A clinical perspective on the 2016 WHO brain tumor classification and routine molecular diagnostics

Abstract

The 2007 World Health Organization (WHO) classification of brain tumors did not use molecular abnormalities as diagnostic criteria. Studies have shown that genotyping allows a better prognostic classification of diffuse glioma with improved treatment selection. This has resulted in a major revision of the WHO classification, which is now for adult diffuse glioma centered around isocitrate dehydrogenase (IDH) and 1p/19q diagnostics. This revised classification is reviewed with a focus on adult brain tumors, and includes a recommendation of genes of which routine testing is clinically useful. Apart from assessment of IDH mutational status including sequencing of R132H-immunohistochemistry negative cases and testing for 1p/19q, several other markers can be considered for routine testing, including assessment of copy number alterations of chromosome 7 and 10 and of TERT promoter, BRAF, and H3F3A mutations. For "glioblastoma, IDH mutated" the term "astrocytoma grade IV" could be considered. It should be considered to treat IDH wild-type grades II and III diffuse glioma with polysomy of chromosome 7 and loss of 10q as glioblastoma. New developments must be more quickly translated into further revised diagnostic categories. Quality control and rapid integration of molecular findings into the final diagnosis and the communication of the final diagnosis to clinicians require systematic attention.

Keywords: 1p/19q codeletion; 7+/10LOH; IDH; WHO classification; glioma.

Fig. 1

Glioblastoma diagnostics 2016. (A) T1-weighted MR images of a 40-year-old male with a short history of headache and difficulty walking. At histopathology a glioblastoma was diagnosed, targeted sequencing showed an IDH2 mutation, combined 1p/19q loss, and deletion of chromosome 9 consistent with the diagnosis of anaplastic oligodendroglioma. (B) T1-weighted contrast enhanced MR image of a 50-year-old female who developed over months progressive memory and behavioral complaints. No contrast enhancement was present; at biopsy, histopathology showed a grade II astrocytoma, next generation sequencing failed to show an IDH mutation but instead documented gain of chromosome 7, loss of 10q, and mutations in the EGFR and PTEN gene consistent with a glioblastoma.

Fig. 2

T2-weighted images of a 25-year-old male who underwent 2 biopsies for a mesencephalic lesion. On both occasions, histopathological examination failed to show clear evidence of tumor. On mutational analysis, a BRAF mutation was found (c.1795_1797dupACA;p.T599dup).

Fig. 3

T1 contrast enhanced MR images of a ring right frontal enhancing lesion tumor histopathologically classified as glioblastoma. At molecular examination, 1p/19q codeletion was found but with neither an IDH nor a TERTp mutation.

Fig. 4

T2-weighted MR images of a right frontal low-grade astrocytoma in a 20 year old, diagnosed as IDHwt because of negative IHC. After referral to a tertiary care center, sequencing demonstrated an IDH c.394C>T; p.R132C mutation in combination with a TP53 and an ATRX mutation.