Background/Objectives: Pituitary neuroendocrine tumors (PitNETs) are heterogeneous intracranial neoplasms with variable clinical behavior. Reliable prognostic tools are needed for postoperative risk stratification. We aimed to evaluate the prognostic performance of the PANOMEN-3 classification in a real-world surgical cohort of patients with PitNETs.

Methods: This single-center retrospective observational cohort study included 92 consecutive adult patients with histologically confirmed PitNETs who underwent pituitary surgery at a tertiary academic center in northern Portugal between 2017 and 2024. Postoperative PANOMEN-3 scores were calculated from clinical, biochemical, radiological and histopathological variables. Progression-free survival (PFS) was analyzed using Kaplan–Meier curves (log-rank test) and Cox proportional hazards regression.

Results: Median follow-up was 69 months (IQR 36). Postoperatively, 5.4% of patients were classified as grade 0, 27.2% as grade 1, 57.6% as grade 2 and 9.8% as grade 3. Increasing PANOMEN-3 grade was associated with progressively shorter PFS (log-rank p < 0.001). Median PFS was not reached for grades 0 and 1, was 43 months (95% CI 10–NR) for grade 2, and only 5 months (95% CI 1–NR) for grade 3. On multivariate Cox regression, grade 2 tumors showed a more than 6-fold increase in progression risk (HR 6.13; 95% CI 2.15–17.51; p = 0.001) and grade 3 tumors an approximately 15-fold increase (HR 15.58; 95% CI 4.32–56.26; p < 0.001), compared with grades 0–1 combined. Gender and age were not independently associated with outcome.

Conclusions: The PANOMEN-3 classification effectively stratified postoperative progression risk in surgically treated PitNETs, supporting its role in personalized postoperative surveillance and treatment planning.