Cervical intraepithelial neoplasia

Introduction to cervical intraepithelial neoplasia Cervical intraepithelial neoplasia (CIN) is a collective term for precancerous lesions that are closely related to cervical invasive carcinoma. Including cervical dysplasia and cervical carcinoma in situ, reflecting the continuous development process of cervical cancer, that is, a series of pathological changes from cervical atypical hyperplasia (light medium heavy) carcinoma in situ early invasive carcinoma invasive carcinoma Variety. basic knowledge The proportion of illness: 0.03% Susceptible people: good for adult women Mode of infection: non-infectious Complications: cervical invasive cancer

Cervical intraepithelial neoplasia

(1) Causes of the disease

Human papillomavirus infection

In recent years, with the deepening of the research on the relationship between human papillomavirus (HPV) infection and the lower genital tract, HPV infection has been associated with the occurrence of cervical precancerous lesions. HPV infection is a special type of sexually transmitted disease. It is the cause of cervical intraepithelial neoplasia. Molecular biology and epidemiological studies have shown that human papillomavirus is carcinogenic. HPV can be divided into different types according to its carcinogenicity: HPV16, 18, 45, 56 High-risk type, HPV31, 33, 35 and other 11 kinds are medium-risk type, HPV6, 11, 26 and other 8 kinds are low-risk type, CINI and subclinical HPV infection are often HPV6, 11 type, CINIII 80% is HPV16 type infection.

Severe dysplasia of the cervix The intracellular chromosomes are often associated with the integration of the HPV gene, thereby triggering the E1, E2 gene, leading to the expression of viral genes in the cervical epithelium, after which the E6, E7 genes encode synthetic multifunctional proteins that interfere with cell growth. High-risk HPV E6 protein can bind to the tumor suppressor gene p53 and cause p53 degradation. The E7 gene product is a nuclear phosphoprotein and tumor suppressor gene retinoblastoma. Binding of the gene (PRb) product results in its functional inactivation, thereby affecting its role in inhibiting cell growth.

2. Other factors

(1) Smoking: smoking has a certain relationship with the occurrence of cervical intraepithelial neoplasia. The degradant nicotine and cervical irritant similar to lung cancer play an important role in the occurrence of cervical intraepithelial neoplasia.

(2) Microbial infection: Neisseria gonorrhoeae, herpes simplex virus (HSV), trichomoniasis infection can increase the susceptibility to HPV, and thus related to the occurrence of cervical intraepithelial neoplasia.

(3) Endogenous and exogenous immunodeficiency: Infection with immunodeficiency virus can increase the incidence of CIN, such as Hodgkin disease, leukemia, collagen vascular disease and HPV infectious diseases.

(two) pathogenesis

Cervical dysplasia

The squamous epithelial dysplasia cells have both atypical and differentiated ability. The characteristics under the microscope are: 1 cell nucleus enlargement, deep staining, different size and shape; 2 chromatin increased, coarse; 3 nucleoplasm ratio increased; 4 Increased mitosis; 5 cell polarity disorder to disappear, according to the degree of cell abnormality and epithelial involvement, cervical atypical hyperplasia is divided into light, medium and heavy three (or three).

(1) mild dysplasia (or grade I): the cell is atypical, the abnormally proliferating cells are limited to the lower third of the epithelial layer, and the surface cells are normal.

(2) Moderate dysplasia (or grade II): The cell is heterogeneous, and the abnormally proliferating cells are limited to the lower 2/3 of the epithelial layer and do not involve the surface layer.

(3) Severe dysplasia (or grade III): Cellular atypia is significant, and abnormally proliferating cells occupy more than 2/3 of the epithelium or reach the full layer.

2. Cervical genital warts: histologically divided into 3 categories: 1 exogenous, microscopic growth under the microscope; 2 endogenous, epithelial to interstitial growth; 3 flat, most common, lacking the characteristics of the above two types, However, cells have atypical changes and are easily mistaken for CIN.

The main microscopic features that Meisels et al. first described were:

(1) Knockout cells appear in the epithelium of the epithelium, the cells enlarge, the nucleus is heterotypic, and there are binuclear or multinuclear, irregular opacity in the perinuclear cytoplasm, and dense cytoplasm in the periphery.

(2) spine cell proliferation.

(3) The surface layer may be over-keratinized or incompletely keratinized.

(4) Interstitial papillary hyperplasia protrudes to the surface, and the hollowed out cells are the most typical expression of HPVI. In 1981, the author also pointed out that the hollowed out cells are the main identification points of wet sputum and dysplasia, and describe in detail the hollowed out cells. Histological performance.

3. Cervical carcinoma in situ

(1) The basic characteristics of cervical squamous cell carcinoma: The cancer cells are confined to the epithelium, the basement membrane is intact, and there is no interstitial infiltration. The pathological features are: 1 cells are disordered and non-polar; 2 cell nuclei are large, and the proportion of nucleoplasm is increased; 3 nuclear atypia is large, the staining depth is different; 4 abnormal mitotic figures are more common, can be found in all layers of the epithelium.

(2) According to the site of occurrence, three different cell types are formed: 1 large cell keratinization type; 2 large cell non-keratinized type; 3 small cell type, in situ cancer involving gland is very common, still has a basement membrane intact without The characteristics of interstitial infiltration, in situ cancer involving glands refers to dysplasia of squamous epithelial cells extending to the basal part, involving the glandular neck of the cervical canal mucosa, the tumor boundary is clear, and there is no inflammatory reaction in the surrounding interstitium. The residual high columnar glandular epithelium can be seen. If the affected glands are obviously enlarged, deformed or merged with each other, the cells may be infiltrated when the cells are poorly differentiated. It should be paid attention to and need to be identified by microscopic infiltration.

(3) The pathological features of adenocarcinoma in situ described by Friedll and Mckay are:

1 often occurs near the transition zone of the lower neck.

2 can also be limited to a cervical canal mucosa polyp.

3 can involve a group of glandular structures or a single gland, which grows into the interstitium in a bud shape, causing the gland to change in a sieve shape. The nipple composed of epithelial cells can also penetrate into the gland or protrude from the surface of the neck tube. But it is not infiltration.

4 In situ adenocarcinoma is composed of pseudostratified columnar epithelium (Shu Yijing et al., 1995).

4. CIN rating

(1) CIN is also divided into three levels according to the degree of cell type:

1CINI grade: equivalent to extremely mild and mild dysplasia.

2CINII level: equivalent to moderate dysplasia.

3CINIII: equivalent to severe dysplasia and carcinoma in situ.

(2) Recently, some authors have proposed to divide into three subtypes according to the maturity of CIN cells: 1 keratinized; 2 non-keratinized; 3 small cell type, which is considered to provide a more complete histopathology. The morphological basis associated with cytopathology and associated with the pathogenesis of carcinogenesis of cervical cancer (Table 1).

CINI: epithelial maturation, less nuclear abnormalities, less mitosis, see Figure 1, undifferentiated cells are limited to the deep epithelium (lower 1/3), mitosis is visible, but not much, the pathological changes of HPV infection can be observed in the whole layer of epithelium. .

CINII: The cell changes of atypical hyperplasia are mainly 1/2 or 1/3 of the subepithelial. The nuclear abnormalities are more obvious than CINI. Figure 2 shows the mitotic image in the lower 1/2 of the epithelium.

CINIII: Epithelial differentiation and stratification can be absent or only present in 1/4 of the epithelial surface with many mitotic figures (Fig. 3, 4). Nuclear abnormalities can be found throughout the epithelial plexus, and many mitotic figures are abnormal.

The communication between cytologists, pathologists, and colposcopy scholars can improve the reporting level of three levels of CIN, especially to identify mild CIN.

Cervical intraepithelial neoplasia prevention

Some scholars believe that no special treatment is needed, and follow-up observation, because the mild lesions seen under colposcopy caused by low HPV infection have less chance of malignant transformation, and some believe that treatment should be performed because a small part of CINI is high-risk type. HPV infection has a twin tendency.

Cervical intraepithelial neoplasia Complications Cervical invasive carcinoma

Atypical hyperplasia of carcinoma in situ often coexists with invasive cancer.

Cervical intraepithelial neoplasia symptoms common symptoms vaginal discharge increased cervical hypertrophy cervical erosion polyp medullary cancerous purulent vaginal discharge

CIN generally has no obvious symptoms and signs, some have increased leucorrhea, vaginal discharge with blood, contact bleeding and cervical hypertrophy, congestion, erosion, polyps and other chronic cervicitis, the normal cervix also accounts for a considerable proportion (10% to 50%), Therefore, it is impossible to diagnose CIN by visual observation. Most of the literature reports that about half of patients with carcinoma in situ have no clinical symptoms. Shu Yijing (1995) counts 172 cases of carcinoma in situ, only 5.2% have contact bleeding, and 12.2% have a small amount of irregularity. Bleeding, the rest of the asymptomatic, Li Nan et al (2001) statistics of 150 cases of CIN, leucorrhea increased and contact bleeding accounted for 26.0% and 20.7%, respectively, asymptomatic accounted for 38.0%.

Examination of cervical intraepithelial neoplasia

Cytological examination

Since the establishment of vaginal exfoliative cytology in Papanicloaou and Traut in 1941, long-term clinical practice has proved that this method is simple, economical and repetitive, and has become an important part of routine gynecological examination and cervical cancer screening. The first screening tool of choice, from the clinical point of view, the following points deserve attention:

(1) The correct rate of diagnosis: Although the cytological positive diagnosis rate is 95.4%, the accuracy rate reported by different authors is very different (67%~92.6%), and there are certain false negatives and false positives, and CIN is detected. False negatives range from 10% to 35%, even as high as 50% (Coppleson, 1992). The accuracy of cytological diagnosis depends mainly on the following factors:

1 extraction site: is the key to affect the quality of smear, routinely taken at the junction of the scalp outside the cervix, but because a certain proportion of cervical cancer originates from the cervical canal, especially adenocarcinoma and premenopausal, post-menopausal or cervical partial After treatment, the scale column junction moves up, so attention should be paid to the material of the cervical canal. At present, the double smear method (ie, simultaneous cervix and neck smear) and repeated smear are used to improve the smear quality and positive rate. Some scholars reported random use of cervical "double take" and small feet. The comparison between the two showed that the abnormal cell detection rate was significantly different, 85.7% and 42.8% respectively. The "double extractor" is easy to use and completes once. The advantages of double smear, but the neck tube is difficult to obtain when the cervix is atrophy. Shanghai has a small squeegee, which is considered to be suitable for elderly patients. Some studies have found that more than 80% of the cells in the conventional smear are taken with the machine. Discard, visible cytology tools need to be improved.

2 Strengthen quality control, improve production, dyeing technology and diagnostic level: poor smear quality affects the correctness of diagnosis, accounting for 40%, liquid-based cytology almost retains all specimens on the material extractor, and made thin smear Improve the quality of the smear, easy to read and observe.

(2) Unified diagnostic criteria, applying new reporting methods (TBS): For a long time, most of the traditional Pap's five-level classification method has been adopted at home and abroad. With the progress of cytopathology, it is gradually felt in the scope of open vaginal cytology diagnosis. The classification method has been unable to adapt to the diagnosis and clinical requirements of the disease. In 1988, WHO proposed a descriptive report and a reporting system consistent with CIN. In the same year, the National Cancer Institute of the United States proposed the Bethesda system TBS reporting method, which is gradually improving in clinical practice. system.

(3) Diagnosis of cervical genital warts: Gradually recognized in the late 1970s, Meisels (1981) proposed that atypical wet warts are precancerous lesions, and the positive rate of cytology for detecting wet warts is low. The detection rate of wet warts in the census is 3%. 4%, Meisels (1992) reported that the wet sputum accounted for 3.23% in the census, atypical wet sputum accounted for 0.57%, the cytological morphology of wet sputum is similar to CIN, and its cavitation cells are easily mistaken for cancer cells, and atypical genital warts are often misdiagnosed as invasive horns. Chemotherapy should be paid attention to, attention to recognition, the cytological characteristics of wet warts are:

1 nuclear week hole cells or hollow cells.

2 keratinized cells.

3 wet bottom layer cells.

(4) Pay attention to the cytological diagnosis of cervical adenocarcinoma: Most people think that cervical adenocarcinoma is not easy to find early, and early diagnosis is mostly discovered by cytology predicting histological examination after CIN. The positive rate of cytological diagnosis of adenocarcinoma is low. For about 48%, the positive predictive value of cytology in recent years is 71% to 79% (Laverty, 1988). Conventional scraping of the external cervix and cervical smear may increase the detection rate of adenocarcinoma.

2. Apply acetic acid to the naked eye (VIA)

VIA refers to the degree of reaction of the cervical epithelium to acetic acid directly after visual application of 3% to 5% acetic acid solution on the surface of the cervix. According to the thickness of the vinegar white epithelium, the boundary contour and the speed of disappearance, the 20th century 90 After the age has been used for cervical cancer screening in developing countries and economically backward areas, Belinson et al (2001) reported that the sensitivity and specificity of VIA in cervical cancer screening were 70.9% and 74.3%, respectively, this method is simple and easy, Cost-effective.

3. Iodine solution test

Also known as the Schiller test, the iodine solution is applied to the cervix to observe the staining site. The normal cervical squamous epithelium contains glycogen. The glycogen and iodine are mixed to produce a deep reddish brown or dark brown color, which is not stained positive, cervicitis. The squamous epithelium of cervical precancerous lesions and cervical cancer lacks glycogen or glycogen-free, and does not stain after iodine application, which helps to locate abnormal epithelium and identify dangerous lesions in order to determine the site of the tissue examination.

After the abnormal part of the cervix is determined, the peripheral and distal boundaries should be determined. Through the application of the above solution, the lower pole of the lesion can usually be recognized under colposcopy, but occasionally the lesion can extend to the vaginal dome. The upper edge of the lesion can be observed by colposcopy. Its scale column junction.

4. Colposcopy and colposcopy guided biopsy

(1) Colposcopy: Colposcopy is a simple and effective method for diagnosing the presence or absence of lesions in the cervix. Abnormal epithelium and abnormal capillaries that cannot be seen by the naked eye can be clearly seen by colposcopy. Colposcopy The characteristics of the underlying epithelium include:

1 Cell and nuclear density increase.

2 squamous epithelial contours are irregular, accompanied by special vascular changes, manifested as punctation or mosaic, the former is due to the distortion or bending of the capillaries in the epithelium, the latter is due to the blood vessels Expanded, arranged in a honeycomb shape, and the inner epithelial islands are separated.

3 White epithelium is the first feature of CIN, with a thick layer of keratinized protein on the epithelial surface.

Colposcopy can further help to find the lesions, thus guiding the correct biopsy of the cervix, but can not distinguish between carcinoma in situ and dysplasia. The correctness of the colposcopy results is related to whether the transition zone is fully observed.

(2) Colposcopy guided cervical biopsy: Cervical biopsy is the most reliable method for diagnosing CIN. Multi-point biopsy of suspicious sites under colposcopy is the best way to diagnose CIN. The biopsy tissue should be adequate. Depth, including squamous epithelium and a sufficient amount of interstitial tissue, is best achieved by surrounding tissue.

2. Cervical biopsy and neck tube scraping

The diagnosis of CIN and cervical cancer must be based on the pathological examination of cervical living tissue.

Note the following points during cervical biopsy:

1 It is advisable to perform multi-point biopsy under iodine staining, VIA or colposcopy, and respectively send the disease test;

2 The material includes the lesion and its surrounding tissue;

3 bite the cervical epithelium and enough interstitial tissue;

4 When the clinical or cytological is suspicious, the biopsy should be repeated or the biopsy should be taken.

Cervical tube scraping (ECC): scraping the endometrial tissue of the neck tube for pathological examination, which helps to determine whether there is any lesion in the neck tube and whether CIN or cancer affects the neck tube. However, there is no consensus on routine neck examination. The indication for scraping is:

1 cytological abnormalities or clinically suspicious women before and after menopause, especially when adenocarcinoma is suspected;

2 colposcopy lesions involving the neck;

3 Cytology was positive or suspicious multiple times, negative or unsatisfactory colposcopy or negative biopsy under colposcopy.

5. Cervical conization

It is a traditional and reliable diagnosis method for cervical cancer. Due to the extensive development of colposcopy, the diagnostic cone rate is significantly reduced. In the 1990s, several groups abroad reported comparing colposcopy biopsy and cone biopsy in the diagnosis of CIN and invasive carcinoma. The effect is quite comparable (Coppleson, 1992), and the diagnostic cone-cut indications are:

(1) Cytology was positive multiple times, colposcopy was normal or no conversion area or colposcopy biopsy and ECC negative were observed.

(2) The cytology report did not match the results of the colposcopy biopsy or neck tube scraping.

(3) VIA or colposcopy biopsy suspected early infiltration.

(4) The higher grade CIN lesion extends into the neck.

(5) Suspected adenocarcinoma, clinical or colposcopy for suspected invasive cancer is a contraindication for surgery.

6. Cervical ring electrotomy (LEEP) and large annular cervical transformation (LLETZ) have been widely used in the diagnosis and treatment of CIN since the 1990s, so it also has the dual role of diagnosis and treatment.

Diagnosis and diagnosis of cervical intraepithelial neoplasia

Because CIN often lacks typical clinical manifestations, it is difficult to diagnose CIN according to clinical examination. At present, it tends to use a combination of multiple auxiliary diagnostic methods, but the final diagnosis depends on pathological examination, cervical cytology smear + cervical multi-point biopsy (iodine dyeing). , visual observation of VIA or colposcopy) + neck tube scraping has become a comprehensive early diagnosis method commonly used in CIN and early cervical cancer. In recent years, there has been great progress in early diagnosis techniques.

Cervical intraepithelial neoplasia should be differentiated from normal metaplasia and subclinical wetness.

CIN can be identified under the microscope by Pap cytology smear staining. Individual cell changes can be observed in cytology for CIN diagnosis and grading. Histological diagnosis can also observe other characteristics of the whole tissue, cytological evaluation. CIN is often difficult to judge based on changes in the nucleus and cytoplasm (Figure 5).

It is recognized that all dysplasia nuclei are increased in size and morphologically diverse. Another major feature is deep nuclear staining, uneven distribution of nuclear chromosomes, mitotic and nucleoli are rare, and abnormalities in surface or middle cells. The nucleolus is mostly low CIN, and the basal and basal nucleoli abnormalities are high CIN. The relationship between cytoplasm and nuclear size (nuclear pulp ratio) is one of the most important criteria for evaluating CIN level, and the proportion of nucleoplasm is increased. The higher the CIN level, the more frequently varying cells in the same cytology smear, including cells with diagnostic controversies, which need to be identified by experienced cytologists.

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