Residual Cervical Intraepithelial Neoplasia Research Articles

Machine Learning Prediction of Residual and Recurrent High-Grade CIN Post-LEEP.

This study aims to develop a machine learning (ML) model to predict the risk of residual or recurrent high-grade cervical intraepithelial neoplasia (CIN) after loop electrosurgical excision procedure (LEEP), addressing a critical gap in personalized follow-up care. A retrospective analysis of 532 patients who underwent LEEP for high-grade CIN at Cangzhou Central Hospital (2016-2020) was conducted. In the final analysis, 99 women (18.6%) were found to have residual or recurrent high-grade CIN (CIN2 or worse) within five years of follow-up. Four feature selection methods identified significant predictors of residual or recurrent CIN. Eight ML algorithms were evaluated using performance metrics such as AUROC, accuracy, sensitivity, specificity, PPV, NPV, F1 score, calibration curve, and decision curve analysis. Fivefold cross-validation optimized and validated the model, and SHAP analysis assessed feature importance. The XGBoost algorithm demonstrated the highest predictive performance with the best AUROC. The optimized model included six key predictors: age, ThinPrep cytologic test (TCT) results, HPV classification, CIN severity, glandular involvement, and margin status. SHAP analysis identified CIN severity and margin status as the most influential predictors. An online prediction tool was developed for real-time risk assessment. This ML-based predictive model for post-LEEP high-grade CIN provides a significant advancement in gynecologic oncology, enhancing personalized patient care and facilitating early intervention and informed clinical decision-making.

Clinical Outcomes Associated with Endocervical Glandular Involvement in Patients with Cervical Intraepithelial Neoplasia III.

This study aimed to determine whether endocervical glandular involvement (GI) affects the clinical prognosis of patients with cervical intraepithelial neoplasia (CIN) III who underwent the loop electrosurgical excision procedure (LEEP). This retrospective study included 250 patients who underwent LEEP for the treatment of CIN III between August 2005 and May 2020. The medical records of 234 patients were analyzed; 137 (58.5%) patients were GI negative, and 97 (41.5%) were GI positive. Margin involvement of the LEEP specimen was found in 59 (45.4%) patients in the GI-negative group and 54 (58.7%) patients in the GI-positive group (p = 0.051). The additional surgical procedures (repeat conization or hysterectomy) were significantly more performed in GI-positive patients than in GI-negative patients (40.9% vs. 23.1%, p = 0.004). When comparing the LEEP specimens of GI-1 (GI-positive confirmed via cervical biopsy before conization) and GI-2 (GI-positive confirmed via conization), we found that the mean depth was significantly greater in the GI-1 group (10.9 mm) than in the GI-2 group (7.6 mm) (p = 0.024). Surgical margin involvement was more frequently observed in the GI-2 group than in the GI-1 group (p = 0.030). There was no significant difference in the recurrence rates of CIN between the GI-negative and GI-positive groups (p = 0.641). In conclusion, despite no significant differences in residual disease and CIN recurrence between the GI-negative and GI-positive groups, additional surgical treatments were more frequently performed in GI-positive patients. Repeat surgery based on GI positivity should be carefully considered to avoid overtreatment and surgical complications.

Predictors of high-grade residual disease after repeat conization in patients with positive surgical margins.

No consensus exists on the subsequent management strategy of patients who exhibit positive surgical margin (PSM) after re-excision of high-grade cervical intraepithelial neoplasia (CIN). The aim of the study is to examine the predictors related to the persistence of high-grade CIN lesions after re-excision, where PSM was left behind. The present retrospective study included patients with PSM who underwent repeated conization due to residual high-grade CIN lesions between January 2005 and December 2019. The SPSS software v20.0 was used for data interpretation and statistical analysis. P values less than 0.05 were accepted as statistically significant. Repeat conization was performed in 91 patients, 43 (47.3%) presented with PSM with high-grade CIN, 6 (6.5%) presented with micro-invasive carcinoma, and 42 (46.2%) presented with clear surgical margin or CIN 1 at the surgical margin. At the time of conization, patients who presented with lesions > 5 mm in repeat cone specimens, exhibited a significantly higher rate of residual disease (p < 0.001). Besides, the involvement of the endocervical margin with high-grade CIN was the predictor of residual disease in repeat cone specimens (p = 0.006). In the cone specimen, the presence of lesion size greater than 5 mm and involvement of the endocervical margin were the predictors of high-grade residual disease after re-excision. Whether it is the first or second procedure, great care must be given to excise the lesion entirely at the time of the conization, preferably in one piece.

Long-term outcomes of photodynamic therapy for a positive resection margin after conization for cervical intraepithelial neoplasia grade 3

BackgroundPositive resection margins after conization or loop electrosurgical excision procedure (conization/LEEP) are associated with increased risks of recurrence or residual cervical intraepithelial neoplasia (CIN). Herein, we investigated the long-term outcomes of photodynamic therapy (PDT) for incomplete excision of CIN3. MethodsWe retrospectively reviewed the medical charts of 73 patients treated with PDT between 2000 and 2011. Patients who underwent conization/LEEP before PDT within 6 months were included. The primary outcomes were the complete response (CR) rate after 1 year and human papillomavirus (HPV) eradication rate at 6 months after PDT. ResultsA total of 34 patients with positive resection margins were finally enrolled. The median patient age was 33 years. Carcinoma in situ was diagnosed in 25 patients and CIN3 in 7 patients. The CR rate was 97.1% after 1 year. Except for one case of a persistent disease, there was no recurrence or newly developed disease during the median follow-up of 84 months (range, 12–224 months). The HPV eradication rate of PDT following conization/LEEP after 6 months was 96.9% (31/32). Photosensitivity was identified in five patients and cervical stenosis in one patient. ConclusionsIn conclusion, PDT could be an effective therapeutic option for patients with a positive resection margin after conization/LEEP for CIN3. It could reduce the residual or recurrence rate of CIN lesions with tolerable adverse events.

Treatment of Residual or Recurrent CIN with Topical Imiquimod: a Retrospective Study

Abstract Objective In this retrospective case study, we determine the results, side effects and long-term outcome features of treatment with imiquimod 5% in women with recurrent or residual cervical intraepithelial neoplasia (rrCIN). Methods The study was set in three outpatient clinics of hospitals in the Netherlands. Women diagnosed with rrCIN and treated with imiquimod 5% intravaginally between 2010 and up to and including 2017 were included. Data were extracted from medical records. The main outcome measures were complete regression or partial regression of SIL (squamous intraepithelial lesions) (cytology) or CIN (histology), side effects and long-term outcome in terms of the need for further excisional treatment during the follow-up period. Outcomes were assessed using descriptive statistics. Results The 18 studied women tolerated imiquimod well: all completed the treatment, with a temporary stop or dose reduction in two. The treatment was successful in 11 women overall (61%) of whom 8 women (80%) with high grade CIN (grades II-III). Of these 11 women, 4 women developed a recurrence of which 3 women were treated successfully with imiquimod or a LLETZ procedure. One woman died in the follow up without treatment of the CIN lesion. Of the remaining seven women with unsuccessful treatment, four patients underwent additional therapy. Two women underwent a hysterectomy, one woman underwent multiple procedures and the last woman underwent laser therapy and imiquimod, but died in the follow up. Of the remaining three out of those 7 women with unsuccessful treatment, two women refused further therapy and one woman required no further therapy since she cleared HPV and showed no dysplasia in the follow-up period. Conclusions In studied population, imiquimod treatment was well tolerated and associated with resolution or regression of SIL/CIN in 61% of women. We have started a randomized controlled trial to compare the efficacy of imiquimod with that of LLETZ in recurrent or residual CIN.

TOPical Imiquimod treatment of residual or recurrent cervical intraepithelial neoplasia (TOPIC-2 trial): a study protocol for a randomized controlled trial

BackgroundCervical dysplasia (cervical intraepithelial neoplasia (CIN)) is caused by Human Papillomavirus (HPV) and is most common in women of reproductive age. Current treatment of moderate to severe CIN is surgical. This procedure has potential complications, such as haemorrhage, infection and preterm birth in subsequent pregnancies. Moreover, 15% of women treated for high grade CIN develop residual/recurrent CIN or cervical cancer after surgical excision. Finally, 75–100% of patients with a residual and recurrent CIN 2–3 lesion are still HPV positive. They could possibly benefit from an alternative medical treatment, which aims to eliminate HPV.The primary study objective is to evaluate the effectivity of imiquimod 5% cream compared to treatment with Large Loop Excision of the Transformation Zone (LLETZ) for recurrent/residual CIN.Methods/designThis study is a multicentre, non-inferiority randomized single blinded study. The study population consists of female patients with histological proven residual/recurrent CIN after previous surgical treatment. Four hundred thirty-three patients will be included in the Netherlands. The first 35 patients will be included in a pilot study to prove non-futility.Included patients will be randomized to receive either 5% imiquimod cream or LLETZ treatment. Imiquimod will be inserted three times a week intravaginally for a period of 16 weeks using a vaginal applicator. Ten weeks after the end of imiquimod treatment a biopsy will be taken for treatment response. In case of progressive or stable disease a LLETZ will be performed. At 12 and 24 months after the start of treatment cytology will be taken for follow up. The LLETZ group will be treated according to the current guidelines. Throughout the study, HPV typing and quality of life will be tested.DiscussionRepeated LLETZ in women with residual/recurrent CIN lesions has complications. We would like to possibly offer alternative treatment in a selected group to avoid these risks. Moreover, we monitor treatment efficacy, side effects and long-term recurrence rates.Trial registrationMedical Ethical Committee approval number: NL 53792.078.15. Affiliation: Erasmus Medical Center.Registration number ClinicalTrials.gov: NCT02669459, date of registration: 27th January 2016.

Effect of High-Risk Human Papillomavirus but Normal Cytology at Test of Cure on Achieving Colposcopy Standards.

In United Kingdom., test of cure after treatment of any grade of cervical intraepithelial neoplasia (CIN) incorporates high-risk human papillomavirus (Hr-HPV) test and cytology at 6-month follow-up. The aims of the study were to determine the rate of recurrent CIN in women who are Hr-HPV positive and cytology negative and to explore possible associated risk factors. A retrospective observational cohort study was performed in women treated for any grade CIN between 2010 and 2015 from a regional population, who were Hr-HPV positive and cytology negative at first follow-up. A total of 2729 women were identified as treated for any grade CIN, and 213 (7.8%) were re-referred to colposcopy having Hr-HPV-positive test and negative cytology at test of cure. Their mean age was 31.56 years (range = 19-62 years). The mean time of follow-up per woman was 30.50 months (range = 2-63 months). At colposcopy, 171 (80.3%) had colposcopy examination only and 42 women (19.7%) had a biopsy. Twenty-four cases (11.3%) of CIN were identified of which 4 (1.9%) were CIN 2/3. Eleven women (5.2%) in total had a repeat treatment. Five women (2.3%) had biopsy-proven CIN 2/3 within 12-months after treatment. No cases of CIN 3+ after negative colposcopy were identified during the follow-up period. The incorporation of Hr-HPV testing yielded a very small number of women with residual CIN within 12 months of treatment. Our results suggest that women who are Hr-HPV positive and cytology negative after treatment of CIN with normal and adequate colposcopy could be discharged to routine recall if confirmed by larger national data.

Does LLETZ excision margin status predict residual disease in women who have undergone post-treatment cervical cytology and high-risk human papillomavirus testing?

This study looks at the importance of large loop excision of the transformation zone (LLETZ) excision margins and residual cervical intraepithelial neoplasia (CIN) in women undertaking high-risk human papillomavirus (hrHPV) test of cure (TOC). A retrospective cohort study with interval analysis performed June 2007 and June 2012 on all women undertaking treatment for CIN and subsequent hrHPV TOC 6 months post LLETZ. Final analysis group comprised 2093 women treated by LLETZ (1396 completely excised; 697 incompletely excised). 298 out of 1794 women (13%) were hrHPV positive at TOC. Thirty-six women who failed TOC and attended colposcopy had residual CIN. No statistically significant difference existed between the completely and incompletely excised groups with regards to the detection of residual CIN at 6 months post-treatment. There was no correlation of margins of excision with hrHPV status at TOC. The overall cure rate at TOC was 98%. TOC pathways recommend subsequent follow-up in primary care. This study identified no safety issues with TOC pathways. We can no longer assess histological failure rates at 12 months; we, therefore, recommend that this measure of treatment failure be redefined for post TOC women. It seems time to question the benefits of routine excision margins reporting, in the absence of invasion, for treated CIN. Future reporting needs to be reconsidered by the Royal College of Pathologists.

Clinical effectiveness of VIA and colposcopy based management of cervical intraepithelial neoplasia

Cervical cancer develops from early precancerous lesion known as cervical intraepithelial neoplasia (CIN). Khulna Medical college Hospital provides primary screening for preventing cervical cancer and a secondary referral centre for management of CIN by colposcopy. Primary objective of this study was to do an audit between January 2012 to February 2014 to update clinical efficacy of colposcopy based diagnosis, treatment and follow up of 510 CIN cases and also to document any shortcomings in existing services and suggestion for early rectification. Colposcopic findings in our study group were: 309(60.6%) cases were CIN-1, 124 (24.3%) cases was CIN II, and 49 (9.6%) cases were CIN III. Suspicious of invasive lesion was in 7 (1.4%) abnormal looking cervix and biopsy was done in 21(4.1%). Treatment procedure was done with individualization of cases and options were cold coagulation, Loop electrosurgical excision procedure (LEEP), hysterectomy, biopsy and post treatment follow up. Histopathological diagnosis was documented in 387 cases, where CINI was found in 161 (31.6%), CIN II in 92 (18%), CIN III in 26 (5.1%), non specific Inflammatory cervicitis in 87(17.1%), Squamous cell carcinoma in 15(2.9%), abnormalities consistent with koilocytic atypia in 6 (12%) and reports missed in 123 (24.1%). Cases results showed Positive predictive value (PPV) of 53% and 68% respectively for low grade (CIN I) and high grade lesion (CIN II, III). 481 patient were eligible for post treatment follow up but only 99 (20.5%) patient came and among them 74 (74.7%) were colposcopically negative, 25 (25.2%) had residual CIN and Risk Ratio (RR) was 0.25. Colposcopy is gold standard for diagnosis of CIN but our screening program is opportunistic and far way from population based. Histopathological correlation were often inaccurate with colposcopic diagnosis in practice and about one third case reports were missed. Majority of women did not complete follow up protocol. Residual or recurrent CIN lesion in dropped out cases would be a concern in near future. DOI: http://dx.doi.org/10.3329/bmjk.v47i1-2.22557 Bang Med J (Khulna) 2014; 47 : 16-20

Follow-up strategies after treatment (large loop excision of the transformation zone (LLETZ)) for cervical intraepithelial neoplasia (CIN): Impact of human papillomavirus (HPV) test

Development of cancer of the cervix is a multi-step process as before cervical cancer develops, cervical cells undergo changes and become abnormal. These abnormalities are called cervical intraepithelial neoplasia (CIN) and are associated with increased risk of subsequent invasive cancer of the cervix. Oncogenic high-risk human papillomavirus (hrHPV), the causative agent of cervical cancer and its precursor lesions, is present in up to one-third of women following large loop excision of the transformation zone (LLETZ) treatment and is associated with increased risk of residual disease and disease recurrence.HPV testing may serve as a surveillance tool for identifying women at higher risk of recurrence. High-risk human papillomavirus testing will enable us to identify women at increased risk of residual or recurrent CIN and therefore will allow us to offer closer surveillance and early treatment, when indicated. • To evaluate the effectiveness and safety of hrHPV testing after large loop excision of the transformation zone (LLETZ) treatment• To determine optimal follow-up management strategies following LLETZ treatment according to hrHPV status We searched the Cochrane Gynacological Cancer Review Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed and PsycINFO up to August 2013. We searched registers of clinical trials, abstracts of scientific meetings and reference lists of included studies, and we contacted experts in the field. We searched for randomised control trials (RCTs) that compared follow-up management strategies following LLETZ treatment for CIN. Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. No trials were found; therefore no data were analysed. The search identified 813 references on MEDLINE, 418 on EMBASE, 22 on CINAHL, 666 on PubMed, 291 on PsycINFO and 145 on CENTRAL. When all references were imported into EndNote and duplications were removed, 1348 references remained. Initial screening of titles and abstracts of these references revealed that 42 references were potentially eligible for this review. After reading the full-text versions, we identified no relevant trials comparing hrHPV and cytology testing versus cytology testing alone for detecting residual or recurrent disease during follow-up to LLETZ treatment of adult women with CIN.We found no evidence on the effects of hrHPV and cytology testing on residual or recurrent CIN2 or higher lesions, anxiety and psychosexual morbidity outcomes in women undergoing colposcopy and treatment for CIN. We found no evidence from RCTs to inform decisions about the best surveillance strategy for women following treatment for CIN. A prognostic systematic review is needed to investigate the risk of developing recurrent cervical intraepithelial neoplasia 2+ (CIN2+) in women with a positive hrHPV test after large loop excision of the transformation zone (LLETZ) treatment.

Residual disease and HPV persistence after cryotherapy for cervical intraepithelial neoplasia grade 2/3 in HIV-positive women in Kenya.

ObjectiveTo assess residual cervical intraepithelial neoplasia (CIN) 2/3 disease and clearance of high-risk (hr) human papillomavirus (HPV) infections at 6 months after cryotherapy among HIV-positive women.DesignFollow-up study.Methods79 HIV-positive women received cryotherapy for CIN2/3 in Nairobi, Kenya, and underwent conventional cytology 6 months later. Biopsies were performed on high grade cytological lesions and hrHPV was assessed before (cervical cells and biopsy) and after cryotherapy (cells).ResultsAt 6 months after cryotherapy CIN2/3 had been eliminated in 61 women (77.2%; 95% Confidence Interval, (CI): 66.4–85.9). 18 women (22.8%) had residual CIN2/3, and all these women had hrHPV at baseline. CD4 count and duration of combination antiretroviral therapy (cART) were not associated with residual CIN2/3. CIN3 instead of CIN2 was the only significant risk factor for residual disease (odds ratio, OR vs CIN2 = 4.3; 95% CI: 1.2–15.0) among hrHPV-positive women after adjustment for age and HPV16 infection. Persistence of hrHPV types previously detected in biopsies was found in 77.5% of women and was associated with residual CIN2/3 (OR = 8.1, 95% CI: 0.9–70). The sensitivity, specificity, and negative predictive value of hrHPV test in detecting residual CIN2/3 were 0.94, 0.36, and 0.96 respectively.ConclusionsNearly one quarter of HIV-positive women had residual CIN2/3 disease at 6 months after cryotherapy, and the majority had persistent hrHPV. CD4 count and cART use were not associated with residual disease or hrHPV persistence. The value of hrHPV testing in the detection of residual CIN2/3 was hampered by a low specificity.

Human papillomavirus type‐specific persistence and recurrence after treatment for cervical dysplasia

Human papillomavirus (HPV) infection is a necessary factor in the cervical cancer development. Also after treatment for cervical dysplasia, HPV can be present and promote the recurrence of cervical disease. In the present study, the aim was to perform a long-term follow-up on the ability of HPV testing with genotyping, as compared with cytology, to predict recurrence of high-grade cervical intraepithelial neoplasia and to evaluate the effectiveness of treatment with loop electrosurgical excision procedure (LEEP) conization. Cervical samples for HPV DNA testing and cytological analysis were obtained from 178 women with abnormal smears referred for treatment with LEEP conization. These women were scheduled for HPV DNA testing and Pap smears before and 3, 6, 12, 24, and 36 months after treatment. Three years after treatment 3.1% (N = 4) of women were still persistently HPV-positive with the same type as had been detected at treatment. Recurrent or residual cervical intraepithelial neoplasia II+ in histopathology was found among 9 (5.1%) women during follow-up. All of these women had type-specific HPV-persistence (sensitivity 100% [95% CI 63-100%] and specificity 94.7% [89.8-97.4%]), but only 7/9 had abnormal cytology (sensitivity 77.8% [40.2-96.1%] and specificity 94.7% [89.8-97.4%]). No recurrent or residual disease was found among women with any other patterns of HPV positivity (e.g., type change or fluctuating positivity) (sensitivity 0% [95% CI 0-37.1%] and specificity 80.5% [73.5-86.0%]). In conclusion, only type-specific HPV persistence predicted recurrent or residual disease, and HPV genotyping appears useful to improve the specificity when using HPV testing in post-treatment follow-up.

The role of human papillomavirus (HPV) testing in the follow-up of patients after treatment for cervical intraepithelial neoplasia (CIN)

Introduction: The aim of this study was to examine the role of human papillomavirus testing in the follow-up after treatment for CIN, as a prognostic sign for residual/recurrent cervical precancerous lesions.Methods: A hospital-based analysis was performed on 460 patients previously treated for CIN with cold knife conization, at the University Clinic for Gynecology and Obstetrics and General Hospital Remedika, in Skopje, Republic of Macedonia, in a period of 3 years. The patients were followed-up with HPV testing in addition to cytology, colposcopy and/or biopsy. The first after treatment HPV testing was performed8 months after cold knife conization, proceeded by follow-up within 24 months after treatment, at 4 months intervals.Results: Among 460 treated patients, at the fi rst HPV and cytologic testing, 8 months after treat-ment, 69 (15%) were HPV+, and 391 (85%) HPV negative. From the 69 HPV+ patients, 41 (59.4%) were withcytologic abnormalities and 28 (40.6%) without abnormalities. 12 months after treatment, the number of HPV+ patients developing cytologic abnormalities raised to 45/70 (64.29%). Within the 24 months aftertreatment, the number of patients who had recurrent/ residual CIN from the HPV+ patients reached 50/71 (70.42%); which was 10.87% from all 460 treated patients.Conclusion: Persistence or clearance of HPV especially 8 months after treatment even in patients with normal cytology, is an early valid prognostic marker of treatment failure, and is more accurate than cytologyat the same follow-up intervals.

Predictors and clinical significance of the positive cone margin in cervical intraepithelial neoplasia III patients

Background Conization is being widely accepted for diagnosis and treatment of cervical intraepithelial neoplasia (CIN). There is controversy as to which factors are most predictive of a positive cone margin and the clinical significance of it. We conducted this study to identify the predictive factors and to evaluate the clinical significance of a positive cone margin in CIN III patients. Methods A retrospective review was conducted of 207 patients who had undergone conization due to CIN III from January 2003 to December 2005 at Peking Union Medical College Hospital. Of these, 67 had a subsequent hysterectomy. Univariate and multivariate analysis were utilized to define the predictive factors for a positive cone margin, and to compare the pathologic results of conization with subsequent hysterectomy. Results One hundred and fifty-one (72.9%) were margin free of CIN I or worse, 37 (17.9%) had CIN lesions close to the margin and 19 (9.2%) had margin involvement. Atotal of 56 cases (27.1%) had positive cone margins (defined as the presence of CIN at or close to the edge of a cone specimen). Univariate analysis showed that the parity, cytological grade, multi-quadrants of CIN III by punch biopsy, gland involvement, as well as the depth of conization were significant factors correlated with a positive cone margin (P &lt;0.05). However the age, gravidity, grade of dysplasia in punch biopsy, as well as the cone methods were not significantly correlated (P &gt;0.05). Multivariate analysis revealed that the cytological grade (OR=1.92), depth of conization (OR=2.03), parity (OR=3.02) and multi-quadrants of CIN III (OR=4.60) were significant predictors with increased risk for positive margin. The frequency of residual CIN I or worse in hysterectomy specimens was found to be 55.6% (20/36) in patients who were margin free, 71.4% (15/21) in patients with CIN occurring close to margin, and 80.0% (8/10) in patients with margin involvement. The frequency of residual CIN III or worse was found to be 13.9% (5/36), 23.8% (5/21) and 50.0% (5/10) respectively in different groups. Conclusions Cytological grade, depth of conization, parity and multi-quadrants of CIN III in punch biopsy were significant factors with increased risk in predicting a positive cone margin. Margin status of conization did not mean the presence or absence of CIN, but rather the varied frequency of residual CIN in specimens of subsequent hysterectomy. In view of this fact, it is suggested that the margin status of conization be a valuable surrogate marker for clinical management of CIN III.

Factors influencing the choice between cold knife conization and loop electrosurgical excisional procedure for the treatment of cervical intraepithelial neoplasia

To determine whether cold knife conization (CKC) or loop electrosurgical excisional procedure (LEEP) is the better option for the treatment of cervical intraepithelial neoplasia (CIN) under specific circumstances. We retrospectively reviewed the medical records of patients who underwent CKC or LEEP for the treatment of CIN. The proportion of non-negative surgical margins between the two treatment groups was calculated based on their age, parity, previous mode of delivery, and grade of CIN. The Student's t-test and multivariate logistic regression analysis were used to find the better option for the treatment of CIN under the specific circumstances. A total of 118 patients were enrolled in the study. Between the two treatment groups, there was no significant difference in the overall proportion of non-negative surgical margins (P > 0.05). The grade of CIN, the previous mode of delivery, and parity did not affect the surgical margin status. The CKC treatment group had a significantly lower incidence of non-negative surgical margins than the LEEP treatment group (14.3% vs. 52.6%, respectively; P < 0.05) in the patients >45 years of age. Based on multivariate analyses, LEEP was identified as a significant risk factor for non-negative surgical margins in the patients >45 years of age. Of the 11 patients with non-negative surgical margins who underwent a secondary procedure within 6 months of the initial CKC or LEEP, five patients (45.5%) had residual CIN II and III. In patients >45 years of age, CKC is the preferred treatment for CIN.

Incomplete excision of cervical intraepithelial neoplasia and risk of treatment failure: a meta-analysis

Over 60,000 women are treated for cervical intraepithelial neoplasia (CIN) each year in England, most by excision. Management of women who have incomplete excision is controversial and the subject of much debate. Consequently, the completeness of excision is often ignored in the planning of subsequent treatment. We aimed to assess the effect of completeness of excision on the risk of post-treatment disease. We undertook a meta-analysis of studies published between Jan 1, 1960, and Jan 31, 2007, that studied the risk of post-treatment disease (ie, CIN of any grade or invasive cancer) in relation to completeness of excision. Studies were included if they described treatment of CIN by excision; numbers of women with involved margins; prevalence of and numbers of women with post-treatment disease in relation to margin status. Criteria for post-treatment disease had to be stated as a defined abnormal cytology or histology. Studies were excluded if they described treatment of cervical glandular intraepithelial disease (CGIN); if all or nearly all women had reflex hysterectomy done soon after initial treatment; if women were immunosuppressed (eg, if they were HIV-positive); or if no control group with disease-free margins was used. The endpoint of our analysis was the relative risk (RR) of post-treatment disease in those whose treatment histology suggested that excision was complete compared with those in whom excision was incomplete or uncertain. RR meta-analysis was done by use of a random effects model. The initial Medline search identified 1756 publications, from which 125 publications were short-listed. Of these, 65 and one unpublished study met our inclusion criteria; therefore, 66 studies were included in this meta-analysis. These studies described findings in 35,109 women of whom 8091 (23%) had at least one margin of the excision biopsy involved with disease. After incomplete excision, RR of post-treatment disease of any grade was 5.47 (95% CI 4.37-6.83) and RR of high-grade disease (ie, CIN 2 or 3, or high-grade squamous intraepithelial lesion) was 6.09 (3.87-9.60) compared with the reference group who had complete excision. High-grade post-treatment disease occurred in 597 of 3335 (18%) women who had incomplete excision versus 318 of 12 493 (3%) women who had complete excision. Incomplete excision of CIN exposes women to a substantial risk of high-grade post-treatment disease. Some of these women would be safer with a second treatment, especially if deep margins are involved, but most will need close follow-up for at least 10 years. Every effort should be made to avoid incomplete excision. Adding extensive ablation in the treatment crater to compensate for inadequate excision should be avoided because this might delay detection of inadequately treated invasive disease and because the effectiveness of additional ablation to destroy any residual CIN cannot be assessed. Furthermore, extensive ablation does not decrease any risk of preterm delivery in subsequent pregnancies.

Persistence of human papillomavirus as a predictor for treatment failure after loop electrosurgical excision procedure

We aimed to investigate whether postconization human papillomavirus (HPV) DNA testing can predict treatment failure and improve the accuracy of conventional follow-up in women with high-grade cervical intraepithelial neoplasia (CIN). Between March 2001 and October 2005, 120 patients with confirmed CIN 2 or 3 were treated with loop electrosurgical excision procedure (LEEP) and were enrolled. Six patients were lost to the follow-up. Postconization follow-up was performed at every 3-6 months during the first year and then annually. Specimens were tested for the presence of HPV, using the Hybrid Capture 2 (Digene Co, Gaithersburg, MD) and HPV DNA chip (Mygene Co, Seoul, Korea) test. Persistent HPV infection was defined as persistently (two times or more) positive HPV tests with the same HPV subtype(s) at initial diagnosis. Twenty-two (19.3%) patients showed treatment failure after conization. The only significant risk factor for redevelopment of CIN after conization was persistence of the same HPV subtype (P < 0.0001). And women with recurrent or residual CIN had higher HPV load during the 6-month follow-up postconization. In conclusion, the persistence of the same HPV subtype after LEEP conization was an important predictor of treatment failure. The follow-up protocol after conization of CIN should include both cervical cytology and HPV test, and HPV DNA chip test is needed to detect a persistent HPV infection.

Prediction of recurrence after treatment for high‐grade cervical intraepithelial neoplasia: the role of human papillomavirus testing and age at conisation

The aim of this study was to examine the accuracy of the presence of high-risk human papillomavirus (HR-HPV) DNA (HR-HPV DNA test) postconisation as prediction of recurrent or residual cervical intraepithelial neoplasia (CIN) after treatment of high-grade cervical intraepithelial lesions (CIN2+) in a prospective study and to compare this with follow-up cytology and the marginal status of the excised tissue. Prospective follow-up study. Unselected women presenting at colposcopy clinic of University Hospital Gasthuisberg, Leuven. Seventy-two women treated with conisation for CIN2 or CIN3. Women were followed by HR-HPV DNA test (Hybrid Capture II test of Digene) every 3 to 6 months. The same vial was used for cytology and the HR-HPV DNA test (SurePath). All women were further followed by colposcopy and cytology for 24 months at 6-month intervals. The outcome of the study was presence of >CIN2, proven with colposcopy-directed biopsy occurring within 24 months after treatment. HR-HPV status was correlated with recurrent or residual CIN2+. Sensitivity, specificity, predictive values and diagnostic odds ratios to predict treatment failure or cure were computed for HR-HPV testing, marginal status and follow-up cytology. HR-HPV status was also correlated with section margins postconisation and with the first cervical smear. In 6 of the 72 treated women (8%), residual or recurrent CIN occurred. Women with recurrence were significantly older than women without a recurrence (51.5 +/- 9.6 versus 39.8 +/- 12.2 years, P= 0.007). All six women with recurrence were HR-HPV positive, four had a positive follow-up smear (>or=atypical squamous cells of uncertain significance = ASCUS+) and only two had involved section margins. Among the 66 cured women, 15 were HR-HPV positive, 6 had an abnormal smear and 12 had positive section margins. Sensitivity of cytology, positive section margins and HR-HPV DNA positivity was 66.7, 33.3 and 100% to predict treatment failure. Specificity of the three tests was, respectively, 90.9, 81.8 and 77.3%. Women with HR-HPV DNA at 3 to 6 months showed recurrent or residual CIN in 15% (2/13) if they had normal follow-up Pap smears and in 50% (4/8) if they had abnormal Pap smears. Margin status was not statistically significantly associated with human papillomavirus status. Persistence or clearance of HR-HPV DNA is an early valid prognostic marker of failure or cure after treatment for CIN2+ and is more accurate than cytology or section margin status at the time of conisation. The absence of HR-HPV DNA has a 100% negative predictive value. Higher age at conisation may be a previously unrecognised risk factor for recurrence.

Chapter 9: Clinical applications of HPV testing: A summary of meta-analyses

Background More than ever, clinicians need regularly updated reviews given the continuously increasing amount of new information regarding innovative cervical cancer prevention methods. Material and methods A summary is given from recently published meta-analyses on three possible clinical applications of human papillomavirus (HPV)-DNA testing: triage of women with equivocal or low-grade cytological abnormalities; prediction of the therapeutic outcome after treatment of cervical intraepithelial neoplasia (CIN) lesions, and last not but not least, primary screening for cervical cancer and pre-cancer. Results Consistent evidence is available indicating that HPV-triage with the Hybrid Capture-2 assay (HC2) is more accurate (significantly higher sensitivity, similar specificity) than repeat cytology to triage women with equivocal Pap smear results. When triaging women with low-grade squamous intraepithelial lesions (LSIL), a reflex HC2 test does not show a significantly higher sensitivity, but a significantly lower specificity compared to a repeat Pap smear. After treatment of cervical lesions, HPV testing easily detects (with higher sensitivity and not lower specificity) residual or recurrent CIN than follow-up cytology. Primary screening with HC2 generally detects 23% (95% confidence interval, CI: 13–23%) more CIN-2, CIN-3, or cancer compared to cytology at cut-off atypical squamous cells of undetermined significance (ASCUS) or LSIL, but is 6% (95% CI: 4–8%) less specific. By combined HPV and cytology screening, a further 4% (95% CI: 3–5%) more CIN-3 lesions can be identified but at the expense of a 7% (95% CI: 5–9%) loss in specificity, in comparison with isolated HC2 screening. Conclusions Sufficient evidence exists to recommend HPV testing in triage of women with atypical cytology and in surveillance after treatment of CIN lesions. In the United States, recently reviewed knowledge has resulted in the approval of combined cytology and HC2 primary screening in women older than 30 years. However, in Europe, cytology-based screening still remains the standard screening method. The European screening policy will be reviewed based on the longitudinal results of randomised population trials which are currently underway.

Long-term follow-up after large-loop excision of the transformation zone: evaluation of 22 years treatment of high-grade cervical intraepithelial neoplasia

Early treatment of cervical intraepithelial neoplasia (CIN) significantly reduces the risk of invasive cancerous progression. Residual and recurrent high-grade CIN should be detected and retreated in an early phase. Therefore, a postsurgery cytologic follow-up protocol was introduced at 3, 6, 9, and 12 months and yearly thereafter for 5 years. The aim of this study is to evaluate the long-term experience in treating high-grade CIN using large-loop excision of the transformation zone (LLETZ). Additionally, the long-term follow-up in this study gains the opportunity to document the pattern of disease recurrence beyond 5 years. The average follow-up of the 1696 women included in this study was 6.5 years. Overall, 8.5% of the patients who underwent LLETZ showed a high-grade repetitive CIN and three patients had invasive carcinoma. Eighty percent of those lesions were probably residual, whereas 20% of all high-grade repetitive lesions appeared more than 2 years after initial surgery and were considered recurrent lesions. Half of the recurrent lesions occurred more than 5 years after LLETZ.