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.
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.
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.
This study demonstrates the capability to differentiate rapidly between IDH-mutant gliomas and IDH-WT 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.
AndronesiOCKimGSGerstnerEBatchelorTTzikaAAFantinVR: Detection of 2-hydroxyglutarate in IDH-mutated glioma patients by in vivo spectral-editing and 2D correlation magnetic resonance spectroscopy. Sci Transl Med4:116ra42012
BeikoJSukiDHessKRFoxBDCheungVCabralM: IDH1 mutant malignant astrocytomas are more amenable to surgical resection and have a survival benefit associated with maximal surgical resection. Neuro Oncol16:81–912014
ChoiCRaisanenJMGanjiSKZhangSMcNeilSSAnZ: Prospective longitudinal analysis of 2-hydroxyglutarate magnetic resonance spectroscopy identifies broad clinical utility for the management of patients with IDH-mutant glioma. J Clin Oncol34:4030–40392016
EberlinLSDillALGolbyAJLigonKLWisemanJMCooksRG: Discrimination of human astrocytoma subtypes by lipid analysis using desorption electrospray ionization imaging mass spectrometry. Angew Chem Int Ed Engl49:5953–59562010
KanamoriMKikuchiAWatanabeMShibaharaISaitoRYamashitaY: Rapid and sensitive intraoperative detection of mutations in the isocitrate dehydrogenase 1 and 2 genes during surgery for glioma. J Neurosurg120:1288–12972014
LouisDNPerryAReifenbergerGvon DeimlingAFigarella-BrangerDCaveneeWK: The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol131:803–8202016
PirroVAlfaroCMJarmuschAKHattabEMCohen-GadolAACooksRG: Intraoperative assessment of tumor margins during glioma resection by desorption electrospray ionization-mass spectrometry. Proc Natl Acad Sci U S A114:6700–67052017
SøndergaardCBScheieDSehestedAMSkjøth-RasmussenJ: Finding of IDH1 R132H mutation in histologically non-neoplastic glial tissue changes surgical strategies, a case report. Childs Nerv Syst33:1217–12202017
TietzeAChoiCMickeyBMaherEAParm UlhøiBSangillR: Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting. J Neurosurg128:391–3982018
YannellKESmithKAlfaroCMJarmuschAKPirroVCooksRG: N-acetylaspartate and 2-hydroxyglutarate assessed in human brain tissue by mass spectrometry as neuronal markers of oncogenesis. Clin Chem63:1766–17672017