IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO

The WHO 2007 classification of tumors of the CNS distinguishes between diffuse astrocytoma WHO grade II (A II_WHO2007) and anaplastic astrocytoma WHO grade III (AA III_WHO2007). Patients with A II_WHO2007 are significantly younger and survive significantly longer than those with AA III_WHO2007. So far, classification and grading relies on morphological grounds only and does not yet take into account IDH status, a molecular marker of prognostic relevance. We here demonstrate that WHO 2007 grading performs poorly in predicting prognosis when applied to astrocytoma carrying IDH mutations. Three independent series including a total of 1360 adult diffuse astrocytic gliomas with IDH mutation containing 683 A II_IDHmut, 562 AA III_IDHmut and 115 GBM_IDHmut have been examined for age distribution and survival. In all three series patients with A II_IDHmut and AA III_IDHmut were of identical age at presentation of disease (36–37 years) and the difference in survival between grades was much less (10.9 years for A II_IDHmut, 9.3 years for AA III_IDHmut) than that reported for A II_WHO2007versus AA III_WHO2007. Our analyses imply that the differences in age and survival between A II_WHO2007 and AA III_WHO2007 predominantly depend on the fraction of IDH-non-mutant astrocytomas in the cohort. This data poses a substantial challenge for the current practice of astrocytoma grading and risk stratification and is likely to have far-reaching consequences on the management of patients with IDH-mutant astrocytoma.