Introduction
Cervical cancer is by far the most prevalent human papillomavirus (HPV)-related disease, and more than 90% of cervical cancer cases can be attributed to infection with high-risk HPV [
1]. Studies show that roughly 20% of the population carries high-risk HPV. The three most prevalent HPV genotypes are HR-HPV52, HR-HPV16, and HR-HPV58 [
2,
3]. The most common type of HPV infection in China is HR-HPV52, and it is found primarily in the eastern, central, southern, and southwestern regions of the country [
3] A persistent infection with high-risk HPV is linked to both the development and spread of cervical cancer. HPV is linked to high grade squamous intraepithelial lesion (HSIL), an abnormality of squamous cells. These include CIN2, CIN3, moderate and severe dysplasia, and carcinoma in situ, all of which were previously used terms [
4]. Regardless of the results of HPV co-testing, immediate excisional procedure or colposcopy is recommended for women over the age of 24 who have a positive HSIL pap test result and no extenuating circumstances. A diagnostic excisional procedure is recommended if the colposcopic examination is insufficient. Ablation of the transformation zone or excision is considered acceptable if HSIL (CIN2, CIN3, or CIN2-3) is confirmed on biopsy and an adequate colposcopy was performed. It is not recommended that pregnant women who test positive for HSIL have excisional treatment; only colposcopy is safe. A literature review concluded that birth defects, low birth weight, and premature membrane rupture before 37 weeks of pregnancy were more common in women who had CIN surgery compared to those who did not [
5]. There is widespread agreement that treating high-risk HPV strains early can avert the progression of cervical cancer and improve its treatment. Cervical cancer screening tools, such as high-risk HPV typing and quantitative detection and thinprep cytology test (TCT), have improved and standardized in recent years.
In this study, we aimed to determine the association between HPV infection characteristics, age, and cervical intraepithelial lesions, as well as the association between the high-risk HPV positive population with negative cytology results and cervical intraepithelial lesions, using a retrospective analysis of clinical data from 240 patients with cervical intraepithelial lesions.
Discussion
The results of this study showed that HSIL was more prevalent than LSIL among patients diagnosed with cervical intraepithelial lesions. HR-HPV16, HR-HPV33, and HR-HPV52 were the most frequent type of HPV infection in patients with HSIL, while HR-HPV16, HR-HPV52, and HR-HPV58 were the most common types of HPV infection in patients with LSIL. The highest percentage of single infections occurred in the HSIL group, followed by the LSIL group. HSIL was present in a significant number of patients (28.6%) aged 30 years and above who tested positive for 12 HPV types but negative for TCT.
In a multicenter study in New Mexico, HR-HPV16, HR-HPV33, and HR-HPV31 had the highest positive predictive value for CIN2+, followed by HR-HPV18, HR-HPV35, and HR-HPV58 [
6]. The most prevalent HPV types in CINI in 2020, according to a survey, were HR-HPV52 (20.31%), HR-HPV16 (16.81%), HR-HPV58 (14.44%), HR-HPV18 (6.44%), and HR-HPV53 (5.76%). HR-HPV16 infection rate was the highest (45.69%), followed by HR-HPV58 (15.50%), HR-HPV52 (11.74%), HR-HPV33 (9.35%), and HR-HPV31 (4.34%) [
7], suggesting that HR-HPV16 is the most prevalent oncogenic genotype, and the distribution of HPV genotypes varies by region. This indicates that HPV vaccine administration should be adapted to regional needs. The results of this study revealed that among women in the LSIL group, 92% were infected with high-risk HPV, the most common strains of which were HR-HPV16, HR-HPV52, and HR-HPV58. In the HSIL group, 98.3% were infected with high-risk HPV, with HR-HPV16 being the most common type of HPV present, followed by HR-HPV33 and HR-HPV52. As a result, the prevalence of various HPV genotypes in cervical lesions of varying severities, as well as the predominant types of HPV infection in the LSIL and HSIL groups, are clearly distinguishable. When a patient has a normal cytology result but is positive for HR-HPV33, HR-HPV52, or HR-HPV58, a colposcopy examination and positioning biopsy of suspicious lesions under colposcopy should be performed to rule out cervical HSIL.
The prevalence of HPV infection is thought to be highest in young and middle-aged women. Young women, especially those between the ages of 25 and 35, may be more likely to contract HPV if they engage in more frequent sexual activity [
8]. Women between the ages of 55 and 65 have a significantly higher risk of contracting HPV due to low levels of education and weakened cervical resistance caused by autoimmune disease and hormones [
9]. However, the detection rate of HSIL varies among patients of different ages. There are clear differences in the age distribution of patients with various grades of cervical lesions, with the highest detection rate of HSIL occurring in patients under the age of 40 who only have a single HPV infection [
10], while another study demonstrated that the detection rate of HSIL is highest in individuals aged 41 to 50 years (32.37%) [
11]. Yang et al. compared the HSIL detection rates among individuals aged between 35 and 45, 46 to 55, and 56 to 65 [
9]. The rate of CINII + detection increased with age, but the difference was not statistically significant (
P = 0.414). Based on our findings, the average age of the HSIL group was 37.38±9.63 years old, which is significantly lower than the average age of the LSIL group, which was 39.06±11.60 years old. Among patients aged between 31 and 40 years, the incidence of HSIL was 40.7%, which is significantly higher than that of the LSIL group (31.3%), possibly due to the intraepithelial cervical lesions being more prevalent among the younger age group. The relatively high education levels of young women, combined with the successful promotion and popularization of cervical screening, have led to a greater public awareness of cervical precancerous lesions. Many high-grade squamous lesions have been detected and effectively treated, and few patients have contracted disease as a direct result of skipping cervical screening. Therefore, the incidence of HSIL is lower in patients older than 40 than that of LSIL.
According to research, over 80% of sexually active people have been infected with HPV at some point [
12], and persistent infection with high-risk HPV is strongly associated with intraepithelial lesions in the cervical epithelium. However, there is no conclusive evidence that having multiple HPV infections raises the risk of developing precancerous cervical lesions. Patients with cervical epithelial lesion typically have a single high-risk HPV infection, and these infections are most often HR-HPV16, HR-HPV33, HR-HPV52, or HPV58 [
13]. Xiang et al. found that the rates of single, double, and multiple HPV infections were 8%, 1%, and 0% among CINI patients, 24%, 7%, and 1% among CINII-III patients, and 57%, 25%, and 3% among cervical cancer patients, respectively [
14]. We hypothesize that the proportion of single infections, double infections, and multiple infections of HPV would increase with the severity of cervical lesions; however, no statistically significant difference was found, which may be due to the small sample size. Another study found that multiple high-risk HPV infection rates were highest in cervical CINIII lesions [
15], indicating that multiple HPV types appear to play a synergistic role in the development of cervical cancer [
16]. Maria et al. examined the results of 900 patients who underwent cervical cytology, HPV typing test, and colposcopy biopsy. The results indicated that the lesion type with the highest percentage of high-risk HPV single infection was SCC (100%), followed by CIN3 (78%), and the lesion types with the highest percentages of multiple infections were CIN1 (60.4%), CIN2 (43.7%), and CIN3 (22.1%). It is assumed that a single HPV infection poses a greater risk of developing into SCC than multiple infections [
17]. Other studies also show that multiple high-risk HPV infections are not a direct risk factor for the development of cervical cancer [
18,
19], as the mechanism may involve inter-gene competition, or an enhanced immune response triggered by multiple infections. Multiple HPV infections did not significantly increase the risk of cervical intraepithelial lesions (
P > 0.05).
In 2018, the United States Preventive Services Task Force (USPSTF) recommended combining TCT and HPV testing in cervical cancer screening for individuals aged between 30 and 65 [
20]. Therefore, women over the age of 30 make up the bulk of the population screened with the combined approach; however, the cytological screening is affected by a number of variables, such as the sampling standard of the specimen, the retention time, and the subjective judgement of the pathologist. In high-risk HPV-positive individuals with a negative TCT, the missed diagnosis rate of intraepithelial cervical lesions is high because of the test’s low sensitivity. HSIL is also more prevalent among patients older than 30 who test positive for one of 12 types of HPV but are negative for TCT [13]. According to studies, the risk of CIN2 + in TCT-negative, HR-HPV16-positive women is 13.6%, while the risk of CIN2 + in TCT-negative, HR-HPV18-positive women is 7% [
21]. A five-year study by Uijterwaal et al. found that 11.4% of non-HR-HPV 16/18-positive women with normal cytology are also at risk for HSIL [
22]. Multivariate analyses in other studies demonstrate that the risk of high-grade squamous lesions with negative cytology but persistent high-risk HR-HPV31 and 33 positivity is 1.53 times and 2.02 times higher, respectively, and the difference is statistically significant [
23]. The results of our study revealed that the detection rate of HSIL was higher in HR-HPV16 and HR-HPV18 infection than in the other 12 types of HPV infection; however, the detection rate of HSIL in TCT-negative and the other 12 types of HPV-positive was only 28.6%, indicating that simple cytological screening may miss the diagnosis of some HSIL lesions.
When a cervical biopsy reveals HSIL-CINII or CINIII, patients receive additional treatment with LEEP. However, for patients with early stage cervical cancer, radical hysterectomy and plus pelvic node dissection are the main methods of treatment [
24]. For low-risk patients, there is mounting evidence that laparoscopic radical hysterectomy has equivalent 10-year outcomes to open surgery [
25]. This has profound implications for patient care, underscoring the need for future research to examine whether treatment success is linked to HPV infection.
Limitations: In this study we aimed to determine the most common types of HR-HPV infection among patients diagnosed with cervical intraepithelial lesions. For young patients aged 30 and higher, colposcopy should be performed for early detection of cervical lesions and timely treatment regardless of high-risk HPV infection status. Nonetheless, the study suffered from a lack of statistical power due to the small sample size and a single-center design. Therefore, additional confirmation with a larger sample size in multiple centers is recommended.
In conclusion, the incidence of cervical lesions varies with age, and HPV infections other than HPV16/18, should also be considered, especially when cytological screening is negative. Due to the fact that the risk of developing cervical intraepithelial lesions is not greatly increased by a second or subsequent infection with a high-risk HPV strain, those at high risk should be closely monitored, subjected to regular screenings, and administered an HPV vaccine at the optimal time to prevent cervical cancer.
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