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.

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Journal
Brain Pathology
Published
2026-09-29
DOI
https://doi.org/10.1111/bpa.70153
Primary Topic
Glioma Diagnosis and Treatment
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article
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article

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

Caroline Dehais, Patrick R. Benusiglio, Luc Bauchet, Luca Bertero et al.
Brain Pathology
Glioma Diagnosis and Treatment
article

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

Caroline Dehais, Patrick R. Benusiglio, Luc Bauchet, Luca Bertero, Sabrina Rossi, Evelina Miele, Salah Eddine Oussama Kacimi, Jaydutt Digambar Bhalshankar, Franck Bielle, Paola Cassoni, M. Sanson, Thomas Gareau, Giuseppe Kenneth Ricciardi, Valeria Barresi, Valérie Rigau, Guillaume Chotard, Mathilde Filser, Mehdi Touat, Lucia Nichelli, Besma Barka, Emmanuelle Uro‐Coste, Bertrand Mathon, Alessia Pellerino, Alberto Pïcca, Roberta Rudà, Aude Trinquet, Michèle Bernier, Ahmed Idbaïh, Kifah Khouri, Henri Malaizé, Hélène Madry, Marta Iollo, Catherine Carpentier, Irina Coin, Julien Masliah‐Planchon, Karima Mokhtari
article en

Abstract

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.

Brain Pathology
University of Verona (IT), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Montpellier (FR), CTO Hospital (IT), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Toulouse (FR), Sorbonne Université (FR), Centre Hospitalier Universitaire de Montpellier (FR), Azienda Ospedaliera Universitaria Integrata Verona (IT), La Ligue Contre le Cancer (FR), Saint Camillus International University of Health and Medical Sciences (IT), Assistance Publique – Hôpitaux de Paris (FR), Laboratoire d'Aérologie (FR), Hôpital Pellegrin (FR), Pitié-Salpêtrière Hospital (FR), Bambino Gesù Children's Hospital (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Institut de Génomique Fonctionnelle (FR), Hôpital Foch (FR), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), University of Turin (IT), Institut Curie (FR)
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Glioma Diagnosis and Treatment
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