Molecular Biomarker Testing for the Diagnosis of Diffuse Gliomas

Abstract

Context.— The diagnosis and clinical management of patients with diffuse gliomas (DGs) have evolved rapidly over the past decade with the emergence of molecular biomarkers that are used to classify, stratify risk, and predict treatment response for optimal clinical care. Objective.— To develop evidence-based recommendations for informing molecular biomarker testing for pediatric and adult patients with DGs and provide guidance for appropriate laboratory test and biomarker selection for optimal diagnosis, risk stratification, and prediction. Design.— The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. A systematic review of literature was conducted to address the overarching question, “What ancillary tests are needed to classify DGs and sufficiently inform the clinical management of patients?” Recommendations were derived from quality of evidence, open comment feedback, and expert panel consensus. Results.— Thirteen recommendations and 3 good practice statements were established to guide pathologists and treating physicians on the most appropriate methods and molecular biomarkers to include in laboratory testing to inform clinical management of patients with DGs. Conclusions.— Evidence-based incorporation of laboratory results from molecular biomarker testing into integrated diagnoses of DGs provides reproducible and clinically meaningful information for patient management.

WHO CNS5 2021 classification of gliomas: a practical review and road signs for diagnosing pathologists and proper patho-clinical and neuro-oncological cooperation

“…Moreover, p53 strong immunopositivity in more than 10% of tumour cell nuclei and loss of ATRX expression are both sufficient to diagnose IDH-mutant astrocytoma without the necessity of 1p/19q testing. Thus, fluorescence in situ hybridization (FISH) should be done only in cases morphologically suspicious for oligodendroglioma with retention of ATRX expression and detected IDH1/2 mutation [12,44,82].…”

“…Other features like degree of cellularity or nuclear atypia might be also considered. An additional molecular marker is CDKN2A/2B homozygous deletion which was found in a subset of less than 10% oligodendrogliomas grade 3 [1,12].…”

“…Pathogenic variants in TP53 gene and 1p/19q codeletion are nearly, but not entirely mutually exclusive in IDH-mutant gliomas. There is an inverse relationship between ATRX loss and presence of 1p/19q codeletion, because oligodendrogliomas, differently from astrocytomas IDH-mutant, acquire alternative lengthening of telomeres via TERT promoter mutation which concerns about 98% of cases [3,12]. Other genetic alterations observed in around 70% and unique for oligodendrogliomas are mutations of the CIC gene [10].…”

“…The most typical fusions contain EGFR, FGFR3, MET or NTRK1/2/3 genes. p14ARF-MDM2-MDM4-p53, PI3K-AKT-mTOR and CDK4/6-CDKN2A/B-RB1 pathways are highly deregulated [12,79,82]. Some experts propose that histologically lower grade IDH-wildtype astrocytomas with molecular features of glioblastoma, such as TERT promoter mutation, EGFR amplification, +7/-10 chromosome copy-number changes, might be rather G3 due to its better prognosis and lower molecular burden [9].…”

“…Diffuse low grade (WHO G1) astrocytoma MYB/MYBL1-altered is a diffusely infiltrative astroglial neoplasm composed of monomorphic cells with MYB or MYBL1 fusion gene. Immunohistochemical testing for the expression of MAP2 antibody or FISH analysis may help with the diagnosis [12,22]. Polymorphous low-grade neuroepithelial tumour of the young is a glial neoplasm associated with a history of epilepsy, diffuse growth patterns, calcification, presence of oligodendroglioma-like components, CD34 positivity, and MAPK pathway-activating genetic abnormalities.…”