2026 Proffered Presentations
S032: DIFFERENTIAL PRESENTATION AND OUTCOMES IN MICRO VERSUS MACRO PITUITARY ADENOMAS IN CUSHING'S DISEASE: A MULTICENTER RETROSPECTIVE ANALYSIS FROM THE RAPID REGISTRY
Hana Hallak1; Bhuvic Patel1; Jing Wang1; Andrew Little2; Kevin Yuen2; Adam Mamelak3; James Evans4; Jamie Van Gompel5; Carolina Benjamin6; Donato Pacione7; Kyle Wu8; Garni Barkhoudarian9; Juan Carlos Fernandez-Miranda10; Won Kim11; Paul Gardner12; Georgios Zenonos12; Hussein Abdullah12; Gabriel Zada13; Robert Rennert14; William Couldwell14; Michael Catalino15; Varun Kshettry16; Nathan Zwagerman17; Stephanie Cheok17; Ramin Morshed18; Spiros Blackburn19; Debraj Mukherjee20; Andre Beer-Furlan21; Carter Suryadevara7; Marvin Bergsneider11; Michael Karsy22; Michael Chicoine23; Albert Kim1; Julie Silverstein1; 1Washington University; 2Barrow Neurological Institute; 3Cedars Sinai; 4Thomas Jefferson; 5Mayo Clinic; 6University of Miami; 7New York University; 8Ohio State University; 9Providence Medical Center; 10Stanford University; 11University of California Los Angeles; 12University of Pittsburgh Medical Center; 13University of Southern California; 14University of Utah; 15University of Virginia; 16Cleveland Clinic; 17Medical College of Wisconson; 18University of California San Francisco; 19University of Texas Health Science Center at Houston; 20Johns Hopkins University; 21Moffitt Cancer Center; 22University of Michigan; 23University of Missouri
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 to 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) vs. 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 vs. 45 years, p<0.01) and more often female (86% vs. 74%, p<0.01). Male representation was higher among macroadenomas (26%, 48/185) than microadenomas (14%, 35/252; χ² = 10.08; p < 0.01), and among invasive (40%, 28/70) compared to noninvasive macroadenomas (13%, 14/83, χ2 = 10.20; p=0.001). Microadenomas presented with more overt Cushingoid features, including facial plethora (38% vs. 22%, p<0.001), weight gain (77% vs. 64%, p=0.005), low bone density (26% vs. 14%, p=0.008), fatigue (70% vs. 60%, p = 0.03), hirsutism (44% vs. 34%, p=0.04), and the presence of a dorsocervical fat pad (21% vs. 12%, p=0.03). Despite similar cortisol levels, ACTH was lower in microadenomas (65 vs. 92 pg/mL, p<0.01). Microadenomas had higher remission rates both immediately postoperatively (87% vs. 80%, p=0.058) and at last follow-up (73% vs. 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% vs. 73%, p=0.012) and shorter recurrence-free survival (median 6.3 vs. 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 to 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.