To date, cervical cancer remains one of the major life-threatening diseases in women, with a high incidence especially in developing countries. Worldwide, it is the third most common malignant tumor of all female systems and the second most common malignant tumor of the female reproductive system, after breast cancer. With the advancement and promotion of screening technology, the incidence and mortality rate of cervical cancer have been significantly reduced, making it a model for cancer prevention and treatment. The reduction of cervical cancer incidence and death rate is largely attributed to the identification of cervical intraepithelial neoplasia (CIN), a precancerous lesion of the cervix, and reasonable and effective early intervention. I. Histological basis of cervical epithelium The specificity of the histology of the uterine cervix is the pathophysiological basis of cervical intraepithelial neoplasia. The cervical epithelium consists of a compound squamous epithelium in the vaginal part of the uterine cervix and a single layer of columnar epithelium in the cervical canal. The specificity of the cervical epithelium is that it is under dynamic change due to various physiological and pathological factors. The original squamousepithelium is a complex squamous epithelium covering the vaginal part of the cervix, continuous with the epithelium of the vaginal fornix, with about 20 layers of cells, which can be divided into: ① bottom layer: also called the germ layer, the inner bottom layer is a single layer of columnar cells, arranged in a fence on the basement membrane; the outer bottom layer, also called the deep spine layer, is several layers of oval cells with large nuclei. Immunohistochemistry shows that the cells in the bottom layer contain epidermal growth factor receptor, estrogen receptor and progesterone receptor, and are reserve cells, which can proliferate or chemotaxis under the stimulation of certain factors, or can proliferate into atypical squamous cells or differentiate into mature squamous cells. ②Middle layer: also called superficial spine layer, cells polygonal or spindle shaped, cytoplasm more and lightly stained, containing more glycogen is transparent, nucleus is relatively small. ③Surface layer: cells are flattened, with concentrated nuclei and eosinophilic cytoplasm. 2, cervical columnar epithelium (cervical columnar epithelium) is a single layer of mucus-secreting high columnar epithelium, a few cells have cilia, the nucleus oval located in the lower 1/3 of the cell. A few reserve cells were scattered at the base. It covers the inner surface of the cervical canal or extends to the vaginal part of the uterine cervix with villous protrusions and forms fissures or glands into the stroma. 3.Transformation zone (transformation zone, TZ) The intersection of squamous epithelium and columnar epithelium of the uterine cervix becomes the squamous-columnar junction. According to its morphological changes, the squamous-columnar junction is divided into the original squamous-columnar junction and the physiological squamous-columnar junction. The original squamous columnal junction (OSCJ) is the junction of the original squamous epithelium and the columnar epithelium of the cervical canal. The junction is formed at 20 weeks of embryonic life and is located in the vaginal segment of the ectocervix. Physiological squamous-columnar junction (New Sqoamous Columnal Junction, NSCJ): it is the junction between the inner perimeter of the chemosynthetic squamous epithelium and the columnar epithelium. The NSCJ varies with age and sex hormone level, and after menopause, the NSCJ can be extended to the ectocervix and not easily seen. In adolescents without sexual intercourse, the original squamocolumnar junction does not change significantly, and there is mostly normal columnar epithelium outside the cervical orifice; in those with sexual stimulation, there is mostly metaplastic epithelium outside the cervical orifice. In pregnancy, the cervix is dilated and the columnar epithelium is exfoliated, which heals after delivery; in the elderly, the OSCJ is unclear and the NSCJ may extend into the cervical canal. The area between the primitive squamous-columnar junction and the physiological squamous-columnar junction is called the migratory zone. During the formation of the migratory zone, the columnar epithelium covering its surface is gradually replaced by squamous epithelium. The mechanism of replacement is squamous epithelial metaplasia and squamous epithelialization. The mature chemosynthetic epithelium in the migratory zone is insensitive to stimulation by carcinogens. However, immature chemosynthetic epithelium can undergo heterotypic transformation under the stimulation of some substances, forming intraepithelial neoplasia and carcinoma of the uterine cervix. 4.The metaplastic epithelium is a squamous epithelium gradually transformed from the columnar epithelium at the junction of the original squamous columnar epithelium. The monolayer columnar epithelium of the uterine cervix is fragile, and when exposed to the acidic environment of the vagina or to adverse stimulation, the reserve cells under it proliferate and gradually transform into squamous epithelium. At the beginning, immature septated epithelial cells have large dense nuclei, light staining, only 6-10 layers of cells, and thin epithelium. With the gradual maturation of the chemosynthetic epithelium, the cell layers increase, the epithelium thickens, and the cells are rich in glycogen. 5, immature metaplasia epithelium (immature metaplasia epithelium) columnar epithelium in the transformation zone in the early stage of immature metaplasia, multi-layered cells, less cytoplasm, denser. When differentiation and polarity are not obvious, it should be distinguished from atypical hyperplasia and carcinoma in situ. This area is the most important target area for colposcopy. Atypical hyperplastic epithelium (dysplastice epithelium) is a single layer of columnar epithelium that is stimulated by an acidic environment or by oncogenic factors in the vagina, and on the basis of chemosis, cell differentiation and maturation are impaired and atypical. The nuclei are enlarged and irregular, with increased nuclear chromatin, active nuclear division, and increased nuclear/pulp ratio, resembling cancer cells to some extent. The pathology of CIN is characterized by cervical intraepithelial neoplasia (CIN) as a unified name for cervical precancerous lesions, which reflects the continuous process of cervical carcinogenesis and development. CIN is characterized by abnormal cell arrangement and nuclear abnormalities. Cervical intraepithelial neoplasia can be divided into three grades: CINI grade: equivalent to mild atypical hyperplasia in pathology, immature atypical cells are confined to the lower I/3 of the epithelial thickness, showing enlarged nuclei, slightly increased nucleoplasmic ratio, slightly deepened nuclear chromatin, less nuclear fission phase, and disordered cell polarity. CIN grade III: including severe atypical hyperplasia and carcinoma in situ, in the former, almost all epithelial layers are immature atypical cells, but the density of superficial cells is slightly lower or one to two layers of flat cells parallel to the surface can be seen. Carcinoma in situ (CIS): The entire squamous epithelium is composed of closely spaced undifferentiated atypical cells, sometimes mixed with differentiated cells of different degrees, but with significant pleomorphism; the basement membrane is intact, and the division between epithelium and connective tissue is obvious, and the glands can be involved along the basement membrane. Adenocarcinoma in situ: small focal columnar epithelial or single glandular duct carcinoma on the surface of the cervical duct, without breaking through the basement membrane. The cells are pseudostratified, markedly heterogeneous, with little cytoplasm, large deep-stained nuclei, polymorphic, with many nuclear divisions, and clearly demarcated from normal columnar epithelium. Epidemiological studies on the etiology of CIN have found that the occurrence of CIN is closely related to risk factors such as socioeconomic status, sexual behavior, sexual partner behavior, oral contraceptives, smoking, nutritional status and history of menstrual delivery. The most studied and recognized biological etiology is human papilloma virus (HPV) infection. Since the mid-1970s, the relationship between HPV and cervical intraepithelial neoplasia has been increasingly studied, and the key role of HPV in the development of cervical lesions has become clear. Studies have shown that approximately 80-90% of CIN have HPV infection. Usually, most HPV infections are cleared and turn negative after about 12 months, and only a few become persistently infected, when HPV-DNA fragments can be integrated into the host cell DNA group, which in turn causes malignant transformation of the host cells. Currently, nearly 300 serotypes of HPV have been identified. HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56 and 58 are high-risk types that can induce cancer, while CINI is mainly associated with HPV subtypes 6, 11, 31 and 35, while CIN II and III are mainly associated with high-risk types such as HPV 16, 18 and 33. . High-risk HPV subtypes can produce two oncoproteins: E6 and E7. E6 and E7 bind to cell cycle regulatory proteins (such as p53 and RB) in host cells (e.g. cervical reserve cells), leading to cell cycle control malfunction and cancer. Currently, the U.S. and U.S. companies Mercer and GlaxoSmithKline have developed preventive vaccines for HPV infection that have been marketed: HPV4 (quadrivalent vaccine for types 6, 11, 16, and 18, for women and men aged 9-26 years, FDA verified to prevent vulvovaginal and perianal cancers) and HPV2 (bivalent vaccine, for types 16 and 18, for women aged 10-25 years, given before the onset of sexual intercourse, is the most effective form of prevention.) One study reported that 3 years after HPV vaccination, the effectiveness rate of preventing CIN2/3 caused by HPV infection of types 16 and 18 was 99% in women without previous HPV infection of types 16 and 18, but the effectiveness rate was only 44% in women with existing infection. Some studies have shown that the quadrivalent vaccine is effective for 5-9.5 years. The therapeutic vaccine is still in clinical phase I-II. Clinical manifestations of CIN and its regression Clinically, cervical intraepithelial neoplasia often has no specific symptoms. It often manifests as increased vaginal discharge, yellow color or odor. Occasionally, contact bleeding often occurs after sexual intercourse or gynecological double or triple examination. On gynecological physical examination, no obvious lesions on the surface of the cervix or only localized erythema or white changes on the cervix, or chronic cervicitis such as cervical erosion are seen. Studies have shown that the development of cervical intraepithelial neoplasia is a slow and variable process that can take up to 10 years to develop and can regress or reverse spontaneously. Some authors suggest that HPV type and CIN grade are important factors in determining the regression of CIN, while lesions caused by low-risk types such as HPV 6 and 11 are easily reversible, while lesions caused by high-risk viruses such as HPV 16 and 18 have a lower chance of regressing or reversing spontaneously. CINIII has a 40% chance of progressing to invasive cancer. Although only a small proportion of CIN is likely to progress to cervical cancer, we do not have a reliable indicator to predict what kind of lesions can regress spontaneously. V. Diagnosis of CIN Clinically, CIN often has no special manifestations, and its diagnosis is mainly based on pathological examination. Now, with the progress of examination technology, some auxiliary examination means can help to improve the accuracy and target of pathological examination. 1.Visual inspection of the cervix with acetic-acid (VIA) refers to the application of a chemical solution on the surface of the cervix and direct observation of the response of the epithelium on the surface of the cervix to staining by the doctor’s naked eye without magnification in order to diagnose cervical lesions. Visual examination is a relatively simple method that is less dependent on the operating facilities, but the sensitivity and specificity are relatively low, ranging from about 50% to 70% and 85%, respectively. Most of the detected cases are not early lesions. Because of the easy training of operators, low cost and rapid feasibility, it is suitable for screening large populations and still has prospects and practical value in economically underdeveloped areas. 2. Cervical cytology (Pap smear and TCT) Cervical scraping cytology is the simplest and most effective adjuvant test to detect intraepithelial neoplasia in the uterine cervix. Since its clinical application in the 1940s, it has played an important role in the prevention and treatment of cervical cancer and precancerous lesions, and has reduced the death rate of cervical cancer by nearly 70%. However, the traditional Pap smear technique has a certain rate of misdiagnosis and leakage, and a false negative rate of up to 50%, which makes this technique challenging. To overcome the problems of Pap smear technique, some new techniques have been introduced in recent years, such as ThinPrep and AutoCyte Prep, which are thin-layer liquid-based cytology techniques. Liquid-based cytology alters the conventional smear operation by washing the specimen into a container with a special cell preservation solution immediately after removal, preserving almost all the cells on the sampler. Because the cells are uniformly dispersed in the sample, the collection rate of the sample is increased and the cells are uniformly distributed in a single layer on the slide compared to the conventional Pap smear method. The interference of blood, mucus and excessive inflammatory cells is removed during the filming process, avoiding excessive cell overlap. The abnormal cells on the slide are easily observed and make the fixed cell nuclei structure clear and easy to identify, with a sensitivity and specificity of about 85% and 90%, respectively, for identifying highly pathological lesions. Compared with the Pap smear technique, it increases the sensitivity of detecting low and high grade lesions by 10% to 15%. PAPNET, an automated cytology reading system, overcomes the drawbacks of time-consuming and inconsistent manual reading and can be used for quality control of cytology diagnosis and screening. The images are burned onto a CD-ROM for reading by cytopathologists. False-negative smears can be detected by PAPNET. This has improved the efficiency and accuracy of cytopathologists. The Bethesda System, proposed by the American Society of Oncology in 1988, has been revised twice to make diagnostic terminology more standardized and consistent. the Bethesda System, or TBS (The Bethesda System), emphasizes the importance of specimen quality assessment to provide standardized reproducible criteria and terminology for a variety of precancerous lesions in order to achieve reduced variation among different observers, to communicate with clinicians Effective communication helps to develop a uniform and standardized approach to management, and the reporting system also makes recommendations so that clinicians are aware of the subsequent management steps. 3. There are many HPV testing assays, such as cytology, spot blotting, in situ hybridization, PCR, and hybrid capture (Hybrid Capture 2 HPV DNA TEST, HC2), and the new generation cobas 4800 HPV test (which has three results: HPV16/18, and a combined result for 12 other high-risk types); the high-risk HPV test and the 16/18 HPV test are two different methods. The former (testing for the presence of any of the 14 high-risk HPV types) is used only during initial screening, while the latter (testing for the presence of HPV16 or 18) is used only to determine subsequent management if the former is abnormal. High-risk HPV DNA is now best detected with HC-2, which has a sensitivity of 88%-100% and a particularly high negative predictive value of 99%. Currently, high-risk HPV testing should not be used as a separate screening test and does not replace programs such as cytology and gynecologic examinations because HPV infection is often transient and only persistent infection can lead to cervical cancer. 4.Colposcopy colposcopy can understand the subtle conditions such as blood vessels and epithelial morphology and distribution in the lesion area through magnified observation of the examined tissues. Colposcopy can further determine the location and size of the lesion for those with suspicious or positive cytology. The observation of fine structures through colposcopy can make the biopsy target more accurate, differentiate the nature of the lesion and improve the positive rate of biopsy. Early screening and diagnosis are achieved. Colposcopic observation mainly reflects the abnormality of the lesion by four signs: boundary morphology, color, vascular structure and iodine reaction. 5. Cervical biopsy Cervical biopsy is the most reliable method to confirm the diagnosis of cervical intraepithelial neoplasia. Any lesion visible to the naked eye or colposcopically should be biopsied at a single or multiple points. Multi-point sampling or sampling in the iodine test positive area may improve accuracy. 6. Cervical canal scratching Cervical canal scratching is also one of the methods of biopsy. Cervical intraepithelial neoplasia occurs not only on the surface of the vaginal part of the cervix, but also from the columnar epithelium of the cervical canal or squamous intraepithelial neoplasia spreading to the cervical canal, and colposcopy can only observe the lesions on the surface of the cervix but not the lesions in the cervical canal. Therefore, the tissue in the cervical canal should be scraped for pathological examination. VI. Treatment of CIN The choice of treatment depends mainly on the level of CIN, the extent of lesions, the patient’s age and the desire for fertility. With the in-depth research and improved understanding of CIN and early cervical cancer, the following issues must be noted before treatment: (1) the diagnosis must be clear before treatment, and invasive cancer must be excluded; (2) the cervical canal scraping pathology is negative or the cervical canal lesion is superficial; (3) the treatment time should preferably be within 5-7 d after menstruation, and the operation should be performed under colposcopy and iodine test; (4) the treatment scope must include all lesions, the whole transformation area and the lower part of the cervical canal ; ⑤ the depth of treatment must be adequate; ⑥ regular follow-up after treatment must include cytology, colposcopy and pathology, including HPV-DNA testing if available. Common methods of conservative treatment include electrocautery, electrocoagulation, freezing, laser and ultrasound focusing; surgical treatment includes LEEP, cervical conization and total hysterectomy. 1.CINI Among CIN I with satisfactory colposcopic examination and biopsy confirmation, nearly 70% of lesions can regress spontaneously or remain unchanged, and the chance of progression to invasive cancer is extremely low. However, in cases with cytological findings of atypical glandular epithelial cells (AGC) and cervical duct scraping pathology of CINI or even more advanced lesions, cervical conization should be performed to clarify the diagnosis. The persistence and progression rates of CIN II and III lesions are significantly higher than those of CIN I. Studies have shown that about 43% of untreated CIN II can be spontaneously reversed, 35% persist, and 22% will progress to carcinoma in situ or invasive carcinoma, while only 32% of untreated CIN III has spontaneous reversal, 56% persists, and the progression rate is as high as 14%. Therefore, most scholars advocate that both CIN II and III confirmed by tissue biopsy should be treated aggressively. Choice of treatment: If colposcopy is satisfactory and invasive cancer is excluded, resective procedures such as freezing, laser vaporization, electrocoagulation, ultrasound focusing or LEEP, laser conization and cold knife conization can be used; if colposcopy is unsatisfactory, diagnostic resection should be performed. For recurrent cases, LEEP, laser conization or cold knife conization is recommended. Hysterectomy, which was popular in the past, is no longer the preferred treatment method. 3. For those who have residual CIN in the cut edge or cervical canal after diagnostic resection, colposcopy and cervical canal scraping can be performed at the time of follow-up 4-6 months after surgery, and once the residual lesion is diagnosed as CIN II or III, most advocate re-excisional surgery. Hysterectomy may also be considered if reoperation is difficult or if tissue biopsy confirms recurrent/persistent lesions as CIN II or III. VII. Principles of management of cervical lesions in pregnancy 1. In pregnancy, colposcopic recommendations and subsequent management are generally consistent with those outlined previously. 2. Pap cytology is safe in pregnancy and ECC is not recommended. 3. Colposcopy and cervical biopsy are limited to women with high-grade lesions or suspected invasive carcinoma. 4.LSIL and ASC-US can be delayed until 6 weeks after delivery. 5. ASC-H, HSIL, AGC or AIS require colposcopy for evaluation at a minimum during pregnancy. 6. Treatment of CIN lesions of any grade should be postpartum. 7. AIS, microinfiltrate or invasive carcinoma requires gynecologic oncologist consultation and communication with the patient. Treatment should not be routinely delayed until after delivery. 8.Diagnostic resection is only recommended when infiltrating cancer is suspected.