Should attention be paid to the cone depth in the fully visible transformation zone? Retrospective analysis of 517 patients with cervical intraepithelial neoplasia grade 3.

OBJECTIVE: The predictors of positive endocervical margin (EM) and a cone-depth cutoff value are not established in the fully visible transformation zone (TZ). The present study aimed to assess the independent variables associated with positive EM in women with high-grade cervical intraepithelial neoplasia (CIN) and fully visible TZ. METHODS: The current investigation was a retrospective study including women with fully visible TZ and CIN 3 cone histology between 2014 and 2019. The sample was divided into women with positive versus those with negative EM. Univariate and multivariate analyses were performed. Finally, receiver operating characteristic curve analysis was also used. RESULTS: A total of 123 of 517 women (23.8%) showed positive EM at conization. Multivariate analysis found a positive association with type 2 TZ (odds ratio [OR], 2.17 [95% confidence interval (CI), 1.19-3.94]) and lesion extension ≥2 cervical quadrants (OR, 35.57 [95% CI, 17.96-70.45]). Cone depth was inversely related to positive EM (OR, 0.71 [95% CI, 0.63-0.80]). In women with type 2 TZ and lesion extension ≥2 cervical quadrants, the cutoff value was achieved at 8-mm cone depth (area under the curve, 0.79 [95% CI, 0.67-0.90]). CONCLUSION: In women with high-grade CIN and fully visible TZ undergoing conization, the lesion extension and the TZ subtype (1 or 2) should be considered. A no less than 9-mm cone depth provided a fair predictive value in achieving free EM.

Monitoring the activities of Italian colposcopy clinics before and during the COVID-19 pandemic.

OBJECTIVE: To evaluate the impact of healthcare reorganization during the severe acute respiratory syndrome coronavirus 2 pandemic on Italian colposcopy clinic activities, focusing on cervical excision procedures, follow-ups for conservative management of low-grade lesions, and follow-ups post cervical excision. METHODS: Retrospective study conducted in 14 Italian colposcopy clinics. The number and clinical characteristics of cervical excisions, follow-ups for conservative management of low-grade lesions, and follow-ups after cervical excision were compared between the period March 1, 2019 to February 29, 2020 (pre-pandemic) and March 1, 2020 to February 28, 2021 (pandemic) with a Poisson regression analysis. RESULTS: In the pandemic period, the number of cervical excisions was reduced by 8.8% (95% confidence interval [CI]=-15.6% to -2%; p=0.011). Excisions were less frequently performed in the operating room (-35.1%; 95% CI=-47.6% to -22.6%; p<0.001), the number of patients from spontaneous screening was reduced by -14.0% (95% CI=-23.4% to -4.6%; p=0.003), and the CO2-laser technique was used less frequently (-30%; 95% CI=-45.1% to -15.0%; p<0.001). As compared to the pre-pandemic period, the number of follow-ups for conservative management of low-grade lesions was reduced by -26.7% (95% CI=-39.0% to -14.4%; p<0.001), and the follow-up appointments after cervical excision were reduced by -51.0% (95% CI=-58.1% to -43.9%; p<0.001). CONCLUSION: The most significant impact of the healthcare reorganization during the coronavirus disease 2019 pandemic was on follow-ups after cervical excision. The resumption of disrupted activities should follow a risk-based prioritization, starting from women in follow-up after cervical excision. It is advisable that the trend of performing cervical excision as an outpatient procedure is maintained in the post-pandemic period.

Conservative Treatment for Cervical Adenocarcinoma In Situ: Long-Term Results.

OBJECTIVE: This study aimed to evaluate the effectiveness of conservative treatment for cervical adenocarcinoma in situ (AIS). MATERIALS AND METHODS: This is a retrospective study on women with histologically confirmed AIS on cervical loop electrosurgical excision procedure specimen, treated conservatively between 2008 and 2020 in our center, Ospedale Maggiore Policlinico, Milan. The main outcome investigated was the risk of recurrence defined as a subsequent finding of recurrent AIS or invasive adenocarcinoma in a long-term follow-up. The disease-free survival curve was computed using the Kaplan-Meyer method. All patients underwent colposcopy with endocervical curettage and cytology every 6 months for the first 2 years after initial surgery and then annual cytology. RESULTS: Thirty women, aged 26 to 51 years, with histologically proven AIS on excisional specimen with negative margins, negative apex, and negative endocervical curettage were included. The median follow-up was 5.4 years. One woman had a recurrence of AIS after 8 years of follow-up and underwent total hysterectomy. No invasive cervical disease was detected during surveillance. CONCLUSIONS: Women with cervical AIS can be managed conservatively by an excisional procedure, provided that the margins are free and a close and long-term follow-up is guaranteed.

Hysterectomy for cervical intraepithelial neoplasia: A retrospective observational multi-institutional study.

OBJECTIVE: To analyze the clinical management, the outcomes, and the trend in hysterectomy rates (HR) in patients who underwent this procedure for cervical intraepithelial neoplasia (CIN). METHODS: Multicentric retrospective observational study conducted on 242 patients who underwent hysterectomy for CIN between 2010 and 2020 in nine Italian institutions. Hysterectomy for invasive or micro-invasive neoplasia, sub-total hysterectomy, or trachelectomy were excluded. RESULTS: A significant increase in the trend of HR for CIN was recorded (P = 0.002, r = 0.81; C.I. 95%: 0.415-0.949); HR increased from 0.46% in the year 2010 to 3.32% in 2020. The mortality rate was 0.4%, and 5% had operative complications. On definitive histopathology examination, a CIN of any grade was recorded in 71.5% of cases, and an occult invasive cancer in 1.24%. No pathology or CIN1 was found in 26.8% of cases, suggesting over treatment. During follow-up, a vaginal lesion was recorded in 5% of cases. CONCLUSION: A significant increase in the number of hysterectomies performed for CIN in the last 10 years was recorded. Hysterectomy for CIN can lead to complications, risk of the onset of vaginal lesions, and risk of overtreatment, and remains, in the first instance, an unacceptable treatment, to be proposed only after adequate counseling.

Trend of HPV 16/18 Genotypes in Cervical Intraepithelial Neoplasia Grade 3: Data for 2007-2018.

AIM: In the post-vaccination era, the starting age and time intervals of cervical screening could change (older age and longer screening intervals). This scenario may be achieved by significantly reducing human papillomavirus (HPV) 16/18 prevalence (genotypes included in the current vaccines). In this regard, assessing the trend over time of these HPV infections in high-grade cervical lesions can provide information on the objective. The present study aimed to evaluate the trend of HPV 16/18 over the years 2007-2018 in women with cervical intraepithelial neoplasia (CIN) grade 3. METHODS: This is a retrospective multi-institutional study including HPV genotyped and unvaccinated women under 30 with CIN3. The sample was divided into the following periods: 2007-2010, 2011-2014, 2015-2018. HPV genotypes were grouped in genotypes 16/18, genotypes 31/33/35/52/58/67 (genetically related to HPV16), genotypes 39/45/59/68/70 (genetically related to HPV18), genotypes 31/33/45/52/58 (high-risk types included in the nonavalent vaccine), possibly carcinogenic HPV (genotypes 26/30/53/67/70/73/82/85), low-risk HPV (genotypes 6/11/40/42/43/44/54/55/61). The trend between periods and HPV genotypes was measured using the Cochran-Armitage test for trend. RESULTS: The final analysis included 474 participants. HPV 16/18 prevalence decreased significantly over the years (77.8% vs 68.9% vs 66.0%, respectively, Ptrend=0.027). Possibly carcinogenic HPV (genotypes 26/30/53/67/70/73/82/85) showed a significant negative prevalence trend over time (4.9% vs 1.1% vs 1.3%, respectively, Ptrend=0.046). Finally, there was a significant positive trend over the years for high-risk HPV genotypes 31/33/45/52/58 in women under 25 (9.9% vs 17.0% vs 24.0%, respectively, Ptrend=0.048). CONCLUSION: The prevalence of CIN3 lesions related to HPV 16/18 genotypes decreased over time from 2007 to 2018. These data highlight a herd effect of the HPV vaccine. However, fifteen years after HPV vaccine introduction, we are still a long way from herd immunity. The increase in high-risk types 31/33/45/52/58 will need to be reassessed when the nonavalent vaccine impact will be more reliable.

Age-related distribution of uncommon HPV genotypes in cervical intraepithelial neoplasia grade 3.

AIM: Cervical cancer prevention guidelines include Human Papillomavirus (HPV) test, cytology, and HPV-16/18 typing for triage to determine the risk of cervical intraepithelial neoplasia (CIN) grade 3 as the best proxy of cervical cancer risk. In doing that, they do not consider how age can modify the type-specific risk of CIN3. The present study aimed to evaluate the age-related distribution of HPV genotypes affecting the risk-assessment in cervical cancer screening programs: non-screening-type-HPV and non-HPV-16/18 in unvaccinated women with CIN3. METHODS: Retrospective multi-institutional study, including HPV genotyped women with CIN3 on cone histology treated between 2014 and 2019. The sample was divided into three categories of age: <30, 30-44, ≥45. HPV genotypes were grouped in non-screening-type-HPV (not-including genotypes 16/18/31/33/35/39/45/51/52/56/58/59/66/68) and non-HPV-16/18. Associations and trends between different age-groups and HPV genotypes were measured. RESULTS: 1332 women were analyzed. Non-screening-type-HPV CIN3 were 73 (5.5%). Non-HPV-16/18 were found in 417 participants (31.3%). Women over 45 associated with non-screening-type HPV [odds ratio (OR) = 1.87, 95% confidence interval (CI) 1.07-3.25; p = 0.027]. Non-screening-type-HPV prevalence increased significantly with age (3.9% vs 5.1% vs 9.0%, p = 0.016). Women under 30 showed a lower rate of non-HPV-16/18 (OR = 0.65, 95% CI 0.47-0.89; p = 0.007). There was a positive trend with age of non-HPV-16/18 CIN3 (23.6% vs 32.1% vs 38.0%, p = 0.0004). CONCLUSION: The proportion of CIN3 lesions unrelated to genotypes detected by primary screening tests increased with age. This implies that age probably modifies the risk of CIN3 and possibly of cancer associated with HPV types. The risk-based recommendation should take into consideration age to define the management of HPV positive women.

Long-term observational approach in women with histological diagnosis of cervical low-grade squamous intraepithelial lesion: an Italian multicentric retrospective cohort study.

OBJECTIVE: To evaluate the risk of progression to high-grade squamous intraepithelial lesion (HSIL) (CIN2-3) or invasive cancer in women with histopathological diagnosis of low-grade squamous intraepithelial lesion (LSIL) (CIN1), managed in a long-term observational approach up to 5 years. DESIGN: Retrospective cohort study. SETTING: Four tertiary referral hospital. PARTICIPANTS: 434 women with adequate colposcopy and complete colposcopic charts were included in the present analysis. Women with glandular lesions on the referral cytology or previous diagnosis of cervical dysplasia or invasive cervical cancer or with synchronous vaginal, or with HIV infection or immunodepression were excluded. PRIMARY AND SECONDARY OUTCOME MEASURES: The main study outcome was the rate of progression to histopathological HSIL (CIN2-3) or invasive cancer at any time during 5 years of follow-up. The possible risk factors were also evaluated. As secondary outcome, we analysed the possible risk factors at the 24-month evaluation for histopathological HSIL (CIN2-3) or invasive cancer progression between 2 and 5 years from initial diagnosis. RESULTS: A progression to histopathological HSIL (CIN2-3) was found in a total of 32 (7.4%) cases during 5 years of follow-up. A histopathological diagnosis of HSIL (CIN3) was found in four patients (0.9%) and no case of invasive cancer was detected. High-grade cytology at inclusion and the presence of a positive high-risk human papillomavirus (HR-HPV) DNA test at 2 years from inclusion maintained a significant correlation with the risk of histopathological progression to HSIL (CIN2-3). CONCLUSIONS: The results of our study showed a low rate (7.4%) of histopathological progression to HSIL (CIN2-3) in women with LSIL (CIN1) diagnosis during long-term follow-up up to 5 years. In case of positive HR-HPV DNA test at the 2 years evaluation an excisional treatment could be the preferred choice to prevent progression to HSIL (CIN2-3) in the following years, preferring a continuation of follow-up in case of HR-HPV DNA negative result.

Prevalence and concordance of oral and genital HPV in women positive for cervical HPV infection and in their sexual stable partners: An Italian screening study.

OBJECTIVES: This cross-sectional study aimed to evaluate the prevalence and type of oral HPV-infection in women with a cervical HPV-lesion and in the oral and genital mucosa of their male partners. METHODS: The study group comprised 44 sexually-active women, 20-45 years with abnormal PAP smear, not more than 6 months prior to referral together with the male partners cohabiting in stable partnerships. A detailed questionnaire was administered concerning the HPV-related risk factors. Oral swabs, oral rinses, cervical swabs and urine samples were collected. HPV DNA was detected using two different polymerase chain reactions (PCRs): MY09-11 and FAP59-64. Positive samples were genotyped by Sanger sequencing and the INNO-LiPA HPV Genotyping Extra II probe assay. The association with risk factors was assessed by fitting a generalized model, using the General Linear Model function in the R-software; correlations were calculated between all data. RESULTS: HPV was detected in 84% of Cervical Samples, in 24.3% of oral samples and in one urine sample. Only 27% of the HPV-positive results were identical with both PCR DNA assays. 8 male had oral HPV-positive samples different from women cervical samples. In one couple the urine-male sample had the same HPV present in the female-cervical sample. A significant association resulted between women/oral sex practices and men/n. of partners. CONCLUSIONS: This study reports that women (20.4%) with a diagnosis of cervical-HPV and their male partners (30,7%) are at high risk for subclinical oral HPV infection.

Cervical Excision Procedure: A Trend of Decreasing Length of Excision Observed in a Multicenter Survey.

OBJECTIVES: The aim of the present study was to observe the trend of length of cone excisions in women treated with cervical excision procedure in five institutions of Central and Northern Italy. MATERIALS AND METHODS: A multicenter retrospective cohort study was conducted on women who underwent a cervical excision procedure between January 2006 and December 2014. The pertinent clinical, histopathological, and sociodemographic characteristics of each woman were collected. In particular, the length of the cone specimen was evaluated and all of the factors that potentially influenced the length of excision were considered. RESULTS: A total of 1482 women who underwent a cervical excision procedure from January 2006 to December 2014 were included. A mean (SD) cone length of 12.9 (5.0) mm was reported, and mostly, a significant decrease during the whole study period emerged. Age (r = 0.1, p = .007) and preoperative diagnosis of glandular lesions (r = 0.1, p < .001) were significantly related to the length of cone excision on multivariate analysis. Compared with the carbon dioxide laser excisional procedure, loop electrosurgical excision procedure showed a negative correlation with the length of excision (r = -0.2, p < .001). CONCLUSIONS: During the study period, a significant decrease in the length of cone excision was observed, probably reflecting the gynecologists' acquired awareness of the increased risk of adverse obstetric outcomes for future pregnancies in the case of wide cone excisions.

Loop electrosurgical excision procedure and risk of miscarriage.

OBJECTIVE: To evaluate the risk of miscarriage in the subsequent pregnancy after a loop electrosurgical excision procedure (LEEP), also considering time elapsed from LEEP to pregnancy. DESIGN: Multicenter, retrospective cohort study. SETTING: Tertiary care university hospitals. PATIENT(S): Women who had undergone LEEP from January 2000 to December 2011. Women with histologic assessment of low-grade cervical dysplasia, not requiring subsequent surgical treatment, constituted the control group. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The first pregnancy after the procedure was evaluated, and only women with singleton spontaneous pregnancies were considered. Women with time intervals of <12 months and women with intervals of ≥12 months or more from LEEP to pregnancy were then compared, to identify adjusted odds ratios for miscarriage. RESULT(S): In women previously treated with LEEP, a total of 116 cases of miscarriage (18.1%) was reported. The mean time interval from LEEP to pregnancy for women with miscarriage compared with women without miscarriage was significantly shorter (25.1 ± 11.7 months vs. 30.1 ± 13.3 months). A higher rate of miscarriage in women with a LEEP-to-pregnancy interval of <12 months compared with controls emerged (28.2% vs. 13.4%; adjusted odds ratio 2.60, 95% confidence interval 1.57-4.3). No significant difference in the rate of miscarriage in women with a LEEP-to-pregnancy interval of ≥12 months compared with controls emerged. CONCLUSION(S): Women with a time interval from LEEP to pregnancy of <12 months are at increased risk for miscarriage.

The impact of loop electrosurgical excision procedure (LEEP) for CIN 2,3 on spontaneous preterm delivery in twin pregnancies by assisted reproductive technique: preliminary data.

The objective of this study was to compare the frequency of spontaneous preterm delivery before 35 weeks in 7 dichorionic twin pregnancies obtained after loop electrosurgical excision procedure (LEEP) for cervical intraepithelial neoplasia (CIN) 2,3 with respect to 21 twin pregnancies without previous cervical treatment. All the pregnancies were obtained after assisted reproduction techniques (ART). Same age at delivery was observed between two groups (p = 0.81) and none of our twin pregnancies after LEEP had a threatened preterm labor while four controls (19%) underwent a spontaneous preterm delivery (p = 0.35). These preliminary data seem to indicate that LEEP may not be responsible of spontaneous preterm delivery in twin pregnancies subsequent to ART.

Towards the eradication of HPV infection through universal specific vaccination.

BACKGROUND: The Human Papillomavirus (HPV) is generally recognized to be the direct cause of cervical cancer. The development of effective anti-HPV vaccines, included in the portfolio of recommended vaccinations for any given community, led to the consolidation in many countries of immunization programs to prevent HPV-related cervical cancers. In recent years, increasing evidence in epidemiology and molecular biology have supported the oncogenic role of HPV in the development of other neoplasm including condylomas and penile, anal, vulvar, vaginal, and oro-pharyngeal cancers. Men play a key role in the paradigm of HPV infection: both as patients and as part of the mechanisms of transmission. Data show they are affected almost as often as women. Moreover, no screening procedures for HPV-related disease prevention are applied in men, who fail to undergo routine medical testing by any medical specialist at all. They also do not benefit from government prevention strategies. DISCUSSION: A panel of experts convened to focus on scientific, medical, and economic studies, and on the achievements from health organizations' intervention programs on the matter. One of the goals was to discuss on the critical issues emerging from the ongoing global implementation of HPV vaccination. A second goal was to identify contributions which could overcome the barriers that impede or delay effective vaccination programs whose purpose is to eradicate the HPV infection both in women and men. SUMMARY: The reviewed studies on the natural history of HPV infection and related diseases in women and men, the increasing experience of HPV vaccination in women, the analysis of clinical effectiveness vs economic efficacy of HPV vaccination, are even more supportive of the economic sustainability of vaccination programs both in women and men. Those achievements address increasing and needed attention to the issue of social equity in healthcare for both genders.