Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Leonille Schweizer,Ruben Jödicke,Andreas Jödicke,Anne Schöler,Dag Moskopp,Hee-Yeong Kim,Martin Hasselblatt,Diaa Al Safatli,Andreas Unterberg,David Kaul,Lars Wessels,David Reuß ,Christian Thomas,Andreas Von Deimling,Wolfgang Hartmann,Alexander Younsi,Felix Thierfelder,Michael Bockmayr,Georgios Ntoulias,Patrick Soschinski,David Capper,Frank L Heppner,Daniel Teichmann,Bettina Knie,Jan Walter,Martin Misch,Damian Stichel,Christian Hartmann,Annika K Wefers,Peter Vajkoczy,Sven-Axel May,Abigail Suwala ,Johannes Kahn,Arend Koch

doi:10.1007/s00401-020-02218-7

Abstract

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile.

Highlights

Paragangliomas and pheochromocytomas are rare, neuroendocrine tumors developing from the autonomous nervous system
Comparing molecular signatures to those of non-spinal PGLs, including abdomino-thoracic and head and neck PGLs, we provide evidence that CEP represents a molecularly distinct tumor entity characterized by a unique epigenetic profile, unrelated to that of non-spinal PGLs, as well as the absence of common PGL-associated genetic driver alterations including germline mutations
We included a cohort of head and neck paragangliomas (n = 24) which had not been previously analyzed within the The Cancer Genome Atlas (TCGA) framework

Summary

Introduction

Paragangliomas and pheochromocytomas are rare, neuroendocrine tumors developing from the autonomous nervous system. Extended author information available on the last page of the article extra-adrenal location are called paragangliomas (PGL) [5]. Paragangliomas of the CNS almost exclusively occur in the cauda equina region or the cerebellopontine angle, often referred to as glomus jugulare tumors or jugulotympanic paragangliomas [13]. Compared to the more prevalent abdominal (85%), thoracic (12%) and head and neck (3%) PGLs, paragangliomas in the cauda equina region (CEP) are exceptionally rare (< 1% of all PGLs, Fig. 1b),

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