What is cervical intraepithelial neoplasia?

Today, cervical cancer is still one of the main diseases that endanger women's lives, especially in developing countries. Worldwide, its mortality rate ranks third among all malignant tumors of female system and second among malignant tumors of female reproductive system, second only to breast cancer. With the progress and popularization of screening technology, the incidence and mortality of cervical cancer have obviously decreased, which has become a model of tumor prevention and treatment. The reduction of incidence and mortality of cervical cancer is largely due to the identification of cervical precancerous lesion-cervical intraepithelial neoplasia (CIN) and reasonable and effective early intervention.

(1) Histological basis of cervical epithelium. The particularity of cervical histology is the pathophysiological basis of cervical intraepithelial neoplasia. Cervical epithelium consists of stratified squamous epithelium of cervix and vagina and single columnar epithelium of cervical canal. The particularity of cervical epithelium lies in its dynamic changes under the influence of various physiological and pathological factors.

① Primitive squamous epithelium. The stratified squamous epithelium covering the cervix and vagina is continuous with the vaginal vault epithelium, with about 20 layers of cells, which can be divided into 3 layers.

Bottom layer: also known as mucus 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 known as the deep spinous layer, is several layers of oval cells with large nuclei. Immunohistochemistry showed that the bottom cells contained epidermal growth factor receptor, estrogen receptor and progesterone receptor, which were reserve cells. Stimulated by some factors, they can proliferate or metaplasia, or proliferate into atypical squamous cells or differentiate into mature squamous cells.

Middle layer: also known as shallow spinous layer, the cells are polygonal or spindle-shaped, with numerous cytoplasm and light staining, transparent glycogen and relatively small nucleus.

Surface layer: flat cells, dense nuclei and eosinophilic cytoplasm.

② Cervical columnar epithelium. It is a single layer of high columnar epithelium secreting mucus, and a few cells have cilia. The oval nucleus is located in the lower part of the cell 1/3. There are a few spare cells at the base. Covering the inner surface of the cervical canal, or extending to the cervix and vagina, there are villous protrusions, and cracks or glands are formed in the matrix.

③ Transformation zone. The junction of cervical squamous epithelium and columnar epithelium becomes the scale-column junction.

According to morphological changes, scale column connection can be divided into primitive scale column connection and physiological scale column connection.

Primitive squamous junction (OSCJ): It is the junction of primitive squamous epithelium and columnar epithelium of cervical canal. This boundary is formed in the 20th week of the embryo, located in the vaginal segment of the external cervix.

Physiological scale-column junction is a new scale-column junction (NSCJ), which is the connection between the inner periphery of metaplastic squamous epithelium and columnar epithelium. The boundary of the new scale column changes inward and outward with age and sex hormone level. After menopause, the boundary of the new scale column can extend to the external cervix, which is not easy to see. For those who have no sexual life in adolescence, there is no big change at the junction of primitive scales and columns, and most of them are normal columnar epithelium outside the cervical orifice; Sexual stimulation is mostly metaplasia epithelium outside the cervix. Cervical dilatation during pregnancy, columnar epithelial eversion, postpartum healing; The elderly OSCJ is not clear, NSCJ can extend into the cervical canal.

The area between the original scale column junction and the physiological scale column junction is called the transition zone.

During the formation of transition zone, columnar epithelium covering its surface was gradually replaced by squamous epithelium. Another mechanism is squamous metaplasia and squamous epithelial formation. The mature surface epithelium in the transitional zone is insensitive to carcinogen stimulation. However, under the stimulation of some substances, the immature superficial epithelium can undergo dysplasia, forming cervical intraepithelial neoplasia and canceration.

④ Surface epithelium. Squamous epithelium is gradually transformed from columnar epithelium at the junction of original squamous epithelium. The single-layer columnar epithelium of the cervix is fragile, exposed to vaginal acid environment or bad stimulation, and the reserve cells under it proliferate and gradually transform into squamous epithelium. At the beginning, the nuclei of immature surface epithelium are densely arranged and lightly stained, with only 6 ~ 10 layers of cells, and the epithelium is thin. With the gradual maturity of metaplastic epithelium, the number of cell layers increases, the epithelium thickens and the cells are rich in glycogen.

⑤ Immature surface epithelium. At the early stage of metaplasia, when the columnar epithelium in the transformation area is immature, the cells are multi-layered, with less cytoplasm and higher density. When differentiation and polarity are not obvious, it should be differentiated from atypical hyperplasia and carcinoma in situ. This area is the most important target area for colposcopy.

⑥ Atypical hyperplastic epithelium. Single-layer columnar epithelium is stimulated by acidic environment or hit by carcinogenic factors in vagina, and cell differentiation and maturation are blocked on the basis of metaplasia, resulting in atypical. From the immature basal cells, the cells proliferate and extend upward, and the nuclei become larger and irregular, and the nuclear chromatin increases, and the nuclear division is active, and the nuclear/plasma ratio increases, which is similar to cancer cells to some extent.

② Pathology ②CIN. Richart put forward the concept of cervical intraepithelial neoplasia (CIN) in 1967, which quickly gained international recognition. CIN is the unified name of cervical precancerous lesions, reflecting the continuous process of occurrence and development of cervical cancer. The pathological feature of CIN is the neoplasia confined to the squamous epithelial layer of the cervix, which is characterized by abnormal cell arrangement and nuclear abnormality.

Cervical intraepithelial neoplasia can be divided into three grades.

CINⅰ Ⅰ: Pathologically equivalent to mild atypical hyperplasia. Immature heteroembryonic cells are confined to the lower part of epithelial thickness 1/3, which is characterized by enlarged nucleus, slightly increased nuclear-cytoplasmic ratio, slightly deepened nuclear chromatin, reduced mitotic period and disordered cell polarity.

CINⅱ Ⅱ grade: it is equivalent to moderate atypical hyperplasia, and immature atypical cells are confined to the lower 2/3 of epithelium, showing obvious enlargement of nucleus, increased ratio of nucleus to cytoplasm, darker staining of nucleus, more mitotic stages, and obvious increase of cell number and polarity.

CINⅲ: including severe atypical hyperplasia and carcinoma in situ. The former are almost all immature atypical cells, but the surface cell density is slightly lower or 1 ~ 2 layers of flat cells parallel to the surface can be seen.

Carcinoma in situ (CIS): The whole squamous epithelium is composed of closely arranged undifferentiated atypical cells, sometimes mixed with differentiated cells of different degrees, but it has remarkable pleomorphism; The basement membrane is intact, the boundary between epithelium and connective tissue is obvious, and glands can be involved along the basement membrane.

Cancer in situ: small columnar epithelium or single glandular duct on the surface of cervical canal becomes cancerous without breaking through the basement membrane. The cells are pseudostratified, obviously heteromorphic, with few cytoplasm, large and dark nucleus, pleomorphism and mitosis, and the boundary with normal columnar epithelium is clear.

(3) the etiology of 3)CIN. Epidemiological studies have found that the occurrence of CIN is closely related to social and economic status, sexual behavior, sexual partner behavior, oral contraceptives, smoking, nutritional status, menstrual delivery history and other risk factors. At present, the most researched and recognized biological cause is human papillomavirus (HPV) infection. Since the mid-1970s, the research on the relationship between human papillomavirus and cervical intraepithelial neoplasia has been increasing, and the key role of human papillomavirus in the process of cervical lesions has gradually become clear. Studies have shown that about 80% ~ 90% CIN people are infected with human papillomavirus. Usually, after about 12 months of human papillomavirus infection, most of them are cleared and turned negative, and only a few become persistent infections. At this time, human papillomavirus -DNA fragments can be integrated into the DNA group of host cells, which will cause malignant transformation of host cells.

At present, nearly 300 serotypes of human papillomavirus have been found. According to its correlation with cervical cancer, it can be divided into high-risk type and low-risk type. HPV 16, 18, 3 1, 33, 35, 39, 45, 5 1, 52, 56, 58 are high-risk types and can induce cancer. CIN Ⅰ is mainly related to human papillomavirus subtypes 6, 1 1, 3 1, 35, while CIN Ⅱ and Ⅲ are mainly related to HPV 16, 18, 33 and other high-risk types. High-risk human papillomavirus subtypes can produce two kinds of cancer proteins:

E6, E7 .E6 and E7 combine with cell cycle regulatory proteins (such as p53 and RB) of host cells (such as cervical reserve cells), resulting in abnormal cell cycle regulation and canceration. At present, the vaccines for the prevention of human papillomavirus infection developed by Merck and GlaxoSmithKline in the United States have been listed respectively: HPV4 (tetravalent vaccine, targeting 6, 1 1, 16, 18, suitable for men and women aged 9-26, and FDA has verified that it can prevent vulvar and vaginal cancer and perianal cancer) and. It has been reported that after three years of vaccination with human papillomavirus, the effective rate of preventing CIN2/3 caused by human papillomavirus infection 16 and 18 was 99% for uninfected women, while only 44% for infected women.

Studies have shown that the effect of tetravalent vaccine can last for 5 ~ 9.5 years. Therapeutic vaccine is still in clinical stage I-II.

(4) Clinical manifestations and prognosis of 4)CIN. Clinically, cervical intraepithelial neoplasia often has no special symptoms. Often manifested as increased vaginal secretions, yellow color or odor. Occasionally, it is contact bleeding, which mostly occurs after double crane needle or three tests in sexual life or gynecology. Gynecological examination showed that there were no obvious lesions on the cervical surface or only local erythema and white changes in the cervix, or chronic cervicitis such as cervical erosion.

Studies have shown that the occurrence and development of cervical intraepithelial neoplasia is a slow and changeable process, which can last for more than ten years and can naturally fade or reverse. Some authors believe that the type of human papillomavirus and CIN level are important factors to determine the outcome of CIN. Lesions caused by low-risk viruses such as HPV6 and 1 1 are easy to reverse, while those caused by high-risk viruses such as HPV 16 and 18 have a low probability of spontaneous regression or reversal. More than 70% of CIN ⅰ and ⅱ can fade naturally or remain unchanged, about 30% will progress to CIN ⅲ, and the probability of CIN ⅲ progressing to invasive cancer is as high as 40%. Although only a few CIN may develop into cervical cancer, at present, we do not have a reliable index to predict which lesions can naturally subside.

(5) Diagnosis of 5)CIN. Clinical CIN often has no special manifestations, and its diagnosis mainly depends on pathological examination. With the development of examination technology, some auxiliary examination methods are helpful to improve the accuracy and pertinence of pathological examination.

① Visual inspection (VIA). The naked eye examination refers to smearing a chemical solution on the surface of the cervix, and the doctor directly observes the reaction of the epithelium on the surface of the cervix to staining without amplification, so as to diagnose the cervical lesions. Visual inspection is a relatively simple method, which is less dependent on surgical facilities, but its sensitivity and specificity are relatively low, about 50% ~ 70% and 85% respectively. Most of the detected cases are not early lesions. Because the operators are easy to train, low in cost, fast and feasible, it is suitable for screening large crowds, and it still has popularization prospects and practical value in economically underdeveloped areas.

② Cervical cytology (Pap smear and TCT). Cervical smear cytology is the simplest and most effective auxiliary examination method to find cervical intraepithelial neoplasia. Since its clinical application in the 1940s, it has played an important role in the prevention and treatment of cervical cancer and precancerous lesions, reducing the mortality rate of cervical cancer by nearly 70%. However, the traditional Pap smear technique has a certain misdiagnosis rate and missed diagnosis rate, and the false negative rate is as high as 50%, which challenges this technique. In order to overcome the problems of Pap smear technology, some new technologies, such as thin-layer smear and automatic cell smear, have been popularized in recent years. Liquid-based cytology has changed the operation method of conventional smear. After the specimen is taken out, it is washed into a container filled with special cell preservation solution, and almost all the cells on the sampler are preserved. Because the cells are evenly dispersed in the sample, compared with the traditional Pap smear method, the collection rate of the sample is improved, and the cell monolayer is evenly distributed on the glass slide.

In the production process, the interference of blood, mucus and excessive inflammatory cells is removed to avoid excessive cell overlap. The abnormal cells on the glass slide are easy to observe, and the fixed nucleus structure is clear and easy to identify. The sensitivity and specificity of differentiating high-grade lesions are about 85% and 90%, respectively. Compared with the Pap smear technique, the sensitivity of low-grade and high-grade lesions was improved by 10% ~ 15%.

PAPNET is an automatic cytology reading system, which overcomes the shortcomings of time-consuming and poor consistency of traditional manual reading, and can be used for quality control of cytology diagnosis and screening. PAPNET scans the traditional Pap smear or liquid-based cytology technology under an automatic microscope, selects 128 images containing relatively "abnormal" cells in each case, and engraves them on a CD for cytopathologists to read. PAPNET can detect false negative smear. The work efficiency and accuracy of cytopathologists are improved.

Bethesda system proposed by American Cancer Society 1988 has been revised twice, which makes the diagnostic terms more standardized and consistent. Bethesda system, abbreviated as TBS, emphasizes the importance of specimen quality evaluation, provides standardized and repeatable standards and terms for various precancerous lesions, reduces the differences between different observers, effectively communicates with clinicians, and helps to form a unified and standardized treatment method. The report system also puts forward suggestions to let clinicians know the follow-up treatment steps.

③ Detection of human papillomavirus. There are many detection methods, such as cytology, dot blot hybridization, in situ hybridization, PCR and hybrid capture method (HC2), and the detection of new generation cobas 4800 human papillomavirus (it has three results: HPV/KOOC-0/6/KOOC-0/8 and the combined results of other high-risk types/KOOC-0/2). High-risk HPV detection and 16/ 18 HPV detection are two different methods. Only the former is used for primary screening (detecting whether there is any high-risk human papillomavirus in 14), and the latter (detecting whether there is HPV 16 or 18) is only used for determining the follow-up treatment when the former is abnormal. HC-2 is the best high-risk human papillomavirus DNA at present, and its detection sensitivity is 88% ~ 100%, especially the negative predictive value is as high as 99%. At present, high-risk human papillomavirus detection should not be regarded as a separate screening item, nor can it replace cytological examination and gynecological examination, because human papillomavirus infection is often transient, and only persistent infection will lead to cervical cancer.

④ Colposcopy. Colposcopy can understand the morphology and distribution of blood vessels and epithelium in the diseased area by magnifying the examined tissue. Colposcopy can further determine the location and size range of lesions. Observing the fine structure through colposcopy can make the target of biopsy more accurate, distinguish the nature of lesions and improve the positive rate of biopsy. Realize early screening and early diagnosis. Colposcopy observation mainly reflects the abnormality of lesions through four signs: border shape, color, vascular structure and iodine reaction.

⑤ Cervical biopsy. Cervical biopsy is the most reliable method to diagnose cervical intraepithelial neoplasia. Any lesions visible to the naked eye or colposcopy should be biopsied at one or more points. More sampling or sampling in the positive area of iodine test can improve accuracy.

⑥ Curettage of cervical canal. Curettage of cervical canal is also one of the methods of biopsy.

Cervical intraepithelial neoplasia (CIN) occurs not only on the surface of cervix and vagina, but also from columnar epithelium or squamous intraepithelial neoplasia of cervical canal and spreads to cervical canal. Colposcopy can only observe the lesions on the cervical surface, but can't understand the lesions of cervical canal. Therefore, the tissue in the cervical canal should be scraped for pathological examination.

(6) treatment of 6)CIN. The choice of treatment mainly depends on the level of CIN, the scope of the lesion, the age of the patient and the desire to have children. With the in-depth study and understanding of CIN and early cervical cancer, the following problems must be paid attention to before treatment: the diagnosis before treatment must be clear, and invasive cancer must be excluded; Pathologically negative cervical curettage or superficial cervical canal lesions; The best treatment time is within 5 ~ 7 days of clean menstruation, and it is operated under colposcopy and iodine test. The scope of treatment must include all lesions, the whole transformation area and the lower segment of cervical spinal canal; The treatment depth is sufficient; Regular follow-up after treatment, including cytology, colposcopy and pathological examination, can include human papillomavirus -DNA detection if conditions permit. Common methods of conservative treatment include electrocautery, electrocoagulation, freezing, laser and ultrasonic focusing; Surgical treatment includes LEEP, cervical conization and total hysterectomy.

① For CINⅰ Ⅰ with satisfactory colposcopy and confirmed by biopsy, nearly 70% of the lesions can naturally subside or remain unchanged, and there is little chance of progression to invasive cancer. At present, it is suggested that such lesions can only be followed up and cannot be actively intervened. However, for the lesions with atypical glandular epithelial cells (AGC) and CIN grade ⅰ or higher, it is necessary to perform cervical conization to make a definite diagnosis.

② The persistence rate and progress rate of CIN Ⅱ and CIN Ⅲ were significantly higher than that of CIN Ⅰ.

Studies have shown that about 43% of untreated CIN ⅱ can be reversed naturally, 35% will continue, and 22% will progress to carcinoma in situ or invasive carcinoma. In untreated CINⅲ Ⅲ, only 32% naturally reversed, 56% persisted, and the progress rate was as high as 14%. Therefore, most scholars advocate that CIN ⅱ and ⅲ confirmed by tissue biopsy should be actively treated. Selection of treatment methods: if colposcopy is satisfactory and invasive cancer is excluded, excision operations such as freezing, laser vaporization, electrocoagulation, ultrasonic focusing or LEEP, laser conization and cold knife conization can be used; Those who are not satisfied with colposcopy should undergo diagnostic resection. Recurrent patients advocate LEEP, laser conization or cold knife conization. Hysterectomy, which used to be popular, is no longer the first choice for treatment.

③ Patients with residual CIN at the margin or cervical canal after diagnostic resection can be followed up for colposcopy and cervical canal curettage 4 ~ 6 months after operation. Once the residual lesions are diagnosed as CINⅱ or ⅲ, most of them advocate re-resection. Hysterectomy can also be considered if reoperation is difficult or the recurrent/persistent lesions confirmed by tissue biopsy are CIN ⅱ and ⅲ.

(7) Principles of management of cervical lesions during pregnancy.

① During pregnancy, the suggestions and follow-up treatment of colposcopy are generally consistent with the previous overview.

② Pap cytology during pregnancy is safe and ECC is not recommended.

③ Colposcopy and cervical biopsy are limited to women with high pathological changes or suspected invasive cancer. ④ LSIL and ASC-US can be delayed until 6 weeks after delivery.

⑤ ASC-H, HSIL, AGC or AIS should be evaluated by colposcopy at least during pregnancy.

⑥ Any level of CIN lesions should be treated after delivery.

⑦ AIS, minimally invasive or invasive cancer needs to consult a gynecologist and communicate with patients. It should not be postponed until postpartum as usual.

⑧ Diagnostic resection is recommended only when invasive cancer is suspected.