In recent years, the onset age of cervical cancer has tended to be younger, so early detection, early diagnosis and early treatment are more important for improving the prognosis of patients. Epidemiological data show that the highest incidence age of cervical cancer in situ is 30–35 years old and that of invasive cancer is 45–55 years old, and its incidence tends to be younger than in the past [14]. The age distribution curve of HPV infection is U-shaped [15]. The infection rate is the highest in the age group ≤ 25 years old, followed by the age group > 55 years old. In contrast, the results of this study showed that the highest proportion of HPV E6/E7 mRNA-positive patients was 31–40 years old, the second highest was 41–50 years old, and the lowest was > 60 years old, which may be due to the differences in HPV infection rate and subtype distribution among different regions and nationalities. All of the subjects in this study were ASCUS patients, which is different from most studies. Among them, HPV16 + was highest in the 31–40 years old group, followed by the 41–50 years old group, and for HPV18/45+, it was highest in the 41–50 years old group, followed by ≤ 30 years old.
It has been reported that most CIN2 lesions, especially in young women (< 30 years old), disappear spontaneously [16]. Therefore, the 31–50 years old group needs to be screened. The 2011 ACS, ASCCP, and ASCP joint guidelines and USPSTF guidelines recommend joint screening for women aged 30 to 65 [17], which is consistent with the results of this study. Patients over 50 years old will be further analyzed later in this article.
Ren et al. [18] found that the expression level of HR-HPV E6/E7 mRNA is a risk factor for high-grade cervical lesions and cervical cancer. However, the mechanisms of HSIL + and LSIL- are different. The mechanism of HSIL + is the persistent infection of HR-HPV, the integration of virus DNA into the human cell genome, and the persistently high expression of E6 and E7 in the host genome [19]. The mechanism of LSIL- is that low-risk HPV E6 and E7 proteins play a less important role in blocking the function of p53 and pRb than HR-HPVE6 and E7 proteins [20].
With regard to HR-HPV genotyping, some studies have shown that in patients with simple HPV positivity, the detection rate of HSIL + in HPV16/18-positive patients is significantly higher than that in other high-risk-positive patients [21], so the pathogenicity of HPV16 and HPV18/45 is worthy of further research and analysis. Consistent with this result, this study showed that the detection rate of HSIL + in the HPV16/18/45 group was 43.9%, significantly higher than that of the 15% in the Other HR-HPV + group. The detection rate of HSIL + in the HPV16 group was 48.4%, which was significantly higher than that of the 18.8% in the HPV18/45 + group; that is, the high-grade (HSIL+) morbidity of HPV16/18/45 to the cervix was significantly higher than that of the Other HR-HPV, while HPV16 was significantly higher than HPV18/45. Pruski et al. [22] found that high-grade squamous intraepithelial lesions were closely related to the positive expression of HPV E6/E7 mRNA. HPV-16 is the most common genotype in CIN2 + lesions diagnosed by LSIL in Chinese women, while HPV-18 is the most common genotype in CIN1 lesions [23], which is basically consistent with this conclusion. The results of this study also showed that the proportion of LSIL in the HPV18/45 + group (42.5%) was significantly higher than that in the HPV16 group (26.4%). Furthermore, it was concluded that HPV16/18/45 was more helpful than Other HR-HPV in screening for the pathogenesis of HSIL + in patients with ASCUS. Therefore, further colposcopy referral and biopsy diagnosis and treatment for HPV16/18/45-positive patients is necessary, but at the same time, Other HR-HPV still has 51.7% morbidity (including LSIL and the above lesions) and 15% high-grade morbidity. If this portion of ASCUS patients do not receive further examination, some HSIL or cervical cancer lesions will be ignored.
Moreover, undergoing colposcopy is not harmful, and the impression of colposcopy may help to increase the detection rate of high-level lesions compared with the psychological burden on patients. In cases of good communication by clinicians, the importance of avoiding missed diagnoses of high-level lesions is self-evident. It has been reported that for patients with simple HR-HPV infection, a treatment model based on risk stratification is feasible, and random biopsies are of little significance for patients with no abnormalities on colposcopy [24]. Therefore, we suggest that Other HR-HPV E6/E7 mRNA-positive ASCUS patients should also be referred for colposcopy according to the specific situation, and some biopsies can be performed according to the impression of colposcopy. Some studies suggest that unified referral for colposcopy examination should be considered for different subtypes of HPV E6/E7 mRNA-positive patients [25], which is consistent with the conclusions of this part.
In addition, the high proportion of ASCUS in the diagnosis of TCT is partly due to the difference between postmenopausal and premenopausal patients. In postmenopausal women, due to changes in hormone levels and cervical atrophy, the junction of the squamous epithelium and columnar epithelium returns to the cervical canal [26], and the lesions are difficult to detect. TCT cells in premenopausal women mainly come from the middle and surface layers, and the cervical cells of postmenopausal women generally atrophy, and thus their TCT cells mostly come from the bottom and sublayer cells. The ratio of nucleus to cytoplasm of these cells is slightly larger, which brings some difficulties to the diagnosis by cytologists. Due to changes in the physiological structure, the number of cells decreases in postmenopausal women, resulting in difficulties in TCT production and affecting the interpretation results [27].
Studies have shown that the percentage of HSIL detected by cervical curettage in postmenopausal patients (9.9%) is higher than that in premenopausal patients (2.6%) [28]. Combined with the HR-HPV test, it can provide better cervical cancer protection for postmenopausal patients than a simple TCT test [29]. Therefore, we compared the difference between premenopausal and postmenopausal patients with HPV E6/E7 mRNA detection. The incidence of HSIL + in postmenopausal patients was 31.5%, significantly higher than that in premenopausal patients (23.8%). The detection rate of HPV16/18/45 in premenopausal patients was 34.3%, which was significantly lower than that in postmenopausal patients (42.4%); that is, the HPV16/18/45 infection rate in postmenopausal patients was higher than that in premenopausal patients. However, some of the literature shows that [30] there is no significant difference in the positive rate of HPV between postmenopausal women and premenopausal women. The infection rate of high-risk HPV increases after 65 years of age, which is not contradictory to the results of this study because this study used HPV E6/E7 mRNA detection, which has higher specificity and sensitivity than simple HPV DNA detection in the previous literature. The object of this study is ASCUS patients, which is also different from the research subjects in most of the literature.
The percentage of HSIL + biopsies was 42.3% in the premenopausal HPV16/18/45 group and 49.6% in the postmenopausal HPV16/18/45 group; that is, there was no significant difference in the HSIL + morbidity of HPV16/18/45 between premenopausal and postmenopausal patients; at the same time, Other HR-HPV had no significant difference in HSIL + morbidity between premenopausal and postmenopausal patients. Then, the difference between premenopausal and postmenopausal morbidity caused by HPV16 and HPV18/45 was analyzed in detail: the proportion of HSIL + in the premenopausal HPV16 group was not significantly different from that in the postmenopausal HPV16 group. That is, there was no significant difference in high-grade morbidity between premenopausal and postmenopausal patients with HPV16. The proportion of HSIL + in the premenopausal HPV18/45 group was significantly lower than that in the postmenopausal HPV18/45 group, and the difference was statistically significant; that is, the high-grade morbidity of HPV18/45 in postmenopausal patients was significantly higher than that in premenopausal patients. Therefore, except for HPV18/45, there was no significant difference in the high-grade morbidity of HR-HPV between premenopausal and postmenopausal patients.
Combined with the above conclusions of this study, we can explain some of the reasons why the HSIL + incidence of postmenopausal patients is higher than that of premenopausal patients: 1. The high-grade morbidity of HPV16/18/45 was significantly higher than that of Other HR-HPV, 2. At the same time, the infection rate of HPV16/18/45 in postmenopausal patients was higher than that in premenopausal patients. 3. The high-grade morbidity of HPV18/45 in postmenopausal patients was significantly higher than that in premenopausal patients. Some studies have found that the older the age of acquiring an HPV infection, the higher the degree of cervical lesions [31], which is partly consistent with the conclusions of this study because we did not conduct a correlation analysis between the specific age and the degree of cervical lesions.
In the CastanonA literature [32], the incidence of cervical cancer in postmenopausal women showed an increasing trend. The results of this study showed that the incidence of cervical cancer in premenopausal women was 2.6%, which was significantly lower than that in postmenopausal women (12.7%), consistent with the above results. In addition, the proportion of premenopausal cervical cancer in the HPV16/18/45 group was significantly lower than that in postmenopausal women. That is, the pathogenicity of HPV16/18/45 in postmenopausal patients with cervical cancer is significantly stronger than that in premenopausal patients. These results also showed that the proportion of premenopausal cervical cancer in the Other HR-HPV group was significantly lower than that in the postmenopausal group; that is, the pathogenicity of Other HR-HPV in postmenopausal patients was also significantly stronger than that in premenopausal patients. Postmenopausal patients positive for Other HR-HPV should also be given attention. Therefore, the pathogenicity of HR-HPV to cervical cancer in postmenopausal patients is higher than that in premenopausal patients, which may be part of the reason why the incidence of postmenopausal cervical cancer is higher than that in premenopausal women.
It is mentioned in the literature that the incidence of cervical cancer in postmenopausal women is increasing, which may be due to the decrease in immune function in postmenopausal women [32], but it may not only be due to postmenopausal immunity. Combined with the results of this study: 1. The pathogenicity rate of the HPV16/18/45 subtype to HSIL + is significantly higher than that of Other HR-HPV. 2. The infection rate of HPV16/18/45 in postmenopausal patients was higher than that in premenopausal patients. 3. The pathogenicity rate of HPV18/45 to HSIL + in postmenopausal patients was significantly higher than that in premenopausal patients. 4. The pathogenicity rate of HR-HPV to cervical cancer in postmenopausal patients was higher than that in premenopausal patients. All of these factors may contribute to a significant increase in the incidence of cervical cancer in postmenopausal women.
In summary, this study suggests that colposcopy referrals and biopsy diagnosis and treatment should be performed for all HPV16/18/45 E6/E7 mRNA-positive and postmenopausal HR-HPV E6/E7 mRNA-positive ASCUS patients, and premenopausal ASCUS patients with other HR-HPV E6/E7 mRNA positivity should also be examined by colposcopy if possible according to the specific conditions to achieve early detection, early diagnosis and early treatment. However, while 16 and 18 of the high-risk HPV subtypes were reported separately in this study, no specific reports were made on the other subtypes. The pathological changes of the cervical epithelium may also need to consider other factors, such as the number of pregnancies and deliveries and sexual history, which need to be further analyzed to provide a more comprehensive and specific basis for further standardized clinical treatment of ASCUS patients, provide effective data for the accurate diagnosis of ASCUS in pathology, and make a modest contribution to the maximum improvement of the prognosis of patients.