How to prevent and treat cervical cancer?

  To date, cervical cancer remains the most common malignancy of the female reproductive system worldwide, second only to breast cancer in terms of incidence. 520,900 new cases of cervical cancer and 275,000 deaths were reported worldwide in 2011, with 80% of new cases and 85% of deaths in developing countries. The region with the highest incidence of new cervical cancer is Africa, followed by South and Central Asia and South America; the country with the highest mortality rate is India. As a large population country, the incidence of cervical cancer in China is not optimistic. 12,19/100,000 new cases of cervical cancer in 2008, located in the 6th place of new malignant tumors in women; 3,90/100,000 deaths of cervical cancer; in the country, especially in the city, its mortality rate is no longer among the top 10 malignant tumors in women, but in rural areas, the mortality rate of cervical cancer is in the 8th place. Among ethnic minority women in China, the incidence of cervical cancer is even more severe, with the incidence rate of 17/100,000 for Uyghur women, 15/100,000 for Mongolians, and 12/100,000 for Hui. Therefore, the focus of cervical cancer prevention and treatment in China is in rural areas.  Since Nobel laureate Professor zur Hausen confirmed that high-risk HPV infection is closely related to the development of cervical cancer, malignancies caused by infectious agents have received increasing attention worldwide. It is now known that cervical cancer caused by high-risk HPV infection accounts for 5.4% of all malignancies.1 A large sample study showed that in paraffin specimens from 8977 cervical cancer patients in 38 countries, the HPV DNA positivity rate reached 85%, with the most common types being HPV 16, 18, 31, 33, 35, 45, 52 and 58, which accounted for 91% of the total positivity rate. Among them, three HPV subtypes, HPV type 16, 18 and 45, had the top three positive rates in different pathological types of cervical cancer (including cervical squamous carcinoma, adenocarcinoma and adenosquamous carcinoma), and the positive rate of these three HPV subtypes in cervical adenocarcinoma tissues was as high as 94%, which was higher than that of cervical squamous carcinoma. It is suggested that the infection of these 3 HPV subtypes is associated with the pathogenesis of cervical adenocarcinoma. Regarding the current status of HPV infection in China, in a large sample study, HPV typing was performed on tissue specimens from 5218 patients with cervical cancer and its precancerous lesions in 7 provinces and municipalities (Shanxi, Jiangxi, Henan, Xinjiang Uyghur Autonomous Region, and Shenzhen, Shanghai, and Beijing), and the results showed that the major subtypes of HPV infection in tissues of cervical cancer and its precancerous lesions were the same as those reported globally The results showed that the major subtypes of HPV infection in cervical cancer and its precancerous tissues were roughly the same as those reported globally, namely HPV types 16, 18, 31, 52, and 58; while the most common subtypes of HPV infection in other cervical lesions and normal cervical tissues were HPV types 58 and 52.  In view of the severe global situation of cervical cancer incidence, the prevention and treatment of cervical cancer is especially important. At present, the following issues in cervical cancer screening in China are worth exploring.  I. Screening methods of cervical cancer Regarding the screening of cervical cancer, especially under the situation of China’s vast territory, large population and unbalanced economic development, what method should be used as the primary screening means is a perplexing issue at present. Since it takes a long time of 10 years or more for HPV infection to develop into cervical cancer, cervical cancer screening at the stage of HPV infection and precancerous cervical lesions can interrupt its progression to cervical cancer. Currently, the following methods are commonly used for primary cervical cancer screening  1.Cytological screening: cytological screening is a classical and traditional screening method. Experience from many developed countries shows that cervical cancer screening with cytological screening as the primary screening method has been effective in controlling the occurrence of cervical cancer over the past 60 years as a secondary prevention method. In the United States, the incidence and mortality of cervical cancer decreased by more than 60% after the application of cervical cytology Pap smear screening between 1955 and 1992. To date, cytologic screening is still used as a primary screening method in many countries. In China, a lot of work has been done on cervical cancer screening. As early as in the 1970s, 610,000 people in l0 provinces and cities were screened for cervical cancer, among which 61% of all patients with cervical cancer diagnosed by screening were detected by cervical cytology Pap smear as the primary screening method and those with highly suspicious cervical cancer, which were later confirmed by biopsy. The diagnostic level of cytologic screening is closely related to the clinician’s satisfaction in obtaining the material, the application of Pap smear or liquid-based cytology and staining methods, and the cytopathologist’s reading level. Currently, cytological screening is used as the primary screening method to carry out nationwide cervical cancer screening for a large population. The biggest problem lies in the odd lack of professional personnel for cytological screening, the absence of a training system for cytopathologists, and the failure to establish corresponding specifications, thus greatly affecting the quality of cervical cancer screening.  2.Naked-eye screening: The naked-eye screening method for cervical cancer is the visual observation of white acetate and iodine test (VIA/VILI), which is more commonly used in economically backward regions such as Africa and South Asia. From 2006 to 2008, China implemented the State Council transfer program under the leadership of the government to carry out cervical cancer screening with VIA/VILI as the main method supplemented by electronic colposcopy in 42 work sites nationwide, which promoted the establishment of a cervical cancer screening system, increased women’s awareness of cervical cancer screening, and contributed to a nationwide program of free cervical cancer screening for 10 million cases from 2009 to 2011. This has laid a good foundation for free cervical cancer screening for 10 million rural women from 2009 to 2011. The results showed that the positive rate of VIA/VILI was 11.14%, and 54.12% of the women had biopsies taken under colposcopy for pathological examination. Among the patients with positive VIA/VILI, CIN II and above accounted for 7.2%. However, the limitations of the visual screening method mainly include the lack of permanent records, the inability to evaluate the test results, the difficulty of quality control, the high rate of false positives, which may lead to overdiagnosis and treatment and unnecessary anxiety in some women. However, the main limitations of the visual screening method are that there is no permanent record of the test results, quality control is difficult, the false-positive rate is high, and it may lead to overdiagnosis and treatment and unnecessary anxiety in some women. Therefore, the visual screening method can only be used for a short period of time under limited conditions, and is not suitable for long-term application.  3.High-risk HPV test: The significance of high-risk HPV test in cervical cancer screening is: women with low-grade abnormal results in triage cytology; follow-up of patients with cervical cancer or cervical lesions after treatment; follow-up of patients with negative colposcopy or biopsy; primary screening of cervical precancerous lesions alone or in combination with cytology, which is especially meaningful for women aged >35 years. In recent years, with the recognition of the correlation between high-risk HPV and cervical cancer, more and more scholars have focused on the clinical significance of applying high-risk HPV testing as a primary screening method. In Denmark, 8656 women aged 22-23 years and 1578 women aged 40-50 years were followed up for up to 12 years, and the results were summarized and analyzed, and all women were screened twice with an interval of 2 years before and after. At 10 years of follow-up, the risk of CIN III and cervical cancer was 13.6% for women aged 22-23 years and 21.2% for women aged 40-50 years; at 12 years of follow-up, 26.7% of patients with CIN III and above were HPV16 positive, 19.1% were HPV18 positive, 14.3% were HPV3l positive, and 14.3% were HPV33 positive. The percentage of patients with HPV16 positive was 26.7%, HPV18 positive was 19.1%, HPV3l positive was 14.3%, HPV33 positive was 14.9%, and HPV16, 18, 31, 33 positive was 6.0%. It is suggested that at the time of primary screening for cervical cancer, a high level of vigilance should be exercised in those who are positive for high-risk HPV types, despite negative cytology, and that high-risk HPV testing can predict the risk of CIN III and cervical cancer. In a large sample study conducted in India, 31,746 women were randomized into 4 groups according to the method of initial screening, namely, high-risk HPV testing group, cytological screening group, visual screening group, and control group, and colposcopy and cervical tissue biopsy were performed immediately for those with positive initial screening and appropriate treatment was given to those diagnosed with precancerous cervical lesions or cervical cancer, and compared with the control group, high-risk HPV detection group had a significantly lower incidence of advanced cervical cancer and cervical cancer death rate, while there was no significant change in the cytological screening group and the naked eye screening group. It was concluded that the application of high-risk HPV testing as a primary screening method could significantly reduce the incidence of advanced cervical cancer and cervical cancer death rate. Our scholar Zhao et al. performed a pooled analysis of 28,848 subjects between 1999 and 2008 and showed that the sensitivity and specificity of high-risk HPV testing, cytological screening, and visual screening for the diagnosis of CIN III and above lesions were 97,5% and 85,1%, 87,9% and 94,7%, 54,6% and 89,9%, respectively. This study also suggests that the best screening method is high-risk HPV testing, with cytologic screening being the next most sensitive and visual screening being the least sensitive.  In a multi-unit collaborative study on the need for high-risk HPV diagnosis in the United States), HPV testing included HPV types 16 and 18, and colposcopic biopsies were performed in 4219 of 32 260 cytologically negative women ≥30 years of age who were all high-risk HPV positive and 886 patients who were partially HPV negative, and the results showed that in lesions CIN Ⅱ and older , those positive for HPV 16 and 18 accounted for 11, 4% (95% CI: 8, 4% to 14, 8%) and 6, 1% (95% CI: 4, 9% to 7, 2% ), respectively. Therefore, it is considered that colposcopy is recommended for those who are positive for HPV 16 and 18.  Cervical cancer screening is currently a hot spot of global concern, and in carrying out widespread cervical cancer screening, appropriate methods should be selected in conjunction with local conditions. At present, China still needs a combination of multiple screening methods. In the process of establishing a screening system, the training of professionals should be strengthened and corresponding screening routines should be developed.  CIN regression, treatment and follow-up With the development of cervical cancer screening, more and more CINs are detected, and patients often appear in an anxious state, while clinicians have excessive or insufficient treatment in their treatment process because they are not clear about the regression and treatment principles of CIN.  1. The regression of CIN: (1) CIN I: 57% regressed spontaneously, 11% progressed to CIN II-III, 0, 3% progressed to cervical cancer. (2) CIN II: 43% regressed spontaneously and 22% progressed to cervical cancer. (3) CIN III : 32% regressed spontaneously and 14% progressed to cervical cancer.McCredie et al. conducted long-term follow-up of 10,631 patients with CIN II and showed that the cumulative incidence of progression to cervical cancer after 30 years was only 0,7% in 593 patients who received complete or potentially complete treatment and conventional recurrence prevention therapy at a later stage; whereas biopsy-only Of the 143 patients who underwent histopathological examination only and were not treated, 92 were reviewed for persistent CIN III at 2 years, and the cumulative incidence of progression to stage I b and IIa cervical cancer was 31.3% of the 143 patients after 30 years. This indicates that the probability of subsequent cervical cancer is extremely high if CIN III patients are not treated with interventional therapy. Therefore, the establishment of a routine screening system should be accompanied by appropriate interventions to prevent the progression to cervical cancer.  2. Treatment of CIN: When making treatment decisions for CIN, it is imperative that a clear diagnosis be made first. That is, it must be diagnosed as CIN after cytological examination, high-risk HPV testing, satisfactory colposcopy and by histopathological examination, and then be treated according to the following principles. (1) HPV infection: This includes cervical acromegaly visible to the naked eye and cervical acromegaly subclinical infection (SPI) not recognizable to the naked eye. In case of high-risk HPV positivity, review after 1 year; in case of persistent high-risk HPV positivity (high-risk HPV positivity up to 1 year), give local treatment and follow up. (2) CIN I: It is a low-grade cervical lesion and can be treated or followed up. (3) CIN II-III: belongs to high-grade cervical lesions, tends to persist or progress, and cervical conization or cervical loop electrode excision (LEEP) should be performed. For those who have CIN II-III on pathological examination after colposcopic multi-point sampling, they need to be highly alert to the possible existence of early cervical cancer, so careful pathological examination of the excised specimen is needed. If there is residue on the cut edge, the patient needs to be re-operated or followed up according to the patient’s condition; if there is microinvasive invasive carcinoma of the cervix and occult invasive carcinoma, the patient will enter the stage of routine treatment of cervical cancer.  It is important to mention that CIN III is not an indication for hysterectomy. However, hysterectomy can be considered for the following cases: perimenopausal women, no follow-up conditions or strong patient request (anxiety disorder).  3. Follow-up of CIN II-III: After surgical treatment of CIN II-III patients, 10%-15% of the lesions will persist or recur, and among CIN III patients who underwent cervical conization, about 0.1% progress to cervical cancer every year. This suggests the need for annual follow-up review after treatment of CIN II-III. Most studies have consistently shown that cytology combined with high-risk HPV testing is an effective method for clinical follow-up of persistent and recurrent CIN.  On the one hand, there is an excessive misunderstanding about the treatment of cervical erosion. The modern view is that the cervix is influenced by sex hormones and becomes physiologically ectopic with columnar epithelium after puberty, forming the so-called “erosion” visible to the naked eye. “If there is no abnormality in cervical cancer screening, treatment is not necessary, but when the area of “erosion” is large and there is a lot of discharge, physical therapy can be given. In particular, it is important to note that after treatment, despite a smooth cervix, regular cervical cancer screening is still required. On the other hand, it is important to prevent under-diagnosis of cervical lesions, as the cervix is often “erosive” in the case of CIN. If cervical “erosions” are ignored and not screened, the diagnosis may be missed.  In conclusion, cervical cancer is still one of the most serious diseases threatening women’s health in China. A cervical cancer screening system should be established, appropriate screening methods should be selected to meet national conditions, and patients detected by screening should be treated. In the prevention and treatment of cervical cancer, the task is arduous and there is still a long way to explore.