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Adrenal Incidentalomas
Adrenal Incidentalomas
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Thank you so much for this introduction, it's such a pleasure being here and especially talking on one of my favorite subjects. So I decided to make this presentation practical and I will refer to the recent guidelines from the European Society for Endocrinology. These are my disclosures. I have three learning objectives to review epidemiology of adrenal incidental illness, to review recommendation from the 2023 ECE guidelines, and select hormonal workup targeting imaging characteristics of adrenal mass. Just a definition first, adrenal incidental illness is an adrenal mass discovered serendipitously by radiological examination in the absence of symptoms of clinical findings suggestive of adrenal disease. Certainly above one centimeter, so certainly we see many more smaller lesions with higher resolution CT scans. We would see around five to seven percent of CT scans to have an adrenal mass. And in retrospect, many of these incidental illness occur in patients with active hormonal symptoms. For example, at Mayo Clinic, we found that adrenal Cushing syndrome was found incidentally in 50% of patients. We all are probably seeing many more adrenal tumors than 10 or 20 years ago. This is a graph from our study in Olmstead County, Minnesota, where we showed that since 1995 and until 2017, adrenal incidental illness increased in incidence tenfold. And most of this increase is because we find many more smaller adenomas in older patients. Those are the ones undergoing CT scans. We also found that 8% of all adrenal tumors in a population setting are cancerous. We endocrinologists mainly see adrenal cortical carcinomas, but actually the most common adrenal malignancy is a metastasis. So 7% of all malignant adrenal tumors in Olmstead County were metastasis and never get to see an endocrinologist. Those are the patients seen by our colleagues oncologists. And one of the cases that I will present today will highlight why endocrinologists need to be involved. 92% of all adrenal tumors are benign. Most of these are non-functioning, though mild autonomous cortical secretion can be seen in up to 40% of these patients. Pheochromocytomas are frequently discovered incidentally, and primary aldosterones can be frequently discovered incidentally. So the key distinguishing between malignancy and benign adrenal tumors is imaging phenotype. And I am hoping that the world will move from the size and look at the Hounsfield unit instead. Nevertheless, here's the risk of malignancy based on the size. Size does matter, it just does not matter more than density. The overall risk of malignancy in our population study was 8.6%. It was 6% in patients with adrenal masses under 2 centimeters. It was 9% in patients with adrenal tumors between 2 and 4 centimeters. And it was 34% in patients above 4 centimeters. It also means that majority of tumors above 4 centimeters were not malignant. So that was population study. What about in the endocrine clinics? And this graph summarizes data from 10,000 of patients seen at Mayo Clinic in the last 20 years, and also from the literature published on large cohorts. So if you look at all comers of patients who are seen by endocrinologists, majority would be having adenomas, 84%. 6% will be other benign tumors such as myelopomas, 4% pheochromocytomas, 4% adrenal cortical cancers, and 2% would be other malignancies, metastases. But if you look at all comers with tumor size above 4 centimeters, you'll see almost an equal distribution. Still majority would be adenomas, 31%. 16% will be other benign tumors such as myelopomas or cysts, 22% pheochromocytomas, 13% adrenal cortical cancers, and 18% other malignant tumors such as metastases and sarcomas. And here's a graph that I'm summarizing all categories of adrenal tumors, the five categories based on the median tumor size, the cut of 4 centimeters that we all seem to like, and the laterality. So the median tumor size for adenomas is around 2 centimeters, 95% of these are under 4 centimeters, and up to 20% are bilateral. How do we use this graph? Well, if we look at adrenal cortical carcinomas, the median size is 10 centimeters, so I have to admit, at least at Mayo Clinic in the last couple of years, we see more and more smaller adrenal cortical cancers. But what's important here that they're almost never bilateral. On the other hand, other malignant tumors such as metastases are very frequently bilateral, and actually most of them are under 4 centimeters. So in a patient with bilateral tumors, we have to look at every mass separately because they can have different etiologies, though majority of the patients would have the same etiology. If one is metastasis, it's very likely that the other adrenal mass is metastasis, but it's not 100% rule. That's why we have to look at those separately. So now that I gave you a bit on epidemiology, let me move to the cases. I selected four cases to illustrate several concepts that would be important in adrenal incidentalomas. I'll start with this case, a 45-year-old woman with incidental adrenal mass. She had back pain, had a CT scan, and that's when a 2.8 centimeter adrenal mass was discovered. And now, 11 years later, it is 3.8 centimeters. She has type 2 diabetes and she has obesity, and this is how CT scan is looking. And the arrow points towards a 3.8 centimeter left, not right, adrenal mass, which measures three Hounsfield units. So that brings me to one of the important recommendations from the guidelines. The guidelines recommend that all adrenal incidentalomas undergo an imaging procedure to determine whether the mass is homogeneous and lipid-rich, and therefore benign. For this purpose, non-contrast or unenhanced CT scan is recommended. And here's why. I actually have six slides on that. I think it's that important. Here's just a demonstration of a contrast-enhanced CT first done in emergency room, then a follow-up on enhanced CT showing that the adrenal mass has Hounsfield unit of 8.2. And if the Hounsfield unit is equal or under 10, the guidelines recommend announcing that this is a benign tumor and discharging this patient from the practice. And because 70% of adrenal incidentalomas would fit into this category, it would make a lot of sense to reassure and to eliminate 70% of these patients from further imaging follow-up, anxiety, and healthcare costs associated with that. I'll show this data a little bit differently. So here, again, I looked at thousands of patients with available Hounsfield unit data, again on unenhanced CT only. We cannot use Hounsfield unit from the contrast-enhanced CT scan. And I separated these patients in three categories. When we've looked at all adrenal tumors with Hounsfield unit under 10, we found that none of the theochromocytomas, adrenal cortical cancers, or malignant adrenal tumors, were in that category. None of those tumors had density under 10. But 60% of all benign tumors had Hounsfield unit under 10, and that's, again, in referral center, so we are more biased to see more lipid-poor tumors. What about all adrenal tumors with Hounsfield units between 10 and 20? So now another 26% of all benign tumors fell into this category, but also 4% of theochromocytomas, 1% of adrenal cortical cancers, and 2% of all malignant tumors. And finally, when we looked at Hounsfield unit above 20, we found that another 14% of benign tumors fell into this category, and majority of theochromocytomas, adrenal cortical cancers, and other malignant tumors. So if you find an adrenal mass with Hounsfield unit under 10, you can safely exclude theochromocytoma and any malignant mass, and it means you also don't have to test for theochromocytoma. And this is because I like the density so much, and I think we should all use it much more than we do. I also am providing another graph in the hopes to convince all my audience about rational for Hounsfield units, and this is from the guidelines that performed also systematic review and meta-analysis showing that sensitivity of Hounsfield unit above 10 was 100%. It was a little bit lower with Hounsfield units of 20. Sensitivity of 100% meaning zero false negatives. It means that in the systematic review, there were zero malignant tumors when Hounsfield unit was under 10. Okay, so in any adrenal mass, we have to look in parallel for malignancy potential, and here I showed you some data on the size and more data on Hounsfield unit. And also, independent of that, in parallel, we have to assess for hormonal excess, which means cortisol excess with dexamethasone suppression test, aldosterone excess if hypertension is present, and catecholamine excess. And if we find no adrenal hormone excess, assuming benign imaging characteristics, no further testing or monitoring is required. In overt hormone excess, we usually suggest adrenalectomy, in mild hormone excess, adrenalectomy versus monitoring depending on multiple factors. Okay, as far as assessing malignancy potential, I showed you data on the density. We'll review additional imaging soon, and otherwise, options in indeterminate adrenal tumors remain another imaging, interval imaging to look for the tumor growth. If we are worried, adrenalectomy, adrenal biopsy, only if we suspect metastasis, and never in pheochromocytomas, and hopefully never in adrenal cortical cancers and adenomas, because it's just not useful. What about hormone excess? Dexamethasone suppression test should be performed in everyone, because whether we have symptoms or not, we can, in other words, we can have abnormal dexamethasone suppression test in cortical excess in a patient who is not overtly pushing it, in mild autonomous cortical secretion. We don't want to miss that. Catecholamine excess, only if the adrenal mass is above Hounsfield units of 10, right? Because I've shown you the data that there are no pheochromocytomas with Hounsfield unit is under 10, and the tumor is homogeneous. Aldosterone excess, only if hypertension or low potassium. So let's go back to our case number one, to remind you that was a 45-year-old woman presenting with an enlarging adrenal mass, 3.8 centimeters, 18 millimeter tumor growth in 11 years. She has history of obesity and type 2 diabetes. What is the next best step in management? How comfortable are we raising our hands? Let's try it. Who votes for one milligram dexamethasone suppression test? Who is voting for number two, dexamethasone suppression test and plasma metanephrines? A few. What about same but also aldosterone run in? Who wants just to send to endocrine surgeon and not deal with it anymore? Just because you don't see each other, the majority of you voted for one, and I would say maybe 10% for two, 10% for three, and zero for four. And I agree with the majority of you, and a bit of rational here. She has some symptoms consistent with cortisol excess, or comorbidities at least, but even if she didn't, we would have needed to do that. But she does not have hypertension, so we should not test for aldosterone, and her tumor has Hounsfield unit under 10, so a pheochromatoma is not possible here. So I don't think we should be measuring for plasma metanephrines, but if it makes you feel better, you could. I just don't think if you find slight elevation, it would be because of pheochromatoma, it would be a false positive. So that's what we've done, and she actually did have abnormal dexamethasone suppression test. It was 3.4 microns per deciliter, normal is under 1.8. On a separate day, we measured her ACH and DHA sulfur, and those were low, consistent with ACTH, independent hypercortisolase. I don't have much time during this 25 minutes to talk about max, but I did want to share at least this algorithm, that if max is diagnosed, again, cortisol is above 1.8, we look for physical signs of Cushing's. And by the way, many times we do find it, but let's say we don't, if there is no signs of overt Cushing's, we diagnose max, then we look for comorbidities related to max. In this case, she does have it, diabetes and obesity. And if there are comorbidities, we confirm max, ACTH independence, and consider adrenalectomy in this case. One thing not to forget, just having adenoma and positive dexamethasone suppression test does not confirm us that this cortisol excess is adrenal. I've had quite a few patients where I measured ACH, it was high normal, and actually we ended up diagnosing pituitary Cushing's in a person with coincidental adenoma. So, let's see, I think we already did this, didn't we? Oh, okay, okay, okay, sorry. Yes, it's a different patient, never mind, thank you. I'm too excited. Okay, so this is another 45-year-old woman who was found to have an adrenal incidentaloma because of the workup for cholecystitis. And in her case, adrenal mass was discovered, it was 1.9 centimeter, an unenhanced CT scan was done, and density was, in this case, 38, so above 10. She has medical history consistent with hypertension, started on amlodipine three months ago, and finally, I get to my question. What do we do now? Who votes for one milligram dexamethasone suppression test? Okay, one milligram dexamethasone suppression test on plasma metanephrine, a few. What about same, but also aldosterone renin? Majority. Who just wants to send to endocrine surgeon? No surgeons here. Okay, well, I, again, agree with maturity. Because she has an adrenal mass with Hounsfield units above 10, we have to consider pheochromocytoma, so we have to measure plasma metanephrines. Because she has an adrenal mass, we have to consider dexamethasone suppression test, and because she has hypertension, which was new in her case, we have to consider primary aldosteronin, so aldosteronin renin, so she's a patient who needs to do it all. And we did, and as you see, dexamethasone suppression test was normal. Aldosterone and renin plasma activity were not consistent with primary aldosteronin, but she clearly had elevated plasma metanephrines and normetanephrines consistent with pheochromocytoma. I'm sometimes asked, well, but they are not like five times elevated, and we don't have to have plasma metanephrines five times elevated to diagnose it, especially when it's such a small pheochromocytoma. In fact, probably when it was seven millimeters, metanephrines probably were normal at that time. So that catecholamine production is a measure of the tumor size. Another thing, normetanephrines can be frequently false positives, but metanephrines almost never. So just the fact that she had elevated metanephrines tells me that it's a real disease. So she was diagnosed with pheochromocytoma, and that was confirmed by pathology. Okay, moving on to case number three. This is a 68-year-old man with an enlarging adrenal mass. He was found with it incidentally undergoing subsequent imaging for a renal cyst. Adrenal mass enlarged from 2.1 centimeters to 3.4 centimeters in two years, so more than what's expected in an adenoma. He has benign prosthetic hyperplasia, renal cyst. He is obese. His blood pressure is normal, no cushion good features on exam, and this is his CT scan. Here we have 1.7 centimeter adrenal mass, and that was two years ago. Household unit was 33. Now normally, he would have had to have imaging earlier than two years from then, but he didn't. So here's two years later, and it's double in size. Now it's 3.4 centimeters, and now I'm not sure if you see from here, but it's a bit heterogeneous. So the next thing that we've done, we've done workup, and we did not do aldosterone running because he does not have hypertension, but we did do plasma metanephrines because household unit was above 10, but also because it was heterogeneous adrenal mass. That was negative. We did dexamethasone suppression test, and that was abnormal. So let's look a bit at the guidelines again. He has an indeterminate adrenal mass that doubled in size in two years. I would say that by itself is a bit worrisome. What did the guidelines recommend to do in these cases? And do you see me move that? I don't know if you do. Well, maybe you don't, but if you look at this graph, this graph from the guidelines, you will see that he would fit here in the third category. He has heterogeneous tumor under four centimeter. Previously, he would have fit into the second category. I think he's, oh no, in the third still because his household unit was between, above 20, but the tumor was under four centimeters. So what do the guidelines recommend? Discuss the multidisciplinary tumor meeting. Consider proceeding with additional imaging or adrenalectomy. What other additional imaging should we consider? So I know that a lot of radiologists recommend us to do contrast washout, but more and more data coming up, even recently there was another study that published the same thing, that contrast washout is not great. There are a lot of adrenocortical cancers that have excellent contrast washout, and there are a lot of adenomas that have abnormal washout. The data are weak. Guidelines do not strongly recommend contrast washout. What about chemical shift analysis on MRI? Loss of signal intensity in and out of phase that would signal lipid content and could be done, but it doesn't really bring any extra information from the non-contrast CT scan. So if on non-contrast CT scan you have an indeterminate adrenal mass, which is lipid poor, obtaining MRI would not help you much more. Finally, the PET scan. PET scan, it's considered positive if the uptake is higher than the one in the liver. The guidelines out of this three available tests recommend PET scan as the best next test. If you really wanna do additional imaging right now, PET scan is the way to go. Now, sometimes it's unnecessary and premature, but again, here's sensitivity and specificity for the PET scan SUV max or adrenal liver ratio. As you see, it's between 85 and 100%. So both false positives and false negatives exist. False positives usually in benign functioning adenomas. False negatives in some small metastases. So he decided not to proceed with additional imaging and just said, let's remove it. So this is what we done. And actually, it was adenoma with hemorrhage, which in retrospect explains this increase in size over two years in heterogeneity. Now, what could it have been? It really was between something like this, adenoma with something else happening in it, such as a hemorrhage or adrenocortical cancer. Because remember, cortisol production was, dexamethasone suppression test was abnormal. So it cannot be anything other than a cortical tumor. So that was a good outcome for him. And this is a final case. A 66-year-old woman with early society. She had about four weeks of weight loss, nausea, weakness, and fatigue. Comes to her primary care physician who takes a good medical history. She also has hypertension, control on two medications before, but now is slightly hypotensive. She had a history of breast cancer, which was treated with bilateral mastectomy and chemotherapy six years ago and was fine since then. As you see on physical exam, she has tachycardic. Blood pressure is a bit low, but again, she is taking those two medication for medications for hypertension. And she looks ill. So the primary care physician is doing the CT scan, which shows a 12-centimeter right adrenal mass. It's heterogeneous. On unenhanced imaging, Hounsfield unit was 45, though just having heterogeneous adrenal mass is enough to be worried. And the left adrenal mass measures nine centimeter, also heterogeneous, Hounsfield unit of 39. Otherwise, no other lesions anywhere in the body. The biochemical workup was done. Once she saw us, one milligram dexamethasone suppression test was normal. She had negative plasma metanephrines and negative testing for primary aldosterone. So do note increased renin plasma activity and suppressed aldosterone here. So in this case, this patient clearly has bilateral malignant-looking adrenal masses. She has history of breast cancer. So the question is, could it be bilateral metastasis? Or could it be something else, like another extraadrenal malignancy? So this would be the case to consider biopsy, actually. I would not do steroid profiling in this test because steroid profiling would help diagnose adrenal cortical cancer. And adrenal cortical cancers are exceptionally bilateral. I've never seen a case of bilateral adrenal cortical carcinoma that is bilateral. So what would you do? Again, six to seven-year-old woman with bilateral heterogeneous, non-functioning adrenal masses. What is the next step in management? I'll just raise my hands for everything. Who votes for cortisol and ACTH? Okay, a few people. Who wants to do a PET scan? Okay, a few more. Who wants to do biopsy? Majority. What about bilateral adrenalectomy? Few more. Wow, we have like 15, 20%, 40% and the rest. Well, we have something to talk about. So I think we should do cortisol and ACTH first. I kept trying to convince you that she has adrenal insufficiency. So she has bilateral infiltrative masses. She's hypotensive now. Her readiness is high, suggestive of adrenal cortical deficiency. She lost weight, she looks ill. I actually think biopsy would be a great thing to do, but she will develop adrenal crisis if I do biopsy without diagnosing adrenal insufficiency and treating her for that, right? So I think we should first at least exclude adrenal insufficiency and then send her for biopsy. Now, out of all of this, probably bilateral adrenalectomy is the one thing that probably is least recommended just because if it's a systemic disease, I think most oncologists would prefer to treat with chemotherapy. So this is why oncology colleagues need us endocrinologists because they see a lot of these patients. We've actually, one of my mentees, Dr. Mao, who is now an endocrinologist in San Diego, looked at 565 patients with adrenal metastasis at Mayo Clinic. And he found that when he looked at bilateral adrenal metastasis, primary adrenal insufficiency was diagnosed at 12.4%. If patients had adrenal metastasis more than four centimeters, so more likelihood of adrenal cortex destruction, it was 20%. But the thing that I would like sort of to drive home, that most of these patients were never suspected or tested for adrenal insufficiency. So I actually think that many more than 12% had primary adrenal insufficiency. We just did not think about it. And mortality in the study was high. Obviously, these patients had widely metastatic disease, but nevertheless, I wonder how many of them actually died of adrenal crisis and untreated adrenal insufficiency and not the actual cancer. Okay, and this is my last slide. In summary, I hope you remember that Hounsfield unit of 10 and below does not need any concern for theochromostomal malignancy, but I recommend you measure it yourself and you don't trust the report. 10 to 20, 1 to 2% risk of malignancy in theochromocytoma. Above 20, anywhere between 5 and 20% risk, depending on other factors. If you want to do something else, as far as imaging, other than non-contrast CT scan, do PET scan. Steroid profiling, if available. Again, I did not have time to include a case on that. Adrenalectomy, especially if you have an expert, good surgeon. Biopsy, almost never. As far as hormone excess, think about dexamethasone suppression test. That's the most common abnormality you will find. Theochromocytoma test, only if Hounsfield unit is above 10. And if you have bilateral metastasis, think adrenal insufficiency before doing something else. And if a patient has only one adrenal metastasis, recommend your oncologist that if a patient does develop contralateral one, to monitor for adrenal insufficiency. Thank you so much. Thank you.
Video Summary
The presentation focuses on the practical application of recent guidelines from the European Society for Endocrinology regarding adrenal incidentalomas. These are adrenal masses discovered accidentally, typically over one centimeter, often found during routine CT scans. An increase in such findings has been noted largely due to advanced imaging technologies. The presentation aims to explain the epidemiology and recommended hormonal workup for adrenal masses, highlighting that most of these masses are benign. However, some masses demonstrate malignancy risk, requiring careful evaluation based on imaging characteristics and hormonal excess. The density measurement using Hounsfield units is emphasized to categorize masses as benign or malignant. The importance of assessing for hormonal excess, such as cortisol, aldosterone, and catecholamines, is noted in conjunction with imaging assessments to determine required medical or surgical management. Various patient cases are discussed to illustrate these concepts and the significant role of endocrinologists in patient management.
Asset Subtitle
Dr. Irina Bancos
Keywords
adrenal incidentalomas
European Society for Endocrinology
hormonal workup
Hounsfield units
benign vs malignant
endocrinologist role
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