Prognostic Role of Pyruvate Kinase M2 in High-Grade Gliomas: A Quantitative Immunohistochemistry Study

TL;DR

This study explores how the enzyme PKM2 affects survival in patients with aggressive brain tumors called high-grade gliomas.

Contribution

The study quantitatively evaluates PKM2 immunohistochemistry expression and its prognostic significance in GBM and ASTROG4.

Findings

High PKM2 intensity scores were significantly correlated with increased mortality risk (p=0.041).

ATRX-negative tumors showed elevated PKM2 levels, suggesting metabolic adaptations.

Severe preoperative motor deficits were associated with a threefold increase in mortality risk.

Abstract

Background: Glioblastoma (GBM) and grade 4 astrocytoma (ASTROG4) are aggressive primary brain tumors characterized by rapid growth, invasiveness, and poor prognosis, differentiated by the presence or absence of isocitrate dehydrogenase (IDH) mutation according to the World Health Organization (WHO) 2021 classification. Essential molecular markers, in addition to IDH mutations, include alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and p53 expression, which significantly influence their classification and prognosis. Pyruvate kinase M2 (PKM2), a critical enzyme in tumor metabolism, has been implicated in glioma progression, but its prognostic significance remains unclear.

Methods: This prospective study aimed to quantitatively measure PKM2 immunohistochemistry (IHC) expression in GBM (IDH wildtype) versus ASTROG4 (IDH R132H mutant), to assess the correlation between PKM2 expression and prognosis in these two patient groups, and to investigate the prognostic significance of ATRX and p53 expression in relation to PKM2 levels. A total of 67 patients with high-grade gliomas (43 GBM, 24 ASTROG4) were analyzed using IHC for IDH1, ATRX, p53, and PKM2. PKM2 expression was quantified using 3DHISTECH (Budapest, Hungary) image analysis software, and correlations with clinical parameters, survival, and other molecular markers were evaluated. Kaplan-Meier survival analysis and Cox regression models assessed the impact of PKM2 expression and clinical factors on prognosis.

Results: PKM2 expression was observed in both GBM and ASTROG4, with no significant differences in positivity rates. However, high PKM2 intensity scores significantly correlated with increased mortality risk (p=0.041). ATRX-negative tumors showed elevated PKM2 levels, suggesting compensatory metabolic adaptations. ASTROG4 cases had better survival outcomes than GBM. Severe preoperative motor deficits were associated with a threefold increase in mortality risk, highlighting the critical role of clinical factors in determining prognosis.

Conclusions: PKM2 plays an important role in glioma metabolism and can serve as a potential therapeutic target. Its association with ATRX highlights its involvement in tumor progression and genomic instability. Combining molecular markers with clinical parameters can improve prognostic accuracy and inform personalized treatment strategies for astrocytic tumors.

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