Prognostic Associations between HPV-16 and HPV-18 in cervical cancer: a systematic review

doi:10.21203/rs.3.rs-8484982/v1

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Systematic Review

Prognostic Associations between HPV-16 and HPV-18 in cervical cancer: a systematic review

https://doi.org/10.21203/rs.3.rs-8484982/v1

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Cervical cancer is a major health problem for women worldwide and is most commonly caused by high-risk human papillomavirus (HPV) infections, particularly HPV-16 and HPV-18. This systematic review examines 13 studies that investigated how these two HPV types affect survival outcomes in cervical cancer patients, including overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Across multiple studies, HPV-16 was generally associated with better survival outcomes, especially in patients with advanced-stage disease. This may reflect the increased sensitivity of HPV-16-positive tumors to treatments such as chemoradiotherapy. In contrast, HPV-18 was consistently linked to poorer prognosis, particularly in early-stage cervical cancer and adenocarcinoma, with higher rates of recurrence and mortality. Several molecular markers, including p16 overexpression, HPV DNA methylation, and E6 oncoprotein expression, further helped explain differences in patient outcomes. Overall, these findings highlight the importance of HPV genotyping for predicting prognosis and guiding personalized cervical cancer treatment.

Oncology

Cervical cancer is one of the most common cancers affecting women worldwide and continues to be a major public health concern, particularly in low- and middle-income countries where access to screening and treatment may be limited (Xu et al., 2020; Chen et al., 2020). A long-lasting infection with high-risk human papillomavirus (HPV) is the main cause of cervical cancer. Although there are over 200 identified HPV genotypes, HPV-16 and HPV-18 are considered the most dangerous because together they cause about 70% of all cervical cancer cases worldwide (Hang et al., 2017; Lombard et al., 1998). HPV-16 is most commonly found in squamous cell carcinoma, while HPV-18 is more frequently associated with adenocarcinoma, a type of cervical cancer that is often linked to worse outcomes (Burger et al., 1996; Yang et al., 2014). Because of these differences, understanding how HPV-16 and HPV-18 affect patient outcomes is important for predicting risk, choosing treatments, and managing long-term care.

HPV-related cervical cancer develops when viral DNA becomes integrated into the DNA of infected cervical cells. This leads to increased production of viral oncoproteins called E6 and E7. These proteins interfere with important tumor-suppressing pathways, especially those involving p53 and retinoblastoma (Rb), which normally help control cell growth (Dong et al., 2020). When these pathways are disrupted, cells can grow uncontrollably and become cancerous. One important molecular marker related to this process is p16, which is often overexpressed when the Rb pathway is damaged. High levels of p16 are commonly used to identify tumors caused by high-risk HPV and have been linked to better survival outcomes (Mata et al., 2021). In addition, changes in HPV DNA methylation, particularly in the L1 and long control region (LCR), have been shown to help predict disease progression, especially when combined with E6 oncoprotein expression (Dong et al., 2020).

Survival outcomes in cervical cancer differ depending on the HPV genotype. Several studies have shown that HPV-16 positivity is often associated with better overall survival (OS) and disease-free survival (DFS), especially in patients with advanced-stage cervical cancer (Hang et al., 2017; Onuki et al., 2018). For example, Onuki et al. (2018) found that patients with FIGO stage III or IV tumors who were HPV-16 positive had significantly higher 10-year overall survival compared to patients without HPV-16. This suggests that HPV-16-positive tumors may respond better to treatments such as chemoradiotherapy. Similarly, Hang et al. (2017) reported that HPV genotypes belonging to alpha-9 group, which includes HPV-16, were linked to improved OS and DFS even after accounting for factors like age, tumor stage, and treatment.

In contrast, HPV-18 has been consistently linked to worse outcomes. Studies have reported higher overall mortality, increased cervical cancer-specific mortality, and lower progression-free survival (PFS) in patients with HPV-18-positive tumors (Schwartz et al., 2001; Kang et al., 2011). This negative effect is especially noticeable in early-stage tumors (FIGO IB-IIA) and in adenocarcinomas, suggesting that HPV-18-positive cancers may behave more aggressively than HPV-16-positive cancers (Burger et al., 1996; Yang et al., 2014).

Even though HPV genotyping is clearly important, not all studies report the same results. Some research shows that the impact of HPV genotype on survival may depend on factors such as tumor stage and treatment method. For example, de Araújo Catão Zampronha et al. (2013) found no significant difference in five-year overall survival or disease-free survival between HPV-16– and HPV-18–positive patients who were treated surgically for early-stage cervical cancer. Similarly, a meta-analysis by Xu et al. (2020) showed that HPV-18 was consistently associated with worse OS, DFS, and PFS, while HPV-16 did not significantly affect survival. Chen et al. (2020) also reported differences between studies and noted that variation in study design and patient populations could influence results.

Using molecular biomarkers along with HPV genotyping may improve the ability to predict patient outcomes. P16 overexpression has been associated with better survival and lower risk of recurrence, although some studies found that FIGO stage was still the strongest independent predictor of outcome (Mata et al., 2021). In addition, HPV-16 DNA methylation and E6 oncoprotein detection have shown potential for identifying patients at higher long-term risk, performing better than traditional screening methods such as cytology and viral load testing (Dong et al., 2020). These molecular tools may help doctors make better treatment decisions, especially for patients with higher-risk disease.

Understanding the prognostic differences between HPV-16 and HPV-18 is also important for public health. HPV vaccines targeting these high-risk types have been successful in reducing cervical cancer rates, but infections can still occur, and differences in genotype prevalence make continued monitoring necessary (Xu et al., 2020). In addition, knowing which HPV genotype a patient has can help guide follow-up care after treatment by identifying patients who may need closer monitoring for recurrence (Schwartz et al., 2001; Wang et al., 2012).

In summary, HPV-16 and HPV-18 show important differences in their biological behavior and effects on cervical cancer outcomes. HPV-16 is generally associated with better survival, especially in advanced-stage disease and squamous cell carcinoma, while HPV-18 is more often linked to poorer prognosis, particularly in early-stage disease and adenocarcinoma. Molecular markers such as p16 expression, HPV DNA methylation, and E6 oncoprotein status further help explain these differences. This systematic review analyzes 13 cohort studies to better understand how HPV-16 and HPV-18 affect prognosis in cervical cancer, with the goal of improving patient risk assessment and guiding future research.

Literature Search Strategy

A structured literature review was conducted to identify studies that examined the prognostic significance of HPV-16 and HPV-18 in cervical cancer. The search was limited to peer-reviewed studies found on PubMed and SpringerLink, as well as other records identified from outside websites, published between 1996 and 2021 (Burger et al., 1996; Lombard et al., 1998; Schwartz et al., 2001; Hang et al., 2017; Onuki et al., 2018; Kang et al., 2011; Yang et al., 2014; Xu et al., 2020; Chen et al., 2020; Dong et al., 2020; Wang et al., 2012; Mata et al., 2021; de Araújo Catão Zampronha et al., 2013). These studies were selected because they directly analyzed the relationship between HPV genotype and cervical cancer prognosis, with a focus on survival outcomes such as overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Search terms included combinations of “HPV-16,” “HPV-18”, “cervical cancer,” and “disease-free survival”.

Studies were included if they involved patients with histologically confirmed cervical cancer and reported outcomes based on HPV-16 and/or HPV-18 positivity. Studies that provided survival or recurrence outcomes, including OS, DFS, or PFS, were also included. Studies with cohort designs, prospective analyses, or meta-analyses were also included.

Studies were excluded if they did not report genotype-specific survival outcomes, or were published in a non-English language. They were also excluded if they were case reports, review articles, editorials, or studies not focused on cervical cancer prognosis. Studies with insignificant survival data or no direct comparison were also excluded.

Data Extraction

Data extraction was performed independently by one reviewer. Various pieces of data were collected from each study: author name, year of publication, study design, sample size, distribution of HPV genotypes, tumor stage based on FIGO classification, histological subtype, treatment approach (surgery or chemoradiation), length of follow-up, and reported survival outcomes (OS, DFS, and PFS).

Quality Assessment

The quality of the included studies was assessed using principles consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key factors that were evaluated included clarity of the study design, defined inclusion criteria, reliability of HPV genotyping methods, completeness of follow-up, and reporting of potential confounding variables. Most studies demonstrated moderate to high methodological quality and included multivariate analyses adjusting for factors such as age, FIGO stage, tumor histology, and treatment type (Hang et al., 2017; Onuki et al., 2018; Xu et al., 2020). No studies were excluded based on quality assessment. However, differences in sample size and follow-up duration were considered when interpreting results.

Data Synthesis

Due to differences across studies in design, patient populations, tumor stage, and treatment methods, a narrative synthesis approach was used. Descriptive statistics were applied to summarize study characteristics. Hazard ratios (HRs) and confidence intervals (CIs) for OS, DFS, and PFS were extracted when available. Outcomes associated with HPV-16 and HPV-18 were compared across studies to identify trends in survival, recurrence, and treatment response.

PRISMA Flow Diagram

A PRISMA flow diagram was created to visually represent the study selection process. A total of 13 studies were identified, all of which met the inclusion criteria and were included after full-text review. The diagram outlines the identification, screening, eligibility, and final inclusion stages in accordance with PRISMA 2020 standards, and a detailed diagram is provided in Fig. 1. Meta-analyses were included for contextual comparison and were not pooled with primary cohort data.

The included studies comprised multiple independent cohorts with sample sizes ranging from 77 to 1,742 participants, in addition to two meta-analyses summarizing data from previously published cohorts. Study populations included both early-stage (FIGO I-IIA) and advanced-stage (FIGO III-IV) cervical cancer. Patients were treated with either primary surgery, chemoradiotherapy, or combined modalities depending on stage and institutional practice. HPV genotyping was performed using polymerase chain reaction (PCR)-based assays, DNA hybridization, or DNA chip technology. Follow-up durations ranged from 38 months to 10 years. This table summarizes key study characteristics, including sample size, HPV-16 and HPV-18 prevalence, tumor stage, treatment modality, follow-up duration, and main survival outcomes.

Across studies, HPV-16 was the most frequently detected genotype, accounting for 40.5% to 69% of cases, whereas HPV-18 prevalence ranged from 8.8% to 33.3%. HPV-16-positive tumors were more commonly associated with squamous cell carcinoma and tended to present at earlier stages (Mata et al., 2021; Hang et al., 2017). In contrast, HPV-18 was more frequently observed in adenocarcinomas and was identified in both early and advanced-stage disease depending on the cohort (Burger et al., 1996; Lombard et al., 1998). Co-infection with HPV-16 and HPV-18 was reported in 26.9% of cases in select early-stage cohorts (de Araújo Catão Zampronha et al., 2013).

HPV-16 positivity was generally associated with improved overall survival in several cohorts, particularly among patients with advanced-stage disease. In a cohort of 306 patients, Hang et al. (2017) reported that HPV-16 positivity was independently associated with improved OS (HR 0.36; 95% CI: 0.18–0.74). Similarly, Onuki et al. (2018) demonstrated superior 10-year OS in HPV-16-positive FIGO stage III/IV tumors (73.7%) compared with HPV-18-positive tumors (45.7%), with HPV-16 remaining a significant prognostic factor after multivariable adjustment (HR 0.30; 95% CI: 0.09–0.86; P = 0.02).

In contrast, multiple studies reported poorer survival outcomes for HPV-18-positive patients. Schwartz et al. (2001) observed significantly higher total mortality (HR 2.2; 95% CI: 1.3–3.6) and cervical cancer-specific mortality (HR 2.5; 95% CI: 1.4–4.4) in HPV-18-related tumors compared with HPV-16-related tumors, particularly in early-stage disease. Lombard et al. (1998) similarly reported worse outcomes for HPV-18-associated tumors, with 5-year disease-free survival rates of 38% compared with 58% for HPV-16-positive tumors and higher mortality risk for HPV-18 (RR 2.4; 95% CI: 1.29–4.59).

DFS and PFS outcomes were consistently worse for HPV-18-positive patients across multiple cohorts. Kang et al. (2011) reported significantly lower 5-year PFS in HPV-18-positive early-stage patients (54.1%) compared with HPV-18-negative patients (83.8%), with HPV-18 positivity identified as an independent predictor of disease progression (HR 2.664; 95% CI: 1.437–4.938; P = 0.003). Yang et al. (2014) likewise demonstrated that HPV-18 positivity independently predicted poorer PFS in surgically treated stage I-IIA disease (HR 5.2; 95% CI: 1.29–20.90; P = 0.02).

At the meta-analysis level, Xu et al. (2020) reported that HPV-18 infection was consistently associated with worse DFS (HR 2.10; 95% CI: 1.73–2.54; P < 0.0001) and PFS (HR 2.97; 95% CI: 1.69–5.23; P = 0.00012), whereas HPV-16 positivity did not significantly affect DFS or PFS.

HPV genotype was also associated with differential treatment response in advanced-stage disease. Wang et al. (2012) demonstrated that HPV-18-positive patients experienced a significant survival benefit from concurrent chemoradiation therapy (CCRT), with 5-year disease-specific survival of 60.9% compared with 30.4% for radiation alone (P = 0.019). In contrast, no significant survival advantage with CCRT was observed in HPV-16-positive patients (P = 0.86). These findings suggest that HPV-18 status may influence sensitivity to chemoradiation and could have implications for individualized treatment planning.

Beyond HPV genotype, epigenetic factors were shown to influence long-term risk. Dong et al. (2020) evaluated HPV-16 DNA methylation and E6 oncoprotein expression in a 10-year cohort of 77 HPV-16-positive women. High methylation levels at multiple CpG sites were associated with significantly increased CIN3 + risk (HR range 3.0–5.4), while combined methylation–E6 panels further amplified risk prediction (HR range 9–19.7). These findings highlight the potential utility of molecular stratification within HPV-16-positive disease.

In early-stage (IB) cervical cancer, the prognostic impact of HPV-16 and HPV-18 was less consistent. De Araújo Catão Zampronha et al. (2013) observed no significant differences in overall or disease-free survival between HPV-16- and HPV-18-positive tumors, with 5-year OS exceeding 90% in both groups. Similarly, Mata et al. (2021) found that although HPV-16 and α-9 species were associated with improved outcomes in univariate analyses, FIGO stage was the only independent prognostic factor in multivariate models.

Ultimately, the evidence indicates that HPV-16 positivity is generally associated with more favorable survival outcomes, particularly in advanced-stage cervical cancer, whereas HPV-18 positivity is consistently linked to poorer survival, increased recurrence risk, and higher mortality, especially in early-stage disease. The observed associations between HPV genotype, treatment response, and molecular risk stratification underscore the clinical relevance of genotype-specific prognostic assessment in cervical cancer.

This systematic review brings together evidence from multiple cohort studies to examine how HPV-16 and HPV-18 affect prognosis in cervical cancer. Across nearly all included studies, HPV-16 was the most common genotype, accounting for approximately 40.5% to 69% of cervical cancer cases, while HPV-18 was less frequent, ranging from 8.8% to 33.3% (Hang et al., 2017; Mata et al., 2021). Despite its lower prevalence, HPV-18 consistently demonstrated a stronger association with poor clinical outcomes. In contrast, HPV-16 positivity was generally linked to improved overall survival (OS) and disease-free survival (DFS), particularly in patients with advanced-stage disease (Onuki et al., 2018; Hang et al., 2017).

Several studies reported that patients with HPV-18-positive tumors experienced higher recurrence rates and increased mortality, especially in early-stage cervical cancer. This pattern highlights an important biological and clinical distinction between HPV-16 and HPV-18, even though both are considered high-risk genotypes (Schwartz et al., 2001; Lombard et al., 1998; Kang et al., 2011). These findings suggest that HPV genotype plays a meaningful role in determining patient outcomes and should not be viewed as interchangeable across disease stages.

In advanced-stage cervical cancer (FIGO stages III–IV), HPV-16-positive tumors were associated with significantly higher overall survival compared to HPV-16-negative tumors (Onuki et al., 2018). This observation suggests that HPV-16-positive tumors may respond more effectively to chemoradiotherapy. On the other hand, HPV-18-positive tumors showed higher hazard ratios for disease progression and death, particularly in early-stage disease (Burger et al., 1996; Yang et al., 2014). These trends align with the findings from the meta-analyses, which reported that HPV-18 consistently predicts worse progression-free survival (PFS) and DFS, while HPV-16 shows limited prognostic impact in early-stage disease (Xu et al., 2020; Chen et al., 2020).

The observed differences in prognosis between HPV-16 and HPV-18 may be explained by underlying biological mechanisms. HPV-16 is most commonly associated with squamous cell carcinoma, which tends to be detected earlier and respond more favorably to treatment. In contrast, HPV-18 is more frequently linked to adenocarcinoma, a subtype often associated with aggressive tumor behavior and poorer outcomes (Burger et al., 1996; Lombard et al., 1998).

Variations in the expression of viral oncogenes, particularly E6 and E7, may further influence tumor growth, treatment response, and survival. Dong et al. (2020) demonstrated that epigenetic changes in HPV-16, such as DNA methylation combined with E6 oncoprotein expression, can help stratify long-term risk for high-grade cervical lesions (CIN3+). These findings highlight the complex interaction between HPV genotype, viral gene regulation, and cancer progression.

HPV genotype may also play an important role in determining response to treatment. Wang et al. (2012) reported that patients with HPV-18-positive advanced-stage squamous cell carcinoma experienced significant survival benefits from concurrent chemoradiation therapy (CCRT), whereas HPV-16-positive patients did not show the same level of benefit. This suggests that HPV-18-positive tumors may be particularly sensitive to combined treatment approaches.

In early-stage disease, HPV-18-positive tumors were associated with higher recurrence rates following surgical treatment, emphasizing the need for closer monitoring and consideration of adjuvant therapy in this patient group (Yang et al., 2014; Kang et al., 2011). Overall, these findings support the integration of HPV genotyping into clinical decision-making, not only for screening but also for prognostic evaluation and treatment planning.

In contrast to advanced-stage disease, several studies found that HPV genotype had limited prognostic value in early-stage cervical cancer treated surgically. De Araújo Catão Zampronha et al. (2013) reported no significant differences in OS or DFS between HPV-16- and HPV-18-positive tumors, with both groups demonstrating five-year survival rates exceeding 90%. Similarly, Mata et al. (2021) found that while HPV-16-positive and α-9 species tumors appeared to have better outcomes in univariate analysis, FIGO stage was the only independent predictor of survival in multivariate analysis.

These findings suggest that when early-stage cervical cancer is completely resected, tumor stage may be a stronger determinant of prognosis than HPV genotype alone.

The results of this review are consistent with prior studies identifying HPV-18 as a negative prognostic factor (Xu et al., 2020; Chen et al., 2020). Historical cohort studies have also reported reduced OS and DFS among HPV-18-positive patients (Lombard et al., 1998; Schwartz et al., 2001). This review highlights stage-specific differences, showing that HPV-18 has a particularly negative impact in early-stage disease, while HPV-16 appears to confer a survival advantage in advanced-stage tumors (Onuki et al., 2018).

Several limitations should be considered when interpreting these findings. To begin, heterogeneity across studies in terms of their design, sample size, follow-up duration, and treatment strategies may affect their comparability. Furthermore, differences in HPV detection methods, such as PCR, DNA hybridization, or DNA chip assays, could influence genotype classifications. Third, most included studies were observational, limiting the ability to establish causation. Finally, this review primarily focused on HPV-16 and HPV-18, while other high-risk genotypes were not consistently evaluated, which represents an important gap in literature. Data extraction and study selection were conducted by a single reviewer, which may increase the risk of bias.

Future research should prioritize prospective, multi-center studies with standardized HPV testing methods, detailed reports of tumor characteristics, and long-term follow-up. Incorporating molecular and epigenetic markers, such as DNA methylation patterns and viral oncoprotein expression, may further refine risk stratification and improve personalized treatment strategies (Dong et al., 2020). Clinical trials examining genotype-specific responses to chemoradiation and emerging therapies are especially needed for HPV-18-positive patients, who consistently demonstrate higher-risk profiles.

This systematic review demonstrates clear prognostic differences between HPV-16 and HPV-18 in cervical cancer. Across multiple studies, HPV-16 was the most prevalent genotype and was often associated with improved OS and DFS, particularly in advanced-stage disease (Hang et al., 2017; Onuki et al., 2018). In contrast, HPV-18 consistently predicted poor outcomes, including higher recurrence rates and increased mortality, especially in early-stage disease (Schwartz et al., 2001; Lombard et al., 1998; Yang et al., 2014).

These differences likely reflect variations in tumor histology, viral oncogene activity, and epigenetic regulation. HPV-16 is commonly associated with squamous cell carcinoma and improves response to chemoradiation, whereas HPV-18 is more frequently linked to adenocarcinoma and aggressive tumor behavior (Burger et al., 1996; Wang et al., 2012). Epigenetic factors such as DNA methylation and E6 oncoprotein expression further influence prognosis and may enhance risk stratification (Dong et al., 2020).

Overall, this review confirms that HPV genotype is a meaningful prognostic factor in cervical cancer. Incorporating genotype-specific insights into clinical practice and future research may improve survival outcomes, guide personalized treatment strategies, and support progress toward precision medicine in cervical cancer care.

HPV (Human Papillomavirus)

OS (Overall Survival)

DFS (Disease-Free Survival)

PFS (Progression-Free Survival)

FIGO (Fédération Internationale de Gynécologie et d’Obstétrique)

CIN3+ (Cervical Intraepithelial Neoplasia grade 3 or higher)

CCRT (Concurrent Chemoradiotherapy)

NR (Not Reported)

PCR (Polymerase Chain Reaction)

HR (Hazard Ratio)

CI (Confidence Interval)

RR (Relative Risk)

Acknowledgements

Artificial intelligence tools, such as ChatGPT, were used to assist with language, editing, organization, and clarity of the manuscript. The study selection, data extraction, data interpretation, and conclusions were performed by the authors.

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The authors declare no competing interests.

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Prognostic Associations between HPV-16 and HPV-18 in cervical cancer: a systematic review

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