Diagnostic discrepancies in malignant astrocytoma due to limited small pathological tumor sample can be overcome by IDH1 testing

Abstract

The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc [odds ratio (OR) 2.57, 95% confidence interval (CI) 1.6-4.06, P < 0.0001]. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95% CI 0.48-1.36, P < 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95% CI 1.88-3.28, P < 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected (P < 0.05). No volume-dependent differences were observed in patients with GBM (P < 0.4), IDH1 wild type (P < 0.1) or IDH1 mutation (P < 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under-diagnosis of GBM may occur when analysis is restricted to histopathology alone.

Fig. 1. Tissue volume-dependent diagnosis of malignant astrocytomas

(A, B) The rate of GBM diagnosis is dependent on the MR volume of tumor resected. As the total tumor resection volume decreases, the percentage of GBM diagnosis also decreases. In contrast, the proportion of IDH1 WT tumors remained constant regardless of tumor resection volumes. The divergence between the rate of histopathological GBM diagnosis and IDH1 WT occurs at 20 cc. (C,D) The rate of histopathological GBM diagnosis is significantly reduced for tissue samples <10 cc. (C) The percentage of GBM diagnosis among all patient samples is inversely proportional to the tissue specimen volume. (D) For tissue samples > 10cc, there is a significantly higher likelihood that patient will have been diagnosed with GBM as compared to tissue samples < 10cc. No difference was observed for IDH1 WT status (* denotes P < 0.05).

Fig. 2. Survival analysis of malignant astrocytomas based on histopathology and IDH1 status

Kaplan-Meier curves show that in patients with histological diagnosis of GBM (A), the overall survival is similar with resection volumes > 20 cc or < 20 cc. However, in patients diagnosed with AA (B), resection volume < 20 cc correlated with worse prognosis (P < 0.05). Neither IDH1 WT (C) nor IDH1 mutants (D) demonstrated significant differences in patient survival between the two resection volume groups.