Morbidity after local excision of the transformation zone for cervical intra-epithelial neoplasia and early cervical cancer.

The awareness that cervical intra-epithelial neoplasia (CIN) treatment increases the risk of preterm birth has led to major changes in clinical practice. Women with CIN have a higher baseline risk of prematurity but local treatment further increases this risk. The risk further increases with increasing cone length and multiplies for repeat excisions; it is unclear whether small cones confer any additional risk to CIN alone. There is no evidence to suggest that fertility is affected by local treatment, although this increases the risk of mid-trimester loss. Caution should prevail when deciding to treat women with CIN of reproductive age. If treatment is offered, this should be conducted effectively to optimise the clearance of disease and minimise the risk of recurrence. Colposcopists should alert women undergoing treatment that this may increase the risk of preterm birth and that they may be offered interventions when pregnant. The cone length should be clearly documented and used as a risk stratifier.

Is nuchal translucency measurement feasible in early pregnancy?

BACKGROUND: To investigate whether early nuchal translucency measurement at 7+0 to 9+0 weeks (NT7-9w) is feasible, obtain normal values for different crown-rump lengths (CRL) in the above weeks and create percentile tables. METHODS: A prospective study was conducted in the Obstetrics and Gynecology Department of the University Hospital of Ioannina, including data from women with singleton pregnancies, examined in the early pregnancy unit between November 2010 and May 2015 at a CRL of 10-27 mm. The early pregnancy scan was performed vaginally, and the NT7-9w, CRL, fetal heart rate, and mean yolk sac diameter were measured. Demographic data, including body mass index and smoking, were recorded. RESULTS: NT7-9w was measured successfully in 192 fetuses out of 210 (91.4 %), with a CRL ranging from 10-27 mm. The median maternal age was 31 (range 18-43) years, and the median CRL was 19.9 (range 10.0-27.0) mm. Considering the above measurements, we created normal values and percentiles tables of NT at 7+0 to 9+0 weeks in relation to the corresponding CRL measurement. CONCLUSION: According to the literature, this is the first attempt to measure NT in such weeks of pregnancy. NT measurement as early as 7+0 to 9+0 is feasible and normal values can be created and correlated with CRL measurements. HIPPOKRATIA 2021, 25 (4):151-155.

HPV vaccination and cancer prevention.

Prophylactic vaccines have been found to be highly effective in preventing infection and pre-invasive and invasive cervical, vulvovaginal and anal disease caused by the vaccine types. HPV vaccines contain virus-like particles that lack the viral genome and produce high titres of neutralising antibodies. Although the vaccines are highly effective in preventing infections, they do not enhance clearance of existing infections. Vaccination programmes target prepubertal girls and boys prior to sexual debut as efficacy is highest in HPV naïve individuals. School-based programmes achieve higher coverage, although implementation is country specific. Vaccination of older women may offer some protection and acceleration of impact, although this may not be cost-effective. HPV-based screening will continue for vaccinated cohorts, although intervals may increase.

Incidence and mortality from cervical cancer and other malignancies after treatment of cervical intraepithelial neoplasia: a systematic review and meta-analysis of the literature.

BACKGROUND: Although local treatments for cervical intraepithelial neoplasia (CIN) are highly effective, it has been reported that treated women remain at increased risk of cervical and other cancers. Our aim is to explore the risk of developing or dying from cervical cancer and other human papillomavirus (HPV)- and non-HPV-related malignancies after CIN treatment and infer its magnitude compared with the general population. MATERIALS AND METHODS: Design: Systematic review and meta-analysis. Eligibility criteria: Studies with registry-based follow-up reporting cancer incidence or mortality after CIN treatment. DATA SYNTHESIS: Summary effects were estimated using random-effects models. OUTCOMES: Incidence rate of cervical cancer among women treated for CIN (per 100 000 woman-years). Relative risk (RR) of cervical cancer, other HPV-related anogenital tract cancer (vagina, vulva, anus), any cancer, and mortality, for women treated for CIN versus the general population. RESULTS: Twenty-seven studies were eligible. The incidence rate for cervical cancer after CIN treatment was 39 per 100 000 woman-years (95% confidence interval 22-69). The RR of cervical cancer was elevated compared with the general population (3.30, 2.57-4.24; P < 0.001). The RR was higher for women more than 50 years old and remained elevated for at least 20 years after treatment. The RR of vaginal (10.84, 5.58-21.10; P < 0.001), vulvar (3.34, 2.39-4.67; P < 0.001), and anal cancer (5.11, 2.73-9.55; P < 0.001) was also higher. Mortality from cervical/vaginal cancer was elevated, but our estimate was more uncertain (RR 5.04, 0.69-36.94; P = 0.073). CONCLUSIONS: Women treated for CIN have a considerably higher risk to be later diagnosed with cervical and other HPV-related cancers compared with the general population. The higher risk of cervical cancer lasts for at least 20 years after treatment and is higher for women more than 50 years of age. Prolonged follow-up beyond the last screening round may be warranted for previously treated women.

Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity.

Persistent infection with oncogenic Human Papillomavirus (HPV) is necessary for cervical carcinogenesis. Although evidence suggests that the vaginal microbiome plays a functional role in the persistence or regression of HPV infections, this has yet to be described in women with cervical intra-epithelial neoplasia (CIN). We hypothesised that increasing microbiome diversity is associated with increasing CIN severity. llumina MiSeq sequencing of 16S rRNA gene amplicons was used to characterise the vaginal microbiota of women with low-grade squamous intra-epithelial lesions (LSIL; n = 52), high-grade (HSIL; n = 92), invasive cervical cancer (ICC; n = 5) and healthy controls (n = 20). Hierarchical clustering analysis revealed an increased prevalence of microbiomes characterised by high-diversity and low levels of Lactobacillus spp. (community state type-CST IV) with increasing disease severity, irrespective of HPV status (Normal = 2/20,10%; LSIL = 11/52,21%; HSIL = 25/92,27%; ICC = 2/5,40%). Increasing disease severity was associated with decreasing relative abundance of Lactobacillus spp. The vaginal microbiome in HSIL was characterised by higher levels of Sneathia sanguinegens (P < 0.01), Anaerococcus tetradius (P < 0.05) and Peptostreptococcus anaerobius (P < 0.05) and lower levels of Lactobacillus jensenii (P < 0.01) compared to LSIL. Our results suggest advancing CIN disease severity is associated with increasing vaginal microbiota diversity and may be involved in regulating viral persistence and disease progression.

The thickness and volume of LLETZ specimens can predict the relative risk of pregnancy-related morbidity.

OBJECTIVE: The aim of this study was to determine if the individual physical characteristics of the extirpated transformation zone after large loop excision of the transformation zone (LLETZ) might predict the relative risk of adverse obstetric outcome, specifically preterm labour (PTL). DESIGN: A retrospective observational study. SETTING: University teaching hospital in Dublin (Coombe Women & Infants University Hospital, CWIUH). POPULATION: Women who had LLETZ treatment for cervical intraepithelial neoplasia (CIN) in the colposcopy service between 1999 and 2002, and who subsequently had a pregnancy at the CWIUH. METHODS: Case records and histology reports for eligible women were examined. Age, parity, smoking history, pregnancy complications and CIN grade were recorded. Exclusion criteria were age >42 years, previous treatment for CIN, previous premature labour or twin pregnancies. The Student's t-test, Mann-Whitney U-test, analysis of variants (ANOVA) and logistic regression were employed to analyse the data. MAIN OUTCOME MEASURES: Gestational age at birth, PTL (i.e. <37 weeks of gestation) and miscarriage rate (<24 weeks of gestation). RESULTS: Out of 1808 women who underwent LLETZ treatment, a total of 353 women were identified who subsequently had a pregnancy at the CWIUH, with 321 being eligible for inclusion in the study. Of these, 76.3% delivered at term, 9.1% delivered at <37 weeks of gestation and 14.6% miscarried at <24 weeks of gestation. There was a three-fold increase in the risk of PTL if the excision volume exceeded 6 cm(3) (RR = 3.00; 95% CI 1.45-5.92), or when the thickness of the excised tissue was greater than 12 mm (RR = 2.98; 95% CI 1.27-7.01). The time interval between LLETZ and pregnancy did not appear to have an effect on PTL rates. We found no association between the grade of CIN and the risk of PTL. CONCLUSIONS: This study reveals that the thickness and the total volume of the excised transformation zone are associated with an increased risk of PTL. Excisions thicker than 1.2 cm and larger than 6 cm(3) carry a three times greater risk for PTL.

Apparent diffusion coefficient values of the normal uterus: Interindividual variations during menstrual cycle.

OBJECTIVES: To assess the apparent diffusion coefficient (ADC) changes of the normal uterine zones among reproductive women during the menstrual cycle. METHODS: The study included 101 women of reproductive age, each with regular cycle and normal endometrium/myometrium, as proved on histopathology or MR imaging examination. Diffusion-weighted (DW) imaging was performed along the axial plane, using a single shot, multi-slice spin-echo planar diffusion pulse sequence and b-values of 0 and 800s/mm(2). The mean and standard deviation of the ADC values of normal endometrium/myometrium were calculated for menstrual, proliferative and secretory phase. Analysis of variance followed by the least significant difference test was used for statistical analysis. RESULTS: The ADC values of the endometrium were different in the three phases of the menstrual cycle (menstrual phase: 1.25±0.27; proliferative phase: 1.39±0.20; secretory phase: 1.50±0.18) (F: 9.64, p: 0.00). Statistical significant difference was observed among all groups (p<0.05). The ADC values of the normal myometrium were different in the three phases of the menstrual cycle (menstrual phase: 1.91±0.35; proliferative phase: 1.72±0.27; secretory phase: 1.87±0.28) (F: 3.60, p: 0.03). Statistical significant difference was observed between menstrual and proliferative phase and between proliferative and secretory phase (p<0.05). No significant difference was noted between menstrual and secretory phase (p>0.05). CONCLUSIONS: A wide variation of ADC values of normal endometrium and myometrium is observed during different phases of the menstrual cycle.

Regeneration of cervix after excisional treatment for cervical intraepithelial neoplasia: a study of collagen distribution.

OBJECTIVE: To study the distribution of collagen in the regenerated cervical tissue after excisional treatment for cervical intraepithelial neoplasia (CIN). DESIGN: Cohort study. SETTING: A large tertiary teaching hospital in London. POPULATION: Women who underwent repeat excisional treatment for treatment failure or persistent CIN. METHODS: Eligible women who underwent a repeat excisional treatment for treatment failure, including hysterectomy, between January 2002 and December 2007 in our colposcopy unit were identified by the Infoflex(®) database and SNOMED encoded histopathology database. Collagen expression was assessed using picro-Sirius red stain and the intensity of staining was compared in paired specimens from the first and second treatments. MAIN OUTCOME MEASURE: Differences in collagen expression were examined in the paired excisional treatment specimens. RESULTS: A total of 17 women were included. Increased collagen expression in the regenerated cervical tissue of the second cone compared with the first cone was noted in six women, decreased expression was noted in five women, and the pattern of collagen distribution was equivocal in six women. CONCLUSION: There is no overall change in collagen distribution during regeneration following excisional treatment for CIN.

The role of p16(INK4a) immunostaining in the risk assessment of women with LSIL cytology: a prospective pragmatic study.

BACKGROUND: The detection of high-grade cervical intraepithelial neoplasia (CIN2 or worse) among patients with low-grade cytology (LSIL) is challenging. The aim of this study was to assess the efficacy of p16(INK4a) in the risk assessment of women with LSIL cytology. METHODS: Consecutive liquid-based cytology specimens of 95 LSIL smears were selected and stained for p16(INK4a). All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy-confirmed CIN2 or worse. RESULTS: The overall sensitivity and specificity of p16(INK4a) for diagnosis of CIN2+ among LSIL smears were 41% and 86%, respectively. The positive predictive value of the biomarker was 62% and the negative predictive value 72%. CONCLUSIONS: The study shows that p16(INK4a) has low sensitivity but acceptable specificity for evaluation of LSIL smears harbouring high-grade lesions. The marker needs to be further assessed as an adjunct to other tests in an attempt to improve the triage of LSIL cytology smears.

Women's knowledge and utilization of gynecological cancer prevention services in the Northwest of Greece.

PURPOSE OF INVESTIGATION: In Greece an organized cervical or breast cancer screening program does not exist and the population coverage is unknown. METHODS: Women of all ages completed a questionnaire, which assessed women's awareness of and participation in breast and cervical screening and human papillomavirus (HPV) vaccination. The women were randomly approached in public areas. RESULTS: 1,012 women completed the questionnaire. 52% of the women over 39 years old had undergone mammography in the last year and 76% of the women over 20 years old had a cervical smear test within the last three years in an opportunistic basis. In addition, the likelihood of having regular mammograms was positively associated with the likelihood of having regular cervical smears. Fifty percent of the responders did not identify HPV as the cause of cervical cancer and 38% were not aware of the HPV vaccine. From the women aged 16 to 28 years old, 11% had been vaccinated against HPV and an additional 23% intended to have the vaccine in the next six months. CONCLUSION: Knowledge and utilization of mammography and cervical screening was quite satisfactory, although HPV vaccination coverage was low. Preventive services could be improved through the development of a plan for the information of the public and the distribution of the HPV vaccine.

Molecular epidemiology of HPV infection using a clinical array methodology in 2952 women in Greece.

The molecular epidemiology of human papillomavirus (HPV) infection in a sample of Greek women (n = 2952, mean age 42.2 ± 13.3 years) was examined. HPV prevalence was 50.7% (95% confidence interval, 48.8-52.6). The most frequent HPV types were HPV 53, 51 and 66 (10.2%, 9.4% and 9.3%, respectively). HPV positivity was associated with age, age of sexual debut, number of sexual partners and duration of sexual relationship, while marriage or multiparity protected against infection (all p <0.001). Follow-up of this cohort will assist in predicting the effect of vaccination with the new HPV vaccines on future screening with HPV-based tests for cervical cancer.

Alterations in human papillomavirus-related biomarkers after treatment of cervical intraepithelial neoplasia.

OBJECTIVE: This study aims to assess the alterations in various HPV-related biomarkers 6 months post-treatment and how these relate to various risk factors and individual characteristics; their role for the prediction of treatment failure was also evaluated. DESIGN: Prospective observational study. POPULATION: Women planning to undergo treatment for cervical intraepithelial neoplasia. INTERVENTION: A liquid-based cytology sample was taken pre-operatively. This was tested for HPV genotyping, Nucleic Acid Sequence Based Amplification, flow cytometric evaluation and p16 immunostaining. A repeat LBC sample was obtained 6 months post-treatment and was tested for the same biomarkers. OUTCOMES: The alterations of the biomarkers 6 months post-treatment were recorded. Their relation to individual characteristics and risk factors (age, smoking, sexual history, use of condom, CIN grade, excision margin status, crypt involvement) as well as their role for the prediction of residual/recurrent disease were assessed. ANALYSIS: The accuracy parameters (sensitivity, specificity, positive and negative predictive value and the likelihood ratios) of each biomarker for the prediction of recurrent/residual CIN were calculated. RESULTS: A total of 190 women were recruited. All biomarkers had significantly higher negativity rates post-treatment compared to pre-treatment ones. Multivariate analysis demonstrated that consistent condom use post-treatment significantly reduces the high-risk HPV positivity rates in comparison to no use (OR=0.18; 95% CI: 0.09-0.38). Sensitivity and specificity for all high risk HPV DNA testing were 0.5/0.62, respectively; the relevant values for only type 16 or 18 DNA typing were 0.5/0.92, for NASBA 0.5/0.94, for flow 0.5/0.85 and for p16 0.25/0.93. CONCLUSION: CIN treatment reduces positivity for all HPV-related biomarkers. Consistent condom use significantly reduces high-risk HPV positivity rates. More cases of treatment failures are required in order to specify whether different combinations of HPV-related biomarkers could enhance the accuracy of follow up, possibly in the form of a Scoring System that could allow tailored post-treatment surveillance.

High-risk human papillomavirus DNA test and p16(INK4a) in the triage of LSIL: a prospective diagnostic study.

OBJECTIVE: The detection of high-grade cervical intraepithelial neoplasia (CIN) amongst patients with low-grade cytology (LSIL) is challenging. This study evaluated the role of high-risk HPV (HR-HPV) DNA test and p16(INK4a) immunostaining in identifying women with LSIL cytology at risk of harboring CIN2 or worse (CIN2+) and the role of p16(INK4a) in the triage of a population of HR-HPV positive LSIL. METHODS: We conducted a prospective study including women with LSIL cytology. Detection of HR-HPV was carried out by means of a polymerase chain reaction based assay. p16(INK4a) immunostaining was performed using the Dako CINtec cytology kit. All patients had colposcopically directed punch biopsies or large loop excision of the transformation zone of the cervix. The endpoint was detection of a biopsy-confirmed CIN2+. RESULTS: A series of 126 women with LSIL cytology were included. HR-HPV test had sensitivity 75% and specificity 64% for an endpoint of CIN2+. p16(INK4a) had significantly higher specificity of 89% (p=0.0000) but low sensitivity of 42%. The role of p16(INK4a) immunostaining in the triage of LSIL positive for HR-HPV was also evaluated. p16(INK4a) triage had 70% positive predictive value (PPV); however, this was not significantly higher than the PPV (56%) of HR-HPV test alone (p=0.4). CONCLUSIONS: The results indicate that HR-HPV or p16(INK4a) cannot be used as solitary markers for the assessment of LSIL. The addition of p16(INK4a) immunostaining led to an increase in HR-HPV specificity; however, the biomarker needs to be assessed further to establish its role as an adjunct test in the triage of LSIL.

Clinical management of HPV-related disease of the lower genital tract.

Cytology remains the mainstay for cervical screening. The need to achieve effective management, limit complications, and preserve reproductive function led to the popularity of local treatment. Although the cure rates for ablative and excisional methods are similar, the excisional method provides a more reliable histopathological diagnosis. Recent evidence revealed increased perinatal morbidity after treatment that appears to be related to the proportion of cervix removed. The human papillomavirus (HPV) DNA test appears to enhance the detection of disease in primary screening, in the triage of minor cytological abnormalities, and in follow-up. Further research on the clinical application of a scoring system is ongoing. The vaccines are now available and appear to be safe, well tolerated, and highly efficacious in HPV naive women. A synergy of vaccination and screening will be required. Treatment for early cervical cancer is increasingly shifting toward more fertility-sparing surgical techniques. Careful selection of patients is essential.

Proportion of excision and cervical healing after large loop excision of the transformation zone for cervical intraepithelial neoplasia.

OBJECTIVE: To determine how the proportion of the cervical volume excised affects cervical regeneration. DESIGN: Prospective observational study. SETTING: University Hospital. POPULATION: Women planning to undergo excisional treatment for cervical intraepithelial neoplasia who wish to have future pregnancies. METHODS: The cervical volume (and dimensions) is calculated with magnetic resonance imaging (MRI) before treatment. The volume (and dimensions) of the cone is assessed before fixation by a volumetric tube and a ruler; the percentage (%) of excision is computed. Cervical regeneration is estimated by repeat MRI at 6 months. MAIN OUTCOME MEASURES: Cervical regeneration in relation to proportion of excision. Statistical analysis was performed by box plots and analysis of variance. RESULTS: A total of 48 women have been recruited; 29 have completed 6 months follow up. Both the total cervical volume (from MRI) before treatment and the volume of the excised/ablated cone varied substantially. The estimated proportion of excision varied significantly between 4% and 39% (median 11%). Multivariate linear regression revealed that the proportional deficit at 6 months post-treatment was determined mainly by the proportion of the excised volume. CONCLUSIONS: Careful assessment of risks and benefits of treatment is essential when deciding to treat women who wish to have future pregnancies. Assessment of the proportion of the cervical volume and length excised might identify those that need further surveillance during future pregnancy.