1. Overview of human papillomavirus infection
Human papillomavirus (HPV) infection is a common female lower genital tract infection and is a sexually transmitted infection. HPV viruses are small DNA viruses that primarily invade the basal cells of the squamous epithelium and the saprophytic cells located in the cervical transformation zone, with direct skin-to-skin contact being the most common route of transmission.
More than 100 types of HPV viruses have been identified, and more than 40 of them are associated with reproductive tract infections. Based on their potential to cause cervical cancer, in 2012 the International Agency for Research on Cancer (IARC) classified them into high-risk, suspected high-risk and low-risk types. The first two are associated with cervical cancer and high-grade vulvar, vaginal, and cervical squamous intraepithelial lesion (SIL), while the latter is associated with genital warts and low-grade vulvar, vaginal, and cervical SIL. There are 12 common high-risk types: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59; 8 suspected high-risk types: 26, 53, 66, 67, 68, 70, 73, 82; and 11 low-risk types: 6, 11, 40, 42, 43, 44, 54, 61, 72, 81, 89.
HPV infection in the lower genital tract is relatively common, and the rate of infection in the general population is reported to be about 10% abroad. In China, there are discrepancies in reports on the population prevalence and distribution of high-risk HPV types, and there is a lack of multicenter studies with large samples.
The majority of HPV infections in the genital tract are transient and without clinical symptoms; about 90% of HPV infections regress within 2 years, and the regression time is mainly determined by the HPV type, which takes 5-6 months for low-risk HPV and 8-24 months for high-risk HPV; only a very small number of HPV-infected patients develop clinically visible lower Only a very small number of HPV-infected patients develop clinically visible lower genital tract warts, squamous intraepithelial lesions and cancer.
2.HPV testing methods
At present, the clinical application of HPV detection methods are mainly for the DNA testing of the viral genome, the detection methods are many, mainly divided into HPV typing test and not typing test. At present, there are also partial typing tests based on HPV non-typing, mainly detecting 12 high-risk types and 2 suspected high-risk types 66 and 68, of which 16 and 18 are typing tests, while the others are non-typing tests. The advantage of fractional testing is that it can identify the specific type of HPV infection and can identify multiple types of mixed infections. Fractional testing can be used clinically to determine if HPV infection is persistent or re-infected with the same type. HPV testing without typing can identify high-risk HPV infections, but not specific types, and can be used clinically to screen for cervical SIL and cervical cancer, but not to determine persistent infection or reinfection with a particular HPV type.
Other HPV detection methods include cytological examination of dug-out cells, immunohistochemical detection of HPV antigen, and HPV antibody detection, but they are less commonly used clinically due to low sensitivity and poor specificity. At present, high-risk HPV mRNA detection technology, especially the detection of E6 and E7 mRNA and quantitative HPVDNA detection technology has emerged, and its clinical significance needs further study.
3. Clinical application of HPV testing
(1) High-risk HPV testing for cervical cancer screening Currently, high-risk HPV testing has become one of the main methods for cervical cancer screening, and three methods are commonly used, namely combined cytology and HPV screening, cytology screening and HPV screening alone.
a. Combined HPV and cytology testing for cervical cancer screening The starting age for combined screening is 30 years and the ending age is 65 years. For women 65 years and older, screening is discontinued if there is no history of cervical intraepithelial neoplasia (CIN) 2 or greater in the past 20 years and if screening has been adequately performed with negative results. Combined screening can be performed with both typed and untyped HPV assays. (1) Combined screening with negative results: Combined screening once every 5 years. (2) HPV-positive with atypical squamous cell cytology (ASC-US): direct colposcopy. (3) HPV-positive and cytology negative: then repeat combined screening at 12 months, or perform typing test for HPV 16 and 18. If HPV 16 or 18 positive, colposcopy should be performed, and if HPV 16 and 18 negative, then combined screening at 12 months. (4) HPV negative with ASC-US cytology: 1 combined screening every 3 years. In addition women with cytology of low grade squamous intraepithelial lesions (LSIL), high grade squamous intraepithelial lesions (HSIL) and squamous epithelial cell carcinoma of the cervix, regardless of HPV results, undergo direct colposcopy.
b. Role of HPV testing in ASC-US triage with cytology results of undefined diagnostic significance Currently, cytology is still used as the primary primary screening protocol for cervical cancer in most regions of China, with the starting age of cytology screening being 21 years and the ending age being 65 years. Direct colposcopy is recommended for women with LSIL and HSIL cytology; HPV testing can be used for triage or repeat cytology testing for ASC-US in women 25 years and older. Due to the poor sensitivity of cytology, there may be inadequate sampling of cells from the cervical canal or transformation zone, which also affects the sensitivity of cytology. Therefore, HPV triage is preferred and both typed and untyped HPV tests may be used. Colposcopy is recommended if the high-risk HPV test is positive, and if the high-risk HPV test is negative, the combined screening regimen is repeated at 3 years. When repeat cytology is chosen for triage, return to routine screening if repeat cytology is negative at 1 year; colposcopy is recommended if the result is ASC-US and above. ASC-US is handled differently in women aged 21 to 24 years, and repeat cytology at 12 months is preferred because HPV infection is mostly transient in women in this age group.
c. High-risk HPV testing in primary screening for cervical cancer With the publication of a large amount of clinical trial data, there is a new change in the screening strategy for cervical cancer. 2008 EuropeanResearch Organization on Genital Infection and Neoplasia (EUROGIN) recommended the use of high-risk HPV testing in primary screening for cervical cancer. In 2015, the Society of Gynecologic Oncology (SGO) and the AmericanSociety of Colposcopy and Cervical Pathology (ASCC) published their recommendations for high-risk HPV testing as a primary screening tool for cervical cancer in Europe. Cervical Pathology (ASCCP) and 13 experts from various societies have proposed transitional guidelines for cervical cancer screening in which primary screening for high-risk HPV is used as an alternative to cervical cancer screening.
The starting age for high-risk HPV for primary cervical cancer screening is 25 years and the ending age is 65 years. Triage management for those with positive high-risk HPV test results is as follows: (1) Perform HPV 16 and 18 typing tests, and recommend colposcopy directly if HPV 16 or 18 is positive. (2) Apply cytology for triage if other high-risk types are tested positive, and perform colposcopy directly if the test result is ASC-US and above; follow up at 12 months if the cytology test result is normal. The interval between re-screening for those with negative high-risk HPV test results is currently recommended to be 3 years.
The main advantages of using HPV testing as a primary screening regimen for cervical cancer: (1) Compared with cytology primary screening, HPV testing primary screening has higher sensitivity, high sensitivity and high specificity for the diagnosis of CIN2 and above lesions. (2) HPV testing primary screening has a higher negative predictive value, allowing for longer screening intervals and lower screening costs. Of course, HPV testing as a primary screening protocol for cervical cancer screening has its shortcomings, mainly the relatively low specificity and low positive predictive value of HPV testing for primary screening, which leads to increased psychological stress and even trauma for the subject, high colposcopy rate, and even overtreatment.
(2) Assessment of treatment effect and post-treatment follow-up of cervical intraepithelial lesions The incidence of recurrence, persistence and progression to invasive carcinoma after reasonable and standardized treatment of cervical SIL is still higher than normal, and the use of HPV DNA testing can help determine whether the lesion is excised cleanly, predict the risk of lesion progression or recurrence after surgery, and effectively guide the postoperative follow-up of patients. The chance of recurrence is increased and should be followed up closely for early intervention, while the follow-up interval can be extended for HPV-negative patients. It is recommended that HPV typing tests be used to determine whether HPV positivity is persistent infection or reinfection.
(3) Evaluation of HPV vaccine application Currently, HPV vaccines in clinical use are mainly preventive vaccines, while therapeutic vaccines are still under development or clinical trials. Prophylactic vaccines include quadrivalent vaccine (covering HPV 16, 18, 6 and 11) and bivalent vaccine (covering HPV 16 and 18), both of which can effectively prevent cervical cancer caused by HPV 16 and 18, and quadrivalent vaccine can prevent genital warts caused by HPV 6 and 11. HPV testing can be used to determine the efficacy of the vaccine and to understand the presence of other types of HPV infection. HPV typing test is recommended.
4. Diagnosis and treatment of HPV infection-related diseases
(1) Diagnosis and treatment of condyloma acuminatum
The actual diagnosis of condyloma acuminatum is a warts-like lesion of squamous epithelium caused by HPV infection, which is common in young women aged 20 to 29. The diagnosis of warts is usually based on the typical lesions observed by the naked eye. The lesions are usually found near the navicular fossa, labia majora and minora, around the anus, vaginal vestibule, urethra, and may also involve the vagina and cervix. The lesions start as single or multiple reddish papules with sharp apices and increase in size as the lesions progress; they may be papillary, cauliflower, coronary, or mass-shaped; they are often pink, gray, or tan; they are soft, brittle, and may break down or become infected. 50% to 70% of vulvar condyloma acuminata are associated with vaginal and cervical condyloma acuminata. For those with atypical signs, ancillary tests are needed to confirm the diagnosis.
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(2) external genital warts
The actual fact is that you can find a lot of people who are not able to get a good deal on a lot of things. The foci can subside after 1~3 times of application. 6 times of application should be changed to other methods. c. 5% Imiquimod cream, 3 times a week, wash off after 6~10h of application, can be used for 16 weeks. Patients can self-administer the medication, mostly in 8~10 weeks after the medication warts fall off. This drug is a topical immunomodulator that works by stimulating the local production of interferon and other cytokines.
The actual physical or surgical treatment: physical treatment are microwave, laser, freezing. The number, area or failure of other treatment methods of condyloma acuminata can be microwave knife or surgical excision.
(3) vaginal warts: 50% trichloroacetic acid or 10%-25% footleaf ester topical, but also can choose physical therapy, but the treatment to prevent mucosal damage. Liquid nitrogen freezing is not recommended because it may cause vaginal perforation and fistula formation.
(4) Cervical warts: cytological examination, colposcopy and biopsy if necessary to exclude cervical SIL and cervical cancer are required before treatment of cervical warts, and the treatment of cervical warts is not yet standardized.
(5) The treatment of sexual partners: It is recommended that sexual partners be examined for warts at the same time, and that patients be informed that warts are contagious and that sexual intercourse is prohibited until they are cured. The risk of warts can be reduced by the consistent and correct use of condoms, but there is still the possibility of HPV infection in areas that cannot be covered by condoms.
Follow-up visits are required after treatment, once every 2 weeks for 3 months after treatment. For recurring recalcitrant warts, biopsies should be taken promptly to rule out malignancy.
5. Treatment of cervical precancerous lesions
Currently, the principles of management of cervical precancerous lesions are mainly based on the extent of lesions, age, cytological results, HPV test results, transformation zone in colposcopy and the need to preserve reproductive function, etc., so as to develop an individualized treatment plan. 2014 WHO made a new secondary classification of cervical precancerous lesions, CIN1 is equivalent to LSIL, CIN2 and CIN3 are equivalent to HSIL.
(1) Management of CIN1 CIN1 mostly regresses spontaneously, especially in young women and pregnant women, and the management of CIN1 is conservative and requires observation. Only a few cases persist for a longer period of time and require treatment. At present, the management of CIN1, except for young women and pregnant women, needs to be evaluated in combination with previous cytology and HPV test results. a. For patients with CIN1 who have ASC-US or LSIL on cytology or HPV test for HPV16 (positive) or 18 (positive) or persistent HPV infection: combined screening is recommended at 12 months, and if all combined screening is If the combined screen is negative, then age-based screening will be performed at 3 years, and if the screen is negative again at 3 years, then return to routine screening. Colposcopy if cytology is ASC-US and above or HPV positive. b. For CIN1 patients with high-grade squamous intraepithelial lesions (ASC-H) or HSIL on cytology, if colposcopy is adequate and cervical canal sampling is negative, diagnostic conization or combined screening at 12 or 24 months is recommended, with referral for diagnostic conization if HSIL is detected once on combined screening; if combined screening is negative, referral is made for diagnostic conization. Diagnostic conization; colposcopy if HPV positive on combined screening or cytologic changes not reaching HSIL; and rescreening at 3 years based on age if all combined screening is negative. In addition, review of cytologic, histologic, and colposcopic findings is acceptable for CIN1 patients with cytologic detection of ASC-H or HSIL, and if the results of the review need to be revised, the revised results are treated as such.
The management of CIN1 is relatively conservative in young women aged 21 to 24 years and pregnant women, and management needs to be individualized.
(2) Management of CIN2 and CIN3 The probability of CIN3 progressing to cancer is very high, and once diagnosed, it needs to be actively managed. There are controversies in the management of CIN2, which includes both neoplastic and non-neoplastic lesions (reactive squamous epithelial metaplasia, atrophy and epithelial repair changes), because of the poor consistency and reproducibility of CIN2 diagnostic results. In order to better differentiate neoplastic lesions, in 2014 the WHO recommended the use of p16 immunohistochemical staining for the controversial diagnosis of CIN2 to improve the histological diagnosis of cervical lesions and the consistency of diagnosis between pathologists. p16-positive CIN2 is treated as CIN3 and p16-negative CIN2 is treated as CIN1. In addition Ki67 immunohistochemical staining is a more promising method in the triage of CIN2. Currently some pathologists classify indistinguishable CIN2 and CIN3 as CIN2,3. The management of histologically diagnosed CIN2, CIN3 and CIN2,3 includes initial management and post-treatment follow-up. a. Initial management: except for young women and pregnant women, if colposcopy is adequate, cervical conization or destruction treatment are possible. For recurrent CIN2, CIN3 and CIN2,3, inadequate colposcopy or cervical canal biopsy for CIN2, CIN3, CIN2,3 and ungradable CIN, diagnostic conization is recommended and destructive therapy is not recommended. In addition hysterectomy is not the treatment of choice for CIN2, CIN3 and CIN2,3. b. Post-treatment follow-up: combined screening is recommended at 12 and 24 months post-treatment and re-screening at 3 years if combined screening is negative; colposcopy with cervical canal sampling is recommended if any result in combined screening is abnormal; if all screening is negative, even if the age is over 65 years, it is still necessary to return to routine screening at least If all screening is negative, it is still necessary to return to routine screening at least 20 years, even if the age is over 65 years. Cytology and cervical canal sampling are recommended at 4-6 months after treatment for positive margins or for CIN2, CIN3, and CIN2,3; repeat diagnostic conization is also acceptable, and hysterectomy is acceptable if repeat diagnostic conization is not possible.
The management of CIN2, CIN3 and CIN2,3 in young women aged 21 to 24 years is relatively conservative and needs to be individualized.