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. 2025 Aug 8.
doi: 10.1007/s40618-025-02674-6. Online ahead of print.

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

Betina Biagetti  1   2 , Andres Cardona-Arias  3 , Edelmiro Menéndez Torre  4 , Anna Aulinas  5 , Ignacio Ruz-Caracuel  6 , Rogelio García Centeno  7 , Laura González  7 , Ana Irigaray Echarri  8 , María Dolores Moure Rodríguez  9 , Miguel Paja  10 , Fernando Guerrero-Pérez  11 , Justo P Castaño  12 , María Dolores Ollero García  8 , Cristina Novo-Rodríguez  13 , Carmen Tenorio-Jimenéz  13 , Rocío Villar-Taibo  14 , Ignacio Bernabéu  14 , Everardo Díaz-López  14 , María Calatayud  15 , Cristina Alvarez-Escola  16 , Patricia Martín Rojas-Marcos  16 , José María Recio-Córdova  17 , Claudia Lozano-Aida  4 , Queralt Asla Roca  5 , María Dolores Aviles  18   19 , Elena López Mezquita  18   19 , María Fernández Argueso  14 , Inmaculada González Molero  18   19 , Iban Alberoa  20 , Cindy Idrobo  21 , Estefanía Achote  21 , Elena Martínez-Sáez  22 , Mónica Marazuela  23 , Manel Puig-Domingo  24 , Felicia Hanzu  25 , Marta Araujo-Castro  26   27
Affiliations

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

Betina Biagetti et al. J Endocrinol Invest. .

Abstract

Background and purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Clinical behavior outcomes; Non-functioning; Pituitary adenoma; Progression free survival; Recurrence.

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Conflict of interest statement

Declarations. Conflict of interest: The authors declare no conflict of interest. Ethical approval: The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the Hospital Universitario Ramón y Cajal. Madrid. Spain (approval date: 28 of May 2024, code: ACTA 467) and in each center that collaborate. Informed consent: Patient consent was waived due to the retrospective nature of the study. Only for patients who continued follow-up or prospectively included informed consent was requested.

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