Mutation Status and Epithelial Differentiation Stratify Recurrence Risk in Chordoid Meningioma-A Multicenter Study with High Prognostic Relevance.

Maria-Magdalena Georgescu,Bret C Mobley,Yan Li,Anil Nanda,Phyllis L Faust,Jack M Raisanen,Adriana Olar

doi:10.3390/cancers12010225

Abstract

Chordoid meningioma is a rare WHO grade II histologic variant. Its molecular alterations or their impact on patient risk stratification have not been fully explored. We performed a multicenter, clinical, histological, and genomic analysis of chordoid meningiomas from 30 patients (34 tumors), representing the largest integrated study to date. By NHERF1 microlumen immunohistochemical detection, three epithelial differentiation (ED) groups emerged: #1/fibroblastic-like, #2/epithelial-poorly-differentiated and #3/epithelial-well-differentiated. These ED groups correlated with tumor location and genetic profiling, with NF2 and chromatin remodeling gene mutations clustering in ED group #2, and TRAF7 mutations segregating in ED group #3. Mutations in LRP1B were found in the largest number of cases (36%) across ED groups #2 and #3. Pathogenic ATM and VHL germline mutations occurred in ED group #3 patients, conferring an aggressive or benign course, respectively. The recurrence rate significantly correlated with mutations in NF2, as single gene, and with mutations in chromatin remodeling and DNA damage response genes, as groups. The recurrence rate was very high in ED group #2, moderate in ED group #3, and absent in ED group #1. This study proposes guidelines for tumor recurrence risk stratification and practical considerations for patient management.

Highlights

Meningiomas are heterogenous tumors and their pathologic classification in the WHOClassification of Tumors of the CNS comprises 13 recognized histologic variants [1]
Mutations have been found to correlate with tumor location and histologic variant: mutations of TRAF7, KLF4, SMO, POLR2A, and AKT1 have been found to correlate with a skull base location [4,5,6] whereas mutations of
We have found that immunohistochemistry (IHC) for NHERF1, an adaptor protein that interacts with the ezrin-radixin-moesin (ERM)-NF2 family of proteins to structure microvilli [14,15], highlights microlumens [13,16]

Summary

Introduction

Meningiomas are heterogenous tumors and their pathologic classification in the WHOClassification of Tumors of the CNS comprises 13 recognized histologic variants [1]. Cancers 2020, 12, 225 meningiomas are segregated based on numerous different histologic criteria into three grades of increasing aggressiveness, WHO I to III, with higher grade correlating with increased potential for recurrence. These criteria include mitotic rate, histologic variant, brain invasion, necrosis, increased cellularity, sheeting, prominent nucleoli and decreased nuclear-cytoplasmic ratio [1]. This rather complicated histologic classification does not always accurately predict tumor recurrence, and recent efforts have attempted to more precisely stratify meningiomas using genetic profiling. Mutations have been found to correlate with tumor location and histologic variant: mutations of TRAF7, KLF4, SMO, POLR2A, and AKT1 have been found to correlate with a skull base location [4,5,6] whereas mutations of SMARCE1, BAP1 or a combination of TRAF7 and KLF4 mutations have been shown to be associated with clear cell, rhabdoid or secretory variants, respectively [5,7,8,9]

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Conclusion