Molecular biomarkers and integrated pathological diagnosis in the reclassification of gliomas

Abstract

The present study aimed to evaluate the impact caused by the 2016 World Health Organization (WHO) diagnostic classification of gliomas in 139 patients studied in Argentina. Formalin-fixed paraffin-embedded tissues were used for histological and immunohistochemical analysis [glial fibrillary acidic protein, KI67, synaptophysin and isocitrate dehydrogenase (IDH)1-R132H]. DNA from formalin-fixed paraffin-embedded tissues was used for molecular analysis: 1p/19q co-deletion and mutation status of the IDH gene. These experiments were performed by direct Sanger sequencing and multiplex ligation-dependent probe amplification. According to the new classification, diagnoses included oligodendroglioma IDH-mutant and 1p/19q co-deletion (4.20%), anaplastic oligodendroglioma IDH-mutant and 1p/19q co-deletion (2.52%), diffuse astrocytoma IDH-mutant (6.72%), diffuse astrocytoma IDH-wild type (1.68%), anaplastic astrocytoma IDH-mutant (5.04%), anaplastic astrocytoma IDH-wild type (8.40%), glioblastoma IDH-mutant (5.88%) and glioblastoma IDH-wild type (65.56%). Regarding tumor histology, 60% of oligodendrogliomas, 35% of astrocytoma and 100% of unclassified gliomas were re-classified, while glioblastomas maintained their initial classification. Additionally, the present study evaluated the prognostic value of the histological grade for the 2007 and 2016 WHO classifications of gliomas. The histological subgroup associated with longer overall survival (OS) was grade II glioma (OS-2007WHO, 35.6 months; and OS-2016WHO, 47.7 months). Glioblastoma was the subgroup associated with a poor outcome (OS-2007WHO, 10.4 months; and OS-2016WHO, 11.1 months). The present study evaluated the OS of tumor grade subgroups with respect to their IDH status. For all subgroups, IDH-mutant tumors were associated with an improved prognosis compared with IDH-wild type tumors. The results suggested that the incorporation of molecular biomarkers in the new WHO classification improves tumor characterization and prognostic value of the subgroups.

Keywords: astrocytoma; diffuse glioma; glioblastoma; molecular classification; oligodendroglioma.

Figure 1

Simplified algorithm for integrated diagnosis of diffuse gliomas (2016 World Health Organization classification). IDH, isocitrate dehydrogenase.

Figure 2

Reclassification of 119 tumors according to the updated 2016 WHO classification. A, astrocytoma; UG, unclassified glioma; O, oligodendroglioma; OA, oligoastrocytoma; DA, diffuse astrocytoma; AO, anaplastic oligodendroglioma; AA, anaplastic astrocytoma; GBM, glioblastoma; IDH, isocitrate dehydrogenase; wt, wild-type; mut, mutant; WHO, World Health Organization.

Figure 3

Survival probability according to the (A) previous World Health Organization classification and (B) updated classification. The mean survival time is reported with 95% CI. 95% CI, 95% confidence interval; DF, degrees of freedom.

Figure 4

Survival probability of tumor subgroups according to the 2016 World Health Organization classification. (A) Tumor grade-based Ki-67 labeling index and IDH status. (B) Classification of tumor grade based on the patient's overall survival. The mean survival time is reported with 95% CI. 95% CI, 95% confidence interval; DF, degrees of freedom; IDH, isocitrate dehydrogenase; wt, wild-type; mut, mutant.