Cervical microinvasive cancer

　　1. Etiology

　　Cervical microinvasive cancer is an important pathological stage in the development process from cervical intraepithelial neoplasia (CIN, mainly in situ carcinoma) to invasive cancer. The main causes of CIN are as follows:

　　1. Human papillomavirus infection:In recent years, with the continuous deepening of research on the relationship between human papillomavirus (HPV) infection and the lower genital tract, it has been found that HPV infection is associated with the occurrence of precancerous lesions of cervical cancer. HPV infection, as a special type of sexually transmitted disease, is a cause of CIN. Molecular biology and epidemiological studies have shown that human papillomavirus has carcinogenic potential. HPV can be divided into different types based on its carcinogenicity: HPV16, 18, 45, 56 are high-risk types, HPV31, 33, 35, and 11 others are intermediate-risk types, and HPV6, 11, 26, and 8 others are low-risk types. CIN I and subclinical HPV infection are often caused by HPV6 and 11 types, and 80% of CIN III is caused by HPV16 type infection.

　　Severe atypical hyperplasia of the uterine cervix often has chromosomal integration of HPV genes within the cells, thereby initiating the E1, E2 genes, leading to the expression of viral genes within the cervical epithelium. Subsequently, the E6, E7 genes encode multifunctional proteins that interfere with cell growth, playing an important role in the carcinogenic process of high-risk HPV types 16 and 18. The high-risk HPV E6 protein can bind to the tumor suppressor gene p53, leading to the degradation of p53. The product of the E7 gene is a nuclear phosphoprotein that binds to the product of the tumor suppressor gene retinoblastoma (PRb), leading to the inactivation of its function, thereby affecting its inhibitory effect on cell growth.

　　2. Other factors

　　(1) Smoking: There is a certain relationship between smoking and the occurrence of cervical intraepithelial neoplasia (CIN), and its metabolite nicotine, which has a similar cervical irritability to lung cancer, plays an important role in the occurrence of CIN.

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

　　(3) Endogenous and exogenous immune deficiencies: The infection of immune deficiency viruses can increase the incidence of CIN. For example, Hodgkin's disease, leukemia, collagen vascular disease, and HPV infection-related diseases are related.

　　Second, pathogenesis

　　1, Ia1 stage:Cancer cells have slight infiltration into the deep layer of the epithelium. At the initial stage of cancer cell infiltration, they appear in a bud-like form, followed by round, branched, or lingual shapes, and sometimes infiltration appears at the edge of the lesion on the basis of extensive involvement of the glands, with many lymphocytes infiltrating in the surrounding stroma.

　　2, Ia2 stage:The cancer focus can be measured, the depth of infiltration under the invasive epithelium does not exceed 5mm, and the width does not exceed 7mm. The lesion has small infiltrative foci fusion, and cancer cells can present various degrees of differentiation, sometimes in a mass-like form, sometimes in a reticular structure formed by many spicules. There are many round cell infiltrates in the surrounding stroma, and sometimes giant cells can be seen, and the stromal fibers are relaxed or contracted.

　　Infection and the development of lesions into invasive cervical cancer. Invasive cervical cancer is often found during gynecological examination and confirmed by pathological biopsy and histological examination. Some cervical cancers are asymptomatic and have no visible abnormalities, known as preclinical invasive cervical cancer. The age of onset of invasive cervical cancer ranges from 20 to 90 years, with irregular vaginal bleeding as the main clinical symptom in patients with cervical cancer, accounting for 80% to 85%, especially postmenopausal vaginal bleeding should be paid attention to.

　　Microinvasive cervical cancer, like in situ cancer, has no special symptoms and signs. Betsill (1985) reported that 33% to 81% of cases were asymptomatic, some had increased leukorrhea, contact bleeding, or irregular vaginal bleeding, and various manifestations of chronic cervicitis. According to statistics, 56.7% of microcarcinomas had contact bleeding and irregular bleeding, asymptomatic cases accounted for 40%, some authors reported that chronic cervicitis accounted for 39.6%, mild to moderate erosion accounted for 28.3% to 75.0%, severe erosion accounted for 7.5%, leukoplakia accounted for 3.8%, clinically suspicious cancer accounted for 12.5%, while the proportion of smooth cervix (9.4% to 12.5%) was lower than that of CIN.

　　The diagnostic criteria for stage Ia of the 1985 and 1994 FIGO not only require clear infiltration depth but also require the calculation of the horizontal spread range of the lesion, indicating that the diagnosis of microinvasive cervical cancer is a histological diagnosis, which must be confirmed by the continuous or subcontinuous section microscopic examination of the specimens of cervical resection or conization, and total hysterectomy, including all cervical neoplasms. Therefore, two points are emphasized in the diagnosis of MICA: ① The necessity of combined use of auxiliary diagnostic methods; ② The importance of careful sampling and tissue preparation.

　　Invasive cervical cancer is often found during gynecological examination and confirmed by pathological biopsy and histological examination. Some cervical cancers are asymptomatic and have no visible abnormalities, known as preclinical invasive cervical cancer. The age of onset of cervical invasive cancer ranges widely, from 20 to 90 years old. Irregular vaginal bleeding is the main clinical symptom of cervical cancer patients, accounting for 80% to 85%, especially postmenopausal vaginal bleeding should be paid more attention to. The disease description includes the uterine corpus and cervix. The cervix is located at the bottom of the uterus, accounting for about 1/3 of the entire uterus, 2.5 to 3 cm long, divided into the upper vaginal segment and vaginal segment, that is, the cervical canal and the cervical vaginal part. Malignant epithelial tumors occurring at this site are called cervical cancer.

　　1. Cytological examination:The accuracy of cytological diagnosis is related to the degree of lesion. The survey data of the Cancer Hospital of the Chinese Academy of Medical Sciences in high-incidence areas of cervical cancer show that in early cervical cancer (including in situ cancer and early invasive cancer) and cervical atypical hyperplasia, the incidence rate of cytological abnormalities is significantly different, respectively, 3.1% and 31.6% of Pap smear IIa, 21.5% and 32.9% of IIb, 18.5% and 15.2% of III, 35.4% and 7.6% of IV, and 18.5% and 10.1% of V. There is a significant difference in the positive rate of cytology (IV + V levels) between the two, respectively, 53.8% and 17.7%, indicating the important significance of cytology in the initial screening of early cervical cancer. See Table 1. Frable et al. (1998) reported that the positive predictive value of traditional cytological examination is 80%, with 10% to 15% of false negatives. Recently, the application of new cytological examination technology thin-layer liquid-based cytology (TCT) has improved the detection rate, with positive rates of HSIL and cancer being 92.9% and 100% respectively, and conventional smears being 77.8% and 90.9% (Martha et al., 1999). The Cancer Hospital of the Chinese Academy of Medical Sciences was the first to use TCT in China in the Sino-US cooperative project, with a positive detection rate of 93.2% and 100% for HSIL and squamous cell cancer in 1997 cases.

　　2. Colposcopy examination:Colposcopy and cytology are indispensable auxiliary diagnostic methods for diagnosing CIN and early cervical cancer. The colposcopic images of early invasive cancer are similar to CIN III, but more abnormal. 'Triad images' are more common, the acetic acid white epithelium is thicker, the boundary is clear, the surface is slightly raised or irregular, punctate vessels and (or) irregularly large and mosaic vessels, vessel dilation, spacing increase, atypical vessels such as spiral, hairpin or comma-shaped can be seen. Some studies have applied colposcopy in screening, according to Coppleson's (1986) colposcopic image classification standard, the proportion of severe abnormalities (i.e., grade III) in early cancer and atypical hyperplasia is 87.1% and 20.98% respectively. In 62 cases of early cancer, except for 2 cases with normal or benign colposcopic findings, abnormal images reached 96.7% as shown in Table 2. The combination of colposcopy and cytology with cervical canal scraping did not miss any invasive cancer, but colposcopy is difficult to differentiate whether there is invasion in the stroma of the cervix.

　　Three, cervical biopsy and cervical canal scraping:It is advisable to perform multiple cervical biopsies under gross observation (ⅥA) or colposcopic guidance, take deep biopsy or large wedge biopsy at suspected cancer sites, especially when clinical suspicion of adenocarcinoma is present, it is more necessary to take biopsy and cervical canal scraping (Teshima et al., 1985; Zhang Wenhua et al., 1993). Due to various reasons, even with multiple colposcopic biopsies, there is still a possibility of missing early invasive lesions, leading to insufficient preoperative diagnosis.

　　Four, cervical cone resection:It is still the most important and reliable diagnostic method for microsatellite invasive cancer. Most authors believe that only cone biopsy can make an accurate diagnosis of MI-CA, but strict technical requirements for sampling, slicing, preparation, and pathological diagnosis are needed. Otherwise, it is easy to cause misdiagnosis or overdiagnosis. With the application of early combined diagnostic methods, the rate of diagnostic cone biopsy has decreased significantly. In recent years, due to the youngening trend of CIN and early cervical cancer, the application of cervical cone resection has increased.

　　1. The indications are revised to:

　　(1) Multiple positive cytology, negative or unsatisfactory colposcopy, or both negative cervical canal scraping and biopsy under colposcopy.

　　(2) Cytology results do not match those of colposcopic biopsy or cervical canal scraping.

　　(3) Iodine staining, VIA, or biopsy under colposcopy suspected of early invasive cancer.

　　(4) High-grade CIN lesions extend beyond the range of colposcopy to the cervical canal inside.

　　(5) Clinical suspicion of early adenocarcinoma, cytology normal or abnormal, no obvious CIN or squamous cell carcinoma abnormalities seen on colposcopy.

　　For young patients with only SPI or CIN I level suggested by cytology and/or colposcopy, cone biopsy should be avoided as much as possible. For those with clinical or colposcopic suspicion of invasive cancer, it is a contraindication for surgery.

　　2. Pay attention to the following points during cone biopsy:

　　(1) There must be a cytology smear, colposcopy, or iodine test before cone biopsy.

　　(2) Avoid excessive preparation of the vagina and cervix to prevent damage to the cervical epithelium.

　　(3) Use cold knife cone biopsy.

　　(4) Expand the cervical canal preoperatively and perform cervical canal scraping.

　　(5) The cone biopsy range includes the abnormal range of colposcopy, transformation zone, and lower cervical canal.

　　Five, cervical loop electrosurgical excision procedure (LEEP) and large loop excision of transformation zone (LLETZ):As a new diagnostic and treatment method for CIN and early cancer, many authors have reported since the 1990s. Meesing et al. (1994) believe that the indications for LLETZ cone biopsy are:

　　1. Dissatisfaction with colposcopy.

　　2. Positive cervical canal scraping.

　　3. Inconsistent results between cytology and cervical biopsy (more than 2 grades).

　　4. Severe lesion, such as severe atypical hyperplasia or cytological indication of invasive changes.

　　This diagnostic method has thermal damage, and whether it is suitable for the diagnosis of early invasive cancer needs further research. After the 1990s, although LEEP treatment has been widely used as a diagnostic and treatment method, for those suspected of early invasive cancer by cytology or colposcopy, it is still recommended to use cold knife conization (CKC) as more appropriate.

　　In terms of diet, pay attention to a reasonable nutritional balance. Try to make the food diverse, eat more high-protein, vitamin and trace element-rich, low animal fat, easily digestible foods, as well as fresh fruits and vegetables. Do not eat too much salty and spicy food, and do not eat too much food containing sex hormones.

　　In daily life, avoid staying up late, avoid having unprotected sex, and avoid multiple abortions.

　　Prevention: In addition to taking good care of health during menstruation, postpartum, or after abortion, in daily life, attention should be paid to the hygiene of the external genitalia, preventing vaginal inflammation and cervical erosion. At the same time, maintain sexual hygiene. In addition, dry the bedding often, wear cotton underwear, and change them frequently. On this basis, regular women's disease examination is also very important.

　　First, treatment

　　The treatment of microinvasive cervical cancer focuses on surgery, but the methods and scope of treatment vary greatly, ranging from conization to extensive hysterectomy with pelvic lymph node dissection.

　　1. Factors affecting treatment

　　(1) Inconsistent diagnostic criteria, many of the data are reports of retrospective studies.

　　(2) Incorrect diagnosis before surgery: Simon et al. (1986) reported that 30% of early invasive cancers were missed. Coppleson (1992) mentioned that 4% to 28% of invasive cancers were diagnosed as microscopic invasion, and 7% to 50% of CIN were actually microscopic invasive cancers, indicating that accurate diagnosis of early stromal invasive cancers is not easy and often too high or too low.

　　(3) Inadequate understanding of the nature of the lesion:

　　① Lymph node metastasis in stage Ia: The literature reports are inconsistent. The lymph node metastasis rate in foreign data from the 1960s to 1970s was 0.8% (only 9 out of 1118 cases), and the Chinese data was 0.64% (only 4 out of 624 cases). Most believe that lymph node metastasis is closely related to the depth of invasion. No lymph node metastasis was found in cases with invasion depth within 1mm, and the lymph node metastasis rate was less than 1% within 3mm. For those with invasion depth of 3 to 5mm, the rate reached as high as 14.8%. Benson et al. (1977) reported that the lymph node metastasis rates for invasion depth ≤3mm and 3.1 to 5.0mm were 0% and 2.7%, respectively. Coppleson (1992) statistically collected data from 5 authors in the 1980s, with only 2 cases (0.5%) of lymph node metastasis in 404 cases with invasion depth ≤3mm, and 12 cases (8.0%) in 146 cases with invasion depth of 3.1 to 5.0mm. Some authors reported that among 36 cases with invasion depth between 3 to 5mm, only 2 cases had metastasis, accounting for 5.6% (Sevin et al., 1992).

　　② The relationship between vascular invasion and lymph node metastasis: There is no definite conclusion at present. Boyce et al. (1981) found that there were more lymph node metastases in patients with vascular invasion. However, some authors have reported the opposite, with little lymph node metastasis in patients with vascular invasion, but lymph node metastasis in patients without vascular invasion (Creasman et al., 1985; Simon et al., 1986). It is generally believed that vascular invasion may be related to lymph node metastasis and recurrence. However, recent research data show that the rate of metastasis and recurrence in stage Ia cervical cancer is low, and it is not related to vascular invasion (American GOG, 1998).

　　③ Lack of understanding of microinvasive cervical adenocarcinoma: It is even difficult to identify, so it is prone to misdiagnosis or missed diagnosis. Bertrand et al. (1987) believe that such lesions are rare, and there are no clear cytological, colposcopic, and histological criteria, as adenocarcinoma and squamous cell carcinoma lesions often coexist and are easily overlooked.

　　2. Treatment principles and methods:The treatment of microinvasive cervical cancer, currently most advocate for reducing the scope of surgery. In principle, it should be based on the depth of invasion, the extent of the lesion, whether there is involvement of blood vessels, whether the lesions are fused, and the pathological type, etc., to choose an appropriate surgical method on the basis of accurate diagnosis. In the diagnostic criteria for cervical cancer, for stage Ia, it is recommended to perform a subtotal hysterectomy (Jiangsen et al., 1990; Wu Aiyu, 1999). In recent years, some authors have used conservative surgery (combined use of laser conization and vaporization) to treat 90 cases of MICA, with a cure rate of 96.7%, incomplete resection rate of 17.8%, and true residual tumor rate of 10% (Ueki et al., 1994). Creasman et al. (1998) reported the results of a study by the American GOG, in which 188 cases of stage Ia2 (stromal invasion 3-5mm) in the specimens of hysterectomy after cervical cone biopsy (CKC), the risk of lymph node metastasis, recurrence, or death in patients without invasion was quite low, with a 5-year survival rate of 100%, and it was believed that such patients could undergo conization alone, but need to be followed up closely. It can be seen that there is still inconsistency. In view of the above-mentioned special characteristics of foreign views in China, the following treatment plan is for reference only:

　　(1) For Ⅰa1 stage (invasion depth ≤3mm): A radical extrafascial hysterectomy should be performed. Young patients who wish to retain fertility or patients who wish to retain the uterus can undergo cervical cold knife cone resection (CKC).

　　(2) For Ⅰa2 stage (invasion depth 3～5mm): For patients without vascular invasion and limited focus, a radical extrafascial hysterectomy should be performed (vaginal resection 1～2cm), about 1cm below the focus. Patients who wish to retain fertility or the uterus can undergo CKC, but strict follow-up observation is required after the operation.

　　(3) For patients with Ⅰa2 stage accompanied by vascular invasion, focus fusion, multiple foci, and poor cell differentiation, subtotal hysterectomy with selective pelvic lymph node dissection should be adopted.

　　(4) Patients who refuse surgery or have contraindications to surgery can undergo radiotherapy (simple intracavitary treatment is sufficient). Patients with poor cell differentiation in Ⅰa2 stage should be supplemented with extracorporeal radiotherapy.

　　(5) If the preoperative diagnosis is insufficient or missed, the tumor volume is large, the operation is not clean, or there is vascular invasion, or the focus fusion is suspected of invasive cancer, postoperative radiotherapy should be supplemented to reduce postoperative recurrence and pelvic lymph node metastasis, and its value is yet to be explored.

　　(6) There is no consensus on the treatment of microfocus adenocarcinoma at present. According to the unique biological characteristics of adenocarcinoma, it is considered appropriate to take more radical radical surgery than early invasive squamous cell carcinoma.

　　II. Prognosis

　　Taipei General Hospital (1975～1986) followed up 226 cases of microscopic invasion (Ⅰa) and the recurrence rate was 2.2% (5/226). Among them, the recurrence rate of invasion less than 3mm in Ⅰa1 was 1.8% (3/167); the recurrence rate of invasion 3～5mm deep and less than 7mm wide in Ⅰa2 was 3.4% (2/59).