Neutrophil extracellular trap biomarkers as indicators of vulvovaginal atrophy severity after cancer treatment

Background. Vulvovaginal atrophy (VVA) following antitumor treatment is a common and clinically significant complication. At the same time, the immunoinflammatory mechanisms determining the severity and persistence of atrophic changes are yet to be sufficiently studied. The role of extracellular neutrophil traps (NETs) in the pathogenesis of genital tract mucosal damage remains virtually unexplored.

Objective: To evaluate blood levels of NET markers – citrullinated histone H3 (CitH3), myeloperoxidase (MPO), cathepsin G (CatG) – in various VVA phenotypes after antitumor therapy and to determine their significance as potential biomarkers of atrophy severity.

Material and methods. A cross-sectional comparative study enrolled 215 postmenopausal women divided into five groups as follows: VVA after surgical treatment (n=52), chemoradiotherapy (n=27), antiestrogenic therapy (n=48), VVA without a history of cancer (n=53), and control (n=35). Clinical symptoms, vaginal pH, vaginal health index (VHI), epithelial thickness, and plasma levels of CitH3, MPO, and CatG were evaluated. Statistical analysis was performed using the Mann–Whitney test with Bonferroni correction and calculation of the r effect size.

Results. The NETs profile varied depending on the nature of the treatment received. Maximum levels of CitH3 (0,65 [0,50–0,80] ng/ml), MPO (24 [18–30] ng/ml) и CatG (14 [12–16] ng/ml) were found in women after chemoradiotherapy. Antiestrogenic therapy was accompanied by pronounced immunoinflammatory activation of NETs, while surgical menopause and VVA without a history of gynecological cancer were associated with moderate and minimal levels, respectively. Intergroup differences between the oncological groups and the control group were statistically significant (p<0.005) with a large effect size according to the Mann–Whitney criterion (r≥0.50).

Conclusion. VVA after antitumor therapy is characterized by various immunoinflammatory phenotypes, which are reflected in specific NET profiles. CitH3, MPO, and CatG can be considered pathogenetically significant markers reflecting the degree of immunoinflammatory changes in VVA, thus representing candidates for further research aimed at patient stratification and the development of personalized therapy.

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