It's actually a case presentation or roundtable discussion. There will be three cases presented by our panel or our expert, and the three experts are from bitury and adrenal field, and they are top experts. So I'm sure you will enjoy their presentation. Each one will present a case, and they will have a discussion among themselves. And then at the end, there will be five minutes, actually, or some time for a discussion around the cases, or if you have any questions for the expert as well. So I'll just briefly introduce each one. The first presenter will be Dr. Suzanne Sandlin. She is actually the president of American Association of Clinical Endocrinology. She is a professor and associate consultant in endocrinology and neurosurgery from Mayo Clinic, Rochester. She is currently practicing in Jacksonville, Florida. She has been trained in Canada, and as well, Baylor College of Medicine. And you know her. She is also editor of Bitury Across the Lifespan. The second expert is Irina Brankus. You heard her yesterday talking about adrenal incidental loma. She is associate professor of medicine. She runs Adrenal Lab, principal investigator, and division of endocrinology at Mayo Clinic. Again, she's trained in Romania, and then she did her training also in Mayo Clinic, and she went also to Birmingham to do further fellowship training as well. The third expert is Adriana Ikemaku. She is a professor of medicine, division of endocrinology and molecular medicine, and neurosurgery. She is at the College of Wisconsin-Milwaukee, and also she is originally from Romania. She did her training at Cleveland Clinic, and she is also experienced in pituitary adrenal disease. And they have, all of them, they have written guidelines. They have extensive publications. So please welcome, and we will start our sessions. Thank you. Thank you, Dr. Alfutaisi. I'm going to make sure my colleagues have their microphones all working, because we're going to do a little bit of an interactive session. We thought we'd actually do the ... Hello, yours is working. We thought we would do actually the three cases in a row, and then with the time we have left, if you've picked up on any nuances in the cases and want to make any comments or have questions, then we will take those at those times, just to make sure that we stay on time. So we're going to have one case on prolactinomas, and then two cases dealing with adrenal disorders. So I wanted to start with this slide. This actually isn't the case, because this is an illustration of what we like to see as endocrinologists when we deal with prolactinomas. So I'm not saying you want to see a tumor this large, but you want to see the response that this young man had. So this is a 25-year-old male who presented with headaches, visual changes, had an MRI, and you can see his pituitary macroadenoma, large, giant, invasive. So what choices do we have here? Well, for most of us, we will start our patients on cobergelin, and actually, he's on quite conventional doses. And I will tell you that the MRI to the right was only three months later. So this is one of those tumors that just melts away as you treat them. So you can imagine that with this kind of decrease in size that a patient like this might present with a CSF leak, which had to be repaired, and he had transphenoidal resection of his tumor. And you can see it on the right side, almost minimal tumor within a year of that presentation. So this is what we like to see, but sometimes we don't. We see those resistant cases. So this is a patient of mine who is a 19-year-old female with primary amenorrhea, so never had a period. Finally, he went to see gynecology and had a negative progestin withdrawal. So she's hypoestrogenemic. And she had never been on any estrogen-containing oral contraceptive pills. And she was referred to a reproductive endocrinologist. And in the course of that kind of assessment, it was noted that she also had headaches every day. And so because of that, an MRI was performed. And until that point, in this young woman with primary amenorrhea, she had never had a prolactin performed. And her prolactin was over 1,000. So she was treated, just like the last case I showed you, with cobergeline 0.5 milligrams twice a week. And this was titrated up. And you can see that after a full year on cobergeline, she did look like she had a good tumor response. But the problem was her prolactin was still elevated. So in this young woman, without giving her back estrogen, she is not going to have a period. She's not going to start having cycles. And she's going to be hypoestrogenemic unless you can normalize that prolactin. So I guess what I would ask my panelists at this point, here's this young woman, primary amenorrhea. She's on cobergeline 1 milligrams twice per week. What would you do next? So I guess I'll start. She did have some response to cobergeline. So we cannot really call it complete failure. So I think we could try increasing cobergeline for a while. Obviously, other choices would be to consider surgery or radiotherapy. But I think I would try cobergeline increase first. OK. And I agree. I mean, yes, hello. And I do agree. I mean, there are publications that indicate that as you increase the cobergeline dose, additional response in terms of prolactin lowering occurs. And this woman without any, who has not started a family and so on, I think it's something that we can pursue further. So yeah, I think we're very used to getting up to maybe 1 milligram twice per week. And then sometimes we get uncomfortable with going beyond that. But I would agree that there's sometimes when this is appropriate. So in fact, her endocrinologist continued to titrate her medication until she was up to 15 tablets per week. So 7.5 milligrams total. And you can see that that tumor has just stalled where it was at before. And there was a little bit of shrinkage if you let the tincture of time continue. So after two years of therapy. We still have a problem. She is a prolactin of over 500. So we still have not achieved control in this young woman. And if you look over at the MRI on the right, and you can see the course of the internal carotid artery coursing through that cavernous invasion of this tumor. So even though surgery is definitely an option, we have to think about the fact that she has a tumor that is invasive and could not be removed by transpinoidal. So are there any other options at this point? Yes. So definitely resistant, right? Her prolactin response is really suboptimal despite increasing the dose. And the dose has been increased to levels that, of course, we can try for a while. But given the age of this patient, trying this in the long run is really not something that is indicated. So I think debulking might be helpful because perhaps after that, even though she's going to continue to need dopamine agonist treatment, perhaps she could do away with smaller doses. Yeah. Yeah, I agree. I think that would be my next step here too. And one of the things, if you look at the literature on what else is available to us after dopamine agonist, there isn't a lot of options that have great evidence. So you might find literature on tamoxifen, you know, as an estrogen receptor antagonist helping to sensitize to cabergoline. You might find some data on somatostatin receptor ligands. And in prolactinomas, the most prevalent ligand or receptor tends to be the number five receptor. And so you want to think about, okay, would these work? But again, the evidence is not very strong in those areas. And I think for every treatment you will find that one case report that responded so nicely, but you don't see the other 20 that didn't. So I agree that I think if you have access to an expert pituitary surgeon for this young woman, this might be the next best option. So she did have a transphenoidal resection in 2022 at an outside center. And you can see here that she, in the post-operative images, that she still has that substantial right cavernous invasion of tumor. And again, this is the post-operative results. So substantial debulking of this tumor in the hope that you can gain control of that prolactin. But unfortunately, still on those very high doses of cabergoline, the prolactin was not controlled. And so just in the last year, she had a cavernous walrus section at our institution. So this is a very, very specialized neurosurgery technique done in very few centers. Because one of the issues with these cavernous invasive tumors is that they are actually invading into the surrounding tissues and you will not cure them without thinking about a cavernous walrus section. But again, very specialized with only the most experienced surgeon. So she underwent that resection. You can see here, we're now at the point where she's got pituitary gland with the stock kind of deviated over to the left. You can see that the majority of that tumor on the right near that carotid has been debulked. If you look over at the most rightward panel, although there's still some hypo-enhancing tissue there that I think could be target. But for the most part, much improved beyond her original presentation. And certainly the pathology showed us that this was tumor. And it's so interesting that no matter how resistant or aggressive sometimes, these pituitary tumors are, that they can still have a KI-67 that's completely reasonable, that it doesn't actually reflect the resistance of that tumor. So if you look here, she had a KI-67 or a MIB of just 1%. And that's the top pathology panel. These are strongly pit 1 staining cells as we expect. And they were prolactin positive without any additional staining that might make you think this was an atypical tumor. So you can see here, for my esteemed panelists, that as she had her surgery, you can see the drop in her prolactin. We actually take patients off of cobergeline in the two months before their surgery. So she started with a baseline of 1,000 coming into that second transphenoidal. You can see on post-op, even at two hours, that at least her prolactin has been cut in half and continued to drop to the next morning. And then by her first post-operative week, her level is now 357. Her cobergeline was added back daily, so still a high dose. And you see that drop in her prolactin in the first few weeks to 231. But unfortunately, when she came back for her follow-up, you're seeing a rise again in that prolactin. And whether that actually is escape from the cobergeline or just a variation in the prolactin level is not clear at this point. So I guess I would ask my panelists, what do we do now? Well, I guess at this point, it would be quite reasonable to consider stereotactic radiosurgery or gamma knife therapy, especially considering that her disease is in cavernous sinus. I would definitely look at the risk of pituitary dysfunction in this young woman with gamma knife therapy. And I think also step back and consider that on a smaller dose of cobergeline, the tumor did not shrink, but it also did not grow. So I think it's important sometimes to step away and say, is it still the right thing to do to try to normalize that prolactin and what are we risking here? But again, for this lady, I think radiosurgery probably would be safe enough. And throughout this time, correct, she still did not develop spontaneous periods. Her estrogen remained low. She was taking the medicine consistently, I mean, things that are important to know about. Yeah, we rarely need to do radiation for prolactinomas. That's definitely not something that we do often, but I think we need to give this lady a chance to start her periods and to be able to be pregnant. And with the advances in radiation, especially centers that do this often, hoping that just the tumor in the cavernous sinus is targeted and the normal pituitary function stays normal. But she also can have the help of a reproductive endocrinologist to conceive later on. So I agree. Yeah. Okay. I agree. I'm not wanting to recommend radiation in a young woman who's now 20 after going through all of this, has her whole life ahead of her and the concerns about hypopituitarism. But again, I think when you have an expert center involved, that risk probably goes down to about a quarter to maybe a third of patients. And if you remember from her imaging, I don't want to flip all the way back. Her pituitary is kind of pushed over to the left and the tumor's on the right and it's in the right cavernous area. And to me, this becomes one of the most ideal characteristics for a patient that I'm going to refer to my colleagues in radiation oncology. So I agree with both of you because there's a couple things to consider here. She's going to be on cobergeline for a long, long time. This isn't your typical prolactinoma patient. So we know that the signal for valvulopathy in patients on cobergeline with prolactinomas is probably not as concerning as it was for those on high doses for Parkinson's disease. But she's on 7.5 milligrams per week or 7.5 tablets anyway right now. And those are starting to get up into Parkinsonian doses. So we have a problem. We do not want to treat her with cobergeline high doses long-term. And we have several warnings both from the literature as well as in the U.S. from our own FDA telling us how we need to monitor for valvulopathy. The other issue with cobergeline is in some patients, and this has happened to me with my patients very rarely, but it does occur, that we can see issues with compulsive behaviors, also worsening of anxiety, depression. And so we have to be very careful to counsel our patients, especially as we increase these doses. Now my patient in this case did not have any of those symptoms. But at the same time, these are the concerns we have to think about with all of our patients. So I agree with my panelists and actually did refer her for stereotactic radiosurgery. And you can see even with a short period of time that the right targeting has led to improvements already in that very resistant prolactin. And that 75 value is from last week, knowing that the upper limit of normal in our lab is around 30. So I'm hoping that in the near future we can achieve full control of this tumor. If I have to consider replacing her estrogen once I have control of that tumor, I will do that. I'm really hoping that she will now go on in her 20s to have a very full life. And one thing I'm very pleased about is she has never yet manifested any other hypopituitarism in spite of the treatment, the size of the tumor, and the two surgeries that she's undergone. So thank you. I'm going to flip through these because I wanted to give you your full time. Okay. We're changing gears a little bit. We're going to present three challenging cases here. So this is mine. This is a 55-year-old woman who a few years back was admitted to a local hospital for chest pain, shortness of breath, and dizziness in the emergency room. She was found with hypertensive emergency and EKG abnormality suggestive of a non-ST elevation myocardial infarction. When talking to the patient, she reported a 30-kilogram weight gain over three months prior to admission, new leg swelling, muscle weakness, easy bruising, new striae, and hair thinning, and that was just for the previous month. She also reported that diabetes and hypertension were new for her in the past three months, and her primary care physician tried to control the blood pressure by adding and increasing medications. While hospitalized, her potassium was low at 2.9 milliequivalents per liter and hemoglobin A1C 7.5%. A random serum cortisol was 53.9 microgram per deciliter, and an ACTH significantly elevated at 450 picogram per milliliter. She was discharged home on aspirin, atorbastatin, metformin, benazeprime, spironolactone, potassium supplement, and nitroglycerin, so she was treated medically, and she was advised to follow with a local endocrinologist who repeated the laboratory studies, and as you can see, a random serum cortisol level was still generous at 27 microgram per deciliter, ACTH remained significantly elevated, maybe six, seven times above normal at 307 picogram per milliliter. UFC stands for urinary free cortisol, and so there were two levels measured on two different days over 24 hours, 499 and 663, so that's somewhere around 10 to 11 times above upper normal range. The low-dose dexamethasone overnight, dexamethasone suppression, one milligram taken at bedtime next morning, cortisol was 18.5, and normally the cortisol should go below 1.8 microgram per deciliter, and then the next day, the local endocrinologist performed a high-dose eight milligram overnight dexamethasone suppression test with no response, in fact, the cortisol went up a little bit. So this is the case so far, and I would like to ask my colleagues what would they do next. So we clearly have a patient with clinical presentation of severe overt Cushing's syndrome, and laboratory findings indicate ACTH-dependent hypercortisol. So the presentation, I would say, is much more consistent with ectopic Cushing's syndrome here rather than pituitary. I was also impressed by the fact that eight milligram dexamethasone suppression test, the cortisol after eight milligrams is actually higher than one milligram, and that would not be expected in pituitary. Nevertheless, I feel that we have to also consider the logical approach here, and the next step is pituitary MRI. Now, I always like thinking, why am I doing things? What would I expect to see on MRI? And I would say, with such a severe hypercortisolase, there must be a macrodenoma for this to be a convincing case of pituitary coagulants. Agree. Pituitary. Okay. So, this was done, and this is actually in line with the consensus guidelines, a very beautiful document that has been published years back that I think we recommend it. So, what you see here, it's a coronal section, an MRI, and the arrow is pointing to the lesion, right? And it is larger than one centimeter in its largest diameter. The lesion is on the left side, right? Patient is laying down face up. So, our right is the patient's left. So, this was the MRI. So, then she was referred to the pituitary center where I was. So, that's when I saw her. She appeared tired. She had full supraclavicular force and dorsal cervical fullness, discolored abdominal and thigh striae. So, keeping in mind that whenever the striae affect the thighs or arms, typically the urinary frequency levels are high, very high, not just a little high. She was actually quite weak and unable to raise from a chair without assistance, came with a relative to help out. She had a rounded face when we looked at the picture from the driver's license taken just a year ago. Her blood pressure was almost in good control, but she was tachycardic, and physical exam findings that I've just mentioned, I'm not sure why I repeated them there. This is, and I had available all the workup that was done by her local endocrinologist. So, what would my colleagues do next? What do we tell this patient the next step is to address her ACH-dependent Cushing's syndrome? Thank you. So, I hope our audience will not fault us for doing the pituitary MRI, but then feeling a little bit scared that this is an ectopic type of picture, right? So we have hypokalemia. She has severe weakness. She's had really a rapid presentation. And I think even though she's got this lovely pituitary adenoma that could be a surgical target, we better make sure it's the culprit because we could be missing something else. And this is one of those cases that is the disclaimer in the guideline, right? So you have a pituitary tumor that's six to nine millimeters. Maybe you don't even need IPSS. You just go for surgery, except when it's an ectopic presentation. So I'm afraid, my friend, that we have to do more looking around. What would that be? What would be the ideal test to differentiate between ectopic and pituitary? Well, normally we would say, hey, let's do an IPSS and make sure this is central. But there are other approaches to that, too. If you're in a center that doesn't have a very experienced interventionalist that can do that testing for you, you can look at a couple of dynamic tests and also some cross-sectional imaging. And I can let Dr. Bankos comment as well. So just to sort of combine it all together, despite the fact that this patient has a large pituitary adenoma, which would be consistent with severe ASTH-dependent hypercortisolase, her history is a bit going against it. Women with pituitary clushing or men with pituitary clushing usually describe symptoms over years of time. So just this acute onset over the last one year, if I remember, makes this a bit worrisome. The next thing I'm going to say, it's important to consider urgency of treatment, too. I just feel like we talk about different approaches and so on, and sometimes it takes weeks or months to wait for things to happen. So I think I would consider that as well. And in my experience, IPSS takes a bit longer to find, to schedule, especially for most people outside experience centers. Well, cross-sectional imaging is easier. So I think going with a CT chest and abdomen would be what I would do. Now because I am at an experience center, I have access to gallium deltate scan. I could consider that as well. But again, I feel like we have to be also practical and do the test that is most likely to answer the question. Right. So my colleagues agree with the fact that we are not sending this patient directly to the neurosurgeon, even though she does have evidence of ACTH-dependent Cushing syndrome and a pituitary macrodenoma. This patient was seen during the pandemic, so in COVID-19. So even though normally I could arrange at my institution an IPSS to be done fairly quickly in the situations that was impossible back then, but what I did have available in clinic is corticorelin. So that's CRH. So that's the synthetic hormone that stimulates ACTH production. So there are published protocols and the testing unit really was in my clinic, so it was easy for me to do this. As you can see, the protocol is to draw two baseline measurements and you can see the cortisol and the ACH levels at baseline elevated. And then we inject the corticorelin and then we repeat the testing four times over the course of one hour, 15 minutes apart. So there is no need for calculations here that are complicated. You see very clearly that both her cortisol and ACTH levels pretty much remained the same. It's a flat response. What we expect in patients with Cushing disease where the ACTH is produced by pituitary adenoma is a significant increase, at least of the ACTH level, but many times also of the cortisol level. So that to me was the surrogate for IPSS in terms of additional endocrine testing. Then I pursued cross-sectional imaging, which was much quicker to obtain. So I'm just showing you pictures of the abdominal CT scan. Her chest CT scan was fine. So there are several arrows there. So starting from the left to the right on the scan on the left, you see some white arrows there and they show a large pancreatic mass in the tail of the pancreas. In the middle there, there is just a little arrowhead that is black and that points towards the left adrenal gland, which has a nodular thickening or lipid-poor adenoma. Incidental finding, I would say here, but just to make this case even more complex, we wouldn't expect this to be ACH-independent adrenal based on those ACH levels. And then all the way to the right, we see another view of her pancreatic mass. So with that, I've obtained a chromogranin A, which was significantly elevated. I mean, it's not a test that is helping much, but I think in terms of diagnosis, but having a baseline, because now I'm going in the lines of a neuroendocrine tumor, I think it's useful to have the baseline. And then we checked for the usual other tests we do for ectopic Cushing syndrome, calcitonin, gastrin. The metanephrines, because of her adrenal nodule, obviously, and there are some cases with ectopic ACH production, a case report from theochromocytomas. So fortunately, all those were normal. So in terms of treatment, I think there is no need to ask this. We did go for the surgical option of removing what we thought was the culprit for this. So this was a large tumor, it was an extensive surgery with distal pancreatectomy splenectomy unblocked with the transverse colon. The patient did go into biochemical remission. So the serum cortisol and ACH levels dropped precipitously postoperatively, as you would expect with removal of a pituitary tumor that makes ACTH. And then I personally took care of this patient for years, and she did require hydrocortisone replacement for about 18 months. This is the pathology shown in neuroendocrine tumor WHO grade 2, and we asked the pathologist to stain for ACTH, which was positive within the tumor, which obviously goes in line with the biochemical remission. So this gives me an opportunity to bring up this very difficult issue of the ectopic ACH Cushing syndrome. This is due to the abnormal expression of the POMC gene in non-pituitary tumors. Historically, if you look at the old data, these were mostly males with lung cancers and catabolic hypercortisol. So they weren't gaining weight, they have the catabolic manifestation of high cortisol such as muscle weakness, hyperpigmentation from really high ACH levels, compression fractures, opportunistic infection, hypokalemia, and very high ACH and cortisol levels. Currently, there are more benign neuroendocrine tumors, fortunately, that are being diagnosed with EIS. They have gradual onset and sometimes similar manifestations as pituitary Cushing syndrome, but in this case, her onset was within a few months from presentation. What we are doing here is pretty much using all the tests that you've seen and we're using them with clinical judgment and individualization in mind. All these tests are probabilistic rather than algorithmic. If we think about it, patients with ectopic Cushing should not respond to high-dose dexamethasone suppression tests and should not respond to CRH or decimopressin tests. We have both a suppression and two ways to stimulate the ACH production. However, we have to be careful. Not all the tests fall in line. There are caveats. Well-differentiated neuroendocrine tumors may express CRH and V1B vasopressin receptors. You may be confused with one test pointing in one direction and the other in the other direction. In this case, everything pointed towards ectopic. Using multiple tests improves accuracy. As we spoke already, the gold standard would be the IPSS with a lack of central to peripheral gradient in ectopic ACH production, but there are caveats even with this no test. When we are talking about the Cushing patient, no test has 100% precision. Cyclical hypercortisol is the way the test is performed, the way the anatomy is for that patient. Of course, you need an expert center who's doing this more than just once in a while. This is a nice study that has shown both for CRH and decimopressin test how the response is differentiated in ectopic ACH secretion, EAS versus Cushing disease, which is pituitary. But if you're looking carefully at the dotted horizontal line, there will be patients who will respond unexpectedly. This particular paper indicates that if you're using both tests and performing cross-sectional imaging with CAT scan of the neck, chest, and abdomen, you might be in good shape and you might not need to do the IPSS, in particular if the patient lives in an area where the IPSS is not available. Now I must say, we no longer have CRH in the United States. As far as I know, talking to all my colleagues across the world, there are very few places that still have it. So it's not possible to do both tests. We're doing decimopressin test in our office. And we're stimulating during IPSS with decimopressin as well. So in terms of ectopic Cushing, location number one is actually the lung. And it can be an NET, like carcinoid or a small cell lung carcinoma. Other locations, thymus, pancreas. So pancreas is not very common. But it can happen. Thyroid and rarely adrenal. 25% of them remain occult. And these patients may require bilateral adrenalectomy and then close follow-up. And you can see the different imaging modalities that my colleagues talked about. And we need to do better. And because sometimes with PET scans, if the tumor is very small, you don't see it. The role of bilateral adrenalectomy in EIS has changed a little bit now that we have so many medications available to treat Cushing syndrome. So I think the main issue here is that if the patient is uncontrolled, if they have hypercortisol that is quite severe, having an emergent bilateral adrenalectomy may actually associate mortality and definitely significant morbidity. So we really have to kind of cool things down with medicine and optimize the medical situation. So what are the indications nowadays, at least in my practice, severe hypercortisol is unresponsive to medical treatment, indolent tumor not found on serial imaging, unresectable indolent tumor or medical therapy not available or not tolerated. So I think this is my last slide. And I would like to ask my colleague if there is anything else they would like to know about this case that went into remission as a result of surgery. What happened with pituitary tumor? So obviously, initially, we did all the workup for prolactin, IGF-1, hypopituitarism, and it was absolutely normal with the exception of the STH axis. So you see here the first MRI I showed you, coronal section with plump tumor on patient's left. And then three years later, I think you can tell that it's a little bit smaller. So of course, pituitary macrodenomas can stay the same over time or increase in size or a minority of them, close to 10%, actually spontaneously decrease in size. We thought that this was an incidentally detected, non-functioning, probably gonadotroph adenoma. The shrinkage may have been in context also of patients receiving octreotide LAR for treatment of a WHOG stage 2, grade 2, neuroendocrine tumor by the oncology team. As we know, some of these tumors do harbor receptors for somatostatin. So we didn't need to do any surgery for this. And with this, I would like to thank you very much. Okay, well, I hope the audience agrees that this were two challenging cases. So we'll move on to the third one. And this is a case of a 57-year-old man who developed abdominal discomfort over six months of time. His primary care physician ordered an ultrasound of the abdomen, which showed a large adrenal mass that prompted a CT of abdomen. And that showed an 18 by 14 by 15 centimeter left adrenal mass and hepatic lesions, metastases, up to 12 centimeters in diameter. So without any hormonal workup at that time, he's referred to adrenal clinic. And this is when I see him. He knows about this adrenal mass. On history, he is very tired. He is a farmer around Mayo Clinic. He says, look, I'm irritable now. I was always a mellow man. He lost weight, 10 pounds. He says, mainly, I cannot lift anything anymore. I've lost muscle mass. At the same time, he gained weight in the abdomen. So developed abdominal obesity, has objective upper, lower, and extremity weakness, facial rounding and erythema, skin fragility, bruising, and interestingly, curling hair. He always had straight hair, but now he has curly hair, which he found interesting. New hypertension, 152 over 86, no medications, B minus 25, has new low extremity edema, multiple bruises, and several skin tears. And I've noticed on a metabolic panel done earlier that week, he was hypokalemic. Potassium was 2.7. So I've suspected overt Cushing syndrome already based on physical exam. And I have ordered a complete hormonal panel. We have also urine-steroid profiling at Mayo Clinic. And this is his results. So I would like to pause here. And ask our panelists, what do they think about this lab results? Yeah, go ahead. Sure. So, I mean, this patient, the clinical scenario, you alluded to that. And it does seem like the biochemical workup confirms ACTH-independent Cushing syndrome, right? So we see the ACH undetectable. We see the cortisol level. I mean, we don't yet have the confirmatory. Oh, no, we do. Oh, that is really high. So look down below, 24-hour urine-free cortisol over 24. So that was 1,700 with the upper normal 45. So this is like an all-hands-on-deck type of situation, very severe hypercortisol. The other thing that we note there is that the adrenal androgens, DHES, and androstened ions are not just a little elevated, they are significantly elevated. And then the precursors, so the 11-deoxycortisol is elevated. So I think what we're dealing here with is an adrenal cancer that produces both cortisol and androgen, not confirming those not-so-good news that were there from clinical evaluation and the imaging. So this is a case that requires immediate attention and treatment. Thank you. So yes, as you see, severe hypercortisol is by stage-independent androgen excess. I'm not sure if you've noticed also estrogen excess and multiple precursor excess. So really demonstrating immature estrogenesis that we see in adrenal cortical cancers, if we look for it. Dr. Bankos, can I ask a quick question about the estrogen? So would you consider this estrogen-producing, or is this peripheral conversion of those really high androgens? Well, his testosterone actually was quite low. So he had severe secondary hypogonadism, and I'm thinking probably those increased androgens were not enough to convert peripheral to testosterone and then to estrogen. So I think it was coming from the mass. Yeah. Well, I guess another thing is why order so much when we already know that it's an adrenal cortical cancer in a person with adrenal mass and metastatic disease? And I think one of the reasons to do more than just standard of care hormonal testing is to have a biomarker to follow. So every cancer is a little bit different as far as signature of steroids it produces. In this case, we have multiple biomarkers, but some would have only 11-deoxycortisol elevated or only DHA sulfate. So it's good to choose to do that before any therapy to follow along. So in the United States, we do have to have histopathological diagnosis to start chemotherapy. So we decided to biopsy liver metastasis in this case because it was easier and with less morbidity to achieve and not surprisingly, it was adrenocortical carcinoma. So what do we do next? So let me ask our panelists, what is the next step here in this patient with metastatic disease? Well, you certainly are gonna wanna leave to tone down this very dangerous situation, but you have to think about all of the things that can come with hypercortisolism and what he could be in immediate danger of, right? So when we write our board exams, they ask us, what is the next best step? It doesn't mean any of them are wrong, but at this point, you have to think about what possible complications could come this patient's way while you're trying to get a handle on this actual disease. Yes, thank you for that. So I think we are so concerned about some of the imaging presentation of metastatic cancer, we forget that this patient's at imminent danger of dying, of complication of a word Cushing's rather than the cancer itself. He's severely hypokalemic, he's severely hypercortisolemic and mortality in this case is quite high. So what are the consequences of severe hypercortisolism infection? And actually most of the data are coming from pituitary Cushing's which is not even that severe. Infection is responsible for up to a third of all deaths in patients with Cushing's syndrome, is associated with a degree or severity of hypercortisolism and there are some studies showing what kind of infections people with Cushing's usually get and it's mainly bacterial. We are concerned about opportunistic infections or both. So, we choose to empirically cover our patients with severe hypercortisol until that is resolved with sulfamethoxazole, trimethoprim, or Bactrim and this patient definitely needs something like that. The second main cause of death because of uncontrolled severe Cushing's is thrombombolism, pulmonary embolism. That is a cause of death for another third of patients with Cushing's syndrome. Again, most of the data are coming from patients with pituitary Cushing's. Again, not surprisingly associated with severity of hypercortisol and anticoagulation. Again, not surprisingly was shown to improve the risk of pulmonary embolism especially after surgery. So, this is why I always anticoagulate my patients with severe Cushing's whether it's because of metastatic adrenocortical cancer or not. So, what did we do for this patient? For risk of opportunistic infections, we started him on Bactrim. We looked at deep vein thrombosis with an ultrasound and we started anticoagulation. He did not have any DVTs and we started aggressive management of his hypertension, hypokalemia, in his case, with piranolactone and potassium supplementation, monitoring of blood pressure, and monitoring of potassium as we were titrating the dose. So, now that we are hopefully avoiding immediate mortality risk, what would be the available options to treat hypercortisol in this patient? Because remember, he has metastatic adrenocortical cancer which is currently is not fully resectable. There are some good data to remove the adrenal mass, even in patients with metastatic disease, but that by itself would not reverse the risk. So, let's ask our panelist, what do we choose then? Right, so I totally agree going after the adrenal mass at this point is both dangerous for the patient, even though there has been some optimization in terms of potential complications, but the cortisol levels are super high. So, that would not be indicated. In addition, with the multiple large liver metastasis, I think, considering the risk of hypercortisol, I think, considering systemic chemotherapy with the help of our oncology colleagues is the way to go here. And perhaps after that, surgical removal of the tumor. So, in terms of treating hypercortisol is because he has adrenal cell carcinoma, mitotane is what's approved for that. The problem with mitotane is that it will take some time until the cortisol level would react to that. So, we do have multiple other medical options in the United States for this type of adrenal cancer. We can use steroidogenesis inhibitors, and we can use those in combination with the mitotane. So, from the list that illustrates everything here. So, metiraponosilodrostar, ketoconazolevo, ketoconazole are steroidogenesis inhibitor. Mifepristone is a glucocorticoid receptor antagonist. And sometimes a combination of two or three of these are necessary. My first choice, besides the mitotane, from that list would be the oscillodrostat for two reasons. Number one, the fairly quick action time. Number two, it's very effective usually in terms of lowering cortisol levels. And number three, actually looking at those cortisol levels, seeing what's going on with them, it's helpful in titrating the medication. But there is no clear consensus in here. It's all a matter of expert opinion, what people are comfortable with. What would you do? Yeah, no, I agree, because you have such a broad dosing range for that. You have the ability to titrate up relatively quickly and monitor and watch that cortisol fall. So that would be a good choice. And I think we're gaining more and more experience and feeling more comfortable with this drug. Mifepristone, also the seismic study included patients with ACC in it. So we know it can be effective as well for this. Challenges with ketoconazole, it may work in some patients and not in others, and you don't have time. You really wanna get control of this cortisol level. So I would agree with my colleague that ozolidrostat's a really good choice, perhaps Mifepristone in this case. Well, thank you for giving this opinion. And to add to that, in the United States, we also have an issue of coverage and cost. So we actually, we did not want to use ketoconazole or levoketoconazole because of liver metastasis and already some abnormal liver function tests. We did a go with mitotin prescription, but we did know that it would not really impact hypercortisolase for weeks, maybe for month. And then it was between miteripon, ozolidrostat, and Mifepristone. And ozolidrostat was our preferred approach at that time, and it was the first one approved. So, he was planned, his own oncology team planned chemotherapy. Meanwhile, we started mitotin along with ozolidrostat, both together. Mitotin was quickly titrated to five grams a day, but again, despite quick titration, we did not see and did not expect cortisol decrease right away. Ozolidrostat, we started right away with slightly higher dose and was recommended at five milligrams twice a day, and then titrated it to seven milligrams twice a day. We did a lot of frequent monitoring for cortisol and potassium, because we've expected that his cortisol would improve, hypokalemia and blood pressure would improve, and we would have to potentially withdraw potassium supplements and spironolactone. We also taught patient how to monitor blood pressure at home and communicate with us. So, this was a successful case of very quick improvement of hypercortisols. Remember, he went from 17 to 1800 to 70 micrograms per 24 hours of cortisol on this regimen, and then almost normal urine cortisol by four months. He also responded very nicely to chemotherapy along with mitotin, because he had an interval decrease of his lesion by two to four centimeters of all lesions, including those in the liver. So, at that time, six months after starting this treatment, he was able to have debulking adrenalectomy and partial hepatectomy. So, that actually led to significant improvement of his hypercortisolism as well, so we were able to stop oselodrostat at six months. But what I want to talk about is another challenge we experienced here, and that's adrenal insufficiency management and glucocorticoid withdrawal. So, first of all, we are so concerned in general, I feel, we, including me, about Cushing's therapy, that we forget to educate our patients in depth about both glucocorticoid withdrawal and adrenal insufficiency. The common pitfalls that I see is that the titration of medical therapy is slow or it's ineffective, and then the person develops complication of hypercortisolism, or we poorly manage or anticipate adrenal insufficiency and glucocorticoid withdrawal that leads to mood changes or potential adrenal crisis in these patients. So, we tried our best to prevent that, but despite that, at two months follow-up visit, when physically speaking, patient was doing really quite well. He was on a smaller dose of mitotain, he was doing well from the oselodrostat point of view, his urine cortisol was nearly normal, his blood pressure was well-controlled, absence of hypokalemia, but he felt mentally very unwell. So, he developed significant apathy and really was suicidal with extreme fatigue and so on. And again, at that point, his cortisol in urine was still 70, so it was almost double the upper normal range and his cortisol in the morning was around 15, so that was clearly not in the adrenal insufficiency range. So, at that time, despite the fact that adrenal insufficiency did not yet develop, we concluded that the symptoms were due to severe glucocorticoid withdrawal. And we decided to start glucocorticoid therapy without waiting for cortisol to drop any further. So, we started hydrocortisone, 20 milligrams each day, and actually, that improved his symptoms almost immediately. So, think about glucocorticoid withdrawal. So, this is the almost final slide here. Again, as promised, six months later, debulking surgery, mitotain oselodrostat was stopped, mitotain because of side effects, oselodrostat because cortisol excess was resolved by that surgery. And he was feeling great one month later. He did have adrenal insufficiency after surgery. Mitotain was restarted a couple weeks later. And he did well for some more time until, ultimately, his adrenal corticoid cancer progressed and he died of disease. In summary, severe Cushing syndrome causes complications, deconditioning, and death much quicker than metastatic cancer. So, emergent treatment is required for severe Cushing. Think about DVTNP prophylaxis, infection prophylaxis, therapy to lower cortisol, and consider potency and don't be too slow. And ultimately, consider glucocorticoid withdrawal and adrenal insufficiency because our patients have to feel well going through all of this. Thank you. Thank you for all our speakers and our panelists. Just housekeeping stuff. There will be lunch served immediately after this session and there will be another talk after this session. So, please, Dr. Hisham, go ahead and ask the first question. Hisham Abu Saoud, endocrinologist, NMC Royal Hospital, Khalifa City, Abu Dhabi. Thank you for the three cases. They were very nice. My question for the second case. When you presented already, there was adrenal tumor or adrenal hyperplasia. How we say that this is not also part of NET or it's already from the hyperplasia by the hypercortisols? Yes, very good question. So, it was unilateral and it was nodular. So, my, and the high-spine units were not, were indeterminate, so they weren't low. So, you know, I looked at it with the radiologist, said most likely lipid poor adenoma because there are no other characteristics of cancer involvement. So, we thought it was incidental and unrelated but still did the workup for pheochromocytoma just to be sure before anything is done. And then we monitored it and it stayed the same over time. So, I don't think it was a hyperplasia from the high CTH levels because that would have involved both glands and it did look like a small lipid poor adenoma and those can happen. So, we had a presentation with all the prevalence from Dr. Bankos yesterday. So, I think it was just another incidental finding. Oh, the other thing is it didn't light up on the PET scan. So, oncologist obviously did several PET scans in this patient and that never had an SUV that was concerning. Okay. For the third case, only one quick question, the role of baseriotide for such patient because Mitotin is not available in most of the world. How come when we use baseriotide, somatostatin receptor antagonist? Any rule? So, remember baseriotide is a pituitary targeting drug. So, it would not work in most people with adrenocortical cancer. I don't remember anyone ever trying. Do you know Dr. Samson? Thank you. Thank you. The red shirt. My question is regarding the case of ectopic coaching. In this case, the laboratory data were going with ectopic scenario for adrenocorticotropic hormone secretion. Was it visible or wise to start with 68-gallium-2-tetate-PTCT for exploration of source of adrenocorticotropic hormone in such case? The question is, can you ask? To start with 68-gallium-2-tetate-PTCT for? Oh, yeah, no, that would have been idea, but during the COVID-19 pandemic, the list of, there were much fewer slots available. The most clinics were barely open and the cancer patients with the cancer diagnosis had priority for that unit. So, we did it later, but we couldn't do it at that time. And remember, cross-sectional CAT scan is easier to obtain and readily available, but that would have been a great option. Absolutely, yes. Thank you. Yes, last question. Go ahead. My name is Dr. Sherif Nekm from Egypt and I'd like to take your opinion about the case in Egypt, a very poor patient, 15 years old, with a state of severe hypercortisolism and a very low ACTH and all the imaging is normal. The PET scan, all the CT, all the body is normal. Okay, and my question is here, we don't have the availability of the adrenal venous assembly to confirm that the origin from the adrenals. So, should I, the best for the patient, she's 15 years old and have all the symptoms, fibrocortisone, to take off the glands or to start medication? So, you're describing a case of micronodular hyperplasia, a very rare case of ACH-independent hypercortisol because imaging would be normal and adrenal vein sampling would be not helpful because it's always bilateral disease. So, it's the only treatment that works will be bilateral adrenalectomy. Genetic testing is needed. And at this age, which would start 15, she's 15 years old. Well, that makes it more likely that it's micronodular adrenal hyperplasia or PPNAD and I guess it would not go away. So, it's all about how long do you want this lady or this child to have Cushing's before she's cured? Okay. Thank you for all your insightful cases. I'm Dr. Yaraid from Ayn Shams University. I'm asking Dr. Susan about the cases of resistant aggressive prolactinomas if we have gone through all the choices and we have left with the choice of temolizumide, how many cycles we can give? And another question, the prolactin carcinoma, when we suspect and how we can reach a diagnosis? So, with regard to the temozolomide, I always partner with my oncologist and I believe the data really shows that you can tell if someone's gonna respond in the first six months with prolactinomas. And so, you know pretty soon if they're gonna be a partial responder or responder. But I really leave that up to them because they are the experts in this area. And there's also data in combination with radiotherapy that you can have a better response. Conventional radiotherapy? It's a stub protocol, yes. So, the other part of the story here was- Prolactin carcinoma. Carcinoma. So, these are really challenging and we call them carcinoma when we see that they actually have distal metastases. It doesn't mean that other ones that don't have metastases are not as aggressive. And we don't have a lot of great choices beyond temozolomide, although there's some data on using checkpoint inhibitors, tyrosine kinase inhibitors and others. And I will tell you that I would be sending this to another colleague with more experience in that area. So, is gallium effective in prolactin carcinoma diagnosis as an imaging? I don't know. Not preferred. Okay, thank you. Thank you so much for amazing cases. I would like to ask about the second case. Should genetic testing be considered for MEN4, MEN1, maybe this? Absolutely. I mean, this patient has at least, has two components of MEN1, right? So, a neuroendocrine tumor and a pituitary adenoma. The calcium was normal and PTH levels were normal. And this was discussed with the patient in terms of genetic testing. And eventually, she had it done and the testing was negative, but this doesn't mean that we're not finding out of new pathogenic variants as they appear. So, but excellent point. Yes, absolutely. Perfect. Last one, please. Or time is up anyway. Hello. Go ahead. Thank you very much for these challenging cases. And actually, for adrenal cases, every case is a challenge. And we learn from it. Regarding second case, we presented with the hypercortisolizoma hypokalemia. And as you rightly mentioned, that's most likely October and then October. However, only last week, I have seen one patient. Similarly, emission presentation, severe hypercortisolism, chemists put down, pharma, non-eligible. Severe hypokalemia, treated in the hospital for two months for severe hypokalemia, not responding to oral IV, and high cortisol, high ACTH. Pituitary image show 0.9 centimeters. However, we did all the abdomen CTs, chest, everything. It was negative. And unfortunately, also he has hepatitis B and abnormal liver function. However, at the end, we have no option only to try. What's the question? Remove this mask. We remove this mask, 0.9. And after the operation, he's off any treatment for hypokalemia. ACTH drop down, cortisone drop down, which is to our surprise. But it was the only option to try in this patient. So again, you see how much everything. What's the question, please? Thank you for presenting this. It's very, we probably would have done the same because there are cases of severe pituitary cushing and you did find a tumor after looking everywhere. So rather than doing bilateral adrenalectomy, if the patient was able to take the transplanoidal surgery, that remission was achieved, yes.

endocrinology

pituitary disorders

adrenal disorders

prolactinomas

ectopic ACTH syndrome

neuroendocrine tumor

adrenocortical carcinoma

multidisciplinary approach

individualized care

treatment strategies