What is the value of pre-surgical variables in addition to cone dimensions in predicting cone margin status?

OBJECTIVE: Previous studies have shown associations between independent pre-conization variables (e.g. smoking, age, cytological grade, menopause) and positive or negative cone margins. However, it is not clear if these pre-surgical variables add predictive value to cone dimensions in the prediction of cone margin status. This study aimed to compare different models predicting positive ecto- or endocervical margins to assess whether pre-conization variables provide significant added value compared with cone dimensions alone. STUDY DESIGN: One hundred and sixty-one consecutive women with high-grade cervical intra-epithelial neoplasia on cone specimens were analysed retrospectively. The sample was divided into women with positive ecto- or endocervical cone margins and women with negative ecto- or endocervical cone margins. Pre-conization clinical features, cone volume and cone length were included among the study variables. Multivariate stepwise regression analysis was used to create different models predicting incomplete cervical excision. The added value of pre-conization predictors was measured with receiver operating characteristic (ROC) curve comparisons. RESULTS: Fifty-seven (35.4 %) women had incomplete cervical excision. Multivariate analysis showed that a positive ectocervical margin was significantly associated with low-grade cervical cytology [odds ratio (OR) = 0.25, 95 % confidence interval (CI) 0.09-0.70] and cone length (OR = 0.69, 95 % CI 0.58-0.82, criterion <9 mm). The area under the curve (AUC) of the combined model for prediction of a positive ectocervical margin was 0.78 (95 % CI 0.70-0.84, p < 0.001). A positive endocervical margin was associated with cone length (OR=0.78, 95 % CI 0.65-0.93, criterion <9 mm) and age (OR=1.07, 95 % CI 1.02-1.11, criterion ≥45 years). The AUC of the combined model for prediction of positive endocervical margin was 0.75 (95 % CI 0.66-0.82, p < 0.001). Comparison of ROC curves showed that the addition of pre-conization variables to cone length did not yield significant predictive results for either ecto- or endocervical cone margins (p = 0.228 and 0.349, respectively). CONCLUSIONS: The addition of pre-conization clinical variables to cone dimensions did not improve the prediction of cone margin status significantly in the study cohort. Among cone dimensions, cone length was the best predictor of come margin status.

Age-Related Changes in the Fraction of Cervical Intraepithelial Neoplasia Grade 3 Related to HPV Genotypes Included in the Nonavalent Vaccine.

OBJECTIVE: The prevalence of some human papillomavirus (HPV) genotypes has been shown to change with age. So, also the distribution of HPV genotypes included in the nonavalent vaccine may not be the same at all ages, and this could mean that vaccine protection against cervical cancer may be affected by age. The present study aimed to evaluate whether there are age-related changes in the fraction of high-grade cervical intraepithelial neoplasia (CIN) attributable to HPV genotypes included in the nonavalent vaccine. METHODS: Two hundred four consecutive women undergoing conization with a histological diagnosis of CIN3 were retrospectively analyzed. All included women had a preconization HPV genotyping (HPV Sign® Genotyping Test). The women were divided into three groups according to age: <35, 35-44, and ≥45 years of age. Based on HPV genotypes detected in cervical lesions, the age-related changes in the expected vaccine protection were evaluated by the Cochran-Armitage test for trend. RESULTS: The fraction of CIN3 attributable to HPV genotypes included in the nonavalent vaccine showed a significant negative trend with increasing age, with potential vaccine protection of 82% after the age of 45 (p=0.006). The rate of HPV-16 and HPV-33, included in the vaccine, showed a negative trend with age (p=0.047 and p=0.044, respectively). Among HPV genotypes not covered by the vaccine, the rate of non-high-risk HPVs (genotypes: 53-54-70-73-82-85-87) showed a significant positive trend with increasing age (p=0.018). CONCLUSIONS: Although the fraction of CIN3 attributable to genotypes included in the nonavalent HPV vaccine was high even after age 45, older women appeared to be more at risk of high-grade CIN related to HPV genotypes not included in the vaccine. Interestingly, older women showed a higher rate of precancerous cervical lesions associated with non-high-risk HPV. The present findings seem to raise the question about the management of cervical pathology at a later age in a future postvaccination era.

Age-related changes in pre- and post-conization HPV genotype distribution among women with high-grade cervical intraepithelial neoplasia.

OBJECTIVE: To assess the effect of age on pre- and post-conization HPV genotype distribution. METHODS: The present retrospective observational study included consecutive women with high-grade cervical intraepithelial neoplasia who underwent conization at the Cervical Cancer Screening Centre of Reggio Emilia, Italy, and University Hospital of Modena, Italy, between February 1, 2012, and October 31, 2014. Pre-conization and 6-month post-conization HPV genotyping results were compared between four age groups (<30, 30-39, 40-49, and ≥50 years) and age-related changes in the HPV genotypes present were evaluated. RESULTS: There were 162 patients included. The lowest occurrence of pre-conization high-risk and probable high-risk HPV genotypes was observed among patients aged at least 50 years when compared with younger patients (P=0.017). Conversely, women aged at least 50 years exhibited the highest level of post-conization high-risk and probable high-risk HPV genotypes (P=0.043). Additionally, an increasing incidence of recording identical pre- and post-conization HPV genotypes was associated with increasing age (P=0.024), as was increasing post-treatment recurrence of cervical intraepithelial neoplasia grade 2+ (P=0.030). CONCLUSION: The presence of high-risk and probable high-risk HPV genotypes was lowest among older patients before conization and was highest among these patients post-conization; post-treatment HPV clearance decreased with age and increasing age could be a risk factor for post-conization recurrence.

Interobserver reproducibility of cytologic p16INK4a /Ki-67 dual immunostaining in human papillomavirus-positive women.

BACKGROUND: The accumulation of cyclin-dependent kinase inhibitor 2A (p16ink4a ) protein in a cell is associated with neoplastic progression in precancerous cervical lesions. Dual staining for p16ink4a and Ki-67 has been proposed as a triage test in cervical cancer screening for women who test positive for human papillomavirus DNA. In this study, interobserver reproducibility of the interpretation of this test was assessed. METHODS: Forty-two immunostained, liquid-based cytology slides were divided into 2 sets and were interpreted by 17 to 21 readers from 9 different laboratories, yielding a total of 816 reports. Immunostaining results were classified as positive, negative, inconclusive, or inadequate. After evaluation of the first set of slides and before circulation of the second set, the results were discussed in a plenary meeting. The 10 slides with the most discordant results were evaluated again by selected expert cytopathologists. RESULTS: The overall κ value was 0.612 (95% confidence interval [CI], 0.523-0.701), it was higher for the positive and negative categories (κ = 0.692 and κ = 0.641, respectively), and it was almost null for the inconclusive category (κ = 0.058). Considering only readers from laboratories with documented experience, the κ value was higher (κ = 0.747; 95% CI, 0.643-0.839) compared with nonexperienced centers (κ = 0.498; 95% CI, 0.388-0.616). The results were similar in both sets of slides (κ = 0.505 [95% CI, 0.358-0.642] and κ = 0.521 [95% CI, 0.240-0.698] for the first and second sets, respectively). Reinterpretation of the slides with the most discordant results did not provide any improvement (first evaluation, κ = 0.616 [95% CI, 0.384-0.866]; second evaluation, κ = 0.403 [95% CI, 0.182-0.643]). CONCLUSIONS: Dual staining for p16 ink4a and Ki-67 demonstrated good reproducibility, confirming its robustness, which is a necessary prerequisite for its adoption as a triage test in cervical cancer screening programs that use human papillomavirus DNA as a primary test. Cancer Cytopathol 2017;125:212-220. © 2016 American Cancer Society.

Outcome of Nonpersonalized Human Papillomavirus Vaccinations During Postconization Follow-up: A Report of Two Cases.

BACKGROUND: The human papillomavirus (HPV) vaccine was conceived to prevent new HPV infections among uninfected young women. From the initial intentions, its use has been extended to older women and also tested as a therapeutic tool. We report two HPV vaccination outcomes during postconization follow-up. CASES: Two young women, with different clinical histories, were subjected to HPV vaccine after a loop electrosurgical excision procedure for high-grade cervical intraepithelial neoplasia (CIN) and persisting low-grade CIN. During follow-up both women experienced a worsening of cervical lesions, which resulted in invasive cervical cancer and severe dysplasia, respectively. CONCLUSION: Limited to our experience, a nonpersonalized HPV vaccine administration during postconization follow-up was expensive and unnecessary.

HPV prevalence and risk of pre-cancer and cancer in regular immigrants in Italy: results from HPV DNA test-based screening pilot programs.

UNLABELLED: ᅟ: Immigrants from low- and medium-income countries have a higher risk of cervical cancer due both to barriers in access to screening and to higher human papillomavirus (HPV) prevalence. In the near future many screening programmes in industrialised countries will replace Pap test with HPV as primary test. In order to plan future interventions, it is essential to understand how the HPV screening performs in immigrant women. METHODS: We conducted a survey on the main performance indicators from some of the HPV DNA-based pilot programmes in Italy, comparing regular immigrant women, identified as women resident in Italy who were born abroad, with women who were born in Italy. All the programmes applied the same protocol, with HPV as stand-alone test starting for women of 25 or 35 to 64 years of age. Cytology triage is performed for positive women; those ASC-US or more severe are referred directly to colposcopy; negative women are referred to repeat HPV after one year. RESULTS: Overall, 162,829 women were invited, of whom 22,814 were born abroad. Participation was higher for Italy-born than born abroad (52.2% vs. 43.6%), particularly for women over 45 years. HPV positivity rate was higher in immigrants: 7.8% vs. 6.1%, age-adjusted Relative Risk (age-adj RR) 1.18, 95% confidence interval (95% CI) 1.13-1.22. The proportion of women with positive cytology triage was similar in the two groups (42%). Cervical Intraepithelial Neoplasia (CIN) grade 2 or more severe detection rate was higher for born abroad (age-adj RR 1.65, 95% CI 1.45-1.89). The difference was stronger when considering only CIN3 or more severe (age-adj RR 2.29, 95% CI 1.90-2.75). Both HPV positivity and CIN2 or more severe detection rate had a different age curve in born abroad compared with Italy-born: in the former, the risk was almost flat, while in the latter it declined rapidly with age. CONCLUSION: Compliance with HPV screening is lower for migrant women, who are affected by higher HPV positivity and CIN3 cancer detection rates.

High-grade CIN on cervical biopsy and predictors of the subsequent cone histology results in women undergoing immediate conization.

OBJECTIVE: To identify the clinical/colposcopic variables that associate with low-grade/negative cone histology in screening-age women undergoing conization for high-grade cervical intraepithelial neoplasia (CIN). The follow-up outcomes of study participants were also compared. STUDY DESIGN: In this retrospective cohort study, 585 consecutive screening-age women who underwent immediate conization for CIN2-3 were divided according to cone histology (CIN2+ versus ≤CIN1) and assessed in relation to clinical/colposcopic variables by univariate and multivariate analyses. RESULTS: Low-grade [adjusted odds ratio (AOR)=52.67, 95% confidence interval (CI) 22.49-123.34] or normal (AOR=9.81, 95% CI 2.38-40.44) colposcopic impression and CIN2 on cervical biopsy (AOR=19.59, 95% CI 6.62-57.92) associated with CIN1/negative cone histology. Multivariate analysis also showed that Eastern European ethnicity (AOR=0.13, 95% CI 0.03-0.52) and high-risk-Human Papillomavirus (hr-HPV)-positivity (AOR=0.38, 95% CI 0.17-0.87), associated with CIN2+ cone histology. Overall, there were no significant differences between the two groups in terms of high-grade recurrence during the 2-year follow-up. Conversely, a higher rate of high-grade recurrence was present in CIN2-3 (positive cone margins) than in CIN1/negative cone histology (21.9% versus 7.4%, P=0.008, respectively). CONCLUSION: The presence of CIN2 on cervical biopsy and a low-grade colposcopic impression were predictive of a minor cone histology, unless the subject was of East European ethnicity or was positive for hr-HPV test. Given the follow-up outcomes, the same women need to perform a close monitoring. However, positive cone margins in women with CIN2-3 cone histology seem to define a population at greater risk of high-grade recurrence.

Cervical cancer epidemiology in foreign women in Northern Italy: role of human papillomavirus prevalence in country of origin.

This study compares the incidence and treatments of cervical neoplasia in foreigners from high migration countries and Italians in the Reggio Emilia province (Northern Italy) in 2002-2009. Standardized incidence ratios (SIRs) and 95% confidence intervals (95% CI) for cervical intraepithelial neoplasia grade 3 (CIN3) and cancer were calculated for foreigners versus Italian women; foreigners were also classified according to the prevalence of human papillomavirus (HPV) in their country of origin. The proportion of hysterectomies is presented as an indicator of inappropriate surgery in CIN3 and microinvasive cancers. A higher risk was observed in women from high human papillomavirus prevalence countries (HHPVC) both for cancer and for CIN3 (SIR=4.1, 95% CI=2.2-6.9; SIR=2.0, 95% CI 1.7-2.5, respectively), whereas in those from low human papillomavirus prevalence countries (LHPVC), no difference for cancer and a lower risk for CIN3 were observed (SIR=1.0, 95% CI 0.2-2.2; SIR=0.6, 95% CI 0.4-0.8, respectively). A lower CIN3/cancer ratio was found in women from HHPVC (2.6) and in women from LHPVC (3.6) than in Italians (7.4). The percentage of hysterectomies for CIN3 or microinvasive cancers was 3.4 in foreigners and 4.7 in Italians. A higher risk of cervical cancer was found in women from HHPVC compared with Italians and women from LHPVC, suggesting a role of HPV prevalence in the country of origin in the excess risk. The CIN3/cancer ratio was lower for both women from HHPVC and women from LHPVC, also suggesting a role of low screening uptake for cervical cancer incidence in immigrants.

A postconization hematometra revealed a rare case of endocervical bone metaplasia.

BACKGROUND: Hematometra is an unusual occurrence in young women undergoing conization; moreover, osseous metaplasia of the uterine cervix is a very rare event, with 7 cases in the literature. A postconization hematometra due to endocervical ossification is a unique occurrence. The authors report such an event. CASE: A young woman undergoing conization developed progressive hypoamenorrhea with pelvic pain. Pregnancy test was negative and a transvaginal ultrasound showed an image of suspected hematometra. Diagnostic hysteroscopy showed an endocervical obstruction due to a bone formation of the uterine cervix, which was removed with an office operative hysteroscopy. After surgery, the patient restored normal menstrual cycle. Histological examination revealed a cervical bone metaplasia. CONCLUSIONS: In premenopausal women undergoing conization, the appearance of a progressive hypoamenorrhea with pelvic pain could suggest a cervical mechanical obstruction that could be an uncommon stenosis. Despite this case represents a very rare event, a postconization hematometra due to an endocervical ossification can be managed with an office operative hysteroscopy.

Cervical nitric oxide metabolite levels and clinical variables as predictive factors of high-grade cervical intraepithelial neoplasia.

PURPOSE: To create a prediction model of high-grade cervical intraepithelial neoplasia (CIN) based on clinical variables and the cervical nitric oxide metabolite (NOx) levels of study participants. METHODS: This comparative study included 694 women undergoing colposcopy due to abnormal pap smear results. On the basis of the cervical biopsy results, the women were divided into the ≤ CIN 1 or CIN 2-3 group. The two groups were compared in terms of cervical NOx levels and clinical variables. Univariate, multivariate, and receiver-operating characteristic curve analysis were performed. RESULTS: Multivariate analysis showed that CIN 2-3 associated with more than two cervical biopsies [odds ratio (OR) = 5.16], high-grade squamous intraepithelial lesion cytology (OR = 16.19), condom non-use (OR = 4.28), cervical NOx levels ≤ 99.9 µmol/L (OR = 16.62), more than four lifetime male sexual partners (OR = 10.56), and age at first coitus of ≤ 15 years old (OR = 3.54). This combined model had a sensitivity of 86.49 %, a specificity of 90.74 %, a positive predictive value of 64.0 %, and a negative predictive value of 97.2 %. CONCLUSIONS: In the present sample, high-grade CIN associated with decreased cervical NOx levels. Thus, along with some clinical variables, cervical NOx levels may be an additional marker of cervical dysplasia.

Loop electrosurgical excision procedure as a life event that impacts on postmenopausal women.

AIM: The aim of this study was to compare the psychological impact of loop electrosurgical excision procedure (LEEP) in pre- and postmenopausal women. MATERIAL AND METHODS: This was an observational comparative study including 231 pre- and 108 post-menopausal women undergoing LEEP who were subjected to an interview inquiring specific psychological domains concerning the impact of this surgical procedure. The associations between women's answers and their hormonal status were tested by logistic regression analysis. RESULTS: Multivariate analysis showed that after LEEP, postmenopausal women were associated with answers that indicated significant psychological changes concerning the impact of cervix disease (Odds Ratio [OR] = 2.38, 95% Confidence Interval [CI] 1.22-4.66), their body image (OR = 6.80, 95% CI 2.30-20.08), interpersonal relationship with their partner (OR = 8.32, 95% CI 1.77-38.99) and sexual health quality (OR = 2.25, 95% CI 1.15-4.39). CONCLUSION: Limited to our sample, the psychological impact of LEEP seems to be greater in postmenopausal than in premenopausal women. We speculate that LEEP could cause failure of psychological domains already weakened by menopause.

Follow-up of screening patients conservatively treated for cervical intraepithelial neoplasia grade 2-3.

OBJECTIVES: To evaluate the frequency and correlates of non-adherence to follow-up among patients conservatively treated for CIN2-3. STUDY DESIGN: Study population comprised 1560 patients aged 25-64 years from a screening programme in northern Italy. The regional standard protocol was used as a reference. Multinomial logistic regression analysis was used to estimate the odds ratio probability of a patient being lost to follow-up (no check-ups within 27 months of treatment) or incompletely followed-up (1-3 negative check-ups) versus having 4 negative check-ups. RESULTS: Three hundred twenty-six patients (21%) were lost to follow-up, 678 (43%) were incompletely followed-up, 352 (23%) presented for 4 negative check-ups and 204 (13%) were diagnosed with persistent disease. The probability of no or incomplete follow-up was greater for patients who lived in the urban district, who were treated in private settings (versus screening centres), who exhibited a visibile squamocolumnar junction on pre-treatment colposcopy, who were treated with cold knife excision and local destructive therapy (versus loop diathermy excision), and whose surgical specimens had positive excision margins. CONCLUSIONS: Adherence to the reference protocol was poor. Factors involved in follow-up failures require greater clinical attention.

Applicability of the Bethesda System 2001 to a public health setting.

BACKGROUND: The degree of applicability of the Bethesda System 2001 (TBS 2001) for cervicovaginal cytology to a public health setting is unknown, and extrapolations from available data are unwarranted. METHODS: A "before/after" study design was used to evaluate the impact of TBS 2001 on an organized, population-based screening program in northern Italy. Between 2003-2004, 6 cytology laboratories converted from TBS 1991 to TBS 2001. A set of screening indicators based on TBS 2001 (85,012 patients) were compared with those based on TBS 1991 (199,833 patients) by means of their laboratory- and patient age-standardized ratio with a 95% confidence interval (CI). RESULTS: The prevalence of cervical intraepithelial neoplasm (CIN)2-3/carcinoma was stable between the 2 populations. TBS 2001 had no effect on the unsatisfactory rate (1.99% vs. 2.03% for TBS 1991) nor on follow-up compliance rate (93.2% vs. 92.3%). The reporting rate of atypical squamous cells (ASC) decreased from 17.1 to 14.7 per 1000 (ratio, 0.86; 95% CI, 0.81-0.91), the total positivity rate from 31.1 to 29.0 per 1000 (ratio, 0.93; 95% CI, 0.90-0.97), and the ASC:SIL (squamous intraepithelial lesion) ratio from 1.38 to 1.16. Compared with the ASCUS (ASC of undetermined significance) reports of TBS 1991, the predictive value for CIN2-3/carcinoma decreased from 5.2 to 3.5% (ratio, 0.68; 95% CI, 0.48-0.93) among ASCUS reports, but increased from 5.1 to 17.2% (ratio, 3.41; 95% CI, 1.64-6.28) among ASC-cannot exclude high grade lesion (ASC-H) reports. ASC-H had a 5.01-fold (95% CI, 2.23-10.2) greater predictive value than ASCUS. CONCLUSIONS: TBS 2001 is applicable to cervical screening in a public health setting.