Differential Presentation and Outcomes in Micro versus Macro Pituitary Adenomas in Cushing's Disease: A Multicenter Retrospective Analysis from the Rapid Registry

Introduction: Cushing’s disease (CD) is rare, with an annual incidence of 0.7 to 2.4 cases per million population. Patients with CD most commonly present with MRI-positive pituitary microadenomas. However, a smaller subset, from 7% to 20% of patients, present with pituitary macroadenomas. Prior studies have suggested that patients with macroadenomas experience different surgical outcomes compared with those with microadenomas, however few have alluded to the differences in clinical phenotypes and symptom burden. Methods: The RAPID registry captures retrospective data from a network of high-volume academic centers across the United States. Patients diagnosed with MRI-positive corticotroph adenomas were included and stratified based on size—microadenoma (< 1cm) versus macroadenoma (≥ 1cm)—and presence of invasiveness within macroadenomas defined by Knosp grade >2. The primary outcome of interest was a comparison of clinical and laboratory features at presentation among tumor groups. Secondary outcomes included comparison of postoperative outcomes among groups. Statistical comparisons were conducted between microadenomas and macroadenomas, and among subgroups of macroadenomas stratified by invasiveness, using appropriate parametric and nonparametric tests. Kaplan-Meier survival analysis evaluated recurrence-free survival by tumor size and invasiveness. Results: Among 438 patients (253 microadenomas, 185 macroadenomas), microadenoma patients were younger (median 40 versus 45 years, p < 0.01) and more often female (86% versus 74%, p < 0.01). Male representation was higher among macroadenomas (26%, 48/185) than microadenomas (14%, 35/252; χ 2 = 10.08; p < 0.01), and among invasive (40%, 28/70) compared with noninvasive macroadenomas (13%, 14/83, χ2 = 10.20; p = 0.001). Microadenomas presented with more overt Cushingoid features, including facial plethora (38% versus 22%, p < 0.001), weight gain (77% versus 64%, p = 0.005), low bone density (26% versus 14%, p = 0.008), fatigue (70% versus 60%, p = 0.03), hirsutism (44% versus 34%, p = 0.04), and the presence of a dorsocervical fat pad (21% versus 12%, p = 0.03). Despite similar cortisol levels, ACTH was lower in microadenomas (65 versus 92 pg/mL, p < 0.01). Microadenomas had higher remission rates both immediately postoperatively (87% versus 80%, p = 0.058) and at last follow-up (73% versus 58%, p = 0.012). Multivariable regression showed that male sex was an independent risk factor for recurrence (HR 3.82, p < 0.01). Among macroadenomas, invasiveness predicted worse outcomes. Invasive tumors had lower remission (47% versus 73%, p = 0.012) and shorter recurrence-free survival (median 6.3 versus 13.2 years, HR 2.85, p < 0.001). Conclusion: Microadenomas present with more overt Cushingoid features and have superior remission and recurrence outcomes compared with macroadenomas. Invasiveness, rather than size alone, emerged as a key predictor of recurrence and remission. Male sex was independently associated with more aggressive disease and worse outcomes, highlighting the need for closer monitoring and tailored treatment in this subgroup. Publication History Article published online: 27 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany