Histomolecular classification of adult diffuse gliomas: the diagnostic value of immunohistochemical markers

Adult gliomas are most often infiltrative. The World Health Organization (WHO) has classed them into three major groups according to the presomptive cell of origin: astrocytoma, oligodendroglioma and mixed oligoastrocytoma. Depending on the presence or absence of a small number of signs of anaplasia (mitosis, nuclear atypia, cell density, microvascular proliferation and necrosis) the WHO distinguishes grade II (LGG), III (anaplastic), and IV (glioblastomas, GBM). Mutation in the isocitrate deshydrogenase I and II (IDH1 and 2) genes distinguishes grade II, III and secondary GBM from primary GBM. Moreover two additional genetic alterations are recorded in grade II and III gliomas: TP53 mutations that characterize astrocytomas and 1p19q codeletion (as the result of t(1;19)(q10;p10) translocation) recorded in oligodendrogliomas. Mixed gliomas, the most non-reproducible category, share with astrocytomas and oligodendrogliomas the same genetic alterations. Interestingly TP53 mutation (p53+) and 1p19q codeletion (1p19q+) are mutually exclusive and involve IDH mutated (IDH+) glial precursor cells. According to IDH, TP53, and 1p19q status, four major subtypes of LGG are recorded: IDH+/p53-/1p19q-, IDH+/p53+/1p19q-, IDH+/p53-/1p19q+ and triple negative, this last subgroup having the worst prognosis. Interestingly, p53 expression and internexin alpha (INA) expression can replace to some extent TP53 mutation and 1p19 codeletion, respectively. Moreover the antibody directed against the IDH1R132H isoform is highly specific. Because this mutation is the most frequent it is sufficient to assess IDH status in more than 80% of grade II and III gliomas. Taken together these three immunohistochemical markers are contribute greatly to the classification of gliomas and should be tested routinely as diagnostic markers. Finally, although GBM are genetically heterogeneous, the vast majority display EGFR amplification, often associated with EGFR expression, which can be helpful for diagnosis in certain cases.