| Background:Currently, cervical cancer is the third most common malignant tumor in women worldwide, second only to breast cancer and colorectal cancer. It is the fourth leading cause of cancer death among women, with 85% of cases occurring in developing countries. Cervical intraepithelial neoplasia (CIN) is a group of precancerous lesions and is closely related to cervical cancer. Active treatment of CIN to prevent the occurrence of cervical cancer has been widely recognized. Cervical conization is currently the preferred method of treating CIN because of its advantages of simple operation, small intraoperative trauma and exact clinical curative effect. The prognosis of patients after conization is also a problem which is closely followed by both doctors and patients. Although this treatment is thought to be extremely effective, it also bring some side effects,such as hemorrhage, infection, cervical stenosis, cervical incompetence, premature rupture of membranes, low birth weight infants, premature birth and considerable distress. Evidence suggests that 5% and 25% of the cases are left with persistent or recurrent high-grade lesion, and the risk of developing cervical cancer after treatment of CIN is five times higher than that in the general population. Previous studies suggest that the increased risk of cervical cancer may be associated with incomplete follow-up. Therefore, patients with CIN after conization should be closely followed up, but current follow-up protocols are mostly based on the assumption that all women are at equal risk of persistent/recurrent disease and consequent cancerous change.While more intensive screening protoclol can facilitate the early detection of persistent/recurrent disease, it also result in psychological pressure and increase medical resource expenditure. Accordingly, it will be of great clinical significance to choose individual follow-up protocol according to the risk of persistence/recurrence.The aim of this study was to investigate the postoperative risk of persistent/recurrent disease, complications and quality of life of patients with CIN, and evaluate whether any clinical or histopathologic variables were able to identify the subclass of patients with a high risk of persistence/recurrence. It is hoped that this study will provide a theoretical basis for ameliorating the prognosis of patients and improving the postoperative follow-up protocol.Part ?:Study on the persistence/recurrence rate in patients with CIN after conization and related clinical factors.Abstract:Objective:To investigate the persistence/recurrence rate in patients with CIN after cervical conization and related clinical factors. Methods:The data was comprised of 502 patients who underwent a CKC or LEEP procedure because of CIN at the QiLu Hospital of Shan Dong University between July 2005 and December 2012. Files were collected from the medical records and supplemented with telephone surveys, containing information about patient's age, parity, menopausal status, human papillomavirus (HPV) infection, colposcopy adequacy, conization method, cone depth, punch biopsy histological grade, conization histological grade and margin status and so on. Post-conization follow-up was advised after 3,6, and 12 months in the first year, then every 6-12 months afterwards. All women with abnormal cytology or/and consistent hrHPV infection for 1 year underwent a colposcopy-directed biopsy (CDB) or/and an endocervical curettage (ECC) if indicated. Any grade of CIN on the histological diagnosis or malignant transformation was considered as persistent/recurrent disease. Multivariate analysis of factors predicting the persistence/recurrence was achieved using Cox hazard regression.Results: After a median follow-up of 33 months (range,1-94 months) persistent/recurrent lesions were found in 50 patients (9.96%), and 86%(43/50) of persistence/recurrence occurred within 2 years after conization. There were no significant variations in. terms of age, parity, menopausal status, kind of conization, punch biopsy, hr-HPV infection, colposcopy adequacy and cone pathology (P> 0.05). Patients who had persistent/recurrent lesions had a higher rate of cone depth less than 18mm (p=0.049).However, the COX regression analysis showed that It confirmed that the most important independent predictors of CIN persistence/recurrence were positive surgical margin [Hazard ratio (HR) 5.777 (95%CI 2.334-14.301), p<0.001; Wald 14.386] and hrHPV persistence more than 6 months [Hazard ratio (HR) 20.685 (95% CI 7.350-57.657), p<0.001; Wald 33.131].After a Kaplan-Meier curve was plotted, it confirmed that women with positive margins recorded worse outcomes than those margins were negative; and among patients with negative margins, those with hrHPV persistence 6 months after conization recorded worse outcomes than those with negative hrHPV at 6 months follow-up (p<0.001).Conclusions:Predictive factors for persistence/recurrence after conization were positive surgical margins, hrHPV persistence 6 months after conization. Follow-up of such Patients should be strengthened, especially in the 2 years after conization.Part ?:Analysis of histopathological parameters and immunohistochemical predictors associated with persistence/recurrence of CIN after cervical conization.Objective:To estimate the histopathological and immunohistochemical predictors involved in the persistence/recurrence of CIN after cervical conization. Methods:The clinical data of 502 patients in the first part of the study were collected and analyzed retrospectively. A total of 50 patients were found with recurrence/persistence. Patients with persistent/recurrent disease were matched to those without persistence/recurrence using the propensity score matched analysis to balance the baseline of each group. The matched nine variables were age, menopausal status, parity, kind of conization, cone depth, cone pathology, surgical margins, glandular involvement and HPV persistence (?6 months). After matching, a total of 100 H & E stained sections and paraffin-embedded conization specimens were obtained from the Department of Pathology. Initial histopathological diagnosis on the H&E sections was reviewed to investigate the number of quadrants involvement, gowth pattern of CIN, depth of gland involvement (GI), extent of GI and inflammatory reaction in the stroma of CIN. Immunohistochemical staining was performed using the following biomarkers mouse anti-TPX2 (targeting protein for Xenopus kinesin-like protein2), rabbit anti-IMP3 (insulin-like growth factor ? messenger RNA binding protein 3), and mouse anti-PD-L1(programmed cell death-1 ligand-1).Results:Although majority of CIN? lesions involved 3-4 quadrants than CINI-? (P=0.027), no statistically significant associations between more quadrants involvement and persistent/recurrent disease were observed (P=0.398). The depth of GI was less than 3mm in about 86.8%(59/68) CIN?-? lesions. In the CIN?-? lesion, the depth of gland involvement (GI) less than 3mm is about 86.8%, and there was significant difference between the CIN? and CIN? groups (P=0.039). However, no statistical significance was noted between the persistence/recurrence group and no persistence/recurrence group (P=0.58). In the patients suffered from high-grade CIN with GI, isolated crypt involvement was detected in 36.8% cases, and multiple crypt involvement was detected in 63.2% cases.There was significant difference between the CINII and CINIII groups (P= 0.016),but no statistical significance was noted between the persistence/recurrence group and no persistence/recurrence group (P= 0.752).Inflammatory reaction in the stroma of CIN was detected in 37.2% cases, However, there was no significant difference between the CINI and CIN?-? groups(P= 0.473),The difference between the persistence/recurrence group and no persistence/recurrence group was not statistically significant (P= 0.608). The positive rate of IMP3 is 24% in no persistence/recurrence group and 22% in persistence/recurrence group, and no significant differences in IMP3 expression were observed between the groups tested (P= 0.812). The positive rate of TPX2 in persistence/recurrence group and no persistence/recurrence group was 66% and 52% respectively. There was not significant differences among the two groups (P= 0.155). However, the positive rate of TPX2 was significantly higher in pathological grade II and III than those in grade I and negative specimens (P<0.001). PD-L1 positivity was seen in 60% of persistence/recurrence group and 46% of no persistence/recurrence group. No significant differences among the two groups were found (P= 0.161), but the PD-L1 positive expression rates were significantly higher in CIN?-? group than that in CINI/Negative group (P=0.032). The co-expression of TPX2 and PDL1 were significantly higher in persistence/recurrence group (50%) than in no persistence/recurrence group (26%) (P=0.013). Conclusions:The lesions of CIN are relatively superficial. With the increase of lesion grade, the depth and extent of GI and the number of the involved quadrants are also increased, but no evidence is observed between these histopathological parameters and persistent/recurrent disease.Combined expression of TPX2 and PD-L1 may be a predictive factor for persistence/recurrence after conization.Part ?:Analysis of complications and change of quality of life among patients with CIN after conization.Objective:To investigate the complications and change of quality of life among patients with CIN after cervical conization. Methods:The clinical data of 502 patients in the first part of the study were collected and analyzed retrospectively.The incidence of postoperative complications of the patients was explored and the related factors were analyzed. In order to investigate change of quality of life after cervical conization, the data was comprised of 147 patients who underwent a CKC or LEEP procedure because of CIN at the QiLu Hospital of Shan Dong University between December 2012 and August 2013. After giving informed consent, FACT-Cx scale was used to measure the change of each patient's quality of life (QOL) preopratively and sixth months after surgery. Each patient's postoperative recovery was also evaluated,including symptoms of patients after surgery, cervical regeneration and so on. Results:Among the 502 patients,17 (3.4%) patients had postoperative hemorrhage, and 3 (0.59%) cases were diagnosed with cervical stenosis. A total of 71 patients had menstrual changes, accounting for 14.3%.51 patients received a total of 57 times of pregnancy. Of 33 patients who gave birth, the rate of cesarean section was 75.8%.The rate of premature rupture of membrane, preterm birth and neonatal mortality was 9.1%,12.1%, and 2.9%, respectively. The overall QOL of patients after conization was significantly lower than that before operation (P <0.001). Among all the 5 dimensions, there was no statistically significant difference only in emotional dimension (P=0.704).Conclusions:The postoperative complications caused by cervical conization are not uncommon, and cervical conization may have adverse effects on pregnancy outcomes. The QOL of patients within 6 months after conization decreased compared with preoperative values. |
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