Genetic and epigenetic characterization of posterior pituitary tumors

Simone Schmid,Jürgen Honegger,Carsten Dittmayer,Caterina Giannini,Arie Perry,L Sylvia ,Damian Stichel,Andreas Von Deimling,Martin Hasselblatt,Annekathrin Reinhardt,Bette K Kleinschmidt‐Demasters ,David Jones ,Anne Thieme,Werner Paulus,Roland Coras,Patrick N Harter,Rolf Buslei,Christin Siewert,Christoph Nagel,Eilís Perez ,Arend Koch,Stefan M Pfister,Özgür Mete ,Elisabeth J Rushing ,David A Solomon,David Capper,Jens Schittenhelm,M Beatriz S Lopes

doi:10.1007/s00401-021-02377-1

Abstract

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.

Highlights

Spindle cell oncocytoma, pituicytoma, and granular cell tumor of the sellar region are rare pituicyte-derived neoplasms
Evaluation of histological features was performed on H&E stained slides which were available for 46 of 47 cases (original institutional diagnosis n = 12 granular cell tumor (Fig. 1a); n = 14 pituicytoma (Fig. 1b); n = 21 spindle cell oncocytoma (Fig. 1c and d))
We here describe the presence of two main molecular groups among posterior pituitary tumors that partially overlap with the established histological classes

Summary

Introduction

Pituicytoma, and granular cell tumor of the sellar region are rare pituicyte-derived neoplasms. They are listed as independent entities in the 2016 WHO Classification of Tumours of the Central Nervous System and are assigned as WHO grade I neoplasms [37] due to their typically low-grade histological appearance, slow growth, and benign clinical course. The morphology of spindle cell oncocytomas is less clearly defined. These tumors vary in appearance and may show, among other patterns, spindled and/or epithelioid cells, with varying oncocytic changes and fascicular growth [37, 38]

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Conclusion