Welcome to the session, Evaluation and Management of Suspicious Adrenal Masses. My name is Irina Benkos and I will be serving as your moderator today. You'll be hearing a lecture from Drs. Anand Vaidya, Mohammad Habra, and Katya Kislyak-Vasilyadz on this very fundamental subject. I would like to introduce our speakers. Dr. Vaidya is Director of the Center for Adrenal Disorders at Brigham and Women's Hospital and Associate Professor at Harvard Medical School. He oversees the multidisciplinary clinical care of patients with adrenal hormonal neoplastic disorders. His research has helped define the severity spectrum of primary aldosterones and optimal approaches to treating primary aldosterones. Dr. Vaidya also directs the endocrinology curriculum at Harvard Medical School and teaches about adrenal disorders at professional societies, CME events, and to fellows, residents, and students. Our second speaker is Dr. Mohammad Amir Habra, who is a professor with tenure at the Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine at the University of Texas MD Anderson Cancer Center. Dr. Habra is an oncologic endocrinologist whose clinical practice focuses on advanced endocrine tumors with special interest in adrenocortical carcinoma and thyroid carcinoma. Dr. Habra has authored more than 100 peer-reviewed articles, reviews, and textbook chapters on endocrine malignancies. And finally, our third speaker is Dr. Katia Kislyak-Vasileides, who is an assistant professor in the Division of Endocrinology, Metabolism, and Diabetes at the University of Colorado School of Medicine in Aurora, Colorado. She received her medical degree from Midwestern University in Glendale, Arizona, and then completed her internship and residency at Johns Hopkins University, where she also served as a chief resident. During her early residency, she also pursued translational research in thyroid cancer. She then relocated to Colorado, where she completed her endocrine fellowship at the University of Colorado, where she remains a faculty. Her research interests are in endocrine neoplasia. She led a project to understand the differences in growth hormone pituitary tumors, specifically in the aggressiveness, recurrence rates, variable response to medical therapies. Recently, her research interest has been in adrenocortical carcinoma, where she's spearheading the effort to create novel human ACC research model, as well as using cutting edge bioinformatic approaches to identify new therapeutic targets for this disease. Her transformative contribution in the field of ACC includes establishing several new preclinical human models in adrenocortical carcinoma, as well as development of in vivo humanized mouse model was the first report of immunotherapy study in adrenocortical carcinoma in vivo. So please help me welcome the three speakers and I'm looking forward to listen to them. Thank you. Hello, everybody. My name is Anand Vaidya. I'm the director for the Center for Adrenal Disorders at Brigham and Women's Hospital and faculty at Harvard Medical School. And my talk is gonna be entitled the Approach to the Incidentally Discovered Adrenal Mass. I believe this is one of three talks in this symposium, all focused on the approach to evaluating, diagnosing and managing adrenal masses. This talk that I'll be giving you will focus on a general overall approach to any incidentally discovered adrenal mass. And subsequently, the next two talks will focus more on malignant adrenal masses, specifically adrenocortical carcinoma. Here are my disclosures. Here are some resources. This entire talk is based on two recently published articles that are available in endocrine practice. These are both ACE publications. The first that focuses on the evaluation of incidentally discovered adrenal mass. And the second that focuses more specifically on malignant adrenal masses and adrenocortical carcinoma. Both of these articles are written in the form of case-based guidelines. So they're very much similar to the talk I'm about to give you. And hopefully you will find them to be very practical and useful in case you want to review anything that I mentioned today. It's very parallel and similar to what I'm going to tell you about. So I'm going to show you three cases today to highlight the approach to the adrenal mass. Here's case one. This is a 50 year old woman. She has normal blood pressure and she underwent a unenhanced CAT scan because she was having abdominal pain. And this is a story that may sound similar to you. The cause of the abdominal pain was not found but there was an incidental finding. And in this case, the incidental finding was a 1.2 centimeter left adrenal mass. It was described as being round and homogenous. And the right adrenal gland was described as being normal. So what happens in these situations is what does this patient need to know about this incidental finding of an adrenal mass? So as you all know, adrenal masses are common. About one to 10% of adults who undergo cross-sectional imaging such as CAT scan or MRI are incidentally found to have an adrenal mass. This prevalence tends to be higher in individuals who are older. And this prevalence is seems to be increasing as the frequency of cross-sectional imaging like CAT scan or MRI increases. Fortunately, only a small number of these turn out to be malignant, having malignancies like primary adrenocortical carcinoma or extra adrenal metastases. However, if you work at a large tertiary care medical center or in conjunction with a cancer center, you will find more and more malignant entities as cancer survival increases. Even though the majority of these adrenal masses are benign about 10 to 15% of adrenal tumors, even when benign autonomously produce adrenocortical hormones or adrenal medullary hormones. These functional tumors or productive tumors can increase the risk of various cardiometabolic outcomes such as cardiovascular disease, diabetes, osteoporosis, fracture, and more. And because of this, every single incidentally discovered adrenal tumor should undergo an evaluation. And the evaluation should focus on two questions. Is the tumor malignant or benign or is the tumor functional and or non-functional? The differential diagnosis is split up into this two by two categories. Is the tumor benign or malignant? Is it functional or non-functional? The vast majority of adrenal tumors fall in the top left category in that they are benign, non-functional, and usually adrenocortical adenomas. You could see the full list of possibilities there, but the non-functional benign adrenocortical adenoma is by far the most common. The second most common entity is an adrenocortical adenoma, benign adrenal tumor, that is functional in that it produces aldosterone or cortisol, or it may not be a solitary adenoma, but rather micro or macronodular disease capable of producing aldosterone or cortisol. It may not be an adenoma at all. It may actually be a benign functional pheochromocytoma. Less common are malignant entities that may be functional or non-functional, such as adrenocortical carcinomas, metastatic lesions from outside the adrenal and or pheochromocytoma. So what's the general diagnostic approach? Is there evidence for malignancy? Is there evidence for adrenal hormone access? And you will answer these questions by looking at three general categories. First, what are the patient's clinical characteristics? In other words, is there any signs or symptoms to suggest adrenal hormone access and or malignancy? What are the biochemical characteristics? In other words, is there laboratory evidence to suggest adrenal hormone access? And finally, what are the radiographic characteristics? We use the imaging to discern whether the tumor might be benign or might be malignant. So let's use these in an example. So the clinical characteristics as endocrinologists or practitioners of endocrinology, I don't have to review for you what we're looking for. We're looking for signs of hypercortisolism, that is signs and symptoms that may suggest Cushing syndrome. We're looking for signs of catecholamine excess, that is signs or symptoms that may suggest a pheochromocytoma or functional paraganglioma. And we're looking for signs and symptoms of aldosterone excess, that is primary aldosteronism. Now, it turns out that the vast majority of incidentally discovered adrenal masses don't have overt signs and symptoms of adrenal hormone access as you may have surmised. These are incidentally found adrenal lesions. They did not present because of signs or symptoms. So usually the signs and symptoms of adrenal hormone excess are not present or subclinical. Let's look at the radiographic phenotype. So on the left is a picture of what normal adrenal glands look like. So the adrenal glands are small and thin. You have one on each side sitting on top of the kidney on the kind of medial superior aspect of the kidney. They look like upside down Ys or Mercedes Benz symbols or peace signs without the middle strut. The left adrenal gland is usually easier to see because it's surrounded by more ample adipose tissue that highlights it. The right adrenal gland, this is a good example of it but it's often more difficult to see because it's somewhat squashed between the liver, the right kidney and the crux of the diaphragm. Here is our patient's unenhanced non-contrast CT. You can see the right adrenal is thin and it's somewhat squashed here. The left adrenal gland is somewhat of an upside down Y but there's a bulbous thing sitting here in the medial limb and body. And that is the 1.2 centimeter left adrenal mass. And it was described as having four Hounsfield unit attenuation on unenhanced CT. So what does that mean? Zero Hounsfield unit is the attenuation of water. The more negative or lower the attenuation, the more fatty it is. So negative Hounsfield units and Hounsfield units in the single digits below 10 are generally indicative of a lipid rich lesion. Higher than that 10, 15, 20 or higher is indicative of a lipid poor lesion. So here's a table that highlights some of the characteristics you might see in an adrenal mass and categorizes them into likely benign or potentially malignant. In other words, more reassuring versus less reassuring. Now, these are not hard and fast rules, but in combination, these can be helpful. For example, if the adrenal tumor has an irregular shape or heterogeneous content, necrosis or calcifications or is rapidly growing on serial imaging, this is all relatively concerning. Perhaps the most specific is the appearance on CAT scan or MRI. On an unenhanced CAT scan without contrast, if the attenuation is suggestive of a lipid rich lesion less than 10 Hounsfield units, this is almost definitely a lipid rich and benign adenoma. If the attenuation is higher than that, it may still be benign, but you start getting more worried as the attenuation rises. If you have a contrast washout protocol, meaning you check an unenhanced image, you give contrast, and then you take another picture at one minute and at 15 minutes to see how avid, contrast avid the mass is, the greater the washout, the more likely it is to be benign. So absolute washouts greater than 60% or relative washout greater than 40% is reassuring that this is likely a lipid rich and benign lesion. When the washout is less than that, it suggests potentially a more concerning or malignant lesion. MRI can also give you similar information using a chemical shift on in and out of phase imaging. And if you do see that chemical shift, it is more likely to be a lipid rich lesion. FDG avidity is generally not a good sign. Large size might be concerning, although large size is not a very specific indicator. There may be benign lesions that are large and malignant lesions that are small. So our patient had a small homogenous round lesion that had a Hounsfield unit attenuation of four on unenhanced CAT scan. This is all very reassuring and strongly suggestive of a benign lipid rich adrenocortical adenoma. So finally, the biochemical characteristics, which labs need to be performed. So testing for cortisol should be done in all incidentally discovered adrenal masses, namely because subclinical or obvious and overt cortisol excess is the most common hormonal abnormality. Some degree of hypercortisolism may be found in five to 15% of adrenal tumors. And this excess cortisol, even without the obvious signs or symptoms of Cushing syndrome may contribute to cardiometabolic disease and death. You certainly do not wanna miss a pheochromocytoma. So all adrenal tumors or most adrenal tumors should be screened for pheochromocytoma. The exception is lipid rich lesions are almost never pheochromocytomas. If you see a lipid rich adrenal mass, it's almost definitely an adenoma. And the probability that it's a pheochromocytoma is close to zero. The false positive probability of plasma metanephrines or urinary metanephrines is higher than zero. So if the adrenal lesion is lipid rich, you can forego metanephrine testing. Screening for primary aldosterism should be done, particularly in individuals with an adrenal mass and hypertension with or without hypokalemia. Benign sex hormone producing adenomas are very rare. So unless the patient has clinical signs and symptoms of virilization, testing for sex hormones is not indicated. So here's an overview of what biochemical evaluation should be done. Hypercortisolism should be evaluated in all patients with an adrenal mass. The test of choice is a one milligram dexamethasone suppression test. This is the most sensitive. Following a low dose of one milligram of dexamethasone the night before, the morning cortisol should be as low as possible close to zero. A normal value is considered to be less than 1.8 micrograms per deciliter. A value greater than five micrograms per deciliter is indicative of a failure to suppress and autonomous hypercortisolism, even without overt signs of Cushing syndrome. Values between 1.8 and five are strongly suggestive of possible and mild autonomous cortisol production. For primary aldosterism, anybody with an adrenal mass with hypertension and or hypokalemia should have a plasma renin activity or concentration along with the plasma aldosterone level measured. What you're looking for is a suppressed renin and inappropriate aldosterone production in the context of this renin suppression. The higher the plasma aldosterone in the context of renin suppression, the more likely it is to be primary aldosterone. Anybody with a lipid poor or contrast avid or heterogeneous adrenal mass should be excluded for having a pheochromocytoma using either plasma or urinary metanephrines. And as I indicated earlier, unless there's some clinical sign or symptom of virilization, adrenal androgen excess may not, adrenal androgen assessments may not be necessary. So this patient had a one milligram dexamethasone suppression test and you can see the morning cortisol was nice and low at 1.1 micrograms per deciliter, excluding the possibility of hypercortisolism. She did not have hypertension or hypokalemia and she had a lipid rich mass. So testing for primary aldosterism and pheochromocytoma was not necessary. So the biochemical phenotype of this adrenal mass is suggestive of no hormone excess. It appears to be non-functional. So this is a case of a benign non-functional adrenocortical adenoma. How should this patient be counseled? I'm gonna summarize what I just described to you into an algorithm that we'll then use in subsequent cases. When a patient is found to have an incidentally discovered adrenal mass, we should evaluate for clinical signs and symptoms of adrenal hormone excess. Should do an assessment, a laboratory assessment for biochemical hyperfunction and look at the radiologic images and radiology report for characteristics that may suggest that it to be benign or malignant. If the biochemical evaluation yields overt hormone excess and or the clinical signs and symptoms yield clinical Cushing syndrome, primary aldosterism and pheochromocytoma, you're almost definitely going to move towards surgery after you confirm the overt hormone excess and the clinical syndrome that matches it. You're gonna go for a curative surgery to remove the Cushing syndrome or primary aldosterism or pheochromocytoma. If the biochemical phenotype is non-functional or there is mild autonomous cortisol production but without a clinical syndrome of Cushing syndrome, we'll rely on the radiographic characteristics to tell us what to do next. If the radiographic characteristics are suspicious or not reassuring, meaning they have a lipid poor mass or other concerning features of a malignancy, poor contrast, washout, heterogeneity, extremely large size, necrosis, calcifications, et cetera. And this mass is unilateral. You're concerned for a primary adrenal malignancy, namely adrenocortical carcinoma should be relatively high. And you're going to move towards a surgery, particularly if it's a unilateral mass. Surgery in this case is not only diagnostic, it's also therapeutic. And when you're not sure what to do, sometimes you're in a great situation where you're not convinced that the mass is potentially malignant, but you don't have enough to reassure yourself that it's benign. You can repeat imaging in a short time interval, maybe three, no more than six months, because if the radiographic characteristics progress or worsen, rapid change in size or worsening, characteristics, features, or biochemical hormone excess, that may convince you that surgery is indicated. If the radiographic characteristics are suspicious and the patient has bilateral adrenal abnormalities or a personal history of malignancy or a personal history of immune suppression, here, you may be concerned for extra adrenal metastases to the adrenal glands and or an infection, particularly in an immune suppressed person with fungal infections or tuberculosis, if that's relevant in the history. When you're concerned for an extra adrenal metastasis or infection, this is the main time when biopsy might be helpful. So to summarize this, biopsy is helpful when you might restage an extra adrenal malignancy that will change management. You may then forego surgery and go with systemic therapy, chemotherapy, or other targeted therapy. If you were able to confirm an infection, the treatment might be systemic antimicrobials rather than surgery. So biopsy is really indicated for these two reasons. Biopsy is not indicated to discern whether it's a primary adrenocortical benign lesion versus primary adrenocortical malignant lesion. In other words, a biopsy is not indicated to differentiate a malignant adrenocortical carcinoma from a benign adrenocortical adenoma. And there are really two main reasons for that. First, adrenocortical carcinomas can be large and heterogeneous. You could stick the needle into an area that doesn't meet criteria for an adrenocortical malignancy and falsely reassures you, meaning you fail to proceed with a surgical or curative adrenalectomy. The second reason is putting a needle into an adrenocortical carcinoma can spread the disease. It can either rupture the capsule or seed the needle track. So when you suspect a malignant adrenocortical carcinoma, as we discussed a little earlier, especially if it's unilateral, surgery is diagnostic and therapeutic. If the radiographic characteristics are reassuring, they suggest a benign lesion, this is usually the most common scenario you'll find yourself in, what should you do? So if the tumor appears benign, lipid-rich, small, round, and other reassuring features, there's no high-grade evidence for surgery. There's no need to remove these. As a result, there's no high-grade evidence to support longitudinal radiographic surveillance. It turns out, if an adrenal mass appears benign on imaging, the probability that it will convert or transform into a malignancy in the future is essentially zero. In multiple longitudinal studies and cohort follow-ups, there have been only isolated cases where this has happened. And so as a result, previous recommendations to repeat serial CAT scans and MRIs are no longer indicated. There's just no good evidence to expose patients to that type of radiation and costly imaging, and there's no reason to proceed with adrenalectomy. So what should you do for these patients? If the mass is initially benign appearing and non-functional, there's no reason to even repeat biochemical imaging. The probability that a non-functional mass will turn functional is relatively low. So unless there are rapidly progressive features to suggest cortisol or aldosterone access, such as rapid weight gain, diabetes, hypertension, osteoporosis, there's no need for repeat biochemical testing. If the adrenal mass initially appeared or radiographically benign, but there was clinical evidence of autonomous cortisol production on biochemistry without obvious Cushing syndrome, the recommendation is an individualized consideration for adrenalectomy. And the reason for this kind of vague recommendation is we do not have high grade that is randomized controlled trial evidence that removing these cortisol producing tumors improves outcomes. However, we do have many observational studies and anecdotal experiences that suggest removing this cortisol excess may improve cardiometabolic outcomes. So as a result, you have to think of an individualized plan for your patient. If your patient has autonomous cortisol production without Cushing syndrome, and they have a series or constellation of core morbidities that make you think that there is a cause and effect, hypertension, obesity, diabetes, osteoporosis that are unexplained, an adrenalectomy may be the right approach for your patient. If not, you should follow these people closely, clinically and biochemically until you can make a decision that seems right for your patient. So this patient was counseled that she had a non-functional adrenocortical adenoma. She was counseled that there were no strong indications to repeat imaging. And there were no strong indications to repeat biochemical testing unless she experienced a dramatic change in her clinical symptoms suggestive of adrenocortical or medullary hormone excess. So let's move to case two and apply the same algorithm there. This is a 71-year-old woman who was found to have a new 3.8 by 2.9 by 1.9 centimeter left adrenal mass on an unenhanced CT done to evaluate abdominal pain for appendicitis. This patient had a personal history of breast cancer about 10 years ago, and the phenotype of that breast cancer was estrogen and progesterone receptor positivity and her two new negativities. She was treated with a lumpectomy and chemotherapy for seven years of an aromatase inhibitor. She's always been in complete remission, and she's had scans twice a year that have shown that she's been in remission and her adrenal glands have always looked normal. So now she has this new left adrenal abnormality. What should we tell her about this? So let's look at the images. Here you can see what the radiology report is describing as a new left adrenal mass. However, if you look at it, and this is the value of looking at the imaging yourself, it's not really a mass. It's more of a poorly circumscribed thickening or abnormality, and it has an unenhanced attenuation of 20 houndsfield units, so it's lipid poor. Actually, if you look at the images yourself, the right adrenal gland doesn't look normal either. It looks thickened or it looks like it has the same abnormality itself. So this is potentially a bilateral problem. So when you look at the radiographic characteristics, this patient has an irregular heterogeneous new, she didn't have it before, new adrenal abnormality. It has an unenhanced attenuation greater than 10, and it borders on four centimeters in one dimension, and it's bilateral. So this is not reassuring. It is suspicious, and in a patient who has a history of cancer, it does raise concern for an extra adrenal metastasis. So 1 mg dexamethasone suppressant test was normal. So the biochemical phenotype is nonfunctional. There's no evidence of hormone excess. So where are we on this algorithm? We're over here. This appears to be a nonfunctional adrenal abnormality that's new and has several suspicious features. Because this patient has bilateral abnormalities and a personal history of malignancy, there is a concern that this could be a breast cancer metastasis, and a biopsy might be helpful here. So if a biopsy shows that this is an extra adrenal metastasis, particularly in this case from breast cancer, the management might completely change to stage four breast cancer and systemic therapy. So this patient had a left adrenal biopsy guided by CT. Remember, we had already excluded a functional pheochromocytoma with plasma adenophrine, so it's safe to biopsy, and it showed malignant cells that turned out to be breast cancer, the same breast cancer profile she had before, ER, PR positive, HER2 negative. Other imaging showed there was no other signs of metastasis, these were focal to the adrenal glands. So she was started on an aromatase inhibitor for stage four recurrent breast cancer to the adrenals. And both adrenal glands had a resolution of these metastases in about one year, so successfully that she actually developed primary adrenal insufficiency, presumptively because the cancer had infiltrated sufficient amounts of her adrenal cortex. So this is an interesting case of a recurrent metastatic breast cancer to bilateral adrenal glands. And you'll see cases like this more and more as survival from breast cancer and other cancers increases with improvements in cancer therapy. Let's move to the last case. This is a 37-year-old woman who is relatively healthy, who underwent a CAT scan for right lower quadrant pain. The cause of the pain wasn't found, but there were a couple of incidental findings. The first incidental finding was a right-sided adrenal mass described as being 2.8 centimeters and having an unenhanced attenuation less than 10 ounce per unit. The second finding was a left adrenal mass that was about three centimeters with an unenhanced attenuation of 18 ounce per unit. So she was told that these are likely benign adenomas, don't worry, follow up in one year. So let's look at the imaging. Here's the right adrenal mass, and I hope you can appreciate it's a nice and round homogenous mass. You can see how dark it is compared to the liver, suggesting that it's lipid rich, and it does have a lipid rich attenuation, less than 10 ounce per unit. Here's the left adrenal mass, three centimeters. It's also relatively round and homogenous, but you could see it's darker than the right adrenal mass, suggesting that it has a higher attenuation, and it does. It has an attenuation of 18 ounce per unit. So higher than 10, but not sky high. So think about what you would tell her. How would you interpret these results? Where are we on this algorithm? It turns out we're in two places. The right adrenal mass actually appears benign. It looks like a lipid rich, round, reassuring mass, and based on its functionality, we would be in this quadrant over here. However, the left adrenal mass is not entirely reassuring. Now it's not a large, ugly looking tumor, but it does have a lipid poor attenuation. Maybe it's a lipid poor adenoma, but you have to start wondering about a potential malignancy. So you can either proceed with surgery, or if you think that's overkill, you're not sure, you can follow up in a short time interval to see whether your concerns are validated or not. Unfortunately, that's not what happened to this patient. She was effectively discharged, and she came back one and a half years later. She had no concerning symptoms, and then she underwent a biochemical evaluation that showed there was no evidence of cortisol or catecholamine excess, and repeat imaging was performed now one and a half years later. So here's the repeat imaging. You can see that the right adrenal mass is unchanged. It looked benign before, and it looks lipid rich and benign now, reassuring and expected. Unfortunately, the left adrenal mass has changed. It's larger. It's 4.3 centimeters. It's now 30 hounds full units, heterogeneous, nodular, and has fat stranding. This is concerning and more suspicious, and certainly concerning for an adrenocortical carcinoma. So she underwent a radical left adrenalectomy, and the pathology indeed did confirm a stage one, high-grade adrenocortical carcinoma. She's lucky in that it was stage one, but she's unlucky in that it was a high-grade ACC, which is one of the reasons that we do all of this workup to avoid a scenario like this. And I won't talk about adrenocortical carcinoma in detail, because the next two talks in this symposium will talk about what to do for a patient like this and beyond. So this is a case of high-grade stage one adrenocortical carcinoma, where the diagnosis was delayed because of a failure to follow up with a proper algorithmic approach. So to summarize, adrenal tumors are common. You can find them in 1% to 10% of adults. Fortunately, only a minority represent malignant entities, but even though most are benign, about 10% to 15% are hormonally active, and this hormone excess or functionality can increase the risk for cardiometabolic outcomes. And it's for these reasons that every single incidentally discovered adrenal tumor should undergo an evaluation to determine its malignant potential and its hormonal functionality. Again, here are the two key resources, ACE publications and endocrine practice, that will outline what was in this talk should you ever need them for reference. And thank you for listening. Hello, everyone. This is Mohamed Habra from MD Anderson Cancer Center, and I will be summarizing the management of advanced adrenocortical carcinoma, and I will abbreviate this in my presentation as ACC. Besides the first disclosure that the gentleman in the first slide was not me, this is also my other disclosure. I would like, again, to continue, I mean, as this is the part three of the bigger presentation, I would like to continue with the case. A young woman presented with weight gain, lower extremities edema, irregular periods, in addition to her cytosome and high blood pressure. Her hormonal evaluation included a suppressed ACTH with elevated random cortisone and elevated urine-free cortisone. In addition to that, she had elevated androgens. And you can see here, CT scan images showing a large necrotic left adrenal mass extending through the inferior vena cava all the way to the right atrium. In addition to that, there are multiple lesions in the liver suggestive of metastasis. By definition, this lady has stage four adrenocortical carcinoma, which is defined as having distant metastasis M1. So this is the only thing which makes it a stage four. And as we've heard before, I mean, stage four has the worst prognosis in ACC. This is one of the main prognostic factors in ACC. And based on the previously published data, the five-year survival is about 13% in patients presenting with stage four ACC. Another important factor to keep in mind that cortisone overproduction mainly is another poor prognostic factor, even in more localized ACC, because this is associated with increased risk for recurrence and reduced overall survival. So our lady presented with stage four. In addition to that, she has cortisone overproduction. So the summary of the outline of the management of advanced ACC, of course, there's plenty of room to do hormonal management. This has many, I mean, unique features depending on the hormonal profile. In addition to that, the importance of controlling the hormonal overproduction is well known to the audience, because having uncontrolled hypertension, uncontrolled blood glucose, poor performance status, cortisone excess, I mean, this can really limit the treatment options for the systemic disease or even make surgery more risky. So for the hormonal management for the cortisone excess, we use either enzyme blockers or glucocorticoid receptor blockers, again, depending on the situation and the patient's condition. We use myocorticoid, I mean, spirolactone and epiluronone, especially if there's hypokalemia. Regardless if there is endosterone excess or not, many of these patients with Cushing disease, they have hypokalemia and they benefit from adding these drugs too. In addition to that, sex hormone excess can be treated, but again, these are the very few cases and the clinical implications of treating sex hormone excess before surgery or chemotherapy is unclear. The key treatments which should go also for the management in these patients would be cytoreductive therapy, and I mean by that, either having surgery, whether it's adrelectomy or metastatic, depending on the situation. Even in the setting of metastatic disease, when feasible, if surgery can be done, this would be favored. There would be new publications coming sooner, just to illustrate the importance of adrelectomy when feasible in these cases. Of course, we use localized therapy, embolization, ablation or radiation therapy, depending on the situation. In addition, the third line of treatment, I mean, would be systemic therapy in these patients, having a cytoreductive plan, mitotine, which was discussed earlier, and I will summarize it, chemotherapy, targeted therapy, such as tyrosine kinase inhibitors and immunotherapy, and lastly, palliative therapy. Many of these patients, they need concomitant palliative therapy to manage their symptoms. These patients have many symptoms and many other comorbidities which need to be managed. Sometimes we use radiation as palliative measure also for symptomatic and painful metastases. The difference between ACC and other malignancies, I mean, in other malignancies, we mostly deal with the cancer morbidity, size, location, metastases, but in ACC, it's unique that there are also many complications and morbidities driven by the hormonal excess, metabolic complications, hypokalemia, hyperglycemia, among others, musculoskeletal complications. We see proximal muscle weakness sometimes. It's very severe. Patients can be bedridden or even, I mean, wheelchair, I mean, bound to their wheelchair. We see fractures even in young ages based on, I mean, having severe osteoporosis in these patients. These patients can be, I mean, immunosuppressed, having many fungal infections. I mean, one easy test, I mean, to see that is opening the patient's mouth, and oftentimes you see thrush. Other complications, hypertension, I mean, PEs, DVTs, I mean, this is part of the increased risk for PEs and DVTs in these patients. So going to the systemic therapy options, mitotain, which was discussed in earlier lectures, has been in use for almost 50 years. The efficacy of single-agent mitotain can be in the 10% to 30%, depending on the papers you read. I would expect that as a single agent to be in the 10% to 15%. In the 1970s to the 1990s, we added chemotherapy, I mean, to mitotain, and in 2012, there was a study firm act. This is the only completed Phase III randomized clinical trial in ACC, and I would like to go over the results briefly. The two most commonly used regimens were etoposide, dextrobus, and cisplatin, in combination with mitotain, and initially, we were under the impression that the efficacy rate would be close to the 50%, 55%. The other regimen is streptozoosin in combination with mitotain, and we thought the efficacy would be in the 40% or so. When these two drugs were studied in a randomized fashion, as we mentioned, through the firm act study, in red, you see the survival curve, again, the progression-free survival curve for the EDP mitotain, and in blue, the streptozoosin with mitotain. The response rates were 23% for EDP mitotain versus 9% for streptozoosin. The median progression-free survival was five months versus two months, and the overall survival was not statistically significant. There was no statistical difference between the two groups because there was a crossover between the two arms of the study. With this, we discovered, after the firm act study, that our highly toxic combination of chemotherapy with mitotain isn't as effective as we hoped and believed in the past, and there's a need to explore other treatment options. After firm act, and since we started seeing tyrosine kinase inhibitors being used in multiple malignancies, and they transformed the way we treat cancer, especially, for example, thyroid cancer and melanomas. This is the summary of the experience with these mostly anti-VGF therapy drugs. I put here, highlighted here, the EDP mitotain, just to give you the feeling, 19% immune partial response, 4% complete response. This, I'm adding these together, this is the 23%. Stable disease was initially seen in 35%. When it comes to the anti-VGF therapy, whether it's, I mean, monoclonal antibodies like bivacizumab in combination with capacitabine, sorafenib in combination with taclitaxel, other drugs, too, we haven't seen even partial responses. So, these drugs were mostly ineffective, and this could be in part because of prior mitotain use, which can render these drugs less effective by increasing the clearance of these drugs. After these multiple experiences with the tyrosine kinase inhibitors, there was a study done to explore the role of IGF-1 receptor inhibition. The reason behind that, because ACC is well known to have increased expression of IGF-2, which signals through the IGF-1 receptor. So, it makes sense to attempt to block this pathway here, and the studies which were done, either using monoclonal antibodies or a linsitinib, really did not show evidence of significant responses, and this is the data from the linsitinib study versus placebo. This study was terminated early because there was no difference in survival or outcomes between placebo and the drug. After that, I mean, in the past, I mean, eight years or so, I mean, we've been exploring many different options. So, one known mechanism for resistance to therapy in cancer is increased progression, increased signaling through the CMAT receptor, and the ligand for that is the hepatocyte growth factor. Looking at the data in ACC compared to adrenal adenomas, we've seen increased, I mean, expression of the phosphorylated CMAT, hepatocyte growth factor, and even the serum HGF levels in these patients. And looking at the data, I mean, using capozantinib, which is a drug mostly anti-BGF, but it also, I mean, targets CMAT. This is a retrospective series, which was only 16 patients, including 13 females with progressive ACC. Many of them had many lines of therapy. The median lines of therapy was three. For example, you see this case, a gentleman with, I mean, widespread metastasis, mostly in the lungs, and you see the response to capozantinib within a few months. So, the summary of this data, again, it wasn't highly effective, keeping in mind this is a group of patients that's heavily pretreated. We've seen three partial responses, five with a stable disease, and 50% of the patients had progressive disease. Because of this initial promising, I mean, data, there are two ongoing, phase two clinical studies. One in the U.S. at MD Anderson, and one in Würzburg, Germany, to study the efficacy of capozantinib in advanced ACC. Going for other lines of therapy, immunotherapy also has been introduced in the past very few years, and there is emerging data about the role of immunotherapy in ACC. So, this is a summary of two published studies in 2019 and 2020, summarizing the experience of pembrolizumab. These were two phase two studies. On the left here, you see our experience at MD Anderson. This was preliminary analysis for a bigger basket study, and there were some responses, and this is the, on the right, is the experience from the Memorial Sloan Kettering group. So, the overall, I mean, impression that the responses to single-agent pembrolizumab will be in the almost 14 to 23%, but again, more data is coming. How about combining tyrosine kinase inhibitors, such as limvatinib, with pembrolizumab? Again, this is a gentleman we treated in 2018 with progressive disease, even after failing many lines of therapy. Again, this is not FDA approved. Again, these studies will likely be very promising if done. And this is the published experience. As you can see, this is a combination, retrospective series, combining and summarizing eight patients, even after failing single agent tyrosine kinase inhibitors and immunotherapy, some patients responded to the combination. So there is, I mean, a strong feeling that the combination therapy will likely be helpful, but again, we need proof for that. So again, this is the simplified approach to these cases with advanced ACC. Advanced ACC cases, mostly metastasis or recurrent disease with metastasis, we look for, is there a room for any cytoreductive intervention? Mostly surgery, if possible. Otherwise, if not, we resort to chemotherapy and EDP mitotine, as we discussed, is our first line therapy. And if patients who are not willing or cannot have immunotherapy, they can be referred for clinical trial. If there's progression, we look for alternative therapy. Otherwise, if patients having significant progression with poor performance status, we'll look for palliative treatment only. Patients who get partial responses and they have improved performance status and surgery deemed feasible, then we send them for surgery. Otherwise, we continue treatment. And this is a summary of the available, I mean, clinical trial options as of, I mean, March 31st. I mean, there is one study, which is ongoing now in the adjuvant setting, comparing mitotine with mitotine and chemotherapy. This is the ADUVA-2 study. Other studies, mostly cabozantinib immunotherapy and heated, I mean, interoperatorial chemotherapy with surgery, combining immunotherapy with tyrosine kinase inhibitors, a vaccine trial, and combining immunotherapy with glucocorticoid receptor blocker. These are the available options for these patients. So in summary, I mean, we need a multidisciplinary team to manage these so many complex medical issues in ECC patients. The available treatment options have been associated with limited efficacy, if any, especially tyrosine kinase inhibitors had, I mean, the published data has been very negative. The combination therapy, again, immunotherapy plus other agents, whether it's mitotine, TKIs, or even glucocorticoid receptor, is promising, but we need to have a proof through clinical trials. And we need also to have innovative approach to change the ACC trajectory. Many of these patients, as we mentioned, the survival curve is very poor. So we need to have better treatment options, such as really novel vaccines or cellular immunotherapy. And with this, I would like to conclude, and I'll be more than happy to take questions. And this is my email in case someone needs to contact me after the lecture. Thank you. I would like to thank American Association of Clinical Endocrinology for the invitation to present this talk on endo-adrenocortical carcinoma approach and management of the localized disease. Here are my disclosures. The objectives for this presentation are including ACC management and surgical resection. Then we will discuss approach to ACC pathology and staging. We will also talk a little bit about adjuvant treatments for ACC and talk a little bit about mitotine as adjuvant treatment and the related endocrine anomalies. So ACC is a rare cancer with about 500 people diagnosed in the US per year in these present times. The five-year survival is less than 35%. And about 60% of patients with ACC have hormone production. Females are more common to be diagnosed than males in the ratio about two to three towards one. And people really present across spectrum of ages. Here you will see the demographic data from the TCGA cohort. And as you can see from ages 20 to 40, there is a predominance of female to male. And as you can see, the patients really present across all the ages. And here in this CT scan, you can see a representative case of ACC. As most of you know here, the masses are large and heterogeneous. So we will now go over some cases. This one is a 42-year-old female who presents to urgent care after a car accident for evaluation. She is cathartic, has elevated blood pressure slightly. On the physical exam, she's obese and she has no signs of crushing. CT scan of the abdomen is performed without contrast. And there is an incidental 4.2 centimeter right here. A left heterogeneous adrenal mass. And density is about 35 pounds per unit. Some labs were done. Cortisol is 12 and ACPH is 13. So what is the next step? As we have seen from Dr. Vaidya's presentation earlier, this is the table that really best represents the characteristics of incidentally presenting adrenal mass. Here in this column are likely benign characteristics and here are potentially malignant. So looking at our case, the adrenal mass is irregular and has heterogeneous content. It is also more than 10 pounds with units attenuation on the unenhanced CT and the size is larger than four centimeter. So taking all of these in consideration, really this mass is likely suggestive for suspicion for having a malignant potential. So the next step is what to do with this mass. And again, this slide is courtesy of Dr. Vaidya and looking at algorithm of incidentally discovered adrenal mass. So the mass is discovered. The number two thing we do is biochemical evaluation and radiographic characteristics. So it seemed like the patient did not have overt hormone access. And looking here in radiographic characteristics, more than 10 Hounsfield units, heterogeneous and large. Unilateral mass, the indication is to go to surgery. So as we continue to this case, patient had metanephins and normetanephins are normal. So ruling out heoglomus atoma, ACTH is nine, DHEAS is 850, one milligram dexamethasone suppression. Cortisol is 1.9, suggested this is a non-secreting tumor. Aldosterone and amino are normal and testosterone is normal. A CT of the adrenal, dedicated CT of the adrenal contracts is performed and 40 Hounsfield units is attenuation in 10 minute delay with 30% washout, which are all characteristics of sort of suspicious mass. There are some other non-essential labs, but potentially informative that we can get in patients that we suspect ACTH, including plasma glucose and hemoglobin A1C to look at potential pre or diabetes. 24-hour urine steroid profiling, which is now available through Mayo Clinic lab is useful, especially in the masses that are intermediate suspicion. And this is helpful to distinguish between that and ACTH. And then some of the other labs, including androsine diene, 11-deoxyprotesto and some other metabolites in the steroid pathway might be helpful. So what are the considerations? When we think of a referral to surgery, we have a general incidentaloma. When incidentaloma is larger than one centimeter on the CT scan, open adrenalectomy is indicated. If the mass is less than four centimeters, then we would consider laparoscopic resection. So what are some of the consideration in the surgical approach? So when we look at laparoscopic approach, some of the pros are lower pain, lower morbidity, shorter time to recovery, shorter hospital stay. However, the cons to this approach are potential partial or complete tumor rupture. And with that, we can get seeding of tumor cells, local recurrence, peritoneal chromosomatosis. The other issue with laparoscopic approach is less visualization of the surrounding tissues and lymph nodes. And also there is a less chance of achieving negative tumor margin. So three large retrospective studies were performed with patients anywhere between 60 to 200 patients in the study and showed less favorable recurrence and shorter survival rates in patients with laparoscopic reception compared to open. Two of the studies did not show the difference. In general, their recommendation is to perform open procedure. So open adrenal mass resection in cases where you have any suspicion for adrenocortical carcinoma. And now we will look whether surgical expertise for ACC resection also is important. So there are two studies that we will discuss. The first study is by Lombardi and colleagues published in 2012. And they looked at the differences between high volume centers and low volume centers. So the high volume centers were defined as more than 10 adrenalectomies for ACC per year and low volume centers less than 10 adrenalectomies for ACC per year. When they looked at the data, it was noted that high volume centers resected larger tumors, performed more lymph node resections and more adjuvant therapy. Despite the fact that high volume centers have tumors that are more aggressive, the local recurrence was actually lower in high volume centers compared to low volume centers, six compared to 19%. It is also important to know that the mean times the recurrence in high volume center was longer than low volume centers. Another study in Denmark looked at similarly ACC specialized centers versus community hospital and found as shown in this graph, that median survival was significantly longer in the ACC specialized centers compared to the community hospital. Five year survival, 63 compared to 42%. So really this suggests that patients with ACC should be operated in expertise centers. Next we will look what kind of pathological evaluation patients with adrenal mass, especially for ACC is required. So first is Weiss criteria. And as outlined here, it's really several different characteristics that need to be evaluated, including nuclear grade, mitotic rate, mitosis, necrosis. And all of these are assigned a score. And if the score is larger than three, this is suggestive of adrenocortical carcinoma. We then note the tumor size and weight, surgical margin, lymph node status, and adrenal extension. And then these are some of the required immunohistochemistry that needs to be done on these tumors. SF1 is shown right here, is really emerged as a most important factor showing that this is adrenocortical tissue. Alpha-inhibin is another stain shown here, then synaptopizin and melanin A. K67 is very important to have as it's a predictor for aggressive disease. And then P53 beta-catenin and mismatch repair stains could be helpful as well. So what about ACC and genetic predisposition? So this is a table that outlined some of the genetic predispositions that have been associated with ACC. And as you can see, Liprameni, MEN1, Lynch syndrome, Beckman's vitamin, and familial adrenomatosis puliposis. Out of all of these, I would probably draw your attention to Liprameni, which has been seen in cases and about three to 7% of adults with ACC can have it. And then Lynch syndrome, anywhere from three to 7% of adults as well. And these are some of the genes that we check usually first on immunohistochemistry. So now moving to case number two. So this is a patient that is 55 years old and presents with abdominal discomfort, acne and weight gain. A hypertensive physical exam shows acne around faces, central obesity, some swelling, and labs show elevated cortisol, suppressed ACTH, high DHEAS, index of methasone suppression cortisol that is 15. All of this consistent with Cushing's syndrome. CT abdomen is performed and shows 15 centimeter right adrenal mass seen right here. And CT of the body also is done and shows no evidence of metastatic disease. So resection is performed in an expert center and path shows adrenocortic carcinoma, KI67 is more than 40%. Three lymph nodes are positive and stage is defined here as a high grade stage three ACC. So what is the next treatment in this patient? So just to go a little bit over the staging system for ACC, as you can see here, stage one is really a tumor that is smaller than five centimeter, no other invasion. And then stage two is a tumor larger than five centimeter with no extra adrenal invasion. When we are starting to talk about stage three, there is usually positive lymph nodes or local extension in stage four is really metastatic disease. And our patient as presented here is stage three. So what do we do next for our patient? So these are some of the adjuvant therapy available for ACC and mitotane is really the only FDA approved therapy for patients with ACC. And as you look at here, the retrospective studies looked at benefit of adjuvant mitotane. Several studies showed significant difference here if they're not crossing one and then several studies have shown that there is no significant difference, but overall there is a trend towards positivity in this high risk disease. Then down here, looking at radiotherapy, again, several studies showed some trends towards benefit, but none of the studies actually show significant benefit as all of the studies cross one. So what about adjuvants? So randomized prospective clinical trial data is lacking. And so we know from these stage three and four retrospective studies that there's compelling evidence that mitotane associated with increase in recurrence-free survival and possibly overall survival. Stage one and two, especially with patients with KI67 less than 10% and gross resection, there is no evidence for or against mitotane and it's really a patient individualized decision. Here, there's a couple of studies. Adjuva is a study that is looking in this stage one efficacy of mitotane and should be coming out soon. And then Adjuva 2 is a study where we're looking at efficacy of chemotherapy as adjuvant treatment in high risk ACC and the study is currently recruiting. So I will talk a little bit about mitotane and associated side effects. So mitotane is usually recommended to start as soon as possible after surgery. We up titrate to three to six grams per day and usually divided in twice per day dosing. And we considered a PPI and anti-emetting to be taken along with mitotane to decrease some of the side effects. So it is important to monitor mitotane blood level and the target levels are above 14 milligrams per liter. It is also important to monitor liver enzymes and some patients have presented with liver failure and those usually present early in starting of the mitotane. So usually we like to monitor liver enzymes shortly after starting mitotane three to four weeks and then after that, every three to six months. Blood count is important also to monitor as there have been some rare cases of leukopenia, thrombocytopenia and anemia. A mitotane is also been associated with some dysregulation of hormones, specifically pituitary adrenal, pituitary thyroid and pituitary gonadal axis. And we'll talk a little bit more that in the next slides. A mitotane has also been associated with elevation in lipids and that needs to be monitored as well as a monitoring of renin. So in this slide, we'll talk a little bit about adrenal and mitotane. So this is the normal physiology and here is a patient that is on mitotane. So ACTH stimulates the cortisol production from the adrenal and so mitotane suppresses the cortisol production here in the adrenal and there is less cortisol getting secreted and there is an increase in ACTH. Mitotane also has an effect on the liver. It increases activity of CYP3A4 and it also, another effect on the liver is increases the synthesis of CBG. So as mitotane effect is bigger, we have to give patients hydrocortisone. It is an exogenous source of glucocorticoids and when patients are mitotane, since liver has increased CYP3A4, there is an increase in activity and metabolism of hydrocortisone and therefore patients will require higher doses than regular physiologic doses. So it's important to remember that mitotane in adrenal axis causes adrenal insufficiency. Also it causes higher circulating CBGs and increased CYP3A4 and therefore patients need much higher doses of hydrocortisone and glucocorticoids to achieve new adrenalism. We need to monitor ACTH running and in some patients also 24-hour urine-free cortisol. So now looking at the thyroid and effect of mitotane on thyroid. So when patients take mitotane, thyroid is actually gonna be affected on the pituitary level and it's gonna cause a low thyrotropin levels and this is gonna seem like a sick euthyroid pattern but it's really reflecting central hypothyroidism. So there is gonna be less TSH going to thyroid and therefore less T4 secreted from thyroid gland. Again, mitotane has an effect on the liver. So there is going to be increased synthesis of TBG. And of course, then again, it's gonna be increased activity of CYP3A4. So if patients are giving levothyroxine, this is gonna be metabolized faster and patients are gonna need higher doses of levothyroxine to achieve euthyroidism. So again, this is gonna be consistent with central hypothyroidism, higher circulating TBGs, increased CYP3A4 activity. Patients need higher levels of levothyroxine. And when we monitor patients to regulate these doses, we need to monitor T4 and TBG and, if possible, reliable free T4 assay, which, for example, would be by equilibrium dialysis. How about gonadal axis? Here is a normal physiology gonadal axis. When patients are given mitotin, again, the effect can be central. It can also be primary. In this case, the effect is central. There is less LH secreted binding to LH receptor in testes, which then secrete less testosterone. Then there is the mitotin effect on the liver, and here there is also increased CYP3A4 activity. Mitotin also impairs 5-alpha reductase activity, and there is increased sex hormone binding globulin production by liver. Because of all of this, patients get exogenous testosterone, which, again, is metabolized faster through the liver due to CYP3A4 activity, and we need to give patients more testosterone. So hypogonadism is usually central. There is higher circulating SHBG and increased CYP3A4 activity, also impaired 5-alpha reductase activity. We need to give patients higher doses of testosterone to achieve eugonadism and monitor testosterone and sex hormone binding globulin or free testosterone. There is a good assay. There also have been, on the women's side, some anecdotal cases of endometrial hyperplasia. Ovarian cysts are also common in women on long-term mitotin therapy, and therefore, regular assessment of menstrual irregularities need to be performed. If patients are symptomatic, pelvic ultrasounds should also be considered in that setting. So going back now to our algorithm, so we have a patient who has ACC that is amiable to complete reception, and if the complete reception is achieved, we'll look at whether the patient is low-risk or high-risk. If a patient is low-risk, we can consider mitotin. If the ACC is high-risk, we use adjuvant mitotin and then perform follow-up every three months or so with imaging and tumor markers. If the patient is tumor-free, we continue the surveillance. If there is a recurrence, then we need to decide whether the recurrence is more than 12 months or less than six months. If it's less than six months, then we proceed to algorithm for aggressive disease, which will be discussed in the next presentation. If a recurrence is more than 12 months from original diagnosis, then we go back to the algorithm, proceed with surgery, and then follow this again. So in summary, adrenocortic carcinoma is a rare endocrine malignancy. It is more commonly found in women, and it is associated with hormone production in about 60% of the cases, and this needs to be managed along with the malignancy. Surgery is the first approach to patients and only chance for cure. It is important to remember that any mass suspicious for ACC should be approached by open adrenolectomy, and it is preferred that this is performed in centers with expertise, as there have been several studies now showing better outcomes. Mitotin is the adjuvant therapy in high-risk ACC, and then in the low-risk patients, it's usually an individualized approach. Patients on mitotin should be carefully monitored. Their levels should be monitored, as well as their CBC and liver enzymes. Patients should also be monitored for endocrinopathies, and the hormones should be readily replaced. A key point here is that ACC patients should really be managed in centers with expertise that have multidisciplinary teams consisting of endocrinologists, oncologists, expert surgeons, pathologists, and radiation oncologists. And with that, I will close. I'll take any questions, and if there are any subsequent questions, you can also send me an email. Thank you very much. I would like to thank our three speakers for a wonderful presentation. Thank you for this very informative topic, and we will now go ahead and open this floor for questions and answers. Please type your questions into the chat, and we will do our best to try to address each question. So what I will do, I will go ahead with rotating questions for our speakers, starting with Dr. Voyadier. So you did mention Hounsfield unit, how informative Hounsfield units are on unenhanced CT scan, but what if the adrenal mass was discovered on contrast-only CT scan? Does it provide any value? What do you do in this case? Do you repeat imaging right away? Do you do an earlier follow-up imaging? What is your approach? Right. So that's a good question, and it's a very appropriate question because the vast majority of the more common scenario is that someone is scanned with IV contrast to look for a source of abdominal pain, and the adrenal finding is incidentally found in the course of that. So the data you have initially is just a post-IV contrast scan. So is the data useful? Ideally, you want unenhanced attenuation before having contrast imaging. It's not totally useless. I would say the two scenarios where it might be useful are the two extremes. If the Hounsfield units are low despite IV contrast, well, that's useful. That really strongly suggests a lipid-rich and non-vascular lesion that didn't enhance despite IV contrast, and you can actually make the diagnosis of a benign and likely adenoma if the Hounsfield units are very low, less than 10 or lower despite IV contrast. So that's one utility. The other is if the Hounsfield units are extremely high, you know, 100-ish or so, around the 100 mark Hounsfield units, that's concerning. Lipid-rich adenomas are unlikely to enhance that high. That might be something in the realm you might see with a pheochromocytoma that's very vascular or a malignancy. But really, if the patient has come to see you, you need to give a formal and complete assessment, and if you want to do a complete assessment, you either need a CT with unenhanced attenuation with or without washout or an MRI. And so if a patient came to see me, I would proceed with one of those because if either of those imaging techniques showed a lipid-rich and benign adenoma, they'd be done. They don't need any further imaging. There's no point in waiting a year to get to the point that you can make at that moment whenever they saw you. At our institution, when we do an adrenal washout protocol, our radiologists and techs do the unenhanced images, and if it has low Hounsfield units, they will just stop the study. They won't give the patient contrast and do the second two phases, one to minimize unnecessary contrast administration and radiation when you can get the answer on the immediate initial scan. I presume that's done at many of your places also, but just to show you that I always order an adrenal washout, and it's at the radiologist's discretion whether to proceed or not based on the initial unenhanced attenuation. So that's what I do, and if any of the other panelists would do something different, feel free to chime in. And just a related question before we move on to the next speaker. Let's say you do have unenhanced CT scan, but the Hounsfield unit is indeterminate, let's say 17. Would you find a value of getting MRI as a second test in this case? This is a, well, one I will say, head-to-head comparisons of these, I think there's none or very limited. I think generally speaking, MRI and CT for looking for lipid-rich versus lipid-poor give you overlapping information. MRI and CT do give you different information for certain features, you know, looking at adrenocortical carcinoma or pheochromocytoma, sometimes you can get different features, but if all you want to know is whether this is lipid-rich or lipid-poor and should I be concerned or not, the overlap between those two studies is very high, and it's rare that I will favor one or the other. It's really driven by kidney function, gadolinium versus contrast issues, radiation versus non-radiation issues. Thank you. Our next two questions are for Dr. Kislyak-Veseliatis. So you've mentioned mitotin therapy in patients with adrenocortical carcinoma. Could you comment on the overall tolerance to mitotin in your patients? I think we have had variable tolerance that I have read from the literature and our own experience. I think overall the tolerance can be potentially improved by two different things. The biggest issue the patients have is feeling of nausea, sometimes diarrhea, and sometimes abdominal pain. So some of the things that we have done at our institution is we try to administer PPIs along with mitotin. In fact, we do PPI twice a day, and usually we do mitotin with the biggest meals, which is breakfast and dinner. So we would give a PPI with breakfast and dinner, and also an anti-emetic. I have been sticking with Zofran mostly, and I started actually with a higher dose. So we do Zofran and PPI with meals, and then they usually take mitotin about 30 minutes after their meal is complete. In our experience, we have seen a little bit less of issues with complaints with mitotin in this way. Some patients sometimes forget to take PPI and Zofran, and then they say, well, actually, we don't have any problems anyway, so then we just don't want to take that. But we give up front everyone that just to make sure that we get them at least started the mitotin they would take it. So I would say not terrible. I don't know if the other speakers today have any other tips. Well, that leads me actually to the next question. You did mention the most common side effects to mitotin would be gastrointestinal and provided some suggestions how to avoid it. But how do you distinguish between gastrointestinal side effects due to mitotin versus to maybe suboptimally replaced adrenal insufficiency, which is a common mitotin-induced side effect? I think the biggest way to distinguish is the labs. So the first thing that we want to assess in our patients is actually the liver enzyme, as I mentioned in my presentation. Mitotin has been associated very rarely with fulminant liver failure, and so we do check LFTs because that would be one of the reasons you will get a GI upset if they have liver failure. So we usually get LFTs in about two to three weeks after starting mitotin. And the approach to adrenal insufficiency can be two different approaches. You can monitor labs in patient symptoms and start them on glucocorticoids, usually anywhere between four to eight weeks after starting mitotin, or you can just start a glucocorticoid replacement as you start mitotin, so you don't have to worry about the fact that patients are actually probably going to develop soon and then have issues with that. So those are two different approaches that somebody can do. Thank you. Dr. Habra, I have two questions for you as well. The first one, somewhat related, that's why two. I go by twos now. So first, have you observed any impact of steroid production from adrenal cortical cancer on the outcomes? I mean, definitely. Even if you do, what's published even from the Insight Group, even in stage one to three, after complete resection by experienced surgeons, verified by pathology, recurrence rate and survival is worse, actually. The outcomes are worse in the cortisol-producing ACCs, and it's even more obvious in the metastatic disease. So this is a clearly poor prognostic sign when we see mostly the cortisol production. It's still unclear about the mostly purely androgen-producing ACCs. I mean, it might sometimes reduce the comorbidities which we see with the cortisol-producing tumors, but mostly for the pure cortisol-producing tumors, prognosis is worse. Okay. And somewhat related question, in your patients with adrenal cortical cancer and severe cushions, let's say metastatic adrenal cortical carcinoma, could you share with us your favorite cocktail on how to treat this patient? So really, I mean, it depends on the patients now. I mean, with the available drugs we have, I mean, if they are hyperglycemic, I mean, potassium is okay, blood pressure is okay. Of course, I mean, I would like to combine maybe glucocorticoid receptor blocker, plus, minus, maybe spironolactone. For the others, when you see the severe hypertension, hypokalemia, I might just choose maybe an enzyme blocker, whatever is available and approved by the insurance. Oftentimes, I mean, sometimes we have no say. This is in addition, I mean, to throwing mitotane, also having a clear discussion with surgery if possible, I mean, or initiating chemotherapy. So all the wheels need to spin at the same speed. I mean, just using hormonal, I mean, management only without, I mean, other plans, it will not be, it won't lead to long-term, I mean, efficacy. So it will be short-lived efficacy if not combined with something else. Thank you. So Dr. Padilla, I see that you did respond to the aldosterone question, so I have two other then. So here we are. The first one, in your adrenal practice, considering the increase in incidence of adrenal tumors and previous reports of usual median tumor size for adrenocortical cancer at the time of diagnosing being like 10 centimeters or around that, have you noticed a shift towards diagnosing adrenocortical cancer at smaller tumor size? Well, I'll say I answered that primary aldo question because you don't want me to get started on talking on that, and I do want to take up an hour of time. I thought it would be better to respond by tech. So I haven't noticed a particular trend that ACCs we're seeing are getting smaller. We're a large referral center. We see a lot of ACCs per year, and they come from all over the place. I would say the majority of ACCs we see are not found incidentally. They're actually found symptomatically. So that I think is the breaking point. I will say, maybe a twist on your question, the number of incidental adrenal findings that are being referred to me, in part because of talks like this that we give, are increasing, and they're getting smaller and smaller. The masses are getting smaller and smaller, and PCPs are starting to do deck suppression tests and then referring to me once they're abnormal. So I think the education and awareness campaign is working. But in terms of ACC, unfortunately, the vast majority of the time, it's flank pain, abdominal pain, bloating, fluorid Cushing syndrome, or hyperandrogenism, amenorrhea, that are resulting in the predominant workups that result in diagnosis. And usually that means the diagnosis is still being at a fairly advanced stage. That's my experience, yeah. So let me ask them a question differently, maybe all panel members. What is the smallest ACC you've diagnosed over the last several years? Mine was 2.3 centimeters. What about yours? One centimeter, but it was in a patient with Li-Fraumeni who, Li-Fraumeni syndrome, TP53 mutation, was being screened annually and had a new one centimeter mass that was dense and not well appearing. We took it out, it was stage one ACC. That's pretty early. What about Dr. Habra? I've seen one centimeter in a patient who otherwise had like uterine carcinoma. This was initially thought it would be metastasis. So clinically, this lady has also Lynch syndrome. So yeah, I think in these syndromes, I mean, because they have other malignancies, you have better chance maybe to catching ACC in early stages. What about Dr. Kislyak-Basilades, the minimum size of ACC? You know, so we recently had a lady who initially presented with a 1.2 centimeter adrenal mass, actually 15 years ago, that now has presented 15 years later with, you know, eight centimeter ACC. The imaging at that time was indeterminate. So it's an interesting story, you know, for something to grow for 15 years, it's probably not happening. So there are some of these cases out there that are interesting. Okay, so this is my only like group question. I'll stay focused for the rest of the two minutes. So I have one more question for Dr. Fetty before we move on. And you presented a case of stage one adrenocortical cancer of high grade that was resected. What was your approach after adrenalectomy for this patient? I mean, let me simplify it. Observation, mitotain, something else? That's for me? Yep. Yeah, so I think the other two panelists, particularly Dr. Kislyak-Basilades just went through this algorithm. And this is, you know, the majority of ACC's are found stage three and four. You're lucky if you get diagnosed at stage one or two. But the unfortunate part is that's where there are fewer cases that there's less robust study, and there's more uncertainty. And so a lot of this is based on expert opinion. But, you know, stage one, very reassuring, high grade, less reassuring. And so the general consensus that was reviewed in the last talk was that the high grade should drive adjuvant therapy. So in that patient's case, she was actually treated with adjuvant mitotain, but not adjuvant radiation. I think at many centers, she might have received radiation, but not mitotain and or both. She did not have a recurrence. I think maybe six, seven years out, she did not have a recurrence. I will also say that she did not tolerate mitotain beyond a few months. So you could argue that she didn't really receive any adjuvant therapy and did not recur, which might actually just reflect the natural course of her disease. Got it. Okay, so maybe one last question. A frequent scenario at our institution is seeing patients only after having laparoscopic surgery elsewhere, and then finding that the diagnosis was adrenocortical carcinoma. Dr. Habro, do you treat this patient differently? Let's say surgery was one month ago, laparoscopic surgery, pathology is adrenocortical cancer. This is another risk factor, which makes me push, especially if KI67 is relatively high. It doesn't have to be 50%, even 15, 20% KI67, laparoscopic surgery, especially for larger tumors. I mean, I push for more aggressive adjuvant therapy. Oftentimes, I mean, we are not pro-radiation here, but again, with these, we worry about peritoneal carcinomatosis. So you need systemic option. Thank you. And we are out of time. This is all the time we have for today. Thank you for participating, and maybe next time we make it a longer session. Thank you.

symposium

adrenal masses

adrenocortical carcinoma

evaluation

management

incidentally discovered

diagnostic approach

treatment modalities

hormonal management

chemotherapy

immunotherapy

multidisciplinary approach