Cervical cancer poses a significant threat to women's health globally, with human papillomavirus (HPV) infection being the primary cause of its development. In recent years, substantial progress has been made in the prevention and early diagnosis of cervical cancer due to the widespread adoption of HPV vaccines and advancements in cervical cancer screening techniques. However, there has been ongoing debate within the academic community regarding the relationship between multiple HPV infections and the risk of cervical cancer development.
Recently, a study titled "Associations of Single Versus Multiple Human Papillomavirus Infections With the Prevalence of Cervical Intraepithelial Neoplasia 2/3 and Squamous Cell Carcinoma Lesions: Human Papillomavirus Type–Specific Attribution," authored by Zhong Fangfang and Tao Xiang from the Obstetrics & Gynecology Hospital of Fudan University, along with Professor Zhao Chengquan from the University of Pittsburgh, was published in the "Laboratory Investigation" journal. This research delves into the impact of single versus multiple HPV infections on the incidence of cervical intraepithelial neoplasia 2/3 (CIN2/3) and squamous cell carcinoma (SCC), providing us with new insights.
Ø Conclusion:
Multiple high-risk human papillomavirus (hrHPV) infections are not associated with a cumulatively higher risk for CIN2+ development. This indicates that the oncogenic progression of multiple hrHPV-associated cervical squamous lesions is neither synergistic nor a cumulative effect at the phylogenetic level, possibly a way of competitive interference.
Ø Research Background:
HPV is a common sexually transmitted virus, with over 200 HPV genotypes identified. Among them, approximately 18 are classified as high-risk types (hrHPV), closely associated with the development of cervical cancer. Women with HPV single infection have shown a greater probability of acquiring a second or multiple new subtypes. The prevalence of multiple hrHPV combinations and their influences on disease pathogenesis have not been fully understood, and their significance remains controversial.
Ø Research Objectives and Methods:
The aim of this retrospective study was to investigate the type-specific attribution and phylogenetic effects of single and multiple hrHPV subtypes in cervical squamous lesions. All cases with cervical histopathologic diagnosis and human papillomavirus (HPV) genotyping results in the 6 months preceding biopsy from October 2018 to December 2022 were studied and analyzed. Over the study period, 70,361 cases with histopathologic follow-up and prior HPV genotyping were identified. The current study aimed to investigate the association of single and multiple HPV infections with the prevalence of cervical intraepithelial neoplasia 2/3 and squamous cell carcinoma (CIN2+) lesions. The study utilized the BMRT reagent (manufactured by Jiangsu BioPerfectus Technologies Co., Ltd) for genotyping testing of 21 HPV types, including 18 high-risk types (hrHPV) (HPV16, 18, 31, 33, 45, 58, 35, 52, 56, 39, 51, 68, 59, 53, 66, 26, 73, and 82) and 3 low-risk types (lrHPV) (HPV6, 11, and 81).
Ø Research Results
HPV Positivity Rates:
The hrHPV-positive rate was 55.6% (39,104/70,361), including single hrHPV detected in 27,182 (38.6%), 2 types of hrHPV detected in 8158 (11.6%), and 3 types of hrHPV detected in 2486 (3.5%).
Incidence of Cervical Squamous Intraepithelial Lesions:
In total, there were 16,457 cases of cervical squamous lesions. The prevalence of single hrHPV infection increased, but the rate of multiple concomitant hrHPV infections showed a negative association as the degree of squamous lesions increased. The infection rate by a single hrHPV subtype sequentially increased in CIN1, CIN2/3, and SCC at 52.4%, 61.2%, and 71.5%, respectively. Conversely, the infection rate by multiple hrHPV subtypes showed a negative association in disease severity as follows: CIN1, CIN2/3, and SCC at 36.3%, 32.1%, and 22.6%, respectively.
Regarding the Impact of HPV16:
Among women with a single HPV16 infection, cervical intraepithelial neoplasia 2/3 and squamous cell carcinoma (CIN2+) diagnostic rate was 30.6%, and it increased to 47.6% when coinfected with HPV33 (P < .001) but significantly decreased when coinfected with all other hrHPV types (P <.05).
Single high-risk human papillomavirus infection rate in women with cervical squamous lesions:
A total of 9159 (55.7%) cases with hrHPV single infection in cervical squamous lesions were found. The most common subtype was HPV16 (25.2%, 827/2307), followed by HPV52, 58, 33, 53, 31, 51, 56, 18, 39, 68, 66, 59, 35, 45, 82, 73, and 26. HPV16 had the highest detection rate in CIN2/3 and SCC among all single HPV infections. HPV52 had the highest single HPV infection detection rate in CIN1.
Among all 70,361 cases with cervical histological diagnoses and previous HPV genotyping results, 39,104 cases were positive for high-risk HPV (hrHPV) (55.6%). Single hrHPV infection was found in 38.6% (27,182/70,361) of women. The most frequent hrHPV subtype causing single infection was HPV52 (7.4%), followed by 16, 58, 53, 39, 56, 51, 68, 18, 66, 33, 31, 59, 35, 45, 82, 73, and 26. HPV16 single infection harbored the highest risk of developing CIN2+(30.6%), followed by 26, 33, 82, 31, 58, 52, 18, 35, 45, 73, 59, 51, 68, 56, 66, 39, and 53. HPV 16, 26, and 33 were the three most prevalent HPV genotypes in patients with CIN2+ lesions. The prevalences of HPV26 and HPV82 genotypes were very low (0.1% and 0.2%), but their risk of CIN2+ lesions was higher at 27.5% and 19.8%, respectively. It is noteworthy that these two HPV subtypes are not included in US Food and Drug Administration-approved HPV testing.
The incidence of multiple combined infections and the risk of Cervical Intraepithelial Neoplasia grade 2 or higher (CIN2+) lesions:
The number of women with cervical squamous lesions with 2 high-risk human papillomavirus (hrHPV) genotype infections was less than that with a single hrHPV genotype infection (3,626 vs. 9,159; 22.0% vs. 55.7%). The most common 2 hrHPV genotype combination was HPV16&52; followed by HPV52+58, 52+53, 51+52, and 53+58 in CIN1, HPV16+58, 52+58, 16+33, and 16+53 in CIN2/3; and HPV16+58, 16+33, 16+53, and 16+18 in SCC. In addition, HPV16 was the most frequently identified genotype in 2 hrHPV genotype pattern SCC cases, accounting for 56.5% of all cases.
The risk of CIN2+ detection in patients with a single infection of HPV16 was 30.6%. Its risk showed a positive association of 47.6% when coinfected with HPV33 (P < .001) and significantly decreased when coinfected with most other high-risk HPV subtypes, including HPV53, 56, 39, 51, 68, 66, and 59. HPV33+52 coinfection showed a significant increase in the detection risk of CIN2+ in comparison with its infection. Twelve (30%, 12/40) HPV coinfection combinations, such as HPV 52+53 and HPV 16+53, significantly decreased the risk of CIN2+ compared with a single HPV infection.
Compared with single hrHPV infection, the cases with 3 types of HPV infections (HPV16+52+68, HPV16+52+51, HPV16+39+52, and HPV16+58+53) showed a statistical significance in decreasing the risk of CIN2+ lesions.
In conclusion, this study presents the epidemiological characteristics of multiple high-risk human papillomavirus (hrHPV) infections and assesses their clinical pathological significance in the carcinogenic process of cervical squamous intraepithelial lesions. The findings contribute to a more accurate assessment of cervical cancer risk and provide targeted guidance for HPV vaccination and cervical cancer screening. In the future, we anticipate further research to unveil the specific mechanistic roles of multiple HPV infections in the development of cervical cancer and how to leverage this knowledge more effectively for the prevention and treatment of cervical cancer.
Reference:
1. Zhang Y, Li H, Li X, Li Z, You Q, Liu H, Zhao Z, Su Y, Zheng X, Chen Y, Chen J, Yi H. Associations of multi-human papillomavirus infections with expression of p16 in a cohort of women who underwent colposcopy: a retrospective study of 5165 patients. Front Oncol. 2023 Oct 26;13:1265726. doi: 10.3389/fonc.2023.1265726. PMID: 37965476; PMCID: PMC10641385.
