Predictors of progression after surgery in non-functioning pituitary macroadenomas: a Spanish multicenter study

Non-functioning pituitary adenomas (NFPAs) have an unpredictable clinical course, with recurrence and progression posing significant challenges. This study aims to evaluate progression-free survival (PFS) and identify predictors and patterns of tumor progression.

We conducted a retrospective multicenter study including 472 patients with NFPAs > 1 cm from 17 Spanish hospitals (416 surgical, 56 conservative management). Tumor progression was defined as > 20% increase in size, >2 mm growth on imaging, or new/worsening clinical symptoms. Kaplan-Meier analysis was used to estimate PFS for both groups and independent predictors of progression were assessed using Cox proportional hazards regression in the surgical cohort.

During a median follow-up of 7.9 years (range: 5.0-46.9), tumor progression occurred in 67 patients (14.2%). Most progression 29/67 (89.6%) events occurred within the first 15 years of follow-up. Multivariate analysis identified residual tumor (HR = 5.1; 95% CI: 2.2-11.9; p < 0.01) and aggressive histopathology (HR = 2.1; 95% CI: 1.1-3.8; p = 0.02) as significant independent predictors of progression. Neither gender, age, radiotherapy nor cabergoline treatment significantly altered progression risk in the multivariate model.

NFPAs show a gradual risk of progression over time, particularly during the first 15 years post-diagnosis. Postoperative residual tumor and aggressive histopathological features are the strongest predictors of progression, highlighting the importance of maximal safe resection when feasible and detailed histopathological assessment for risk stratification. These findings support long-term surveillance for high-risk patients.