Although it can be different, it has its role and it can be used definitely. But what I'm trying to say is that in a patient who may have an issue with the follow-up monitoring or they are too sick, for example, sometimes an aggressive approach like this case that we did and bilateral adrenalectomy may be considered and the patient has done well. Of course, there is always worries about adrenal crisis in these patients, but I think with proper education and patient selection and providing the necessary tools and the guidance to the patient, this can be decreased. Although I can say that there is still in 21st century, we lose patient from adrenal crisis.

Sina Jasim, MD, MPH:

That's so true. Dr. Baraban, Dr. Hamrahian, are there any additional thoughts you would like to share with us regarding the case?

Amir H Hamrahian, MD:

I don't think so. I want to thank you for the opportunity to share these cases.

Sina Jasim, MD, MPH:

It's a pleasure to have you. Dr. Hamrahian, Dr. Baraban, I want to thank you both for joining us today to share your expertise on these interesting cases. To learn more about this case or others or submit your own interesting case or visual vignette, please visit aaceclinicalcasereports.com/. This is Dr. Sina Jasim, thank you for listening.

Speaker 1:

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