18f-fluoromisonidazole positron emission tomography (fmiso-pet) as a dual biomarker reflecting hypoxia and cell proliferation activity in oral squamous cell carcinoma. A systematic review and meta-analysis.

Abstract

Background:
Tumor hypoxia and cellular proliferation are critical determinants of malignancy, resistance to therapy, and prognosis in oral squamous cell carcinoma (OSCC). Conventional imaging methods are limited in capturing these biological features. 18F-fluoromisonidazole positron emission tomography (FMISO-PET) has emerged as a non-invasive tool for quantifying intratumoral hypoxia, potentially reflecting both hypoxic burden and proliferative activity. However, evidence regarding its diagnostic accuracy, correlation with molecular markers, and prognostic value in OSCC remains fragmented.

Objective:
To systematically evaluate the role of FMISO-PET in assessing tumor hypoxia and cell proliferation activity in OSCC, and to perform a quantitative meta-analysis to determine its pooled correlation with hypoxia and proliferation markers.

Methods:
A systematic literature search was performed using PubMed, Scopus, and Web of Science up to October 2025, following PRISMA 2020 guidelines. Eligible studies included clinical investigations utilizing FMISO-PET in histopathologically confirmed OSCC patients, reporting correlations with hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and Ki-67 proliferation index. Data extraction and quality assessment were independently performed by two reviewers using the QUADAS-2 tool. Correlation coefficients were pooled using a random-effects model (DerSimonian-Laird method). Statistical heterogeneity was assessed with the I² statistic, and publication bias was examined using Egger’s test and funnel plots.

Results:
Twelve studies encompassing 476 OSCC patients met the inclusion criteria. The pooled analysis demonstrated a significant positive correlation between FMISO uptake and HIF-1α expression (r = 0.63; 95% CI: 0.49–0.77; p < 0.001) and a moderate correlation with Ki-67 proliferation index (r = 0.52; 95% CI: 0.36–0.67; p < 0.001). No significant publication bias was detected. Subgroup analysis revealed higher correlation strength in advanced-stage tumors and studies employing delayed post-injection imaging (>3 hours). The overall methodological quality of included studies was moderate, with variability mainly arising from heterogeneity in PET acquisition protocols and immunohistochemical scoring.