Background: Squamous cell carcinoma of the cervix (SCC) and its precursors squamous intraepithelial lesions (SIL) remain a major global health burden. The tumor suppressor protein P16(Ink4a), a surrogate marker for high-risk human papilloma virus (HPV) infection, and CD31, an angiogenesis marker reflecting microvessel density (MVD), play critical roles in tumor progression.

Objective: This study aimed to assess the immunohistochemical (IHC) expression of P16(Ink4a) and CD31 in SIL and SCC and assess their correlation with disease severity.

Subjects and Methods: A cross-sectional study was conducted on 77 archived cervical biopsies (17 low-grade SIL [LSIL], 24 high-grade SIL [HSIL], and 36 SCC cases) from archival materials of two Baghdad hospitals (Medical City, The Teaching Hospital and Medical City of Al-Imamain AL-Kadhimein) (2018–2022). IHC staining for P16(Ink4a) (scored by intensity/distribution) and CD31 (for MVD quantification) was conducted. Statistical analysis used SPSS v26, with significance set at p < 0.05.

Results: P16(Ink4a) expression significantly increased from LSIL (35.3%) to HSIL (70.8%) and SCC (91.7%) (p < 0.001), with the highest scores in SCC (30.6%). MVD also rose with cervical lesion severity (p < 0.001), with means of 4.37 (LSIL), 13.11 (HSIL), and 52.81 (SCC). Poorly differentiated SCC showed the highest MVD (67.34). A strong positive correlation was found between P16(Ink4a) and MVD (p < 0.001).

Conclusions: Both P16(Ink4a) and CD31 (MVD) expression correlate strongly with cervical lesion severity, suggesting their potential as biomarkers for disease progression. Further studies are warranted to validate their prognostic utility in cervical cancer management.