<![CDATA[Introduction: Cervical adenocarcinoma (ADC) represents a significant and increasingly prevalent subtype of cervical cancer, yet its etiological relationship with high-risk human papillomavirus (HPV) types, particularly HPV-16 and HPV-18, remains distinct from that of squamous cell carcinoma (SCC). While HPV-16 is the dominant driver of SCC, emerging evidence suggests a unique tropism of HPV-18 for glandular epithelium. This systematic review and meta-analysis aims to synthesize global evidence on the association between HPV-16/18 infection and the risk of cervical adenocarcinoma. Methods: A comprehensive systematic review was conducted following predefined screening criteria. We included observational studies (case-control, cohort, cross-sectional) and meta-analyses that reported on histologically confirmed cervical adenocarcinoma, utilized validated HPV-16/18 detection methods, and provided quantitative association measures. Data from 80 sources were extracted, focusing on study design, population characteristics, HPV assessment methods, and association outcomes (odds ratios, prevalence ratios, hazard ratios). Results: The pooled HPV DNA prevalence in ADC (75–78.4%) was consistently lower than in SCC (87–90.1%). A striking reversal in type distribution was observed: HPV-18 was significantly over-represented in ADC (prevalence ratio ADC:SCC = 3.16, 95% CI: 2.91–3.43), whereas HPV-16 was under-represented (prevalence ratio ~0.57). HPV-18 and related alpha-7 species types accounted for nearly half of HPV-positive adenocarcinomas. Geographic variation was notable, with HPV-18 prevalence in ADC reaching 58.2% in Japan and 45.0% in China. Furthermore, HPV-positive ADC was associated with significantly better survival outcomes compared to HPV-negative ADC. Discussion: The findings confirm a distinct HPV type–histology relationship, underscoring the glandular tropism of HPV-18 and the phylogenetic pattern of alpha-7 species in adenocarcinoma pathogenesis. The substantial proportion of HPV-independent adenocarcinomas, particularly gastric-type variants, highlights the need for complementary diagnostic strategies. The results reinforce the preventive value of HPV-16/18 vaccination against ADC while revealing limitations of HPV-based screening for non-HPV-driven cases. Conclusion: HPV-18 is the predominant oncogenic driver in cervical adenocarcinoma, in contrast to its role in squamous cell carcinoma. This has critical implications for vaccine policy, screening algorithms, and clinical management. Future research should focus on the molecular mechanisms of glandular tropism and strategies for early detection of HPV-independent adenocarcinomas.]]>
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