Citations

Abstract Estrogen-secreting adrenocortical carcinoma (ACC) is exceedingly rare, representing 1% to 2% of all ACCs. We present a case of a 65-year-old man diagnosed with an estrogen-secreting, 4.3-cm right adrenal mass discovered during work-up for bilateral gynecomastia. Gynecomastia and hyperestrogenism resolved after laparoscopic adrenalectomy, and pathology was reported as adrenocortical adenoma. However, 5 years later, he again developed bilateral gynecomastia because of recurrent hyperestrogenism. Imaging revealed multiple metastases in the abdomen. Urine steroid profiling demonstrated increased androgen precursors, androgen metabolites, and glucocorticoid precursors. Ultrasound-guided biopsy of one of the metastases confirmed ACC. Initial therapy included debulking surgery with removal of metastatic lesions. Mitotane therapy was initiated 4 weeks later along with hydrocortisone for anticipated mitotane-induced adrenal insufficiency. Histopathology from the adrenalectomy specimen 5 years earlier was rereviewed and confirmed ACC. Estrogen-secreting adrenal tumors are exceedingly rare, and the majority are malignant. This case underlines the importance of making an initial accurate diagnosis of adrenal malignancy that allows better surgical planning and appropriate monitoring. Indeterminate imaging characteristics of the adrenal mass, as well as the presentation with estrogen excess, suggested an elevated risk for ACC. Initial pathology-based misdiagnosis illustrates the need for an expert adrenal pathologist to review these rare tumors.

Abstract Objective Overnight metyrapone test (OMT) is a dynamic test used to diagnose secondary adrenal insufficiency (SAI). Data on OMT use and its safety are scarce. We aimed to describe the indications and safety of outpatient OMT and compare OMT to the cosyntropin stimulation test (CST). Design Single‐centre retrospective study of adult patients undergoing OMT between 1 April 2018 and 27 January 2023. Measurements OMT‐related adverse events, post‐OMT diagnosis of SAI, and OMT comparison to CST. Results OMT was performed in 114 patients (81, 71% women) at a median age of 48 (interquartile range 37–58). The pretest probability for SAI was low in 52 (46%) patients, moderate in 48 (42%) patients and high in 14 (12%) patients. Adverse events were reported in 7 (6.1%) patients and were mild except for one hospitalization. No baseline or OMT‐related factors were associated with the development of adverse events. Prevalence of the OMT‐based SAI diagnosis was 26 (23%) and 47 (46%) using 11‐deoxycortisol cutoff <7 and <10 mcg/dL, respectively. Higher pretest probability was associated with the OMT‐based diagnosis of SAI. Post‐OMT 11‐deoxycortisol cutoff of 10 mcg/dL was used most to diagnose SAI. Compared to the OMT‐based diagnosis of SAI (11‐deoxycortisol cutoff of 10 mcg/dL), the specificity of CST was 100%, but the sensitivity was only 52%. Conclusions OMT was well tolerated and used in patients with low and moderate pretest probability for SAI. CST can erroneously exclude patients with SAI. Thus, OMT should be considered in selected patients with normal CST.

Abstract Disclosure: S.A. Jacob: None. M. Itani: None. M.J. Hoegger: None. D. Ludwig: None. T. Pandian: None. T.C. Brown: None. L.M. Brunt: None. I. Bancos: None. N. Genere: None. Introduction: Adrenal mass incidence has increased tenfold over the last two decades, with most masses detected in individuals over 40 years of age. The majority of these adrenal masses are benign (&gt;80%), and few are malignant (8%) or hormonally active (4%); most are incidentally detected. Studies suggest higher rates of hormonally active and malignant adrenal masses in younger patients, however, evidence for this age group is scarce. In two recent large cohort studies of adrenal masses, young adults (18-40 years) represented only 0.2-7.1% of individuals studied. This study aimed to characterize clinical, imaging, and biochemical presentation of young adults diagnosed with adrenal masses. Methods: This is a retrospective cohort study of young adults (18-40 years) with adrenal masses detected based on a radiology report text database search between January 2015 and December 2021 at a tertiary medical center. Exclusion criteria included pre-existing adrenal masses before 2015, hyperplasia, or masses &lt;1cm. Images were reviewed by abdominal radiologists, and clinical data were obtained through review of electronic medical records. Results: A total of 255 young adults (56% women, 61% white) were diagnosed with adrenal masses with median age 35 (IQR 30-39) years. Genetic predisposition syndrome was present in 6%. Comorbidities included: BMI &gt;30 kg/m2 in 48%, hypertension in 35%, and diabetes in 10%. Adrenal masses were detected incidentally in 72% and during cancer staging in 16%. Median mass size was 1.9cm (IQR 1.4-2.7cm) and 49% (39/79) were lipid poor (Hounsfield units &gt;10). Only 22% of patients underwent hormonal evaluation. Final diagnoses included 16% malignancy, 9% benign adenoma with overt hormone excess, 40% benign adenoma with incomplete hormonal evaluation and 24% radiographically indeterminate masses. Subgroup analysis showed that adrenal masses in those &lt;30 years old compared to 31-40 year-olds were more frequently associated with tumor predisposition syndrome (15% vs 3%, p&lt;0.01) and more often lipid poor (76% vs 40%, p&lt;0.01); but, no differences in frequency of malignancy or overt hormone excess were identified. Discussion: We found a higher frequency of malignancy and overt hormonal excess in our cohort of young adults compared to previously published studies, though direct comparisons are limited by differences in methodology. These findings, in addition to high frequencies of metabolic disease in our cohort, would suggest the need for hormonal assessment in young adults; yet, this was completed in only a minority of patients. Additional areas of research may include studying hormonal status of adrenal masses in young adults in a multi-center cohort to overcome issues of selection bias and increase the rates of those with complete hormonal evaluation. Presentation: Thursday, June 15, 2023

Abstract Disclosure: S. Paknikar: None. J. McHugh: None. K. Rachmasari: None. I. Bancos: None. Introduction: Ectopic secretion of adrenocorticotropic hormone (ACTH) is a rare and severe form of Cushing Syndrome (CS) that requires an urgent specialized approach for diagnosis and management. Clinical Case: A 50-year-old woman was referred to endocrinology due to concern for CS. Over the previous year she had developed progressive weakness, edema, weight gain with abdominal fat redistribution, hypertension, and multiple compression fractures. On exam, she had a profound proximal myopathy, reported 10/10 pain along the spine, and was hypertensive (170/105 mm Hg) with normal other vitals. The patient's sodium was 141mmol/L [reference range 135-145 mmol/ L], potassium 4.1 mmol/L [3.6-5.2 mmol/L] while on spironolactone, and creatinine was 0.57 mg/dL [0.59-1.04 mg/dL]. Due to the severity of her symptoms, she was admitted to the hospital. Hormonal work up was consistent with an ACTH dependent CS: ACTH was 121pg/mL [7.2-63 pg/mL] and 24-hour urine cortisol was 645 mcg/24 hr [3.5-45 mcg/24 hr]. Workup for ACTH secreting tumor included a pituitary MRI which showed a 3 mm area of delayed enhancement in the pituitary gland, felt to be artifactual. A chest computed tomography (CT) showed a 1.3 cm low-density nodule in the right upper lobe concerning for a neuroendocrine tumor. A Gallium-68 DOTATATE Positron emission tomography/CT scan was performed and demonstrated that the nodule was highly DOTATATE avid (Krenning score of 3, scale of 0-4). These findings supported a diagnosis of ectopic CS caused by an ACTH secreting lung neuroendocrine tumor. Management of ectopic CS was twofold: addressing the underlying ACTH secreting lesion and urgent treatment of hypercortisolism and its consequences. In this case, this was achieved with CT-guided cryoablation of the right upper lobe nodule. The ACTH levels were monitored postoperatively, and when decreased (9.3pg/mL [ 7.2-63 pg/mL], glucocorticoid replacement therapy was initiated. As a result of prolonged hypercortisolism, the patient experienced multiple compression fractures and debility. Physical therapy was recommended for recovery from the compression fractures as well as proximal myopathy. Enoxaparin was initiated due to risk of venous thromboembolism from CS. From an osteoporosis standpoint, she was continued on calcium and vitamin-D supplementation and treated with weekly alendronate. Her hypertension improved allowing medication reduction. Postoperatively, she received education on adrenal insufficiency and biochemical monitoring for adrenal insufficiency recovery was implemented. Conclusion: Ectopic ACTH secreting tumors represent a rare cause of CS and effective management requires consideration of medical comorbidities to determine the approach: surgical, cryoablative, or medical therapy alone, mitigation of Cushing syndrome sequelae, and prompt recognition and treatment of glucocorticoid withdrawal. Presentation: Thursday, June 15, 2023

Abstract Disclosure: R. Gregg Garcia: None. I. Bancos: None. Background: Bilateral adrenalectomy (BLA) is a procedure with limited indications, such as bilateral pheochromocytomas and certain cases of Cushing syndrome. Impaired quality of life (QoL) has been reported in patients with primary adrenal insufficiency (PAI) due to autoimmune adrenalitis (AA). We hypothesized that, when compared to AA, patients post-BLA experience worse QoL due to sequelae of Cushing syndrome or pheochromocytoma. Objective: To compare the QoL and burden of disease in patients with PAI due to BLA versus AA. Methods: A cross-sectional study of adults with PAI due to BLA or AA, August 15 - November 26, 2022. Patients were excluded if PAI was diagnosed within one year from the enrollment date or if active malignancy was present. Participants completed a questionnaire about symptoms, burden of disease, adrenal crisis, and QoL (AddiQoL). Results: Of 120 patients with PAI, 49 (41%) had BLA, and 71 (59%) had AA. Median age was 52 years (range 23-80), without subgroup differences, but a higher proportion of women in the post-BLA vs the AA group (86% vs 69%, p=0.04). Reasons for BLA were Cushing syndrome (44, 90%) and bilateral pheochromocytomas (5, 10%). Duration of PAI was higher in patients with AA (median 12 vs 7 years post-BLA, p=0.02). The majority of patients reported wearing a medical bracelet (82%), having injectable glucocorticoid (90%), and comfort injecting (61%), without subgroup differences. Total daily hydrocortisone dose was higher in patients with AA vs patients post-BLA (mean of 23 mg vs 20 mg, p=0.03). A total of 26 (22%) patients reported at least one adrenal crisis within the last year, with a greater proportion in the post-BLA group (33% vs 14% in AA, p=0.02). No subgroup differences were noted in risk factors for adrenal crisis development, such as hydrocortisone equivalent dose, type of glucocorticoid therapy, duration of PAI, having a medic alert bracelet and injectable glucocorticoids, comfort injecting, or physical activity. Compared to AA, patients post-BLA had a similar QoL (median AddiQoL score 86 vs 84, p-value 0.72). Duration of PAI was not associated with QoL. Physical activity ≥3 times/week was associated with a better QoL (median AddiQoL score 90 vs 80 in those with lower level of physical activity, p=0.001); no subgroup differences in physical activity ≥3 times/week were found (57% in BLA vs 62% in AA, p=0.59). Since the initial diagnosis of PAI, more patients with AA reported that PAI was “harder” to manage (23% vs 6% post-BLA, p-value 0.04), with most patients reporting that management was easier (52% in AA and 63% in BLA) or not different (25% in AA and 31% in BLA). Conclusions: Despite a higher prevalence of adrenal crisis, more patients with BLA vs AA found PAI easier to manage. Moreover, patients with BLA and AA had a similar level of comfort and education managing PAI, similar QoL, and engaged in similar levels of physical activity, despite history of Cushing syndrome. Presentation: Saturday, June 17, 2023

Abstract Disclosure: M. Moazzami: Grant Recipient; Self; Rochester Epidemiology Project. S. Achenbach: None. E. Atkinson: None. I. Bancos: None. Background: Epidemiology of adrenal insufficiency (AI) is incompletely characterized with most data originating from referral centers and registries. We aimed to determine the incidence, morbidity index, risk of hospitalizations, and mortality in patients with AI living in Olmsted County, Minnesota. Methods: We assessed the standardized incidence rate, morbidity index, risk of hospitalizations and mortality of AI in residents (aged 18+) in Olmsted County, MN, USA, from Jan 1, 2005, to December 31, 2021. The data was collected using the Rochester Epidemiology Project (REP), a database of medical records for all Olmsted County residents since 1966. Incidence rates were standardized for age and sex according to the 2020 US white population. Sex- and age- matched referent subjects were selected from the REP. AI was defined based on presence of oral chronic glucocorticoid therapy (hydrocortisone, prednisone, prednisolone, or dexamethasone) defined as (1) any hydrocortisone use or (2) 6 months of consecutive use of prednisone, prednisolone, or dexamethasone or (3) two AI diagnosis codes 6+ months apart plus at least one glucocorticoid prescription within 1 year of the second diagnosis. Elixhauser morbidity index was used. Findings: Between 2005 and 2021, 5419 patients were diagnosed with AI (median age of 62 years, range 18-103), 56% women). Overall standardized incidence rates for AI increased from 206 (95% CI 174-238) in 2005 to 252 (223-280) per 100 000 person-years in 2021. At baseline, patients with AI had a higher morbidity index (median 3 vs median 1, p &lt;0.001) and a higher history of hospitalizations within 5 years prior to baseline (57% vs 30%; p&lt;0.001) when compared to referent subjects. When comparing patients with AI to referent subjects, and after adjusting for age, sex, morbidity index and prior history of hospitalizations, patients with AI were more likely to be hospitalized during follow-up (aHR 1.4, 95% CI 1.3-1.5). When comparing patients with AI to referent subjects, and after adjusting age, sex, and morbidity index, patients with AI had higher mortality (aHR 1.7, 95% CI 1.6-1.9). Patients with AI demonstrated a higher risk of dying from musculoskeletal disorders (aHR 4.9, 95% CI 2.2-10.8), respiratory disorders (aHR 4.7, 95% CI 3.3-6.6), neoplasms (aHR 2.4, 95% CI 2.0-2.9), and infectious disorders (aHR 2.3, 95% CI 1.2-4.3) than referent subjects. Interpretation: We demonstrate an increase in AI incidence between 2005 and 2021. Surprisingly, even after controlling for morbidity and prior hospitalizations, patients with AI were more likely to be hospitalized. In comparison to referent subjects, mortality was higher in patients with AI, even after adjustment for morbidity index. Presentation: Friday, June 16, 2023

Abstract Disclosure: J.P. Frias: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics. Grant Recipient; Self; Corcept Therapeutics. Speaker; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. I. Bancos: None. L. Blonde: Advisory Board Member; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.S. Busch: Consulting Fee; Self; Corcept Therapeutics. Speaker; Self; Bayer, Inc., Novo Nordisk, Amgen Inc, Eli Lilly & Company, AstraZeneca. J.B. Buse: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, GentiBio, Glycadia, Glyscend, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, Stability Health, Valo, Zealand Pharma. Consulting Fee; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Janssen, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, Dasman Diabetes Center (Kuwait), Fortress Biotech, GentiBio, Glycadia, Glyscend, Mediflix, Medscape, Mellitus Health, Moderna, Pendulum Therapeutics, Praetego, ReachMD, Stability Health, Valo, Zealand Pharma. Grant Recipient; Self; Novo Nordisk, Sanofi, VTV Therapeutics, Nanotype, NIH, NovaTarg, Tolerion, Dexcom. Stock Owner; Self; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, Stability Health. Other; Self; AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Novo Nordisk, Dasman Diabetes Institute, Zealand, Association for Clinical and Translational Science. R.A. DeFronzo: None. J.W. Findling: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. V. Fonseca: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. O. Hamidi: Advisory Board Member; Self; Corcept Therapeutics, Lantheus, Recordati Rare Diseases, Neurocrine Biosciences, Amryt, Novo Nordisk, Strongbridge. Consulting Fee; Self; Corcept Therapeutics. Y. Handelsman: Consulting Fee; Self; Amgen Inc, Applied Therapeutic, AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Corcept Therapeutics, Esperion, Mannkind Corporation, Merck, Pfizer, Inc., Novartis Pharmaceuticals, Novo Nordisk, Sanofi, Vertis. Grant Recipient; Self; Amgen Inc, Applied Therapeutic, Ionis Pharmaceuticals Inc., Regor. Speaker; Self; AstraZeneca, Bayer, Inc., Esperion, Novo Nordisk, Vertis, Amarin. R.E. Pratley: Consulting Fee; Self; Bayer, Inc., Corcept Therapeutics, Gasherbrum Bio, Inc, Hanmi, Hengrui (USA) Ltd, Merck, Novo Nordisk, Pfizer, Inc., Rivus Pharmaceuticals Inc, Sun Pharmaceutical Industries, Sanofi, Scohia Pharma Inc, Dexcom. Grant Recipient; Self; Hanmi, Metavention, Novo Nordisk, Poxel SA. Speaker; Self; Novo Nordisk. J. Rosenstock: Advisory Board Member; Self; Applied Therapeutics, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Zealand. Consulting Fee; Self; Applied Therapeutics, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Zealand. Grant Recipient; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly & Company, Hanmi, Merck, Oramed, Novartis Pharmaceuticals, Novo Nordisk, Pfizer, Inc., Sanofi. I. Tudor: Employee; Self; Corcept Therapeutics. Stock Owner; Self; Corcept Therapeutics. A.G. Moraitis: Employee; Self; Corcept Therapeutics. D. Einhorn: Employee; Self; Corcept Therapeutics. Studies suggest that the prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) is higher than is currently appreciated. A recently published meta-analysis suggests that the prevalence of hypercortisolism is higher in persons with T2D who require a greater number of antihyperglycemic agents and/or who have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we describe a 2-part phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5-11.5%) despite receiving multiple antihyperglycemic agents. The study will be conducted at approximately 30 sites in the United States. In Part 1, approximately 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test. Those responding with serum cortisol &gt;1.8 µg/dL (50 nmol/L) and dexamethasone levels ≥140 ng/dL (3.6 nmol/L) will have adrenocorticotropic hormone (ACTH), dehydroepiandrosterone sulfate, and cortisol measured in fasting blood samples obtained between 7-9 AM and a non-contrast adrenal computed tomography scan. Patients who may have ACTH-dependent hypercortisolism will be discontinued from the study and referred for further evaluation. The primary study endpoint is determining the prevalence of ACTH-independent hypercortisolism and will be evaluated in Part 1. Patients identified to have ACTH-independent hypercortisolism will advance to Part 2, a prospective, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of treatment with the glucocorticoid receptor antagonist mifepristone. Patients will be randomized 2:1 to mifepristone or placebo, stratified by the presence or absence of adrenal adenomas on CT, and receive treatment for 24 weeks. The mifepristone dose will be 300 mg once daily for 4 weeks, then increased to 600 mg daily for 20 weeks based on clinical assessment of tolerability and degree of improvement. There will be an option to increase to mifepristone 900 mg. Placebo will be titrated accordingly from 1 up to 3 tablets. Part 2 will assess the secondary endpoint of change in HbA1c from baseline to 24 weeks, as well as changes in hypercortisolism-related comorbidities (e.g., blood pressure, weight, waist circumference, quality of life). This will be the first prospective study to assess the prevalence of ACTH-independent hypercortisolism in persons with difficult-to-control T2D and the first prospective, randomized, placebo-controlled trial to assess the potential benefits and safety of treatment with mifepristone in this patient population. Presentation: Friday, June 16, 2023

Abstract Disclosure: R. Sandooja: None. A. Kittithaworn: None. P. Dogra: None. D. Gruppen: None. E. Atkinson: None. S. Achenbach: None. K. Yu: None. M. Connelly: None. V. Simha: None. R.P. Dullaart: None. I. Bancos: None. INTRODUCTION: Based on the spectrum of cortisol excess, adrenal adenomas are classified as adenomas with Cushing syndrome (CS), adenomas with mild autonomous cortisol secretion (MACS), and non-functioning adenomas (NFA). Patients with adrenal adenomas demonstrate a high prevalence of cardiovascular morbidity and mortality proportional to the degree of hypercortisolism. Evidence on whether dyslipidemia is a contributing cardiovascular risk factor in patients with NFA and MACS is discrepant. We aimed to characterize (apo) lipoprotein abnormalities across the spectrum of cortisol excess in patients with adenomas as compared to referent subjects. METHODS: Study Design: Single center cross sectional study between 01/2015 - 05/2021.Patients: Adults with NFA, MACS, or CS were consecutively enrolled. MACS was diagnosed based on post-dexamethasone cortisol &gt;1.8 mcg/dL. Referent subjects were recruited from local population of patients with available abdominal imaging and no adrenal disorders. All subjects provided fasting ethylenediaminetetraacetic acid (EDTA) venous samples. Measurements: Nuclear magnetic resonance (NMR) spectroscopy measurements included total cholesterol (TC), low-density lipoprotein (LDL) and LDL particle concentrations, high-density lipoprotein (HDL) subclasses, apolipoprotein B (apo B), triglycerides (TG) and TG-rich lipoprotein concentrations. RESULTS: Participants included 101 patients with CS (median age 44 years, IQR 31-58, 85% women), 158 patients with MACS (median age 62 years, IQR 51-70, 62% women), 166 patients with NFA (median age 60 years, IQR 53--66, 63% women) and 136 referent subjects (median age 68 years, IQR 57-77, 52% women). Patients had higher BMI (32 vs 27 kg/m2), higher prevalence of hypertension (72% vs 46%) and diabetes mellitus (27% vs 9%) as compared to reference subjects. Statin therapy was used in 32% of patients and referent subjects. After adjusting for age, sex, BMI, smoking, diabetes, hypertension, and statin therapy, as compared to referent subjects, we found inconsistent increase in TC, LDL cholesterol and TG across CS, MACS and NFA and no consistent differences in LDL size, HDL variables, TG and TG-rich lipoproteins. However, when compared to referent subjects, LDL particle concentrations- CS(OR 1.78, 95% CI 1.33-2.39), MACS (OR 1.31, 95% CI 1.03-1.67), and NFA (OR 1.43, 95% CI 1.12-1.82) and Apo B levels were higher in all patient categories: CS (OR 2.26, 95% CI 1.57-3.24), MACS (OR 1.36 95% CI 1.00-1.85 ), and NFA (OR 1.54 95% CI 1.13-2.09). These differences were particularly evident in patients not on statin therapy. CONCLUSIONS: We found that LDL particle and Apo B concentrations were elevated in all patient groups, including those with MACS and NFA. In comparison to conventional lipid measurements, LDL particle and Apo B may serve as a better biomarker of the future cardiovascular risk in patients with adrenal adenomas. Presentation: Friday, June 16, 2023

Abstract Disclosure: A. Blinder: None. K. Nanba: None. D. Sapiro: None. J. Baker: None. C. Liu: None. I. Bancos: None. M. Lyden: None. W. Young: None. H. Wachtel: None. D. Cohen: None. J. Luther: None. T.A. Williams: None. M. Reincke: None. T. Else: None. T.J. Giordano: None. A. Udager: None. W.E. Rainey: None. Background: There is accumulating evidence that changes in adrenal histology and regulation of renin-angiotensin-aldosterone system occur with age. Primary aldosteronism (PA) is the most common cause of endocrine hypertension. Recent clinical studies suggest unique characteristics of PA in elderly patients, including high prevalence of comorbidities and low clinical cure rate after adrenalectomy. However, histologic and genetic features of PA in late adulthood have not been well elucidated. Objective: To determine histologic and genetic characteristics of PA in late adulthood. Methods: Seventy-six patients who underwent unilateral adrenalectomy at the age of 60 or older were included in this study. Formalin-fixed, paraffin-embedded (FFPE) sections of resected adrenal tissue were used for the analysis. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed to identify the source of inappropriate aldosterone production. Histologic classification was made according to the HISTALDO (histopathology of primary aldosteronism) consensus. CYP11B2 IHC-guided DNA capture followed by sequencing analysis using direct Sanger sequencing or ion torrent based next-generation sequencing (NGS) was performed. Results: Median age of the studied patients was 70 (interquartile range: 64-73). Based on the CYP11B2 IHC, histologic diagnosis was made as follows; aldosterone-producing adenoma (APA, n=23), aldosterone-producing nodule (APN, n=41), and non-functioning adrenocortical adenoma (NFA, n=6). The remaining six cases had multiple CYP11B2-expressing neoplastic lesions, including APA with APN (n=2) and multiple APNs (n=4). Co-existence of NFA with APA or APN(s) was also observed in 13. Sequencing analysis revealed that somatic KCNJ5 mutation was the most frequent genetic alteration in APA (7/23, 30%), whereas somatic CACNA1D mutation was the most common genetic cause of APN (20/39 with successful sequencing, 51%). Of the 18 sequenced NFA DNA samples, two had somatic mutations in CTNNB1 (n=1) and GNAS (n=1). Conclusion: APN is the major histologic feature of PA in late adulthood. Co-existence of NFA also appears to be a frequent observation in this age population. Somatic CACNA1D and KCNJ5 mutations are common in APN and APA, respectively. Presentation: Friday, June 16, 2023