Identification and characterization of a novel distinct Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation (PINNED)

Pineal region tumors are rare neoplasms that occur in all ages and account for less than 1% of all central nervous system (CNS) tumors in adults but are more frequent in children. Here, we describe a previously unrecognized tumor type of pineal origin characterized by a unique and consistent DNA methylation profile that does not match any known CNS tumor class and is distinct from all currently recognized pineal tumor entities. The presented cohort (n = 27) displayed a balanced sex distribution with a mean patient age of 35 years (range 7-75 years). The histopathological analyses demonstrated a highly cellular tumor showing various degrees of necrosis, mitotic activity, papillary structures, rosettes, epithelioid cytology, or signet-ring cells. The tumors consistently expressed cytokeratin 18, synaptophysin, chromogranin A, and OTX2, whereas CRX expression was absent. Four out of 16 tumors (25%) showed ATRX mutations and/or loss of protein expression as revealed by immunohistochemistry. Single-nucleus RNA sequencing confirmed molecular distinctiveness from other pineal neoplasms but revealed the closest similarities to papillary tumors of the pineal region (PTPR). Projection of the transcriptome data onto the cellular trajectory of the developing murine pineal gland suggests that pinealocyte progenitors are the cellular origins. Taken together, our findings define a novel type of pineal region tumor that we provisionally named 'Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation' (PINNED). Recognition of this tumor type appears to be important for the accurate diagnosis of pineal region tumors and may have implications for future tumor classification and treatment strategies.

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Journal
Acta Neuropathologica
Published
2026-10-26
DOI
https://doi.org/10.1007/s00401-026-03111-5
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Identification and characterization of a novel distinct Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation (PINNED)

Stefan M. Pfister, Sebastian Brandner, Chiara Villa, Lindsey Lowder et al.
Acta Neuropathologica
Glioma Diagnosis and Treatment
article

Identification and characterization of a novel distinct Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation (PINNED)

Stefan M. Pfister, Sebastian Brandner, Chiara Villa, Lindsey Lowder, Tyler James Kenning, Lea Altendorf, Paul Kerbs, Christian Thomas, Martin Hasselblatt, Alexandre Vasiljevic, Christian Mawrin, Aaron Gerald Mammoser, Helena Bode, Paul A. Northcott, Jan C. Beckervordersandforth, Andreas von Deimling, Michael Brodhun, Brian L. Gudenas, Isabell Bludau, Felix Sahm, Carlos Rodríguez‐Antolín, Caterina Giannini, Ziedulla Abdullaev, Josefine Radke, Ulrich Schüller, Marcel Kool, Matija Snuderl, Guntis Karelis, Kay Hertel, Neal Geisemeyer, Catherine Godfraind, Rüdiger Gerlach, Abigail Suwala, Karoline Hack, Alicia Fürst
article en

Abstract

Pineal region tumors are rare neoplasms that occur in all ages and account for less than 1% of all central nervous system (CNS) tumors in adults but are more frequent in children. Here, we describe a previously unrecognized tumor type of pineal origin characterized by a unique and consistent DNA methylation profile that does not match any known CNS tumor class and is distinct from all currently recognized pineal tumor entities. The presented cohort (n = 27) displayed a balanced sex distribution with a mean patient age of 35 years (range 7-75 years). The histopathological analyses demonstrated a highly cellular tumor showing various degrees of necrosis, mitotic activity, papillary structures, rosettes, epithelioid cytology, or signet-ring cells. The tumors consistently expressed cytokeratin 18, synaptophysin, chromogranin A, and OTX2, whereas CRX expression was absent. Four out of 16 tumors (25%) showed ATRX mutations and/or loss of protein expression as revealed by immunohistochemistry. Single-nucleus RNA sequencing confirmed molecular distinctiveness from other pineal neoplasms but revealed the closest similarities to papillary tumors of the pineal region (PTPR). Projection of the transcriptome data onto the cellular trajectory of the developing murine pineal gland suggests that pinealocyte progenitors are the cellular origins. Taken together, our findings define a novel type of pineal region tumor that we provisionally named 'Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation' (PINNED). Recognition of this tumor type appears to be important for the accurate diagnosis of pineal region tumors and may have implications for future tumor classification and treatment strategies.

Acta NeuropathologicaVol. 152(1)
Centre National de la Recherche Scientifique (FR), St. Jude Children's Research Hospital (US), Mayo Clinic (US), University College London Hospitals NHS Foundation Trust (GB), Emory University (US), Inserm (FR), German Cancer Research Center (DE), Université Clermont Auvergne (FR), Université Paris Cité (FR), Heidelberg University (DE), Universitätsmedizin Greifswald (DE), Maastricht University Medical Centre (NL), Hospital Universitario La Paz (ES), Piedmont Atlanta Hospital (US), University Hospital Heidelberg (DE), Maastricht University (NL), Universität Greifswald (DE), NYU Langone Health (US), Assistance Publique – Hôpitaux de Paris (FR), Piedmont Cancer Institute (US), Hospices Civils de Lyon (FR), University of Clermont Auvergne (FR), University Hospital Münster (DE), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), National Center for Tumor Diseases (DE), Hopp Children's Cancer Center Heidelberg (DE), Hôpital Lariboisière (FR), Riga Stradiņš University (LV), Princess Máxima Center (NL), University Hospital Magdeburg (DE), National Cancer Institute (US), Institut Cochin (FR), Helios Klinikum Erfurt (DE), Center for Cancer Research (US), Deutsches Konsortium für Translationale Krebsforschung (DE), HMU Health and Medical University Erfurt (DE), UCL Queen Square Institute of Neurology (GB), New York University (US), Leibniz Institute for Neurobiology (DE)
Deutsche Forschungsgemeinschaft, Else Kröner-Fresenius-Stiftung, Gemeinnützige Hertie-Stiftung, Fördergemeinschaft Kinderkrebs-Zentrum Hamburg, Universitätsklinikum Hamburg-Eppendorf
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Glioma Diagnosis and Treatment
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