Is looking at the tip of the iceberg sinking our ship? A longitudinal cohort study on the patterns of evolution on treatment of non-enhancing FLAIR lesions in primary CNS lymphoma.

INTRODUCTION: Current response criteria for primary CNS lymphoma (PCNSL) focus on contrast-enhancing lesions, potentially overlooking the significance of non-enhancing FLAIR abnormalities (NEFA). The significance of these NEFA lesions are poorly understood, and we conducted this study to evaluate the prognostic value of these lesions in patients with PCNSL. MATERIALS AND METHODS: This retrospective IEC approved longitudinal cohort study analyzed 112 PCNSL patients (2008–2024) with serial MRIs spanning baseline, interim, end of induction treatment and subsequent follow up MRIs. Two blinded neuroradiologists assessed the temporal evolution of characteristics of the NEFA lesions (discrete mass forming/convex FLAIR hyperintensities ≥ 5 mm) on standard high dose methotrexate based treatment at baseline, interim (8 weeks), end-of-treatment (16 weeks), and subsequent follow-up scans. Increase in NEFA was defined as new/enlarging NEFA (≥ 25% increase in size) and progression was defined (standard IPCG) as frank areas of new onset enhancement. The end point of the study was determined on the patient’s outcome - relapse / progressive disease. Kaplan-Meier graphs were used for survival analysis. RESULTS: Patients with NEFA anytime during the course of treatment had significantly higher progression rates (46.6% vs. 7.4%, p < 0.001). In patients on post induction therapy follow-up, increase in NEFA lesions was associated with higher risk of death with HR = 11.620 (1.26,106.81), p = 0.007. Baseline NEFA predicted progression in 41.2% (p = 0.004). 91% patients with increasing NEFA at follow up MRI eventually progressed (0.007). Deep/infratentorial lesions and baseline T1 volume > 12.8 cm³ independently predicted poorer PFS (p < 0.05). CONCLUSIONS: NEFA evolution is a robust biomarker of treatment failure in PCNSL, often preceding contrast-enhancing progression. Incorporating NEFA assessment into response criteria could improve risk stratification and enable earlier intervention.