INTRODUCTION
Cervical cancer is the second most common female cancer in women aged 15–44 and the fourth most common cancer among women worldwide, with an estimated 604,127 new cases and 341,831 deaths in 2020.[1]
The high-risk human papillomavirus (HPV) persistent infection is the main cause of cervical cancer. HPV subtypes 16 and 18 are responsible for about 70% of all cervical cancer cases worldwide. Our previous research showed that the overall high-risk HPV infection rate in mainland Chinese women was 19.0% (95% CI, 17.1%–20.9%), and the top five subtypes were 16, 52, 58, 53, and 18.[2]
The ICO/IARC Information Centre on HPV and Cancer (HPV Information Centre) has shown that elderly women still have a high incidence of cervical cancer, especially in regions such as Africa.[1] High-risk HPV infection is still the main cause. Our previous research showed that the overall high-risk HPV infection rate in mainland Chinese women was 12.9%, basically similar to that in women aged more than 45 years (12.5%).[2] The overall high-risk HPV infection rate in patients with cervical cancer was 90.82%, which was lower than that in elderly patients aged more than 65 years (94%).[3]
The screening can be terminated in women aged more than 65 years with standardized cervical cancer screening in the past 20 years, a negative result, and no history of HSIL.[4] HPV vaccine has significantly reduced the incidence of cervical cancer. However, China is a country with a vast territory, a large population, complex landforms, and unbalanced economic development. Elderly women have no chance to get HPV vaccine, and most elderly women do not have the opportunity to receive standardized cervical cancer screening. We should give elderly women outpatients a chance to be screened for cervical cancer. The research on high-risk HPV distribution and screening strategies for elderly women is extremely important.
METHODS
We gave elderly women aged more than 65 years, who did not undergo standardized cervical cancer screening, a chance to get screened for cervical cancer. It was called opportunistic cervical cancer screening.
This retrospective study focused on elderly women aged more than 65 years, who did not undergo standardized cervical cancer screening and were high-risk HPV positive between June 2017 and June 2021. All participants had undergone an opportunistic cervical cancer screening. Any patient with a medication treatment history for HPV infection or a history of cervical intraepithelial neoplasia or cervical cancer was excluded from the analysis.
All participants had undergone liquid-based cytology and HPV testing. Each patient was placed in the lithotomy position, and sterile cotton swabs were used to clear mucus. A dry, sterile cotton swab was inserted into the cervix and rotated clockwise for five to eight circles, and the exfoliated cervical cells were stored in a cell preservation solution. A kit [Qiagen RNA/deoxyribonucleic acid (DNA) Mini kit; TELLGENLife Science Co. Ltd., Shanghai, China] was used to extract DNA from the specimens. The extracted DNA was dissolved in 50 mL of elution buffer and stored at -20°C for use. The purified DNA was placed in the genotyping kit, namely, the HPV nucleic acid typing detection kit (flow fluorescence hybridization) produced by Qiagen, including 17 high-risk subtypes (HPV-16, HPV-18, HPV-26, HPV-31, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-53, HPV-56, HPV-58, HPV-59, HPV-66, HPV-68, and HPV-82). The hybridization products were tested using a Luminex 200 system (Luminex Corporation, TX, USA), which was a multifunctional suspension array system. The pathological medical research laboratories of our hospital performed the liquid-based cytology, and then the pathologists classified the specimens according to the 2001 Bethesda System. Specimens with ASCUS or worse (ASCUS+) were classified as positive. The histopathological results were reported as CINI, CINII, CINIII, or cancer.
The patients with the following screening results underwent colposcopy:
- HPV 16/18 positive
- Liquid-based cytology LSIL+
- Liquid-based cytology ASCUS + and high-risk HPV-positive subtypes.
The following different screening strategies were evaluated:
- Cervical cytology alone: Specimens with ASCUS or worse were classified as positive.
- High-risk HPV testing alone: Specimens with more than 1.0 pg/mL were classified as positive.
- HPV 16/18 only: HPV 16/18—positive specimens were referred for colposcopy.
- Cytology for triage: HPV-positive specimens were referred for cytology and, if they were ASCUS+, they were referred for colposcopy.
- Cervical cytology or HPV 16/18: Specimens with HPV 16/18 positive or specimens with ASCUS or worse are referred for colposcopy.
The measurement data were represented as x ± s (mean ± standard deviation) and analyzed using the t test. The count data were expressed as rate and analyzed using the χ2 test. The sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve of the different screening strategies were calculated. SAS 9.2 software was used. P < 0.05 indicated a statistically significant difference.
RESULTS
Characteristics of participants
The flow diagram is shown in Figure 1. The characteristics of the participants are shown in Table 1. A total of 7683 elderly women had undergone opportunistic cervical cancer screening. Of these, 848 with high-risk HPV subtypes were included in the study (aged 65–88 years; mean age 69 years). These included 68 (8.0%) with CIN1, 42 (5.0%) with CINII, 138 (16.3) with CINIII, and 145 (17.1%) with cervical cancer.
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Figure 1: The flow diagram of patients
Table 1: The characteristic of participants
High-risk HPV distribution
The high-risk HPV distribution is shown in Table 2. The infection rate of high-risk HPV subtypes was 11.04%. The top five HPV subtypes were HPV16, HPV52, HPV58, HPV53, and HPV56, and the infection rate was 31.4%, 21.9%, 19.7%, 11.6%, and 11.6%, respectively; The top five HPV subtypes were HPV16, HPV58, HPV52, HPV33, and HPV53 in participants with CINII+.
Table 2: The distribution of HR-HPV
Different screening strategies for CINII+
Different screening strategies for elderly women are shown in Table 3 and Figure 2. The area under the ROC curve of cervical cytology alone was 0.715 (0.681–0.750) (ASCUS+), 0.732 (0.696–0.768) (LSIL+), and 0.702 (0.664–0.740) (HSIL). The area under the ROC curve of high-risk HPV testing alone was 0.498 (0.458–0.538). The area under the ROC curve of HPV 16/18 only was 0.623 (0.584–0.663). The area under the ROC curve of cytology for triage was 0.714 (0.680–0.748) (ASCUS+), 0.730 (0.694–0.766) (LSIL+), and 0.702 (0.664–0.740) (HSIL+). The area under the ROC curve of cervical cytology for HPV 16/18 was 0.698 (0.664–0.733) (ASCUS+), 0.726 (0.692–0.761) (LSIL+), 0.703 (0.666–0.739) (HSIL+).
Table 3: The accuracy of different screening methods for CINII+
Figure 2: ROC curve of different screening methods (type 1: Cervical cytology alone (ASCUS+), type 1-1: Cervical cytology alone (LSIL+), type 1-2: Cervical cytology alone (HSIL+), type 2: High risk HPV testing alone, type 3:HPV 16/18 only, type 4: Cytology for triage (ASCUS+), type 4-1: Cytology for triage (LSIL+), type 4-2: Cytology for triage (HSIL+), type 5: Cervical cytology or HPV 16/18 (ASCUS+), type 5-1: Cervical cytology or HPV 16/18 (LSIL+), type 5-2: Cervical cytology or HPV 16/18 (HSIL+))
DISCUSSION
The NHS program justifies not screening women aged more than 64 years because “it is highly unlikely that women aged more than 64 years who have been regularly screened will go on to develop the disease.”[5]
The proportion who can develop cervical cancer at the age of 65–84 years is about 1 in 1200 among women who have been regularly screened and 1 in 200 among inadequately screened women.[6,7] These are not negligible risks. Also, evidence shows that more than half of these cases and a larger proportion of patients who died after the age of 65 years might not have undergone a sensitive HPV test. In some countries, screening is not stopped at the age of 65 years.[7–9]
In China, cervical cancer screening is not stopped at the age of 65 years. Cervical cancer is the third most common cancer in women aged 15–44 years in China. In 2018, 106,430 (10.7 per 100,000) new cervical cancer cases were detected in China.[10] By the end of 2014, cytology and HPV tests were used to provide free cervical cancer screening for 42,870,000 rural women. The 2011–2020 Women’s Development Program proposed that cervical cancer screening coverage should reach 80%. However, the screening coverage in 2010 was only 29.1% in urban areas and 16.9% in rural areas.[11]
HPV vaccine application has significantly reduced the incidence of cervical precancerous lesions and cervical cancer. However, the application of HPV vaccine in mainland China is late, and the current coverage rate is low, which is far from the 90% coverage rate required by the World Health Organization (WHO). Women aged more than 45 years have no chance to get the HPV vaccine. Older Chinese women have a higher HPV infection rate.[2,3] Cervical lesions are common in elderly Chinese women, especially older women who have not undergone standardized cervical cancer screening. Although the high-risk HPV subtype infection rate is only 11.04%, we screened 325 (38.3%) CINII+ patients among 848 elderly women with high-risk HPV infection, including 145 (17.1%) patients with cervical cancer. This showed that opportunistic screening was extremely important for older women who had not undergone standardized cervical cancer screening. We should give elderly women outpatients without standardized cervical cancer screening a chance to be screened for cervical cancer at any time in China.
In the “screen, triage, and treat approach,” the decision to treat is based on a positive primary screening test followed by a positive second test (a “triage” test), with or without histologically confirmed diagnosis. There have been many studies about cervical cancer screening strategies.[12–14] And multiple conditions may affect cervical cancer screening efficiency.[15–18] The WHO suggests using an HPV DNA primary screening test either with triage or without triage to prevent cervical cancer among the general population of women.[19] However, HPV testing of cervical samples has now replaced cytology for primary screening in many countries,[7] including China. We analyzed a variety of cervical cancer screening strategies. We found that high-risk HPV testing alone without triage does not seem to be suitable for older women. The area under the ROC curve of high-risk HPV testing alone was only 0.498 (0.458, 0.538). Other screening programs showed similar screening efficiency; all have good sensitivity, specificity, accuracy, and area under the ROC curve. Therefore, the standardized screening program is suitable for elderly women. The high-risk HPV-positive and ASCUS+, or LSIL+, or HPV16/18-positive patients should undergo colposcopy.
Overall, elderly women who have not undergone standardized cervical cancer screening in China should be given a chance to be screened for cervical cancer; the standardized screening program is suitable for elderly women.
Author contributions
Conception: Kemin Li, Rutie Yin
Design: all authors
Data collection: Kemin Li
Data analysis: Kemin Li
Manuscript writing: Kemin Li
Final manuscript approval: all authors
Financial support and sponsorship
Sichuan Provincial Cadre Health Research Project (2021-1703)
Conflicts of interest
There are no conflicts of interest.
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