Radiological and Pathological Features Associated with IDH1-R132H Mutation Status and Early Mortality in Newly Diagnosed Anaplastic Astrocytic Tumours

April Radiological and Pathological Features Associated with IDH1-R132H Mutation Status and Early Mortality in Newly Diagnosed Anaplastic Astrocytic Tumours Jason K. Wasserman 0 1 Garth Nicholas 0 1 Rebecca Yaworski 0 1 Anne- Marie Wasserman 0 1 John M. Woulfe 0 1 Gerard H. Jansen 0 1 Santanu Chakraborty 0 1 Thanh B. Nguyen 0 1 0 1 Division of Laboratory Medicine, Department of Anatomical Pathology , Ottawa, Ontario , Canada , 2 The Ottawa Hospital Cancer Centre , Ottawa, Ontario , Canada , 3 Division of Neuro-imaging, Department of Medical Imaging , Ottawa, Ontario , Canada , 4 University of Ottawa , Ottawa, Ontario , Canada , 5 The Ottawa Hospital Research Institute , Ottawa, Ontario , Canada 1 Academic Editor: Michael Scheurer, Baylor College of Medicine, UNITED STATES - Competing Interests: The authors have declared that no competing interests exist. Glioblastoma can occur either de novo or by the transformation of a low grade tumour; the majority of which harbor a mutation in isocitrate dehydrogenase (IDH1). Anaplastic tumours are high-grade gliomas that may represent the final step in the evolution of a secondary glioblastoma or the initial presentation of an early primary glioblastoma. We sought to determine whether pathological and/or radiological variables exist that can reliably distinguish IDH1-R132H-positive from IDH1-R132H-negative tumours and to identify variables associated with early mortality. Patients diagnosed with anaplastic astrocytic tumours were included. Magnetic resonance imaging was performed and immunohistochemistry was used to identify tumours with the IDH1-R132H mutation. Survival was assessed 12 months after diagnosis. Variables associated with IDH1-R132H status were identified by univariate and ROC analysis. 37 gliomas were studied; 18 were positive for the IDH1-R132H mutation. No tumours demonstrated a combined loss of chromosomes 1p/19q. Patients with IDH1-R132H-positive tumours were less likely to die within 12 months of diagnosis (17% vs. 47%; p=0.046), more likely to have tumours located in the frontal lobe (55% vs. 16%; p=0.015), and have a higher minimum apparent diffusion coefficient (1.115 x 10-3 mm2/sec vs. 0.838 x 10-3 mm2/sec; p=0.016), however, these variables demonstrated only moderate strength for predicting the IDH1-R132H mutation status (AUC=0.735 and 0.711, respectively). The Ki-67 index was significantly lower in IDH1-R132H-positive tumours (0.13 vs. 0.21; p=0.034). An increased risk of death was associated with contrast-enhancement 5 cm3 in patients with IDH1R132H-positive tumours while edema 1 cm beyond the tumour margin and < 5 mitoses/ mm2 were associated with an increased risk of death in patients with IDH1-R132Hnegative tumours. IDH1-R132H-positive and -negative anaplastic tumours demonstrate unique features. Factors associated with early mortality are also dependent on IDH1-R132H status and can be used to identify patients at high risk for death. Glioblastoma is the most common type of primary malignant brain tumour in adults. Despite optimal medical and surgical management, the majority of patients die from the disease within 1216 months of diagnosis.[1] According to the current WHO classification, astrocytic tumours that have an inherent tendency to progress to glioblastoma are defined as diffuse (WHO grade II) or anaplastic (WHO grade III) while glioblastoma is given the highest grade (WHO grade IV).[2] Glioblastoma can either occur de novo ('primary glioblastoma') or it can develop from a previously diagnosed lower grade tumour ('secondary glioblastoma'); the majority of tumours are primary glioblastomas.[3] Important recent discoveries have shown that most secondary glioblastomas arise from lower grade astrocytic tumours that harbor a mutation in the gene for isocitrate dehydrogenase (IDH1); of these, 90% posses the R132H mutation.[4] In contrast, the mutation is absent in the great majority of primary glioblastomas.[4] Anaplastic astrocytic tumours (anaplastic astrocytoma [AA] and anaplastic oligoastrocytoma [AOA]) exist at the interface between these two entities with just over half of tumours harboring an IDH1 mutation. As such, an anaplastic glioma may represent progression of a low-grade glioma into a high-grade lesion or the initial presentation of an early primary glioblastoma. How these tumours differ in their biological behavior at this critical time point in their development still remains poorly understood. Magnetic resonance imaging (MRI) plays a critical role in both the diagnosis and management of patients with glioma. Radiological features that are used to characterize a glioma include the size, shape, and location of the tumour, contrast enhancement (CE), the presence of peri-tumoural edema, apparent diffusion coefficient and mass effect. Recent evidence has shown that IDH1 mutant diffuse gliomas and glioblastomas demonstrate unique radiological features that correlated with outcome.[5, 6] Specifically, a study examining diffuse gliomas demonstrated that IDH1 mutant tumours were smaller and less infiltrative.[6] In contrast, a study examining glioblastoma found that IDH1 mutant tumours were more likely to be nonCE, larger, and in the frontal lobe.[5] To date there have been no similar studies focusing on patients diagnosed with AA despite the wide variability in outcome among patients with this tumour. Knowledge of IDH1 status in the context of specific radiological criteria would allow clinicians to provide patients with a more accurate prognosis and in the future may better predict their response to targeted therapies. The present study assessed a defined set of MRI variables and two markers of cellular proliferation in patients presenting with newly diagnosed anaplastic astrocytic tumours (AA and OAA) in order to better understand their biological evolution. This patient population was selected because diffuse astrocytic tumours (grades II and III) invariably transform into glioblastoma; AA and AOA are entities at a crucial transition point. The purpose of this study was to determine whether any of the radiological or pathological variables assessed could reliably distinguish IDH1-R132H positive from IDH1-R132H negative tumours in this patient population. We also sought to identify radiological and pathological variables associated with early mortality in order to provide clinicians with better prognostic tools for managing this uncommon yet challenging patient population. Study population This study was approved by the Ottawa Hospital Research Ethics Board (20130596-01H). Patient consent was not obtained for this retrospective study however all data were analysed anonymously and no patient identifiers exist in the manuscript. The database of the Department of Anatomical Pathology was used to identify all patients with a histological diagnosis of a WHO grade III anaplastic astrocytic tumour, either AA or AOA, between January 2010 and May 2013. Patients with pure anaplastic oligo (...truncated)