Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Charitéplatz 1, Berlin, Germany. simone.schmid@charite.de.
Department of Pathology, University of California, San Francisco, CA, USA.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Charitéplatz 1, Berlin, Germany.
German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pathology, University of Colorado, Aurora, CO, USA.
Department of Pathology and Laboratory Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Neuropathology, Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Department of Pathology, University Health Network, Toronto, ON, Canada.
Institute of Neuropathology, University Hospital Münster, Münster, Germany.
Division of Neurosurgery, Sankt Gertrauden Hospital, Berlin, Germany.
Institute of Neurology (Edinger Institute), Goethe University, Frankfurt, Germany.
German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Frankfurt am Main, Germany.
German Cancer Research Center (DKFZ), Heidelberg, Germany.
Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
Center for Neuro-Oncology, Comprehensive Cancer Center Tübingen-Stuttgart, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Department of Neuropathology, University Hospital Tübingen, Eberhard Karls University, Tübingen, Germany.
Department of Neurosurgery, University of Tübingen, Tübingen, Germany.
Institute of Neuropathology, University Hospital and University of Zurich, Zurich, Switzerland.
Department of Neuropathology, Institute of Neuropathology, Affiliated Partner of the ERN EpiCARE, Universitätsklinikum Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054, Erlangen, Germany.
Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology and Immunology, University Hospital Heidelberg, Heidelberg, Germany.
Division of Pediatric Neurooncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Pathology, Sozialstiftung Bamberg, Buger Str. 80, 96049, Bamberg, Germany.
Pediatric Glioma Research Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Neuropathology, Charitéplatz 1, Berlin, Germany. david.capper@charite.de.
German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany. david.capper@charite.de.
Department of Pathology, Neuropathology, University of Virginia Health System, Charlottesville, Virginia, USA. msl2e@virginia.edu.
Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.
