Young, William F.

Abstract Disclosure: B. Bahrani Fard: None. N. Nikravangolsefid: None. J. Maroun: None. A. Cross: None. T. Foster: None. T. McKenzie: None. W. Young Jr: None. B.M. Dy: None. M. Lyden: None. I. Bancos: None. Background: Giant pheochromocytomas (PHEO), defined based on size > 10 cm, are rare. Data on clinical presentation, management, and prognosis of giant PHEOs are scarce. Objectives: to determine prevalence of giant PHEO and compare presentation, management, and outcomes of patients with giant vs non-giant PHEOs. Methods: We conducted a single-center retrospective cohort study of consecutive patients with giant PHEO and randomly chosen patients with non-giant PHEO (referents) at 6:1 ratio, evaluated between 2000-2023. All variables were extracted from the electronic medical record. Results: Of 828 patients with PHEO evaluated between 2000 and 2023, 31 (3.7%) had giant PHEO (median size 12 cm, IQR 10.0-13.5). In comparison to referents (n=186, median size 4 cm, IQR, 2.9-5.0), patients with giant PHEO were similar in age (median age 53 vs 55 years, P=.55), more frequently discovered based on symptoms (52% vs 32%, P=.04), and less likely to be bilateral (3% vs 12%, P=.31). Genetic testing was performed in 103 (48%) of patients, without group differences, however, patients with giant PHEO were less likely to have an associated germline mutation detected (7% vs 47%, P=.004). Patients with giant PHEO had more symptoms of catecholamine excess (median of 2 vs 1, P=.04) and presented with a higher prevalence of severe metanephrine excess >10 times above upper normal range (76% vs 30%, P<.0001). Adrenalectomy was performed in 94% of patients with giant PHEOs and in 100% referents, with higher rates of open adrenalectomy in giant PHEO (86% vs 14%, P<.0001). In addition to preoperative alpha-adrenergic blockade (89%), metyrosine was used in 14 (7%) patients, mostly in patients with giant PHEO (26% vs 3%, P<.0001). Patients with giant PHEO had a longer hospital length of stay (laparoscopic: median 5 vs 2 days, P<.0001; open: median 6 vs 5 days, P=.24), and a higher complication rate (31% vs 10%, P=.006).Median follow up was 3 years (IQR 1-8) years, similar in patients and referents. Metastases developed at a much higher rate in patients with giant PHEOs (45% vs 4% in referents, P<.0001). Disease specific mortality was 7% in patients with giant PHEOs and 0% in referents. Conclusion: Patients with giant PHEO were more symptomatic, had a higher degree of catecholamine excess, and a higher rate of perioperative complications. Almost half of patients with giant PHEO developed metastases, warranting a close follow-up. Presentation: 6/2/2024

Abstract Disclosure: S. Mohan: None. O.A. Shariq: None. J.C. Andrews: None. W.F. Young: None. Background: Adrenal vein sampling (AVS) is performed in patients with primary aldosteronism (PA) to subtype surgically curable unilateral disease. During AVS, iodinated contrast is used to confirm catheterization of adrenal veins for accurate sampling. However, in patients with severe contrast allergy, the optimal method of safely and effectively confirming localization is debatable. Premedication with oral corticosteroids has raised concern for suppression of cortisol and confounding of AVS results. We therefore investigated our experience of AVS after corticosteroid premedication in patients with PA and iodine contrast allergy. Methods: Patients with PA who underwent AVS at our center under continuous cosyntropin infusion (50 mcg/hr started 30 minutes before sampling) between September 1990 - October 2023 were identified. Individuals with documented allergy to iodinated contrast who received corticosteroid premedication were matched 1:1 for age and sex with control patients without contrast allergy or premedication. Baseline demographics, biochemical variables, AVS results, and follow-up data were compared between groups. Results: 1273 AVS studies were performed in 1255 patients with PA and 35 (2.8%) patients received corticosteroid premedication for contrast allergy. Methylprednisolone was used in 32 (91.4%) patients while dexamethasone was used in the rest. No patients experienced a severe breakthrough allergic reaction. Mean age was similar in cases vs. controls (53.9 vs. 54.1 years, P=0.92) with 16 females (45.7%) per group. There were no significant differences in baseline aldosterone-to-renin ratios (57.7 vs. 49.3, P=0.57) or daily defined doses of antihypertensives (5.5 vs. 4.4, P=0.21) between the two groups. Absolute cortisol levels (mcg/dL) from both adrenal veins (AV) and the inferior vena cava (IVC) were similar between cases and controls (right AV: 752.5 vs. 813.7, P=0.48; left AV: 527.2 vs. 462.7, P=0.33; IVC: 23.1 vs. 24.5, P=0.18). The ratio of cortisol in the corresponding AV to the IVC (selectivity index) was >5 in all patients, confirming appropriate cannulation, with similar mean selectivity indices between groups (right AV: 33.0 vs. 33.7, P=0.86; left AV: 22.8 vs. 19.0 P=0.17). Unilateral disease (indicated by a lateralization index >4) was present in 20 (57.1%) patients who received premedication compared with 16 (45.7%) controls (P=0.34). Surgery for unilateral disease was performed in 16 cases and 12 controls, with similar post-op day 1 aldosterone levels in both groups (3.8 vs. 3.3, P=0.36), consistent with surgical cure. Conclusion: In patients with PA and iodine contrast allergy, premedication with corticosteroids prior to cosyntropin-stimulated AVS does not significantly suppress cortisol levels or affect interpretation of AVS results, with comparable rates of disease subtyping and surgical outcomes when compared to a control group. Presentation: 6/3/2024

Abstract Disclosure: M.D. Figueiredo: None. J. Wagoner: None. W.F. Young: None. L.M. Fishbein: None. M.T. McDermott: None. Introduction: Primary aldosteronism (PA) accounts for at least 5% of hypertension cases and up to 20% of resistant hypertension. Underdiagnosis leads to delayed treatment and increases cardiovascular morbidity and mortality. Our objective was to assess the impact of an educational series for primary care providers (PCPs) on increasing screening rates for PA. Methods: Educational intervention consisted of a 5-day, 2-minute email series for 111 PCPs on PA screening, confirmation, and treatment (trained group). Following the training, EMR data were extracted for patients with PAC (plasma aldosterone concentration) or PRA (plasma renin activity), new hypertension diagnosis code, or a new MRA prescription within 1 year pre- or post-intervention and data pre- and post- intervention were compared. A proper screen included sending both PAC and PRA simultaneously. IRB approval was obtained. Results: In the pre-intervention year, 57 patients were properly screened for PA by the 111 PCPs. Post-intervention, 151 patients were screened for PA showing a 2.65-fold increase in screening with the educational intervention. Using a paired T-test across quartiles pre- and post-intervention, this increase was statistically significant (P=0.0148). We further demonstrated a sustained effect throughout the 12 months post-intervention per quartile (Q+1 n=29, Q+2 n=45, Q+3 n=33, Q+4 n=42). Of the total cohort screened (both pre- and post-intervention), 28% had a positive screen for PA (defined liberally as PAC >5 ng/dL with PRA <1 ng/mL/h). Discussion: The educational intervention drove an increase in PCP screening for PA in the year post-intervention and this increase was sustained across all quartiles of the year. Of the screened cohort (pre- and post-intervention), 28% screened positive for PA, and those patients were more frequently referred to specialists post-intervention. Our study has some limitations, including the relatively small sample size of PCPs educated and patients screened, and the 2020 start to the COVID-19 pandemic impact during the post-intervention period. Conclusion: Our findings advocate for continued education to reinforce PA screening criteria using an easy, not time consuming and effective educational tool. Continuous education is crucial to reinforce next steps in confirmation and treatment. Presentation: 6/3/2024

Abstract Disclosure: A.Y. Chang: None. D.Z. Erickson: None. W.F. Young: None. K. Grennan: None. J.C. Andrews: None. E. Kapoor: None. Background: While mild androgen excess is frequently encountered in endocrine practices, severe symptoms, rapid onset or markedly abnormal biochemical testing lead to further evaluation for rare ovarian androgen-producing tumors, ovarian hyperthecosis or androgen-secreting adrenal tumors. Combined ovarian and adrenal vein sampling (COAVS) might be necessary to identify the source of androgen hypersecretion and guide treatment. The utility of COAVS has been studied in limited case series, combining case reports and different centers. There is no consensus regarding the testosterone gradient that localizes the androgen source or the added value of COAVS when a pathologic source of androgen excess is suspected. The additional clinical benefit of adrenal vein sampling (AVS) when combined with ovarian vein sampling (OVS) has also not been examined. Objectives: We sought to determine: a) the optimal total testosterone (TT) gradient for identifying unilateral vs bilateral source of hyperandrogenism and b) the utility of AVS in addition to OVS. Methods: We performed a retrospective chart review of all adult women who had COAVS at Mayo Clinic, Rochester from 1996 to 2023. Pathologic sources of androgen excess were defined as ovarian hyperthecosis (OH) as well as ovarian and adrenal tumors. We calculated the ratio of dominant OV or AV divided by the nondominant OV or AV. Results: 22 COAVS procedures from 7 premenopausal and 15 postmenopausal women were included in the study: 12 (55%) women had adrenal abnormalities seen on computed cross sectional imaging and 5 (23%) had unilateral ovarian imaging abnormalities. Of the 22 participants in the case series, successful 4-vessel catheterization was completed in 20 (1 right ovarian vein could not be cannulated, and 1 had bilateral oophorectomy). Nine (41%) women had unilateral and 10 (45%) bilateral ovarian androgen hypersecretion. Eleven (50%) women had pathologic causes for elevated TT (5 ovarian tumors, 6 cases of OH), 5 lacked follow-up pathology and 5 had benign pathology. AVS did not diagnose an adrenal source of androgen hypersecretion. TT concentrations were significantly greater in patients with unilateral compared to those with bilateral ovarian androgen hypersecretion (median 262.5 ng/dL [245- 401.5 IQR] vs 104 ng/dL [82-190], P = 0.01). In addition, TT concentrations were higher in those women with a pathologic source of TT hypersecretion compared to those with benign ovaries (349 ng/dL [251-538] vs 115 ng/dL [93-195], P = 0.03). All cases of unilateral ovarian disease had a dominant OV gradient of TT ≥ 2.1 compared to the nondominant OV. Conclusion: In a series of successful COAVS in women with androgen hypersecretion, an ovarian side-to-side gradient of ≥ 2.1 diagnosed all sources of unilateral ovarian pathology. AVS did not diagnose any pathologic source of adrenal androgen excess in this patient cohort. Presentation: 6/3/2024

Abstract Context Data on giant pheochromocytomas (PHEOs), defined based on size 10 cm or greater, are scarce. Objective This work aimed to compare presentation, management, and outcomes of patients with giant vs non–giant PHEOs. Methods A retrospective cohort study was conducted in a referral center from 2000 to 2023. Consecutive patients with giant PHEOs and randomly chosen patients with non–giant PHEO (referents) were studied at a 1:6 ratio. Outcomes included perioperative complications, metastases, and mortality. Results Of 828 patients with PHEOs, 31 (3.7%) had giant PHEO (median size 12 cm, interquartile range [IQR] 10.0-13.5 cm). In comparison to referents (n = 186, median size 4 cm, IQR, 2.9-5.0 cm), patients with giant PHEO had more symptoms of catecholamine excess (median of 2 vs 1; P = .04) and presented with a higher prevalence of severe catecholamine excess (76% vs 30%; P < .0001). Adrenalectomy was performed in 94% of patients with giant PHEOs and 100% of referents. In addition to preoperative α-adrenergic blockade (89%), metyrosine was used in 14 (7%) patients, mostly in patients with giant PHEOs (26% vs 3%; P < .0001). Patients with giant PHEOs had a higher perioperative complication rate (31% vs 10%; P = .004). During a median follow-up of 3 years, metastases developed at a higher rate in patients with giant PHEOs (45% vs 4% in referents; P < .0001). Disease-specific mortality was 7% in patients with giant PHEOs and 0% in referents (P = .02). Conclusion Patients with giant PHEOs compared to referents were more symptomatic, had a higher degree of catecholamine excess, and had a higher rate of perioperative complications. Almost half of patients with giant PHEOs developed metastases, warranting close follow-up.

Abstract Objective The aim of this study is to assess whether clinical and imaging characteristics are associated with the hormonal subtype, growth, and adrenalectomy for incidental adrenal cortical adenomas (ACAs). Design This is a single-center cohort study. Methods Consecutive adult patients with incidental ACA were diagnosed between 2000 and 2016. Results Of the 1516 patients with incidental ACA (median age 59 years, 62% women), 699 (46%) had nonfunctioning adenomas (NFAs), 482 (31%) had mild autonomous cortisol secretion (MACS), 62 (4%) had primary aldosteronism (PA), 39 (3%) had Cushing syndrome, 18 (1%) had PA and MACS, and 226 (15%) had incomplete work-up. Age, sex, tumor size, and tumor laterality, but not unenhanced computed tomography Hounsfield units (HU), were associated with hormonal subtypes. In a multivariable analysis, ≥1 cm growth was associated with younger age (odds ratio [OR] = 0.8 per 5-year increase, P = .0047) and longer imaging follow-up (OR = 1.2 per year, P < .0001). Adrenalectomy was performed in 355 (23%) patients, including 38% of MACS and 15% of NFA. Adrenalectomy for NFA and MACS was more common in younger patients (OR = 0.79 per 5-year increase, P = .002), larger initial tumor size (OR = 2.3 per 1 cm increase, P < .0001), ≥1 cm growth (OR = 15.3, P < .0001), and higher postdexamethasone cortisol (OR = 6.6 for >5 vs <1.8 μg/dL, P = .002). Conclusions Age, sex, tumor size, and laterality were associated with ACA hormonal subtype and can guide diagnosis and management. Tumor growth was more common with younger age and longer follow-up. Unenhanced HU did not predict hormonal subtype or growth. Adrenalectomy for MACS and NFA was mainly performed in younger patients with larger tumor size, growth, and elevated postdexamethasone cortisol.

Abstract Disclosure: O.A. Shariq: None. T.J. McKenzie: None. W.F. Young: None. Background: Multiple endocrine neoplasia type 2B (MEN2B) is most commonly caused by a germline methionine-to-threonine substitution at codon 918 (M918T) of the RET proto-oncogene. The syndrome is characterized by medullary thyroid carcinoma, pheochromocytoma, and extra-endocrine manifestations (intestinal ganglioneuromas, mucosal neuromas, and skeletal and ophthalmic abnormalities). We describe a patient with MEN2B and bilateral pheochromocytomas, in whom the slow-growing nature of the lesions, and previous history of an extra-endocrine manifestation, precluded the typical approach to surgical resection. Clinical Case: A 58-year-old-male with MEN2B, diagnosed at age 15, presented with a 6-month history of episodic palpitations and labile blood pressures. His past surgical history included a total abdominal colectomy and ileorectal anastomosis at age 7 years for megacolon, secondary to intestinal ganglioneuromatosis. He subsequently required multiple laparotomies and adhesiolysis procedures for recurrent small bowel obstructions. During his most recent laparotomy at age 44, he was noted to have a ‘frozen’ abdomen with dense adhesions involving the small bowel. CT abdomen revealed bilateral adrenal masses, measuring 2.9 cm and 1.5 cm on the right and left, respectively. Review of previous imaging revealed that the right adrenal mass had been present 16 years prior, measuring 1.0 cm at that time, while the left-sided mass was not seen. Biochemical workup was negative previously, but now showed elevated plasma metanephrine (4.1 nmol/L [N<0.5 nmol/L ]) and normetanephrine 2.3 nmol/L [N<0.9 nmol/L ]) levels. In the setting of extensive intra-abdominal adhesions and the slow-growing nature of both masses, the decision was made to perform a unilateral right adrenalectomy through a retroperitoneoscopic, rather than a transabdominal, approach. Pathology confirmed a 4.4 cm pheochromocytoma. The patient was discharged on postoperative day 1 and was symptom free at 1 year follow-up. His most recent plasma metanephrine and normetanephine levels were 0.7 nmol/L and 0.5 nmol/L, respectively. Clinical Lessons: Patients with MEN2B have a 50% lifetime risk of developing pheochromocytoma. Unlike medullary thyroid cancer, which exhibits an aggressive phenotype in this syndrome, MEN2B-associated pheochromocytomas may be slow growing, thereby avoiding the need for an initial bilateral adrenalectomy. Many patients with MEN2B develop gastrointestinal manifestations, including megacolon during infancy, for which multiple surgical interventions may be required. These procedures carry a risk of adhesion formation, which presents a challenge if further abdominal surgery is required later in life for pheochromocytoma. Retroperitoneoscopic adrenalectomy provides a safe approach in such patients, as the need to perform risky adhesiolysis and mobilize adjacent organs is obviated. Presentation: Saturday, June 17, 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

Abstract Disclosure: S. Rolak: None. N. Venkatesan: None. R. Gregg Garcia: None. W.F. Young: None. I. Bancos: None. Background: Bilateral primary hyperaldosteronism (PA) is treated with mineralocorticoid receptor antagonist (MRA) therapy. However, the best way to monitor the success of MRA therapy is unclear. Aims: To compare the impact of curative adrenalectomy versus MRA therapy in patients with PA on plasma renin activity (PRA), renal function, and hypertension control. Methods: Single center retrospective study of patients with unilateral PA treated with adrenalectomy or bilateral PA treated with MRAs, 2017-2021. Patients underwent adrenal vein sampling to confirm laterality. Hypertension control was defined based on blood pressure measurements and the standardized hypertension daily dose (HDD). Minimum follow-up was defined as first nonsuppressed PRA or >1 month from therapy. Results: Of 73 patients, 53 underwent unilateral adrenalectomy for unilateral PA (median age 57, range 25-71 years, 36% women) and 20 had bilateral PA treated with MRA (median age 49, range 30-70 years, 70% women). At baseline, when compared to the bilateral PA, patients with unilateral PA had higher plasma aldosterone concentrations (median 31 ng/dL vs 19 ng/dL, P= 0.001), similarly suppressed PRA, and similar estimated glomerular filtration rate (eGFR). Uncontrolled hypertension (>130/90 mmHg) was seen in 40 (75%) of patients with unilateral PA and 14 (70%) patients with bilateral PA, despite a more intensive antihypertensive regimen in unilateral PA (median HDD 5, range 1-18 vs median HDD 3.5 in bilateral PA, range 0.5-9; P=0.016). Hypokalemia was present in 50 (94%) patients with unilateral PA and 15 (75%) in bilateral PA, P = 0.02.Following treatment, hyperkalemia developed in 10 (19%) patients post-adrenalectomy and in 2 (10%) patients treated with MRAs, P = 0.36. At a median follow up of 108 days, 24 (45%) patients treated with adrenalectomy and 16 (80%) patients treated with MRAs demonstrated PRA >1.5 ng/mL/hr, P = 0.008. eGFR decreased by at least 10 points in 15 (30%) patients treated with adrenalectomy vs in 11 (59%) patients treated with MRAs (P=0.033). Post-adrenalectomy, antihypertensive management lessened by a median of 2.5 HDD, while HDD increased in patients treated with MRAs by a median of 1.25, P<0.0001. Hypertension control improved, with a mean decrease in systolic blood pressure of -11 mmHg (95%CI -16.5-(-5.5)) without between group differences. Diastolic blood pressure decreased by a mean of -4.7 mmHg (95%CI -8.7-(-0.7)) in the adrenalectomy group but did not change in those treated with MRAs. Conclusions: Following curative adrenalectomy in unilateral PA, more than half of patients continue to have suppressed PRA. Despite less severe PA at baseline, patients treated with MRAs, as compared to those treated with adrenalectomy, demonstrate a higher prevalence of non-suppressed PRA, lower eGFR, similar hypertension control, and a more intense antihypertensive regimen during follow up. Presentation: Thursday, June 15, 2023