Risk stratification of high-grade lesions in atypical glandular cells, not otherwise specified: a refined model incorporating HPV phylogenetic clades and multiple HPV infection

To investigate the age, distribution of HPV phylogenetic clades and multiple infections in atypical glandular cells, not otherwise specified (AGC-NOS), and to develop a refined risk prediction model. We retrospectively analyzed 588 patients diagnosed with AGC-NOS at the International Peace Maternal and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, between January 2019 and December 2023. All patients underwent liquid-based cytology testing and high-risk HPV (hrHPV) testing for 14 genotypes, followed by histopathologic evaluation. Precancerous or worse lesions were identified in 9.5% of patients (56/588), and the overall hrHPV positivity rate was 17.7% (104/588). The Alpha-9 and Alpha-7 clades were significantly enriched in the outcome group compared with the non-outcome group (19.6% vs. 8.3% and 17.9% vs. 1.5%, respectively). In multivariable analysis, Alpha-7 (OR = 20.43, 95% CI: 7.22–60.07), Alpha-9 (OR = 3.41, 95% CI: 1.43–7.57), and age (OR = 1.04 per year, 95% CI: 1.01–1.07) were independent predictors. The model showed acceptable discrimination (AUC = 0.74, 95% CI: 0.66–0.82) and good calibration. Observed lesion rates in the low-, intermediate-, and high-risk groups were 4.5% (8/176), 8.2% (30/364), and 37.5% (18/48), respectively ( P for trend = 6.7 × 10⁻⁸). A model incorporating HPV phylogenetic clades, age, infection multiplicity, and AGC subtype provided preliminary evidence of potential value for risk stratification in AGC-NOS. The Alpha-7 clade was the strongest independent predictor. Pending external validation, this approach may support more individualized management of patients with AGC-NOS.