Investigation of outcomes related to adrenal incidentalomas

<p dir="ltr"><b>Background</b>: Adrenal incidentalomas (AIs) are increasingly detected through modern imaging. Most are nonfunctional adrenal tumors (NFATs) in which physiological cortisol secretion is assumed, whereas 20-50% have mild autonomous cortisol secretion (MACS), a subtle cortisol excess without clinical signs of Cushing syndrome. MACS has been associated with increased mortality and a higher prevalence of cardiometabolic comorbidities, whereas NFATs have traditionally been regarded as clinically harmless. However, emerging evidence indicates that NFATs may also be linked to adverse cardiometabolic outcomes and related health risk.</p><p dir="ltr"><b>Aims</b>: To evaluate long-term health risks associated with AIs. <b>Study I</b>: To examine mortality by cortisol secretion status in patients with AIs in a single center. <b>Study II-IV</b>: To characterize major clinical outcomes in patients with Als without overt hormonal secretion (presumed NFATs) compared with matched controls using a nationwide cohort. Specifically, <b>Study II</b> aims to quantify all-cause and cause- specific mortality, <b>Study III</b> to determine overall and site-specific cancer incidence, and <b>Study IV</b> to evaluate fracture prevalence and incidence, including the effects of adrenalectomy.</p><p dir="ltr"><b>Methods and Results: Study I</b>: Single-center 13-year follow-up of 365 patients with AIs showed highest mortality in patients with MACS (18.2%) vs. patients with NFATs (7.8%), mainly from non-adrenal cancers. Higher cortisol concentrations, age, and tumor size predicted mortality.<b> Study II</b>: Nationwide case-control study (17,726 patients with presumed NFATs; 124,366 controls) found increased all-cause mortality (aHR 1.21), particularly cardiovascular (aHR 1.21) and cancer-related (aHR 1.54), with stronger effects in individuals <65 years. <b>Study III</b>: Presumed NFATs were linked to higher cancer incidence (aHR 1.31), including thyroid, lung, gastrointestinal, kidney, bladder, pancreatic and breast cancers. <b>Study IV</b>: In 20,390 patients with presumed NFATs, fracture prevalence (aOR 1.27) and incidence (aHR 1.27) were higher, especially vertebral fractures (aHR 1.83) and in younger men. Adrenalectomy eliminated the excess risk of fracture.</p><p dir="ltr"><b>Conclusions</b>: Both MACS and AIs presumed to be NFATs are associated with adverse long-term outcomes, particularly in younger individuals and men. These entities are better understood as part of a continuum within eucortisolemic individuals, suggesting that even cortisol activity within the normal range may contribute to chronic disease risk.</p><h3>List of scientific papers</h3><p dir="ltr">I. <b>Patrova J,</b> Kjellman M, Wahrenberg H, Falhammar H. Increased mortality in patients with adrenal incidentalomas and autonomous cortisol secretion: a 13-year retrospective study from one center. Endocrine 2017 58(2):267-275. <a href="https://doi.org/10.1007/s12020-017-1400-8" rel="noreferrer" target="_blank">https://doi.org/10.1007/s12020-017-1400-8</a></p><p dir="ltr">II. <b>Patrova J,</b> Mannheimer B, Lindh J. D, Falhammar H. Mortality in patients with nonfunctional adrenal tumors. JAMA Intern Med 2023;183(8):832-838. <a href="https://doi.org/10.1001/jamainternmed.2023.2442" rel="noreferrer" target="_blank">https://doi.org/10.1001/jamainternmed.2023.2442</a></p><p dir="ltr">III. <b>Patrova J,</b> Mannheimer B, Larsson M, Lindh J. D, Falhammar H. The incidence of cancers in patients with nonfunctional adrenal tumors: a Swedish population-based national cohort study. J Endocr Soc. 2024;8(10):bvae154. <a href="https://doi.org/10.1210/jendso/bvae154" target="_blank">https://doi.org/10.1210/jendso/bvae154</a></p><p dir="ltr">IV. Lindh J. D, <b>Patrova J,</b> Mannheimer B, Falhammar H. Prevalence and incidence of fractures in patients with nonfunctional adrenal tumors. JAMA Netw Open. 2024;7(4):e246453. <a href="https://doi.org/10.1001/jamanetworkopen.2024.6453" rel="noreferrer" target="_blank">https://doi.org/10.1001/jamanetworkopen.2024.6453</a></p>