Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization-mass spectrometry

Clint M. Alfaro, Valentina Pirro, Michael F. Keating, Eyas M. Hattab, R. Graham Cooks, Aaron A. Cohen-Gadol

Research output: Contribution to journalArticle

Abstract

OBJECTIVE The authors describe a rapid intraoperative ambient ionization mass spectrometry (MS) method for determining isocitrate dehydrogenase (IDH) mutation status from glioma tissue biopsies. This method offers new glioma management options and may impact extent of resection goals. Assessment of the IDH mutation is key for accurate glioma diagnosis, particularly for differentiating diffuse glioma from other neoplastic and reactive inflammatory conditions, a challenge for the standard intraoperative diagnostic consultation that relies solely on morphology. METHODS Banked glioma specimens (n = 37) were analyzed by desorption electrospray ionization-MS (DESI-MS) to develop a diagnostic method to detect the known altered oncometabolite in IDH-mutant gliomas, 2-hydroxyglutarate (2HG). The method was used intraoperatively to analyze tissue smears obtained from glioma patients undergoing resection and to rapidly diagnose IDH mutation status (< 5 minutes). Fifty-one tumor core biopsies from 25 patients (14 wild type [WT] and 11 mutant) were examined and data were analyzed using analysis of variance and receiver operating characteristic curve analysis. RESULTS The optimized DESI-MS method discriminated between IDH-WT and IDH-mutant gliomas, with an average sensitivity and specificity of 100%. The average normalized DESI-MS 2HG signal was an order of magnitude higher in IDH-mutant glioma than in IDH-WT glioma. The DESI 2HG signal intensities correlated with independently measured 2HG concentrations (R2 = 0.98). In 1 case, an IDH1 R132H-mutant glioma was misdiagnosed as a demyelinating condition by frozen section histology during the intraoperative consultation, and no resection was performed pending the final pathology report. A second craniotomy and tumor resection was performed after the final pathology provided a diagnosis most consistent with an IDH-mutant glioblastoma. During the second craniotomy, high levels of 2HG in the tumor core biopsies were detected. CONCLUSIONS This study demonstrates the capability to differentiate rapidly between IDH-mutant gliomas and IDHWT conditions by DESI-MS during tumor resection. DESI-MS analysis of tissue smears is simple and can be easily integrated into the standard intraoperative pathology consultation. This approach may aid in solving differential diagnosis problems associated with low-grade gliomas and could influence intraoperative decisions regarding extent of resection, ultimately improving patient outcome. Research is ongoing to expand the patient cohort, systematically validate the DESI-MS method, and investigate the relationships between 2HG and tumor heterogeneity.

Original languageEnglish (US)
Pages (from-to)180-187
Number of pages8
JournalJournal of neurosurgery
Volume132
Issue number1
DOIs
StatePublished - Jan 1 2020

Fingerprint

Isocitrate Dehydrogenase
Electrospray Ionization Mass Spectrometry
Glioma
Mutation
Referral and Consultation
Craniotomy
Neoplasms
Pathology
Biopsy
Frozen Sections
Glioblastoma
Diagnostic Errors
ROC Curve
alpha-hydroxyglutarate

Keywords

  • 2-hydroxyglutarate
  • Glioma
  • Intraoperative diagnosis
  • Isocitrate dehydrogenase
  • Mass spectrometry
  • Oncology
  • Oncometabolite

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

Cite this

Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization-mass spectrometry. / Alfaro, Clint M.; Pirro, Valentina; Keating, Michael F.; Hattab, Eyas M.; Graham Cooks, R.; Cohen-Gadol, Aaron A.

In: Journal of neurosurgery, Vol. 132, No. 1, 01.01.2020, p. 180-187.

Research output: Contribution to journalArticle

Alfaro, Clint M. ; Pirro, Valentina ; Keating, Michael F. ; Hattab, Eyas M. ; Graham Cooks, R. ; Cohen-Gadol, Aaron A. / Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization-mass spectrometry. In: Journal of neurosurgery. 2020 ; Vol. 132, No. 1. pp. 180-187.
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AU - Graham Cooks, R.

AU - Cohen-Gadol, Aaron A.

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