I Overview of cervical intraepithelial neoplasia (What is cervical intraepithelial neoplasia?) : The
Cervical intraepithelial neoplasias (CIN) is a collective term for a group of precancerous lesions closely related to cervical invasive carcinoma. It includes cervical atypical hyperplasia and cervical carcinoma in situ, reflecting the continuous process of cervical carcinogenesis, i.e. a series of pathological changes from cervical atypical hyperplasia (mild → moderate → severe) → carcinoma in situ → early invasive carcinoma → invasive carcinoma.
II. Symptoms and signs of cervical intraepithelial neoplasia (What are the symptoms of cervical intraepithelial neoplasia?) : The
CIN usually has no obvious symptoms and signs, some of them have increased leucorrhea, leucorrhea with blood, contact bleeding and chronic cervicitis such as cervical hypertrophy, congestion, erosion, polyps, etc. The normal cervix also accounts for a considerable proportion (10%-50%), so CIN cannot be diagnosed by visual observation alone. most literature reports about half of patients with carcinoma in situ have no clinical symptoms. According to Shu Yi Jing (1995), only 5.2% of 172 cases of carcinoma in situ had contact bleeding, 12.2% had a small amount of irregular bleeding, and the rest were asymptomatic. Li Nan et al. (2001) showed that among 150 cases of CIN, 26.0% and 20.7% had increased leukorrhea and contact bleeding, respectively, and 38.0% had no symptoms.
Cervical intraepithelial neoplasia diagnostic tests (what tests are needed to confirm the diagnosis of cervical intraepithelial neoplasia?) : The
Diagnosis: Since CIN often lacks typical clinical manifestations, it is difficult to diagnose CIN based on clinical examination. Cervical cytology smear + multi-point cervical biopsy (iodine staining, visual observation of VIA or colposcopy) + cervical canal scraping has become a commonly used comprehensive early diagnosis method for CIN and early cervical cancer, and there has been a great progress in early diagnosis techniques in recent years.
Laboratory tests.
Cytological examination Since Papanicloaou and Traut established the diagnostic method of vaginal exfoliation cytology in 1941, long-term clinical practice has proved that this method is easy to perform, economical and effective, and can be repeated many times, and has become an important part of routine gynecological examination and the first choice of primary screening tool in cervical cancer screening.
2. Visual inspection with acetic acid (VIA) VIA refers to the direct visual observation of the reaction of cervical epithelium to acetic acid without magnification after applying 3% to 5% acetic acid solution on the surface of the cervix. It is used for cervical cancer screening in developing countries and economically backward areas since the 1990s, and is based on the thickness of the vinegar-white epithelium, the outline of the border and the speed of disappearance.
3. Iodine solution test Also known as Schiller test. The iodine solution is applied to the cervix to observe the stained area. Normal cervical squamous epithelium contains glycogen, which produces dark russet or dark brown color when mixed with iodine, and does not stain as positive. Squamous epithelium in cervicitis, cervical precancer and cervical cancer lacks glycogen or does not contain glycogen and does not stain when coated with iodine, which helps to locate abnormal epithelium and identify dangerous lesions in order to determine the site of this tissue examination for sampling.
Other ancillary examinations.
1. colposcopy and colposcopy-guided biopsy
(1) Colposcopy: Colposcopy is a simple and effective way to diagnose the presence of lesions in the cervix. Abnormal epithelium and abnormal capillaries that cannot be seen with the naked eye can be clearly seen through colposcopy. Colposcopic features of abnormal epithelium include.
(i) increase in cell and nucleus density.
② Irregular contours of squamous epithelium with specific vascular changes that appear as punctation or mosaic. The former is due to twisted or curved capillaries within the epithelium reaching the surface obliquely, while the latter is due to dilated blood vessels arranged in a honeycomb pattern with separate inner epithelial islands.
(iii) White epithelium is the first feature of CIN, with a thick layer of keratinized protein on the epithelial surface. Colposcopy can further help to detect the site of the lesion and thus guide the correct biopsy of the cervical area, but cannot distinguish between carcinoma in situ and atypical hyperplasia. Correct colposcopic findings are related to whether the migratory zone is fully visualized.
(2) Colposcopy-guided cervical biopsy: cervical biopsy is the most reliable method for the diagnosis of CIN, and a multi-point biopsy of the suspected site under colposcopic guidance is the best way to clarify the diagnosis of CIN.
2. Cervical biopsy and cervical canal scraping The diagnosis of CIN and cervical cancer must be based on pathological examination of cervical biopsies.
3. conical cervical excision is a traditional and reliable method for the diagnosis of cervical cancer. the rate of diagnostic conization has decreased significantly due to the widespread availability of colposcopy. in the 1990s, several foreign groups reported comparable results comparing the role of colposcopic biopsy and conical biopsy in the diagnosis of CIN and invasive cancer (Coppleson, 1992). The indications for diagnostic conization are.
(1) Multiple positive cytology with normal colposcopy or no total transformation zone visible or negative colposcopic biopsy and ECC.
(2) Cytology report is inconsistent with colposcopic localization biopsy or cervical scraping results.
(3) Suspected early infiltration on VIA or colposcopic biopsy.
(4) Higher grade CIN lesions extending into the cervical canal.
(5) Those with suspected adenocarcinoma. Clinical or colposcopic examination of suspected invasive carcinoma is a contraindication to surgery.
4. Loop electrosurgery of the cervix (LEEP) and large loop cervical transformation zone excision (LLETZ) have been widely used for the diagnosis and treatment of CIN since the 1990s, so they also have both diagnostic and therapeutic roles.
IV Treatment options for cervical intraepithelial neoplasia (How is cervical intraepithelial neoplasia treated?) : 1.
1. Treatment principles The recent treatment strategy for CIN tends to be conservative for the following reasons: ① the level of comprehensive diagnosis of CIN and early stage cancer has improved; ② the occurrence and development of cervical cancer takes a long time, about 10 years; ③ 20% to 50% of atypical hyperplasia reverses or regresses naturally; ④ most CIN lesions are limited, and the one-time cure rate of conservative treatment is as high as about 90%; ⑤ the 5-year survival rate of in situ carcinoma is about 5 years. The 5-year survival rate of carcinoma in situ is 100%. However, there are still many debates on the management of CIN at home and abroad.
(1) Whether CIN grade I and cervical SPI should be treated or not, opinions differ. studies on the natural regression of CIN suggest that low grade CIN has a high natural reversal rate, mostly associated with low-risk HPV infection, and has very little chance of progression to cancer. recent years, it is believed that CIN grade I is an unstable state, and these earliest precancerous lesions should be observed by follow-up and not treated (Jordan, 1989; Shu Yijing, 1995). Shu Yijing, 1995). On the contrary, many authors believe that all patients with CIN should be managed regardless of their relationship with the virus and staging, and that appropriate precancerous blockade therapy should be given with a positive attitude mainly from the perspective of cervical cancer prevention and treatment.
(2) The use of conservative treatment for CIN grade III is widely divergent: the failure rate of conservative treatment is reported to be high in foreign literature. Ostergard (1980) reported that the failure rate of CIN grade III treated with cryotherapy was 39.0%, and Benedet et al. (1981) reported the occurrence of invasive carcinoma after treatment with cryotherapy, so it is considered inappropriate to use cryotherapy for CIN grade III. In another study of 343 CIN grade III cone specimens, 99.7% of the glands were involved to a depth of <3.8 mm (Anderson et al., 1980), which not only provides a basis for conservative treatment, but also suggests that treatment needs to reach a certain depth in order to be adequately treated. Conservative treatment of CIN grade III has been repeatedly reported in the literature, with a one-time cure rate of 77% to 96%. Total hysterectomy is the best treatment option for CIN grade III patients who no longer have fertility requirements.
(Demopoulos et al. (1991) reported that in 96 cases of CIN III treated with cervical conization, the positive margin rate was 39.6%, and 38.5% had residual lesions when hysterectomy was performed 8 weeks after the operation. Parson (1978) reported that the residual or recurrent cancer after conization was 3.2% to 9.1%.
2. Common treatment methods of CIN
(1) Cryotherapy (cryosurgery).
Cryotherapy is easy and effective, and the biggest advantage of cryotherapy is that it does not have the pain caused by electrocautery. However, a few patients still feel uncomfortable because of the need for repeated treatment, especially when deep treatment is performed, probably as a result of uterine contractions. Of these, CIN I has a zero failure rate. Notably, re-treatment with cryotherapy after failure reduces the failure rate of CIN II to 3% and the failure rate of CIN to 7%. The results are the same for cold coal, carbondioxide, or nitrous oxide. However, during treatment, the pressure should not be as low as 40 kg/cm2, and the probe in contact with the cervix should be 4-5 mm wide all around, except for the papillae in the middle. At the same time, in order to freeze evenly and quickly, the probe part can be coated with a thin layer of water-soluble lubricant, which is more ideal. It is generally considered appropriate to use cryotherapy for CIN grade I and II with limited lesions.
(2) Laser treatment
The laser is usually operated under the colposcope, and the energy emitted is released by a punctiform beam and absorbed by the tissue, which can destroy the tissue and vaporize it in addition. The laser’s contact coal is also carbon dioxide. Continuous treatment is more effective than intermittent treatment. The depth of treatment can be 5-7 mm, but flammable substances such as alcohol and disinfectants should not be used during the treatment. In addition, the smoke produced during the treatment can be blown off with a straw to make the view a little clearer. In addition to the benefit of deeper tissue destruction, laser has at least two disadvantages: it is more painful than electrocautery and freezing, which is an inevitable phenomenon after deep tissue destruction, and more bleeding as a result.
(3) Electrocoagulation diathermy: There are almost no reports of failure in the treatment of CIN I and CIN II, but very few CIN IIs harbor CIN III or even invasive carcinoma, so careful examination, including colposcopy and even biopsy, as well as cervical dilatation and curettage (D&C) if necessary, should be performed before treatment. and curettage (D&C) if necessary. For CIN III, the treatment failure rate is about 13%. Chanen and Rome reported the highest number of patients, 1734. The failure rate for all patients (CIN I to CIN III) was only 3%, all performed on an outpatient basis. Only a few patients required deep electrocautery to be sufficient to destroy deeper lesioned tissue including glands, requiring anesthetics and possibly hospitalization. The possibility of cervical stenosis is rare, but is more likely to occur after deep electrocautery. This side effect can be reduced by performing a cervical dilation and curettage at the same time as electrocautery. The advantage is that the treatment area is wide and the depth can be 3-4mm, and the treatment effect can be 90%-95%.
(4) Loop electrosurgical excision procedure (LEEP) or large-loop excision of the transformation zone (LLFTZ): LEEP was pioneered by French scholar Cartier ( It is a new type of electrodesiccation therapy.
(5) Cervical conization: It is a traditional treatment method commonly used at home and abroad, and was widely used in Europe for the treatment of CIN, but because many authors reported high rates of residual lesions and recurrence after conization and certain complications, most scholars advocate that the indications for conization should be strictly controlled, and it still has a certain status in the treatment of young and infertile patients with carcinoma in situ, and in addition, for those with limited lesions, refusing or unable to tolerate major surgery CIN grade III patients, conectomy can also be used.
Cone resection is particularly suitable for severe CIN and CIS, both diagnostic and therapeutic. Cone resection can also be considered in microscopically invasive cancers with minimal invasion. This procedure is performed through the vagina and is also called cone resection or cone section when the cut cervix is viewed upside down in a conical shape. The transformation zone of the cervix, the junction of squamous and columnar epithelial cells, must be visible during the procedure, and the specimen from the endocervical curettage must be free of cancer cells. To do this well, the cervix is usually exposed first, the mucus on the surface of the cervix is first washed with a cotton swab moistened with saline, and finally 4% acetic acid is applied evenly to the cervix, which is white from the coagulation of the acetic acid with the protein produced by the epithelial lesion, and the edge of the excised portion has to cover all the white zone. Therefore the shape does not have to be round, the incision is based on the lesion. Of course more margins need to be left, that is, no residual lesions on the margins. It is best to do this procedure under colposcopic guidance, but generally the clinician with good prior colposcopic findings can use acetic acid to assist in the scope determination during the procedure and cut down enough margins to reduce residual lesions and recurrence when there are still cancer cells at the margins of the cone-cut specimen, which requires a second excision because there is occasionally invasive cancer at the problematic margins. Our other suggestion is that a smear can be done first and if the smear result is normal, it can be observed first. Unless there is cervical stenosis that affects the smear result, a second resection is done.
(6) Total hysterectomy: It is the most common and thorough treatment for cervical carcinoma in situ. In cases of precancerous lesions, especially CIN II and CIN III, those who no longer want to have children, or those with other diseases of the uterus, ovaries and fallopian tubes, such as benign tumors, hysterectomy is usually performed; if there is a combination of uterine prolapse, which was more common before, then In combination with the more common uterine prolapse, a total hysterectomy (vaginalhysterectomy) is most often performed vaginally. For carcinoma in situ, Kolstad et al. reported that among 238 patients who underwent hysterectomy, long-term follow-up for 5 to 25 years resulted in a recurrence rate (carcinoma in situ) of 1.2% (3/238) and invasive carcinoma of 2.1% (5/238). There was no statistical difference in comparison with cone resection, although there was a numerical difference. It is almost statistically the same as that of Bjerre et al. (3729): 0.9% recurrence of carcinoma in situ and 0.3% of invasive carcinoma after hysterectomy.
As for surgery, in order to reduce recurrence, physicians used to remove more of the upper vagina; Creasman and Rutledge et al., after analyzing 861 patients, emphasized that this was not necessary and concluded that recurrence of cervical carcinoma in situ was not related to the amount of vagina removed.
Total hysterectomy is also the treatment of choice for patients with no more fertility requirements or for middle-aged or elderly patients with CIN grade III. Parson et al. (1978) emphasized the importance of removing an appropriate portion of the vaginal wall to minimize the risk of recurrence. However, the problem of “high-risk carcinoma in situ” has been noted, and it is believed that multiple glands, deep glands, high and superficial cervical lesions are extensive and multicentric, especially those most likely to reach the upper vagina. It is obviously inappropriate to perform extrafascial extended total hysterectomy or subextensive hysterectomy.
(7) Radiation therapy: For patients with in situ cancer who have contraindications to surgery or refuse surgery, simple intracavitary radiotherapy can be used.
(8) Management of adenocarcinoma in situ and adenosquamous intraepithelial neoplasia: Because the natural history of adenocarcinoma is not well understood, there are few reports on the management of ACIS and CIGN, but several recent studies deserve attention. Kenned et al. (1996) reported that at least 4% of 77 cases of atypical glandular epithelial cells (AGUS) with no clear cytologic diagnosis had invasive carcinoma and 13% had precancerous lesions, including one case in which adenocarcinoma was found within 4 months. “Azodi et al. reported the results of 40 cases of in situ adenocarcinoma, with 24%, 75% and 57% positive endocervical canal margins after cold knife conization, LEEP and laser conization, respectively, and recommended CKC for patients with fertility requirements. CKC evaluation of adenocarcinoma in situ to exclude invasive adenocarcinoma, and in addition, type I hysterectomy is advocated for adenocarcinoma in situ with negative cone biopsy margins and negative ECC. There is no consensus on the management of ACIS and CIGN. In view of their specific biological behavior, careful examination, thorough evaluation, and accurate diagnosis should be followed by appropriate management that is different from that of CIN.
V Prevention and prognosis of cervical intraepithelial neoplasia (how to prevent cervical intraepithelial neoplasia?) Prognosis
Prognosis: Richart has pointed out that the higher the degree of heterogeneity of CIN and the deeper the epithelial thickness involved, the greater the possibility of developing invasive carcinoma, and conversely, the greater the chance of reversal of low-grade CIN to normal. there are three types of CIN regression: ① regression (or reversal); ② persistence (or stable disease); ③ progression (or carcinoma).
1. Factors related to CIN regression
(1) HPV type: Some studies suggest that HPV type is a relevant factor for CIN regression (Richart et al., 1987). Campion et al. (1986) followed 100 cases of CIN grade I for more than 2 years. 56% of those positive for high-risk HPV 16 and 18 progressed to CIN grade III, while only 20% of those positive for low-risk HPV 6 progressed.
(2) Degree of CIN: As the grade of CIN increases, the chance of developing invasive carcinoma increases. 15% of CIN can develop into cervical cancer, and the risk of developing cancer in CIN grade I, II and III is 15%, 30% and 45%, respectively. The risk of CIN grade I, II and III progressing to invasive cancer was 4, 14.5 and 46.5 times that of normal women, respectively.
(3) Age: The reversal rate of CIN lesions decreases with increasing age; Mill et al. found that the overall reversal rate was 77% for CIN patients aged 35-39 years and 61% for those aged 40 years or older.
(4) Others: such as interventional treatment of CIN, follow-up time, etc.
Most scholars believe that SPI has similar clinical and biological characteristics to CIN, and although the regression of SPI is controversial, several reports since the 1980s suggest that there are three regressions of HPV, and they are related to the type of HPV. Of these, 16% progressed, 39% remained unchanged, and 45% regressed.
Mcindoe et al. (1984) reported 300 cases of untreated in situ carcinoma with follow-up of 10-20 years, and the rates of invasive carcinoma were 18% and 36%, respectively. Yang Xuechang et al. (1992) observed 69 patients with in situ carcinoma who refused treatment, 26% of whom developed invasive carcinoma within an average of 5.2 years.
Prevention: Some scholars believe that no specific treatment is needed and can be followed up because mild lesions seen colposcopically due to low HPV infection have a low chance of malignancy. Some believe that treatment should be given because a small percentage of CIN I is high-risk HPV infection and has a tendency to become redundant.
6. Precautions for cervical intraepithelial neoplasia (what should be noted for cervical intraepithelial neoplasia?) : The following
Some scholars believe that no specific treatment is needed and that follow-up can be performed because mild colposcopic lesions caused by low HPV infection have a low chance of malignancy. Some believe that treatment is indicated because a small percentage of CIN I is high-risk HPV infection and has a tendency to become superfluous.