Gliomas with pleomorphic and pseudopapillary features (GPAP) are circumscribed tumors with targetable mutations, prolonged survival, and frequent tumor predisposition.

DNA methylation profiling of CNS tumors led to the identification of HPAP (high-grade glioma with pleomorphic and pseudopapillary features), a recently proposed entity with variable morphology, recurrent MAP-kinase pathway activating events, and longer survival compared to glioblastoma. We aimed to independently validate and further characterize this entity. We retrieved a multicentric cohort of gliomas compatible with HPAP and performed t-SNE dimensionality reduction on their DNA methylation profile. Clinical, radiological, histological, and molecular data were reviewed. Twenty tumors clustering with previously reported HPAP cases were identified. Median age at diagnosis was 37 years. Radiologically, the tumors appeared as expansive lesions with heterogeneous enhancement and frequent cysts. Histologically, they were well-circumscribed, with papillary and pleomorphic features variably present. Marked histological signs of aggressivity were present in seven. Immunostainings showed expression of GFAP, OLIG2, and CD34. All cases were IDH1/2 wildtype and pMGMT unmethylated. Recurrently mutated genes included TP53, ATRX, RB1, and BRAF. Five patients had germline pathogenic variants in genes associated with hereditary tumor predisposition syndromes (MLH1, BRCA2, CHEK2, NF2, RB1). All patients underwent surgical resection, but subsequent management was heterogeneous. Ten-year estimated survival was 85%. CDKN2A homozygous deletion seemed to identify more aggressive tumors. In conclusion, our data suggest the existence of a novel entity of circumscribed gliomas with long-term survival despite possible high-grade histological presentation, for which we propose the nomenclature "Gliomas with pleomorphic and pseudopapillary features" with a spectrum encompassing provisory grade 2 and 3. A proper identification could guide treatment choices.