Cushing's disease and negative MRI: a single-center series, systematic literature review, and meta-analysis

: Cushing's Disease (CD) poses diagnostic and therapeutic challenges, particularly when pituitary MRI is negative for a neuroendocrine tumor (PitNET). This study systematically analyzes literature data on the surgical outcomes of patients with MRI-negative CD and presents a novel single-center series. A systematic review and meta-analysis of PubMed, Scopus, and Cochrane databases (2000-2024) were performed. A retrospective analysis of patients with MRI-negative CD who underwent endoscopic pituitary exploration between 2014 and 2021 at the University of Brescia was conducted. A meta-analysis of 35 studies revealed significant heterogeneity across studies (I2 = 71.09%). The mean surgical disease remission rate of 70% (CI: 65-75%) in MRI-negative CD was significantly lower than in MRI-positive patients (82%; CI: 0.79-0.86). Eight studies reported ACTH hyperplasia in a total of 92 of 470 patients (19.6%). In the institutional series, 21 patients underwent 22 endoscopic pituitary explorations (mean follow-up: 72 months). Histology documented ACTH hyperplasia in 10/22 (45%), ACTH-PitNET in 9, and normal pituitary in 3. Inferior petrosal sinus sampling lateralization was predictive of pathology in 33% of patients. Early and late surgical remission (10/22 and 15/22 patients, respectively) were significantly associated with histology. Surgical complications included one CSF leak requiring reintervention, one case of transient diabetes insipidus, and two patients requiring substitutive therapy for the thyroid axis. About 30% of MRI-negative CD patients do not achieve surgical disease remission. ACTH hyperplasia might partially explain this high rate of failure. Endoscopic pituitary exploration remains a highly effective way to collect important histological data that should be recorded in a multicenter, prospective study.