【摘要】：研究背景在中國,宮頸癌是最常見的婦科惡性腫瘤,嚴重威脅著我國婦女的生命健康。導致宮頸癌的主要原因是人乳頭瘤病毒(human papilloma virus, HPV)的持續(xù)感染,從正常宮頸感染高危型HPV病毒繼而逐漸進展為宮頸癌大概約需8-12年。宮頸上皮內瘤變(cervical intraepithelial neoplasia,CIN)是宮頸癌發(fā)展過程中的癌前期病變。及時發(fā)現CIN并給予合適的治療是預防宮頸癌發(fā)生、降低宮頸癌死亡率的重要手段。宮頸上皮內瘤變根據細胞異型性的程度和累及宮頸上皮層范圍的不同從輕到重分為三級：CIN1、CIN2,CIN3。不同階段對應的治療策略也不同。約57-60%的CINl會自然消退；而CIN3則被認為是真正的癌前病變,CIN3消退的可能性是33%。CIN2通常被認為是與CIN3一樣需要積極手術治療的高級別上皮內瘤變,但CIN2的生物學行為卻更接近CIN1。目前,對陰道鏡活檢病理證實為CIN2-3的患者主要治療方式有兩種：冷刀錐切和環(huán)形電切除術(loop electrosurgical excisional procedure, LEEP)。兩者均能夠有效治療宮頸上皮內瘤變,但卻會帶來一定的副作用,發(fā)生反復流產、嚴重早產及低出生體重兒的風險較一般人群明顯增高。對所有陰道鏡活檢病理為CIN2-3的患者不加篩選的進行手術,會對很多患者造成過度治療。因此如何采用合適的手段箭查出高危的CIN2-3進行針對性的手術對于減少過度治療尤其是減少對年輕、有生育需求的患者的過度治療具有非常重要的意義。本研究意圖探尋有效的方法對宮頸上皮內瘤變的病人進行分流,從而降低對進展為宮頸浸潤癌風險較低的病人進行過度治療的可能。 第一部分關于活檢證實的CINⅡ-Ⅲ患者錐切病理陰性現象的探討。目的：通過評估宮頸錐切距活檢間隔時間對錐切病理陰性率的影響以及年齡等其它可能的影響因素與錐切病理陰性率的相關性,以尋找發(fā)生錐切病理陰性現象的高危因素,從而減少過度治療的發(fā)生。方法：對陰道鏡下活檢病理證實為CIN2-3并接受LEEP治療的391例患者進行回顧性分析。收集每一個研究對象活檢與LEEP間隔時間及年齡等詳細病例資料,用統(tǒng)計學方法分析其與錐切術后病理分級的關系。結果：1、我們將病理結果≤CIN1的患者視為錐切病理陰性,錐切病理陰性的比例是26.9%(105/391)；2、隨著宮頸活檢與LEEP術間隔時間的增加,錐切病理陰性的比例顯著增加,Pearson相關系數為5.44(P=0.020),單因素logistic回歸OR：1.374,95%CI：1.089一1.735,P=0.008；3、錐切病理陰性組與錐切病理陽性組患者的避孕方法、活檢前細胞學結果、HPV感染情況(分型、定量及高危HPV型數量)、陰道鏡結果均無統(tǒng)計學差異。僅活檢病理分級和年齡與錐切病理陰性率密切相關(p=0.002, p=0.015)；4、通過多因素logistic回歸分析,錐切病理陰性的發(fā)生與活檢病理分級(p=0.001)、年齡(p=0.039)和活檢與錐切間隔時間(p=0.028)密切相關。結論：1、26.9%的陰道鏡下活檢證實為CIN2-3的患者在進行LEEP治療時,錐切病理僅提示為CIN1或者無上皮內瘤變；2、活檢病理分級為CIN2的年輕女性當錐切距活檢間隔時間較長時,錐切病理≤CIN1的幾率顯著升高。 第二部分P16在宮頸活檢為CIN2的病理標本中的表達與錐切術后病理分級之間的關系目的：探尋P16在宮頸活檢為CIN2的病理標本中的表達與錐切術后病理級別之間的關系,以此來推測是否可用其分流活檢為CIN2的病人。方法：以128例CIN2患者作為研究對象進行回顧性分析,取其陰道鏡活檢組織的石蠟切片利用免疫組化法檢測P16的表達。結果：1、對115例CIN2活檢標本進行P16染色發(fā)現P16陽性檢出率為87.8%(101/115)；2、宮頸活檢標本P16染色≤++的病人中48.3%LEEP術后病理分級≤CIN1,活檢標本中P16染色為+++的病人中34.9%LEEP術后病理分級≤CIN1。與宮頸活檢標本P16染色≤++的病人相比,活檢標本中P16染色為+++的病人宮頸錐切病理陰性的發(fā)生率較低,但差異沒有統(tǒng)計學意義(P=0.203)。結論：活檢標本中P16免疫組化染色≤++時更容易發(fā)生錐切陰性的現象,這提示P16或許有助于預測CIN2患者的預后。但是差異沒有統(tǒng)計學意義,或許與研究排除了對活檢病理診斷不一致的病例,從而減少了對良性病例的過度診斷有關。 第三部分P16在術前液基細胞蠟塊的表達與錐切術后病理分級之間的關系目的：通過檢測宮頸活檢為CIN病人術前液基細胞石蠟包埋組織中P16表達,并探討其與錐切術后病理及疾病轉歸的關系,以評估細胞塊中P16表達在CIN個性化治療中的預后價值。方法：選擇TCT為ASCUS以上、在1個月內接受陰道鏡下活檢病理提示為CIN的病人,取其TCT保存液中的剩余組織細胞制成宮頸細胞塊,同時在細胞塊上用免疫組化法檢測P16的表達,所有研究對象在活檢后均接受兩年的隨訪。結果：1、與細胞學涂片相比,細胞石蠟切片中細胞的形態(tài)結構與組織切片相似,且方便易行、容易保存；2、宮頸脫落細胞塊中P16染色評分≥++的患者僅29.9%LEEP術后病理分級CIN1,而P16染色≤+的病人中則有71.4%LEEP術后病理分級≤CIN1,與細胞塊標本P16染色≤+的病人相比,細胞塊標本中P16染色≥++的病人宮頸錐切病理陰性的發(fā)生率較低,差異有統(tǒng)計學意義；3、以P16陽性表達為判定標準,其預測宮頸錐切病理陰性的敏感性、特異性、陽性預測值、陰性預測值分別為91.0%、36.8.5%、70.1%、71.4%；4、4例兩年隨訪治療中進展為CIN2-3的GIN1患者和6例錐切后兩年隨訪發(fā)現疾病復發(fā)的患者其細胞塊P16染色均≥++。結論：運用細胞塊技術有利于對患者做回顧性分析和追蹤觀察；根據P16在宮頸脫落細胞塊的免疫組化染色結果,可以較準確地預測疾病的轉歸,有助于對CIN級患者進行有效的分流管理,以減少過度治療的發(fā)生。
[Abstract]:Background in China, cervical cancer is the most common gynecologic malignant tumor, which is a serious threat to the life and health of women in China. The main cause of cervical cancer is the continuous infection of human papilloma virus (HPV). It will take about 8-12 years for cervical cancer to gradually develop to cervical cancer from the high risk HPV virus of normal cervix. Intraepithelial neoplasia (cervical intraepithelial neoplasia, CIN) is a precancerous lesion in the development of cervical cancer. Timely discovery of CIN and appropriate treatment are important means to prevent the occurrence of cervical cancer and reduce the mortality of cervical cancer. Cervical intraepithelial neoplasia is based on the degree of cell heteromorphic and the difference in the range of cervical epithelium involving the cervical epithelium. The light to weight is divided into three levels: CIN1, CIN2, and CIN3. different stages of treatment. The CINl of about 57-60% will disappear naturally; and CIN3 is considered a real precancerous lesion, and the possibility of CIN3 regression is that 33%.CIN2 is usually considered to be a high grade intraepithelial neoplasia that requires active surgical treatment as CIN3, but the biological line of CIN2 To be closer to CIN1., there are two main treatments for CIN2-3 in patients with biopsy pathology confirmed by colposcopy: cold knife coning and circular electrosurgical excision (loop electrosurgical excisional procedure, LEEP). Both can effectively treat cervical intraepithelial neoplasia, but it will bring certain side effects, recurrent abortion, serious early The risk of producing and low birth weight infants is significantly higher than that of the general population. Surgery on all patients with CIN2-3 for all colposcope biopsy pathology will cause excessive treatment in many patients. Therefore, how to use appropriate means to detect high risk CIN2-3 for targeted hand operation is especially reduced to reducing overtreatment. The purpose of this study is to explore effective ways of diverting patients with cervical intraepithelial neoplasia to reduce the possibility of overtreatment of patients with lower risk of invasive cervical cancer.
The first part is about the pathological negative phenomenon of CIN II - III patients confirmed by biopsy. Objective: To evaluate the correlation between the pathological negative rate of the cone-cutting pathological negative rate and the correlation between the other possible factors of age and other possible factors, in order to find the high risk of the pathological negative phenomenon of conical cutting. Factors to reduce the occurrence of overtreatment. Methods: a retrospective analysis of 391 patients with CIN2-3 and LEEP treatment under colposcopy was reviewed. The detailed data of the biopsy and LEEP interval and age of each study were collected, and the relationship between the pathological classification after coning and the correlation of the pathological classification was analyzed by statistical method. Fruit: 1, we regarded the patients with pathological results less than CIN1 as coning pathological negative, and the proportion of conical pathological negative was 26.9% (105/391); 2, with the increase of time interval between cervical biopsy and LEEP, the proportion of conical pathological negative was significantly increased, Pearson correlation coefficient was 5.44 (P= 0.020), and single factor Logistic regression OR:1.374,95%CI:1.089 1.73. 5, P=0.008, 3, the method of contraception, the results of pre biopsy cytology, HPV infection (typing, quantitative and high risk HPV type), the results of the colposcopy were not statistically significant in the conical pathological negative group and the conical pathological positive group. Only the biopsy and age were closely related to the age of coning disease (p=0.002, p=0.015); 4, through multiple factors. Logistic regression analysis, coning pathological negative occurrence and biopsy pathological grading (p=0.001), age (p=0.039) and biopsy and conical interval time (p=0.028) are closely related. Conclusion: 1,26.9% biopsy confirmed that CIN2-3 in patients with CIN2-3, conical pathology only suggests CIN1 or no intraepithelial neoplasia; 2, biopsy pathology When the CIN2 interval was longer, the probability of conization was less than CIN1.
The relationship between the expression of the second part of P16 in the pathological specimens of cervical biopsy and CIN2 and the pathological grade after conization: To explore the relationship between the expression of P16 in the pathological specimens of the cervix biopsy as CIN2 and the pathological grade after coning, in order to speculate on the possibility of using its shunt biopsy as the patient of CIN2. Method: 128 cases of CIN2 A retrospective analysis was carried out as a study object. The paraffin section of the biopsy tissue of the colposcopy was used to detect the expression of P16. Results: 1, the positive rate of P16 positive was 87.8% (101/115) in 115 cases of CIN2 biopsy specimens, and 2, and the pathological grading of 48.3%LEEP after 48.3%LEEP in the cervical biopsy specimens was less than that of + + in the cervical biopsy specimens. CIN1, in the biopsy specimens, the pathological grading of the patients with + + + + + + + + + + + in patients with 34.9%LEEP was less than CIN1. and the cervical biopsy specimens were less than + + with P16 staining and + +. The incidence of pathological negative cervical conization in patients with P16 staining with + + + in the biopsy specimens was lower, but the difference was not statistically significant (P =0.203). Conclusion: P16 immunohistochemical staining in biopsy specimens. Color less than + + is more likely to occur coning negative phenomenon, which suggests that P16 may be helpful in predicting the prognosis of CIN2 patients, but the difference is not statistically significant, perhaps with the study excluded from the pathological diagnosis of biopsy cases, thus reducing the over diagnosis of benign cases.
The relationship between the expression of paraffin block in the third part of P16 and the pathological grading after coning: Objective: To investigate the relationship between the expression of P16 in the paraffin embedded tissues of the liquid base cells in CIN patients by detecting cervical biopsy and the relationship between the pathology and the prognosis of the disease after coning, in order to evaluate the expression of P16 in the cell block in the individualized treatment of CIN. Methods: to select TCT more than ASCUS, the patients receiving the biopsy pathologic hint under colposcopy within 1 months were CIN, and the remaining tissue cells in the TCT preservation solution were made into cervical cells and the expression of P16 was detected by immunohistochemistry on the cell block. All the subjects were followed up for two years after the biopsy. The results were two years after the biopsy. 1, compared with the cytological smears, the cell morphology and structure of cell paraffin sections are similar to those of tissue section, and it is convenient and easy to preserve. 2, the patients with P16 staining score of the cervical exfoliative cell block more than + + are only CIN1 after 29.9%LEEP operation, and the pathological grading of the P16 staining is less than CIN1 after 71.4%LEEP, and the cell block mark. Compared with the patients with P16 staining less than +, the incidence of cervical cone cut pathological negative in patients with P16 staining more than + + was lower and the difference was statistically significant. 3, the sensitivity, specificity, positive predictive value and negative predictive value of P16 positive expression for cervical conization were 91%, 36.8.5%, 70.1%, 71.4 respectively. 4,4 patients who were followed up for two years were followed up with CIN2-3 GIN1 and 6 cases after conical resection. The cell block P16 staining was greater than + +. Conclusion: the cell block technique is beneficial to the retrospective analysis and tracing observation of the patients. According to the immunohistochemical staining results of P16 in the cervix exfoliated fine cell, it can be compared. Accurate prediction of the outcome of disease is helpful to effective shunt management for patients with grade CIN, so as to reduce the incidence of overtreatment.
【學位授予單位】：山東大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R737.33

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