The Misclassification of Diffuse Gliomas: Rates and Outcomes

Background: The integrated histopathological and molecular diagnoses of the 2016 WHO classification of CNS tumors have revolutionized patient care by improving diagnostic accuracy and reproducibility; however, the frequency and consequences of misclassification of histologically-diagnosed diffuse gliomas are unknown. Methods: Patients with newly-diagnosed ICD-O-3 histologically-encoded diffuse gliomas from 2010-2015 were identified from the National Cancer Database-the misclassification rates and overall survival (OS) of which were assessed by WHO grade and 1p/19q status. Additionally, misclassification rates by IDH, ATRX, and p53 statuses were examined in an analogous multi-institutional cohort of registry-encoded diffuse gliomas. Results: Of 74,718 diffuse glioma patients, only 74.4% and 78.8% of molecularly-characterized WHO grade II and III oligodendrogliomas were in fact 1p/19q-codeleted. Additionally, 28.9% and 36.8% of histologically-encoded grade II and III "oligoastrocytomas", and 6.3% and 8.8% of grade II and III astrocytomas had 1p/19q-codeletion, thus molecularly representing oligodendrogliomas if also IDH-mutant. OS significantly depended on accurate WHO grading and 1p/19q status. Conclusions: Based on 1p/19q, IDH, ATRX, and p53, the misclassification rates of histologically-encoded oligodendrogliomas, astrocytomas, and glioblastomas are ~21-35%, ~6-9%, and ~9%, respectively; with significant clinical implications. Our findings suggest that when compared to historical histology-only classified data-in national registry, as well as, institutional databases-there is the potential for false-positive results in contemporary trials of molecularly-classified diffuse gliomas, which could contribute to a seemingly positive phase II trial (based on historical comparison) failing at the phase III stage. Critically, findings from diffuse glioma clinical trials and historical cohorts using prior histology-only WHO schemes must be cautiously re-interpreted.

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