Baker, Jessica

Abstract Objective Recent studies suggest a unique disease profile in elderly patients with primary aldosteronism (PA), who have a high prevalence of comorbidities and low clinical cure rate post-adrenalectomy. This study aims to investigate histopathology and genetic characteristics of PA in late adulthood. Methods Formalin-fixed, paraffin-embedded adrenal tissue sections from 114 patients with PA who underwent unilateral adrenalectomy at age 60 or older were used. Aldosterone synthase (CYP11B2) immunohistochemistry (IHC) was performed for histopathologic analysis. Somatic DNA variants were identified in aldosterone-producing tissue following CYP11B2 IHC-guided sequencing. Results Histopathologic analysis revealed that 56 adrenals contained an aldosterone-producing nodule (APN) (49%), 44 contained an aldosterone-producing adenoma (APA) (39%), 7 contained multiple APN (6%), and 7 contained only non-functioning adenomas [NFA, of which 6 had at least one aldosterone-producing micronodule (APM) in the adjacent tissue] (6%). NFAs were also identified alongside APN/APA in 24 cases. An APN was the most common histologic subtype in men (51/88, 58%), while APA was predominant in women (18/26, 69%). Of 67 APNs with successful sequencing, the majority had variants in CACNA1D (40/67, 60%). KCNJ5 variants were the most common alteration in APA (14/44, 32%). Conclusions Older individuals with lateralized PA exhibit distinct genetic and histologic causes of disease with sex differences in mutation prevalence and adrenal histopathology. In APN, the most frequently altered gene is CACNA1D, while KCNJ5 variants are most common in APA. Unlike young patients with PA, the presence of NFA is a frequent observation in late adulthood individuals with PA.

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 Context Due to its rare incidence, molecular features of primary aldosteronism (PA) in young adults are largely unknown. Recently developed targeted mutational analysis identified aldosterone-driver somatic mutations in aldosterone-producing lesions, including aldosterone-producing adenomas (APAs), aldosterone-producing nodules (APNs), and aldosterone-producing micronodules, formerly known as aldosterone-producing cell clusters. Objective To investigate histologic and genetic characteristics of lateralized PA in young adults. Methods Formalin-fixed, paraffin-embedded adrenal tissue sections from 74 young patients with lateralized PA (<35 years old) were used for this study. Immunohistochemistry (IHC) for aldosterone synthase (CYP11B2) was performed to define the histopathologic diagnosis. Somatic mutations in aldosterone-producing lesions were further determined by CYP11B2 IHC-guided DNA sequencing. Results Based on the CYP11B2 IHC results, histopathologic classification was made as follows: 48 APAs, 20 APNs, 2 multiple aldosterone-producing nodules (MAPN), 1 double APN, 1 APA with MAPN, and 2 nonfunctioning adenomas (NFAs). Of 45 APAs with successful sequencing, 43 (96%) had somatic mutations, with KCNJ5 mutations being the most common genetic cause of young-onset APA (35/45, 78%). Of 18 APNs with successful sequencing, all of them harbored somatic mutations, with CACNA1D mutations being the most frequent genetic alteration in young-onset APN (8/18, 44%). Multiple CYP11B2-expressing lesions in patients with MAPN showed several aldosterone-driver mutations. No somatic mutations were identified in NFAs. Conclusion APA is the most common histologic feature of lateralized PA in young adults. Somatic KCNJ5 mutations are common in APAs, whereas CACNA1D mutations are often seen in APNs in this young PA population.

Abstract Context The detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood. Objective To investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an approach to its diagnosis and management. Methods We conducted a retrospective case series of adult patients with concomitant PHEO and PA at Mayo Clinic from 2000-2020 and an additional review of cases before 2000 and from the medical literature. Clinical, biochemical, radiologic, and histologic parameters were measured. Results Fifteen patients (53% men, median age 53 years) were diagnosed with concomitant PHEO and PA. The majority presented with hypertension (13, 87%) and hypokalemia (13, 87%), and 6 (40%) presented with symptoms suggestive of catecholamine excess. All patients who underwent preoperative workup for catecholamine excess (14, 93%) were found to have biochemical levels above the upper limits of normal. Adrenal vein sampling (AVS) was performed in 9 patients (60%), where 5 (56%) were diagnosed with bilateral PA, and 4 (44%) with unilateral PA. Patients underwent either unilateral (12, 80%) or bilateral (3, 20%) adrenalectomy. Biochemical improvement or resolution of catecholamine excess was confirmed in all cases with documented measurements. Recurrence of PHEO was not observed. Six patients (40%) displayed persistent PA postoperatively. Conclusion Concomitant PHEO and PA is a rare but likely underreported condition. Hypertension with or without hypokalemia should prompt evaluation for PA, while any indeterminate adrenal mass should be assessed for PHEO. Coexisting disease warrants consideration of AVS to determine the laterality of PA to ensure appropriate management.

Abstract Objective: The detection and management of concomitant pheochromocytoma (PHEO) and primary aldosteronism (PA) is not well understood. Our objectives were to investigate varying presentations and outcomes of cases with coexisting PHEO and PA to provide an approach to its diagnosis and management. Design: Retrospective case series from 2000–2020 at a single institution tertiary center; additional review of previously known cases before 2000 and from the medical literature. Patients and Measurements: Adult patients with concomitant PHEO and PA. Clinical, biochemical, radiologic, and histologic parameters were reviewed. Results: Fifteen patients (53% men, median age 53 years) were diagnosed with concomitant PHEO and PA. The majority presented with hypertension (13, 87%) and hypokalemia (13, 87%), but only 6 (40%) presented with symptoms suggestive of catecholamine excess. All patients with preoperative work-up for catecholamine excess (14, 93%) were found to have elevated plasma or urinary metanephrines/catecholamines above the upper limit of normal. Adrenal vein sampling (AVS) was performed in 9 (60%) patients, where 5 (56%) were diagnosed with bilateral PA, and 4 (44%) with unilateral PA. All patients underwent either unilateral (12, 80%) or bilateral (3, 20%) adrenalectomy to treat their PHEO and/or PA. Postoperative catecholamines and/or catecholamine breakdown products normalized or improved in 13 (87%) patients and were not measured in 2. Recurrence of PHEO was not observed. Six (40%) displayed persistent PA postoperatively, where 4 required long-term mineralocorticoid blockade. Conclusions: Concomitant PHEO and PA is a rare but likely under-reported condition. Hypertension with or without hypokalemia should prompt evaluation for PA, while any indeterminate adrenal mass should be worked up for PHEO. Coexisting disease warrants consideration of AVS to determine the laterality of PA to ensure appropriate management.