Heterogeneity of angiogenesis in recurrent cervical cancer and its significance for the choice of antiangiogenic or immune therapy

Background. Recurrent cervical cancer (CC) is characterized by a poor prognosis and limited systemic therapy options. Angiogenesis and integrin-mediated extracellular matrix remodeling are key mechanisms of tumor progression, but the dynamics of microvascular density and integrin expression in the primary tumor – relapse pair remain poorly understood.

Aim. To conduct a comparative morphological analysis of angiogenesis and the expression of integrins α3, α5, and β1 in primary and recurrent lesions of squamous cell CC and evaluate their value as biological markers for the selection of antiangiogenic and / or immunotherapy.

Materials and methods. This prospective study included 20 patients with morphologically confirmed recurrent squamous cell CC (FIGO IB2–IIIB) treated between 2010 and 2025. A comparative immunohistochemical study of CD34 and integrins α3, α5, and β1 was performed in primary and recurrent tumor samples, along with morphometric assessment of microvascular density and relative vascular area. A recurrence / primary tumor ratio was calculated for integrins, with an increase of ≥1.5 considered significant. A scoring model for angiogenic activity (0–5 points) was developed based on the microvessel density ratio and integrin expression. In patients with low / intermediate angiogenic activity, additional testing for HER2, MSI / MMR, and PD-L1 (CPS) was performed.

Results. In primary tumors, the average microvessel density of CD34+ vessels was ~127 vessels / mm², consistent with published data for squamous cell CC. When compared with relapses, three types of angiogenic response were identified: significant increase in angiogenesis (10 / 20, 50 %), no significant changes (4 / 20, 20 %), and decreased microvessel density (6 / 20, 30 %). Clinical examples demonstrate that high total angiogenic activity is associated with pronounced vascularization of relapses and a response to anti-VEGF therapy, whereas with low angiogenesis, immunotherapy may be preferable.

Conclusion. Relapsed CC is characterized by pronounced heterogeneity of angiogenesis and integrin-mediated changes, which determines varying degrees of tumor angiogenic dependence. Quantitative assessment of CD34 microvessel density and α3, α5, and β1 integrin expression in combination with molecular profiling (HER2, MSI / MMR, PD-L1) enables patient stratification and the use of the developed scoring model as a morphological tool for personalized selection of antiangiogenic therapy, immunotherapy, or a combination of both in recurrent CC.