Systematic review and meta-analysis of survival outcomes in HPV-independent versus HPV-associated cervical adenocarcinoma

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Frontiers in Medicine Published May 8, 2026 Medically reviewed May 8, 2026 DOI ↗ By Dr. Julia Lee, PhD · Oncology, Genomics & Drug Development

Key Takeaway

Consider that HPV-independent cervical adenocarcinoma is associated with poorer survival outcomes than HPV-associated disease.

This is a systematic review and meta-analysis comparing outcomes for HPV-independent and HPV-associated cervical adenocarcinoma. The authors synthesized data from comparative studies, reporting pooled hazard ratios for survival. For overall survival, the pooled HR was 3.37 (95% CI 2.12 to 5.36). For progression-free survival, the pooled HR was 2.94 (95% CI 2.01 to 4.31). Disease-free survival was worse in the primary analysis (pooled HR 2.56, 95% CI 1.15 to 5.72) but became non-significant in a sensitivity analysis after excluding one study (HR 2.02, 95% CI 0.87 to 4.66).

The meta-analysis also found higher risks for HPV-independent disease in secondary outcomes. Pooled odds ratios were 2.76 (95% CI 1.88 to 4.05) for distant metastasis or recurrence, 2.76 (95% CI 1.82 to 4.19) for local recurrence, and 3.00 (95% CI 2.07 to 4.35) for lymphovascular space invasion positivity.

Key limitations noted by the authors include the non-significant disease-free survival result in sensitivity analysis. The review does not report sample sizes, follow-up duration, or adverse events. The authors conclude that HPV-independent disease has distinct clinical behavior, which may inform risk stratification, but they caution against inferring causation from association.

Study Details

Study typeMeta analysis

EvidenceLevel 1

PublishedMay 2026

View Original Abstract ↓

BackgroundHuman papillomavirus (HPV)-independent cervical adenocarcinoma is increasingly recognized as a biologically and clinically distinct entity from HPV-associated adenocarcinoma. We aimed to compare the clinicopathological features and survival outcomes of HPV-independent versus HPV-associated cervical adenocarcinoma.MethodsWe performed a systematic review and meta-analysis following PRISMA 2020 guidelines. PubMed, Web of Science, Scopus, Embase, and the Cochrane Library were searched from inception to 01 March 2026. Comparative studies evaluating HPV-independent/non-HPV-associated and HPV-associated cervical adenocarcinoma were included. Primary outcomes were overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Secondary outcomes included distant metastasis/distant recurrence, local recurrence, and lymphovascular space invasion/lymphovascular invasion (LVSI/LVI) positivity. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using fixed- or random-effects models according to heterogeneity.ResultsHPV-independent/non-HPV-associated adenocarcinoma was associated with poorer OS (pooled HR 3.37, 95% CI 2.12–5.36) and PFS (pooled HR 2.94, 95% CI 2.01–4.31) than HPV-associated adenocarcinoma. DFS was worse in the primary analysis (pooled HR 2.56, 95% CI 1.15–5.72), but became non-significant in sensitivity analysis after exclusion of one study requiring reciprocal transformation (HR 2.02, 95% CI 0.87–4.66). HPV-independent/non-HPV-associated adenocarcinoma also showed higher risks of distant metastasis/distant recurrence (pooled OR 2.76, 95% CI 1.88–4.05), local recurrence (pooled OR 2.76, 95% CI 1.82–4.19), and LVSI/LVI positivity (pooled OR 3.00, 95% CI 2.07–4.35).ConclusionsHPV-independent/non-HPV-associated cervical adenocarcinoma is associated with more aggressive clinicopathological features and worse survival outcomes than HPV-associated adenocarcinoma. These findings support the distinct clinical behavior of HPV-independent disease and may inform risk stratification and management.Systematic Review RegistrationPROSPERO, identifier CRD420261348146.