Analogous survival for patients with glioblastoma diagnosed by either histopathological or molecular features

See the article by Tesileanu et al in this issue, pp. 515–523.

The 2016 World Health Organization (WHO) Classification of Tumours of the Central Nervous System integrates histopathology with point mutations in exon 4 of isocitrate dehydrogenase 1 and 2 (IDH1/2) and codeletion of whole chromosome arms 1p and 19q to provide broad classifications of adult diffuse gliomas.¹ Integrating IDH and 1p/19q codeletion status has improved classification agreement for glioma diagnoses across neuropathologists and outperforms histopathology alone in broadly predicting patient survival. However, historical WHO grading schemes of diffuse astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV) based solely on histopathological features (including mitotic activity, necrosis, and microvascular proliferation) were not updated with the integrated classification system and do not take into account IDH-mutational status. Recent efforts have focused on defining molecular alterations (in addition to IDH and 1p/19q status) which may reflect natural history beyond an unevolved histological grading scheme. To keep current with advancing molecular knowledge, the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW)² formed to provide formal expert consensus recommendations to regularly update classification and grading strategies for CNS tumors.

Converging evidence has pointed to specific molecular alterations conferring a more aggressive (“higher-grade”) clinical behavior in traditional histologically determined WHO grades II and III IDH-wildtype astrocytomas. Several groups have reported decreased overall survival in IDH-wildtype diffuse astrocytomas (grade II) and anaplastic astrocytomas (grade III) harboring one or more of the following alterations: (i) amplification of epidermal growth factor receptor (EGFR)^3–5; (ii) telomerase reverse transcriptase promoter (TERTp) mutation^3,4,6,7; and/or (iii) gain of chromosome 7 with concurrent loss of chromosome 10 (+Chr 7/−Chr 10).^3,6 As part of their mission to provide evidence-based recommendations to improve glioma grading through integration of molecular data, the cIMPACT-NOW Working Committee 1 (Update 3) proposed that any histologically determined WHO grades II and III IDH-wildtype astrocytoma with at least any one of these 3 molecular alterations (EGFR amplification, TERTp mutation, +Chr 7/−Chr 10) be designated as diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV (DAG4) (Fig. 1).⁸

Fig. 1.

Algorithm to incorporate cIMPACT-NOW Update 3 recommendations for molecular grading of IDH-wildtype diffuse astrocytic gliomas. *Denotes recommended diagnostic entity of molecular glioblastoma put forth by the cIMPACT-NOW Update 3, which Tesileanu et al show has the same survival as traditional histopathologically determined **glioblastoma, IDH-wildtype. (MVP: microvascular proliferation; Amp: amplification; Chr: chromosome.)

In this issue of Neuro-Oncology, Tesileanu et al⁹ investigate the prognostic utility of the cIMPACT-NOW recommendations for molecularly determined glioblastoma in a large institutional retrospective cohort of adult diffuse gliomas. Within their cohort, they identify and characterize 87 patients who had IDH-wildtype astrocytomas, which were WHO grade II or III by histology and had classic radiographic findings of lower-grade diffuse gliomas. These included 71 (of 87) astrocytomas that had at least one of the 3 molecular alterations sufficient for the designation of DAG4. TERTp mutation was the most common (67 of 71) alteration found in this group, with 22 patients having TERTp mutations exclusively. Through univariate and multivariate analysis, they demonstrated that their 71 molecular glioblastoma patients had overall survival similar to that of 197 histologically determined IDH-wildtype glioblastoma patients. Furthermore, these molecular glioblastoma and traditional histological glioblastoma patients had significantly worse outcomes than grades II and III of the IDH-wildtype astrocytoma cohort (n = 16), which lacked molecular or histological features of glioblastoma. TERTp-only cases were also found to have similar survival as the histological IDH-wildtype glioblastoma cohort. Overall this study provides critical prognostic confirmation for the cIMPACT-NOW recommended designation of DAG4.

With the implementation of molecular grading for IDH-wildtype diffuse gliomas, additional considerations beyond prognostic value need to be examined, such as the therapeutic implications in prospective cohorts. Historically, patients with DAG4 have been unknowingly incorporated into WHO grades II and III astrocytoma clinical trials. Just as we would not proceed into glioma clinical trials without knowing the IDH status, we should consider EGFR amplification, TERTp mutation, and +Chr 7/−Chr 10 along the same molecular genre. As the current molecular designation of glioblastoma is built mostly upon somatic copy number alterations (EGFR amplification, +Chr 7, −Chr 10), it is prudent to take this information into account at clinical trial enrollment. This is especially important because other prognostic copy number alterations found in IDH-wildtype glioblastoma are known to be differentially distributed across clinical/surgical trial populations compared with unperturbed general populations.¹⁰ This molecular information is also necessary to balance specific molecular alterations across clinical trial arms. At a minimum for IDH-wildtype diffuse glioma biomarkers, accounting for EGFR amplification, TERTp mutation, and +Chr 7/−Chr 10 will allow for more precise trials and investigation of molecular alteration-specific therapeutic strategies.

Conflict of interest statement. The author declares that there are no conflicts of interest. The text is the sole product of the author and no third party had input or gave support to its writing.