Huge heterogeneity in survival in a subset of adult patients with resected, wild-type isocitrate dehydrogenase status, WHO grade II astrocytomas

Abstract

<jats:sec><jats:title>OBJECTIVE</jats:title><jats:p>World Health Organization grade II gliomas are infiltrating tumors that inexorably progress to a higher grade of malignancy. However, the time to malignant transformation is quite unpredictable at the individual patient level. A wild-type isocitrate dehydrogenase (IDH-wt) molecular profile has been reported as a poor prognostic factor, with more rapid progression and a shorter survival compared with IDH-mutant tumors. Here, the oncological outcomes of a series of adult patients with IDH-wt, diffuse, WHO grade II astrocytomas (AII) who underwent resection without early adjuvant therapy were investigated.</jats:p></jats:sec><jats:sec><jats:title>METHODS</jats:title><jats:p>A retrospective review of patients extracted from a prospective database who underwent resection between 2007 and 2013 for histopathologically confirmed, IDH-wt, non–1p19q codeleted AII was performed. All patients had a minimum follow-up period of 2 years. Information regarding clinical, radiographic, and surgical results and survival were collected and analyzed.</jats:p></jats:sec><jats:sec><jats:title>RESULTS</jats:title><jats:p>Thirty-one consecutive patients (18 men and 13 women, median age 39.6 years) were included in this study. The preoperative median tumor volume was 54 cm<jats:sup>3</jats:sup> (range 3.5–180 cm<jats:sup>3</jats:sup>). The median growth rate, measured as the velocity of diametric expansion, was 2.45 mm/year. The median residual volume after surgery was 4.2 cm<jats:sup>3</jats:sup> (range 0–30 cm<jats:sup>3</jats:sup>) with a median volumetric extent of resection of 93.97% (8 patients had a total or supratotal resection). No patient experienced permanent neurological deficits after surgery, and all patients resumed a normal life. No immediate postoperative chemotherapy or radiation therapy was given. The median clinical follow-up duration from diagnosis was 74 months (range 27–157 months). In this follow-up period, 18 patients received delayed chemotherapy and/or radiotherapy for tumor progression. Five patients (16%) died at a median time from radiological diagnosis of 3.5 years (range 2.6–4.5 years). Survival from diagnosis was 77.27% at 5 years. None of the 21 patients with a long-term follow-up greater than 5 years have died. There were no significant differences between the clinical, radiological, or molecular characteristics of the survivors relative to the patients who died.</jats:p></jats:sec><jats:sec><jats:title>CONCLUSIONS</jats:title><jats:p>Huge heterogeneity in the survival data for a subset of 31 patients with resected IDH-wt AII tumors was observed. These findings suggest that IDH mutation status alone is not sufficient to predict risk of malignant transformation and survival at the individual level. Therefore, the therapeutic management of AII tumors, in particular the decision to administer early adjuvant chemotherapy and/or radiation therapy following surgery, should not solely rely on routine molecular markers.</jats:p></jats:sec>

Extent of Surgical Resection in Lower-Grade Gliomas: Differential Impact Based on Molecular Subtype

“…Our finding that surgical resection does not impact survival in IDHwt LGGs is not broadly supported in the literature and requires further study. We speculate that disparate results regarding IDHwt LGGs may relate to the known clinical and molecular heterogeneity of this subgroup, especially among grade II IDHwt LGGs, [8][9][10] and further stratification of this subgroup may be forthcoming in future WHO classification schemes. 11 Our study has limitations.…”

“…[3][4][5][6][7] The IDH-wild-type subgroup of LGGs (heretofore collectively referred to as IDHwt) is associated with the most aggressive clinical behavior and worst outcome, similar to that of glioblastomas (WHO grade IV), though heterogeneity in the behavior and molecular features within this subgroup is being increasingly recognized. [8][9][10][11] Multiple studies have provided evidence supporting the maximum safe surgical resection as the front-line treatment of diffuse LGGs. [12][13][14][15][16][17][18][19] However, most studies were undertaken before the 2016 WHO update for the classification of diffuse LGGs, without accounting for defining molecular markers.…”

Isocitrate dehydrogenase (IDH) status prediction in histopathology images of gliomas using deep learning

“…In the future, a pathologist could take a photo of the processed H&E slide and submit it to a system trained according to our method, getting the IDH status prediction back in a few minutes, according to which further tests, whenever necessary, can be arranged. A further future perspective relates to a practical aspect occurring during glioma surgery: considering the increasing evidence on the positive relationship between the degree of surgical resection and extent of the survival in patients affected by gliomas harbouring IDH mutations (i.e., IDH-mutant gliomas patients have a better prognosis when the resection is total or even supra-total vs. the www.nature.com/scientificreports www.nature.com/scientificreports/ ones who undergo a sub-total/partial resection) 23,[39][40][41] , the surgical approach could be tailored intra-operatively according to the IDH status findings. Indeed, the surgical sample might be stained with H&E and, avoiding the delays related to the immunohistochemistry against the IDH antibody, the image of the slide could be computationally processed in a few minutes according to our methodology.…”

Beyond IDH-Mutation: Emerging Molecular Diagnostic and Prognostic Features in Adult Diffuse Gliomas

“…With only rare exceptions noted, these mutations are thought to be mutually exclusive with the 1p/19q co-deletion [ 6 , 36 , 37 ], aiding in distinguishing diffuse astrocytomas from oligodendrogliomas [ 38 , 39 ]. The vast majority of tumors with these histologic and molecular features have relatively benign clinical behavior; median post-surgical overall survival intervals range from 9.3 to 10.9 years in some cohorts, with variation based on patient age, tumor size and location, the extent of resection, post-surgical treatment, and other factors [ 34 ], although examples of outliers with rapid progression to GBM and short survival intervals have been identified in many reports [ 34 , 40 , 41 , 42 ].…”