KS04.6.A GLIOMAS WITH PLEOMORPHIC AND PSEUDOPAPILLARY FEATURES (GPAP) ARE CIRCUMSCRIBED TUMORS WITH LONG-TERM SURVIVAL
Authors: Picca A , Bertero L , Trinquet A , Bernier M , Nichelli L , Gareau T , Kacimi S , Masliah-Planchon J , Filser M , Malaizé H , Mathon B , Marie Y , Barka B , Carpentier C , Mohand Oumoussa B , Coin I , Sanson M , Touat M , Idbaih A , Hoang-Xuan K , Pellerino A , Rudà R , Mokhtari K , Benusiglio P , Bielle F 
Published: October 2024

Abstract

INTRODUCTION
The taxonomy of primary CNS tumors is evolving. DNA methylation profiling led to the identification of HPAP (high-grade glioma with pleomorphic and pseudopapillary features), a proposed tumor entity with variable morphology, recurrent MAP-kinase pathway activating events, and longer survival compared to glioblastoma. Our goal is to independently validate and further characterize this entity.

METHODS
In this multi-institutional study, we retrieved prospective and retrospective cases with histological (pleomorphic xanthoastrocytoma, astroblastoma) or molecular (chromosome 13 loss) features compatible with HPAP and performed t-distributed stochastic neighbor embedding dimensionality reduction on their methylome profile.

RESULTS
We identified ten tumors clustering with previously reported HPAP cases. Median age was 40 years (range 23-66), with a female predominance. Presenting symptoms included intracranial hypertension (50%), focal deficits (36%), and seizures (27%). At MRI, growth pattern was expansive rather than infiltrative in all, with heterogenous enhancement and associated moderate-important edema. Histologically, tumors were constantly well-circumscribed, but papillary and pleomorphic features were variably present. Histological signs of aggressivity (high mitotic activity with microvascular proliferation or necrosis) were present in five. Immunostainings showed expression of GFAP (100%), OLIG2 (90%), and CD34 (90%). All cases were IDH1/2 wildtype and pMGMT unmethylated. Recurrently mutated genes included TP53, ATRX, and RB1. Two cases had BRAF p.V600E mutation. Three tumors had inactivation of a DNA repair pathway (n=2 for Mismatch Repair, n=1 for Homologous Recombination Repair), with an underlying hereditary cancer syndrome (HCS) in two patients. All patients underwent surgical tumor resection, but subsequent management was heterogeneous, including adjuvant radiotherapy plus temozolomide (40%), adjuvant radiotherapy (30%), or no adjuvant treatments (30%). After a median follow-up of 5 years (range 0.4-15), all patients but one are alive (5- and 10-year estimated overall survival: 83%, 95% confidence interval 58-100%). The only observed death was due to intratumoral hemorrhage under bevacizumab. CDKN2A homozygous loss seemed to identify more aggressive tumor courses.

CONCLUSIONS
We confirm the existence of a novel entity of circumscribed gliomas with long-term survival despite possible worrisome high-grade histological presentation, for which we propose the nomenclature “Gliomas with pleomorphic and pseudopapillary features” (GPAP) with a provisory grading spectrum encompassing grade 2 and 3 tumors. Further investigations are required to define grading criteria, and determine the prevalence of HCS among cases. A proper identification could guide neuro-oncologist in treatment decision making.