Cervical cancer prevention in transgender men: a review.

There is increased awareness of transgender physical and mental health widely and in academic research. A significant proportion of transgender men will retain their cervix with an increased risk of cervical cancer. In this review of cervical cancer screening among transgender men, we try to estimate how many transgender men still have a cervix, understand to identify challenges and barriers to cervical screening and propose possible solutions. Organised cervical screening programmes need to consider the needs of this population, in particular the provision of HPV self-sampling. TWEETABLE ABSTRACT: Transgender men need access to cervical screening.

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.

Correlation of pre-operative CT findings with surgical & histological tumor dissemination patterns at cytoreduction for primary advanced and relapsed epithelial ovarian cancer: A retrospective evaluation.

OBJECTIVES: Computed tomography (CT) is an essential part of preoperative planning prior to cytoreductive surgery for primary and relapsed epithelial ovarian cancer (EOC). Our aim is to correlate pre-operative CT results with intraoperative surgical and histopathological findings at debulking surgery. METHODS: We performed a systematic comparison of intraoperative tumor dissemination patterns and surgical resections with preoperative CT assessments of infiltrative disease at key resection sites, in women who underwent multivisceral debulking surgery due to EOC between January 2013 and December 2014 at a tertiary referral center. The key sites were defined as follows: diaphragmatic involvement(DI), splenic disease (SI), large (LBI) and small (SBI) bowel involvement, rectal involvement (RI), porta hepatis involvement (PHI), mesenteric disease (MI) and lymph node involvement (LNI). RESULTS: A total of 155 patients, mostly with FIGO stage IIIC disease (65%) were evaluated (primary=105, relapsed=50). Total macroscopic cytoreduction rates were: 89%. Pre-operative CT findings displayed high specificity across all tumor sites apart from the retroperitoneal lymph node status, with a specificity of 65%. The ability however of the CT to accurately identify sites affected by invasive disease was relatively low with the following sensitivities as relating to final histology: 32% (DI), 26% (SI), 46% (LBI), 44% (SBI), 39% (RI), 57% (PHI), 31% (MI), 63% (LNI). CONCLUSION: Pre-operative CT imaging shows high specificity but low sensitivity in detecting tumor involvement at key sites in ovarian cancer surgery. CT findings alone should not be used for surgical decision making.

The role of cytology and other prognostic factors in endometrial cancer.

The clinical and prognostic value of positive cytology in women with endometrial cancer remains uncertain. The aim of our retrospective observational study was to determine whether in women with disease confined to the uterus, positive peritoneal cytology adversely affects disease-free (DFS) or overall survival (OS); to assess whether positive or negative cytology affects survival in women irrespective of stage and to assess whether the use of hysteroscopy or Pipelle for diagnosis affected cytology positivity rates. We have shown that median DFS and OS were almost identical for tumours confined to the uterus with and without positive peritoneal cytology. Women with tumours extending to the serosa or adnexa had a non-statistically significant shorter survival in comparison with women with stage I disease and negative cytology. Out of 59 women that had their cancer diagnosis based on a Pipelle biopsy of the endometrium, five had positive peritoneal washings. A total of 150 women had pre-treatment hysteroscopy; seven of these had positive peritoneal washings. There was no significant difference in the rates of positive cytology between these groups (4.6% vs 8.4%). In our cohort of un-staged women, positive peritoneal cytology did not adversely affect prognosis when disease was confined to the uterus.

European consensus statement on expert colposcopy.

BACKGROUND: Following the publication of the European consensus statement on standards for essential colposcopy in 2020, the need for standards relating to more complex and challenging colposcopy practice was recognised. These standards relate to colposcopy undertaken in patients identified through cervical screening and tertiary referrals from colposcopists who undertake standard colposcopy only. This set of recommendations provides a review of the current literature and agreement on care for recognised complex cases. With good uptake of human papillomavirus (HPV) immunisation, we anticipate a marked reduction in cervical disease over the next decade. Still, the expert colposcopist will continue to be vital in managing complex cases, including previous cervical intraepithelial neoplasia (CIN)/complex screening histories and multi-zonal disease. AIMS: To provide expert guidance on complex colposcopy cases through published evidence and expert consensus. MATERIAL & METHODS: Members of the EFC and ESGO formed a working group to identify topics considered to be the remit of the expert rather than the standard colposcopy service. These were presented at the EFC satellite meeting, Helsinki 2021, for broader discussion and finalisation of the topics. RESULTS & DISCUSSION: The agreed standards included colposcopy in pregnancy and post-menopause, investigation and management of glandular abnormalities, persistent high-risk HPV+ with normal/low-grade cytology, colposcopy management of type 3 transformation zones (TZ), high-grade cytology and normal colposcopy, colposcopy adjuncts, follow-up after treatment with CIN next to TZ margins and follow-up after treatment with CIN with persistent HPV+, and more. These standards are under review to create a final paper of consensus standards for dissemination to all EFC and ESGO members.

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.

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.

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.

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.

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.

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.

Management of minor cervical cytological abnormalities: a systematic review and a meta-analysis of the literature.

BACKGROUND: A significant number of women are diagnosed with a low grade cytological abnormality on cervical screening. Many authorities recommend surveillance as spontaneous regression might occur. However, protracted attendance for cytological follow-up decreases with time and might put some women at risk of developing invasive disease. The aim of this review was to assess management options for women with minor cervical disease. METHODS: An electronic literature search was conducted. All randomised controlled studies comparing immediate colposcopy to cytological surveillance in women with cervical atypia/borderline nuclear changes or low-grade lesions were included. The main outcomes studied were the default rates from the colposcopy clinic and the histological status of biopsies within immediate management protocols compared to biopsies taken on completion of surveillance. Pooled relative risks and 95% confidence intervals were calculated using a random-effect model and inter-study heterogeneity was assessed with Cochrane's Q-test. RESULTS: Three randomised controlled trials identified from the literature search with different surveillance periods were combined. The analysis revealed that compliance with follow-up declines over time and reaches significance at the end of 24 months of surveillance (RR: 74.10 [10.36, 529.79]). There was a significantly higher incidence of HPV and CIN 1 in those women referred to immediate colposcopy/treatment compared to those at the end of 24 months surveillance period (32% vs 21%) (RR 1.49, 95% CI 1.17-1.90) and (21% vs 8%) (RR 2.58, 95% CI 1.69-3.94), respectively, possibly explained by spontaneous regression of clinically non-important lesions. Finally, there was no significant difference in the incidence of CIN2 or worse at initial colposcopy compared with the observation group (24 months) (RR 1.72, 95% CI 0.85-3.48). CONCLUSION: Cytological surveillance puts women at risk as many show poor compliance and such women might have occult high grade abnormalities. A general policy should be immediate colposcopy for all women after a single low grade cervical smear.

Obstetric outcomes after conservative treatment for intraepithelial or early invasive cervical lesions: systematic review and meta-analysis.

BACKGROUND: Conservative methods to treat cervical intraepithelial neoplasia and microinvasive cervical cancer are commonly used in young women because of the advent of effective screening programmes. In a meta-analysis, we investigated the effect of these procedures on subsequent fertility and pregnancy outcomes. METHODS: We searched for studies in MEDLINE and EMBASE and classified them by the conservative method used and the outcome measure studied regarding both fertility and pregnancy. Pooled relative risks and 95% CIs were calculated with a random-effects model and interstudy heterogeneity was assessed with Cochrane's Q test. FINDINGS: We identified 27 studies. Cold knife conisation was significantly associated with preterm delivery (<37 weeks; relative risk 2.59, 95% CI 1.80-3.72, 100/704 [14%] vs 1494/27 674 [5%]), low birthweight (<2500 g; 2.53, 1.19-5.36, 32/261 [12%] vs 905/13 229 [7%]), and caesarean section (3.17, 1.07-9.40, 31/350 [9%] vs 22/670 [3%]). Large loop excision of the transformation zone (LLETZ) was also significantly associated with preterm delivery (1.70, 1.24-2.35, 156/1402 [11%] vs 120/1739 [7%]), low birthweight (1.82, 1.09-3.06, 77/996 [8%] vs 49/1192 [4%]), and premature rupture of the membranes (2.69, 1.62-4.46, 48/905 [5%] vs 22/1038 [2%]). Similar but marginally non-significant adverse effects were recorded for laser conisation (preterm delivery 1.71, 0.93-3.14). We did not detect significantly increased risks for obstetric outcomes after laser ablation. Although severe outcomes such as admission to a neonatal intensive care unit or perinatal mortality showed adverse trends, these changes were not significant. INTERPRETATION: All the excisional procedures to treat cervical intraepithelial neoplasia present similar pregnancy-related morbidity without apparent neonatal morbidity. Caution in the treatment of young women with mild cervical abnormalities should be recommended. Clinicians now have the evidence base to counsel women appropriately.